SNPMiner Trials by Shray Alag

NCT00511368 (37) NCT00460382 (36) NCT04504071 (35) NCT03783286 (33) NCT04172597 (32) NCT02404233 (29) NCT00959894 (28) NCT00706147 (28) NCT00121017 (28) NCT01685801 (27) NCT04513626 (26) NCT01736761 (26) NCT04495348 (24) NCT02673398 (23) NCT02499978 (22) NCT01605084 (21) NCT04254705 (21) NCT02069834 (21) NCT00939770 (18) NCT01792570 (18) NCT01199939 (18) NCT00356616 (18) NCT02728258 (17) NCT02707601 (17) NCT02770508 (16) NCT00711009 (16) NCT00630864 (16) NCT00491556 (15) NCT04085315 (15) NCT02616029 (15) NCT00830804 (15) NCT04681820 (15) NCT01170962 (14) NCT00984152 (14) NCT03953898 (14) NCT00727597 (14) NCT03212274 (14) NCT01369199 (13) NCT00337467 (13) NCT00098293 (13) NCT01368497 (13) NCT02159599 (13) NCT00424814 (12) NCT04432454 (12) NCT02527096 (12) NCT01849003 (12) NCT03781063 (12) NCT03683524 (11) NCT01614457 (11) NCT00460746 (11) NCT00993148 (11) NCT03061331 (11) NCT02494882 (11) NCT03068312 (11) NCT04453436 (11) NCT01521338 (10) NCT02725567 (10) NCT01614470 (10) NCT01423812 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NCT02554591 (5) NCT01501604 (5) NCT02716116 (5) NCT01136460 (5) NCT00187655 (5) NCT00350272 (5) NCT00837135 (5) NCT03202862 (5) NCT01707199 (5) NCT03839342 (5) NCT01323010 (4) NCT02248324 (4) NCT01698905 (4) NCT01737359 (4) NCT01306045 (4) NCT02804100 (4) NCT01456676 (4) NCT00588172 (4) NCT03434418 (4) NCT03593993 (4) NCT01804140 (4) NCT02882308 (4) NCT03497767 (4) NCT04106024 (4) NCT02716311 (4) NCT04405674 (4) NCT03599518 (4) NCT01675778 (4) NCT01604122 (4) NCT01297777 (4) NCT04519970 (4) NCT00705679 (4) NCT04147351 (4) NCT04129502 (4) NCT03976856 (4) NCT02335944 (4) NCT04625647 (4) NCT03948763 (4) NCT03255083 (4) NCT04002830 (4) NCT02635815 (4) NCT03066206 (4) NCT01331642 (4) NCT00557245 (4) NCT01922583 (4) NCT02893332 (4) NCT03592888 (4) NCT02257424 (4) NCT03874858 (4) NCT00017732 (4) NCT00187720 (4) NCT02593539 (4) NCT01185587 (4) NCT04439292 (4) NCT03884348 (4) NCT01309243 (4) NCT03209063 (4) NCT04160546 (4) NCT03292302 (4) NCT02418234 (4) NCT02535338 (3) NCT02192697 (3) NCT03410043 (3) NCT03845296 (3) NCT02914990 (3) NCT02113813 (3) NCT01532011 (3) NCT04340388 (3) NCT00962533 (3) NCT03856411 (3) NCT04049266 (3) NCT02973763 (3) NCT02926092 (3) NCT00271973 (3) NCT04256941 (3) NCT03812809 (3) NCT02954523 (3) NCT01784068 (3) NCT03446417 (3) NCT02841579 (3) NCT02025114 (3) NCT01288521 (3) NCT01385683 (3) NCT02279004 (3) NCT00998582 (3) NCT03111901 (3) NCT01352715 (3) NCT01619774 (3) NCT01045369 (3) NCT02246998 (3) NCT03969823 (3) NCT00895596 (3) NCT02398929 (3) NCT00724711 (3) NCT04029350 (3) NCT03737994 (3) NCT01443806 (3) NCT02629822 (3) NCT03463525 (3) NCT00710112 (3) NCT03623750 (3) NCT04283955 (3) NCT02743923 (3) NCT01016106 (3) NCT01259089 (3) NCT03971474 (3) NCT02917993 (3) NCT02368990 (3) NCT00279110 (3) NCT02485652 (3) NCT00312169 (3) NCT04541407 (3) NCT02769286 (3) NCT00747487 (3) NCT04267913 (3) NCT01429597 (3) NCT04023617 (3) NCT03790228 (3) NCT01759888 (3) NCT04429152 (3) NCT01810718 (3) NCT02725632 (3) NCT01090011 (3) NCT04544111 (3) NCT02926768 (3) NCT02981108 (3) NCT02459743 (3) NCT00654823 (3) NCT01037127 (3) NCT04439305 (3) NCT01028222 (3) NCT01542411 (3) NCT01031446 (3) NCT02726269 (3) NCT01892644 (3) NCT03260491 (3) NCT01802632 (3) NCT02720094 (3) NCT02630186 (3) NCT01627132 (3) NCT02690675 (3) NCT01013506 (3) NCT04252339 (3) NCT02496663 (3) NCT03386955 (3) NCT03394118 (3) NCT04212702 (3) NCT01754025 (3) NCT01160276 (3) NCT00121979 (3) NCT03228277 (3) NCT04351555 (3) NCT01243346 (3) NCT04510415 (3) NCT02796274 (3) NCT02774005 (3) NCT02064491 (3) NCT04233021 (3) NCT03799601 (3) NCT00260260 (3) NCT02094261 (3) NCT04245085 (3) NCT03058094 (3) NCT01282151 (3) NCT02520778 (3) NCT03161808 (3) NCT04181060 (3) NCT01342679 (3) NCT01443273 (3) NCT01593254 (3) NCT04433481 (3) NCT02529995 (3) NCT03502850 (3) NCT02771314 (3) NCT03823807 (3) NCT03270527 (3) NCT02688881 (3) NCT01005602 (3) NCT02442349 (3) NCT02684591 (2) NCT02282267 (2) NCT03381430 (2) NCT02178397 (2) NCT03608215 (2) NCT02603107 (2) NCT03370770 (2) NCT03322696 (2) NCT03333343 (2) NCT00525473 (2) NCT03127449 (2) NCT01781026 (2) NCT02503722 (2) NCT00975871 (2) NCT03964233 (2) NCT03388099 (2) NCT02317016 (2) NCT03845270 (2) NCT03519958 (2) NCT03918304 (2) NCT02151721 (2) NCT02777658 (2) NCT01016444 (2) NCT02971501 (2) NCT03101254 (2) NCT03178617 (2) NCT01774721 (2) NCT03574753 (2) NCT01357655 (2) NCT01766713 (2) NCT02097225 (2) NCT00658164 (2) NCT03622593 (2) NCT02571036 (2) NCT00969137 (2) NCT00834665 (2) NCT02026011 (2) NCT03622580 (2) NCT03543683 (2) NCT01143493 (2) NCT03671538 (2) NCT04028778 (2) NCT00324961 (2) NCT01915576 (2) NCT02157883 (2) NCT01387022 (2) NCT03864042 (2) NCT03235245 (2) NCT03469960 (2) NCT02795884 (2) NCT04687241 (2) NCT00005541 (2) NCT01242813 (2) NCT03960645 (2) NCT00643058 (2) NCT03443336 (2) NCT02992860 (2) NCT02281760 (2) NCT02201602 (2) NCT04310007 (2) NCT04309019 (2) NCT03720665 (2) NCT00909532 (2) NCT00411944 (2) NCT01604681 (2) NCT01245062 (2) NCT00270231 (2) NCT03256136 (2) NCT03973918 (2) NCT00302692 (2) NCT00125281 (2) NCT02163733 (2) NCT02110407 (2) NCT00475176 (2) NCT03196882 (2) NCT01572818 (2) NCT02556333 (2) NCT04268550 (2) NCT02433717 (2) NCT03428126 (2) NCT01153763 (2) NCT02609776 (2) NCT01420211 (2) NCT03556176 (2) NCT03872440 (2) NCT01405079 (2) NCT03382795 (2) NCT02991950 (2) NCT00013598 (2) NCT03455764 (2) NCT02422628 (2) NCT03831932 (2) NCT03766490 (2) NCT02580474 (2) NCT00499577 (2) NCT02444884 (2) NCT01775943 (2) NCT03544814 (2) NCT01310036 (2) NCT01027663 (2) NCT01928160 (2) NCT01244438 (2) NCT00007150 (2) NCT04462081 (2) NCT02297425 (2) NCT02086071 (2) NCT01050400 (2) NCT03060590 (2) NCT01819428 (2) NCT02709668 (2) NCT02411448 (2) NCT03878719 (2) NCT04622072 (2) NCT04479306 (2) NCT03377023 (2) NCT01378026 (2) NCT03239145 (2) NCT04511533 (2) NCT00226551 (2) NCT02191891 (2) NCT04586270 (2) NCT04669535 (2) NCT04545710 (2) NCT02120222 (2) NCT02738593 (2) NCT00831272 (2) NCT04469543 (2) NCT00573495 (2) NCT04158544 (2) NCT00904150 (2) NCT02110056 (2) NCT02856893 (2) NCT02110043 (2) NCT02182986 (2) NCT04179890 (2) NCT00063232 (2) NCT02197234 (2) NCT03121235 (2) NCT01532089 (2) NCT03887169 (2) NCT02268864 (2) NCT01963845 (2) NCT00866736 (2) NCT03991013 (2) NCT02500927 (2) NCT04657991 (2) NCT02228382 (2) NCT02689570 (2) NCT01513785 (2) NCT02463435 (2) NCT03351361 (2) NCT04527549 (2) NCT03424759 (2) NCT02197247 (2) NCT02321046 (2) NCT04272034 (2) NCT04646824 (2) NCT04027647 (2) NCT02364609 (2) NCT02759835 (2) NCT04349865 (2) NCT00068159 (2) NCT00418015 (2) NCT04310397 (2) NCT03088176 (2) NCT03867175 (2) NCT00339209 (2) NCT00011258 (2) NCT01288430 (2) NCT01616199 (2) NCT03603262 (2) NCT03071705 (2) NCT00969930 (2) NCT00772408 (2) NCT02743468 (2) NCT00277342 (2) NCT04248829 (2) NCT01767454 (2) NCT00933127 (2) NCT03317873 (2) NCT03392246 (2) NCT01909453 (2) NCT03523104 (2) NCT00085917 (2) NCT02507921 (2) NCT03781752 (2) NCT03828422 (2) NCT02193282 (2) NCT03195452 (2) NCT04657289 (2) NCT02294487 (2) NCT01325441 (2) NCT02511106 (2) NCT02997501 (2) NCT04184921 (2) NCT00625092 (2) NCT01657786 (2) NCT01415011 (2) NCT02629523 (2) NCT01718847 (2) NCT02818023 (2) NCT00577707 (2) NCT01943422 (2) NCT00116636 (2) NCT04429542 (2) NCT01841463 (2) NCT03865511 (2) NCT03205267 (2) NCT01218477 (2) NCT02881320 (2) NCT01897480 (2) NCT02810990 (2) NCT04189757 (2) NCT01951001 (2) NCT04254939 (2) NCT03207867 (2) NCT00780949 (2) NCT03355768 (2) NCT00817089 (2) NCT02143466 (2) NCT04499053 (2) NCT01907776 (2) NCT00909727 (2) NCT01562028 (2) NCT03737253 (2) NCT00441974 (2) NCT02155465 (2) NCT04586335 (2) NCT00661999 (2) NCT02705339 (2) NCT04006340 (2) NCT04553887 (2) NCT04645225 (2) NCT03852290 (2) NCT02183922 (2) NCT03970239 (2) NCT00294372 (2) NCT03250676 (2) NCT03792074 (2) NCT00671892 (2) NCT00689182 (2) NCT00106379 (2) NCT01947023 (2) NCT00509652 (2) NCT03683251 (2) NCT02039986 (2) NCT03515837 (2) NCT04081688 (2) NCT03190005 (2) NCT01584648 (2) NCT02292654 (2) NCT03992456 (2) NCT03133546 (2) NCT01485809 (2) NCT01266967 (2) NCT04644315 (2) NCT02909712 (2) NCT00062764 (2) NCT01776684 (2) NCT03042221 (2) NCT01940809 (2) NCT04675008 (2) NCT01161537 (2) NCT01154816 (2) NCT01175759 (2) NCT01199731 (2) NCT02788058 (2) NCT03130452 (2) NCT04687423 (2) NCT01772732 (2) NCT02631447 (2) NCT02525692 (2) NCT02526537 (2) NCT03513666 (2) NCT02027961 (2) NCT03106779 (2) NCT04106544 (2) NCT04258943 (2) NCT00165984 (2) NCT00977470 (2) NCT02092974 (2) NCT03975231 (2) NCT03586453 (2) NCT01998295 (2) NCT02021305 (2) NCT03135197 (2) NCT00432016 (2) NCT04636437 (2) NCT03004625 (2) NCT03851445 (2) NCT04031898 (2) NCT04201418 (2) NCT01911507 (2) NCT03539224 (2) NCT01978236 (2) NCT00866177 (2) NCT00320879 (2) NCT00044304 (2) NCT01999179 (2) NCT00977730 (2) NCT02491775 (2) NCT00212147 (2) NCT02040064 (2) NCT00489385 (2) NCT01713023 (2) NCT04122729 (2) NCT03994393 (2) NCT02438722 (2) NCT02762448 (2) NCT00071903 (2) NCT00626223 (2) NCT01193829 (2) NCT03239340 (2) NCT02991274 (2) NCT02811354 (2) NCT03416530 (2) NCT02522988 (2) 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NCT03678506 (1) NCT02146365 (1) NCT04310943 (1) NCT02619955 (1) NCT02934139 (1) NCT00400387 (1) NCT00375219 (1) NCT00149305 (1) NCT03520946 (1) NCT02787447 (1) NCT04501614 (1) NCT03166631 (1) NCT04213313 (1) NCT02078531 (1) NCT02349048 (1) NCT02981784 (1) NCT04636593 (1) NCT01647711 (1) NCT03231722 (1) NCT03576937 (1) NCT04412070 (1) NCT00554866 (1) NCT03151161 (1) NCT01817166 (1) NCT02220855 (1) NCT02512627 (1) NCT04591197 (1) NCT03402048 (1) NCT04500704 (1) NCT02323724 (1) NCT01166126 (1) NCT03029858 (1) NCT04317599 (1) NCT00300573 (1) NCT00809211 (1) NCT01393730 (1) NCT02318368 (1) NCT02228369 (1) NCT04500717 (1) NCT01074398 (1) NCT03134131 (1) NCT02455167 (1) NCT01004497 (1) NCT02073279 (1) NCT02117817 (1) NCT00323687 (1) NCT01605981 (1) NCT01371955 (1) NCT04147767 (1) NCT04144257 (1) NCT03490123 (1) NCT04423185 (1) NCT02625337 (1) NCT03567629 (1) NCT03360929 (1) NCT00109278 (1) NCT04108156 (1) NCT02132598 (1) NCT00542451 (1) NCT01587573 (1) NCT00868465 (1) NCT01494402 (1) 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SNPMiner SNPMiner Trials (Home Page)


Report for Clinical Trial NCT02673398

Developed by Shray Alag, 2020-2021.
SNP Clinical Trial Gene

Phase II Study of Neratinib in Patients 60 and Older With HER2 Positive Metastatic Breast Cancer

This phase II trial studies the side effects of and how well neratinib works in treating older patients with stage IV HER2-positive breast cancer. Neratinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT02673398 HER2 Positive Breast Carcinoma Stage IV Breast Cancer AJCC v6 and v7
MeSH:Breast Neoplasms
HPO:Breast carcinoma Neoplasm of the breast

4 Interventions

Name: Comprehensive Geriatric Assessment

Description: Ancillary studies
Type: Other
Group Labels: 1

Treatment (neratinib)

Name: Laboratory Biomarker Analysis

Description: Correlative studies
Type: Other
Group Labels: 1

Treatment (neratinib)

Name: Neratinib

Description: Given PO
Type: Drug
Group Labels: 1

Treatment (neratinib)

Name: Pharmacological Study

Description: Correlative studies
Type: Other
Group Labels: 1

Treatment (neratinib)


Primary Outcomes

Description: Will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Tables will be created to summarize the toxicities and side effects by organ system, attribution and severity for all participants that receive at least one dose of neratinib. Rates and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated for grade 2 or higher toxicities attributed to neratinib.

Measure: Incidence of grade 2 or higher toxicities

Time: Up to 30 days after the completion of study treatment

Secondary Outcomes

Description: Will be graded according to the NCI CTCAE version 4.0. Tables will be created to summarize the toxicities and side effects by organ system, attribution and severity for all participants that receive at least one dose of neratinib.

Measure: Incidence of all toxicities

Time: Up to 30 days after the completion of study treatment

Description: Will be graded according to the NCI CTCAE version 4.0. Tables will be created to summarize the toxicities and side effects by organ system, attribution and severity for all participants that receive at least one dose of neratinib. Rates and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated for all grade GI toxicities (diarrhea, nausea and vomiting).

Measure: Incidence of gastrointestinal (GI) toxicities such as diarrhea, nausea and vomiting

Time: Up to 30 days after the completion of study treatment

Description: Rates and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated for dose reduction.

Measure: Rate of dose reduction

Time: Up to 48 months

Description: Rates and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated for holds.

Measure: Rate of holds

Time: Up to 48 months

Description: Rates and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated for hospitalizations.

Measure: Rate of hospitalizations

Time: Up to 48 months

Description: Clearance will be estimated using population pharmacokinetic (PK) methods.

Measure: Clearance

Time: Day 15 of course 1 and day 1 of courses 3-4

Description: Volume of distribution will be estimated using population PK methods.

Measure: Volume of distribution

Time: Day 15 of course 1 and day 1 of courses 3-4

Description: Will be measured by Response Evaluation Criteria in Solid Tumors (RECIST). Rates and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated for objective response (complete response [CR] + partial response [PR]).

Measure: Overall response rate

Time: Up to 48 months

Description: Clinical benefit rate is defined as the proportion of patients who achieved overall tumor response (CR or PR) or stable disease (SD) for at least 24 weeks, measured by RECIST. Rates and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated for clinical benefit (CR+PR+SD).

Measure: Clinical benefit rate

Time: Up to 48 months

Description: EFS will be estimated using the product limit method of Kaplan and Meier.

Measure: Event free survival (EFS)

Time: Up to 48 months

Description: Rates and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated for PFS. PFS will be estimated using the product limit method of Kaplan and Meier.

Measure: Progression-free survival (PFS)

Time: From the date of randomization until the first date on which recurrence, progression or death due to any cause, assessed up to 16 weeks

Description: OS will be estimated using the product limit method of Kaplan and Meier.

Measure: Overall survival (OS)

Time: Time from randomization to death due to any cause, assessed up to 48 months

Description: Generalized linear models and graphical methods will be used to explore factors as identified by a cancer-specific geriatric assessment.

Measure: Geriatric assessment score

Time: Up to 48 months

Description: Descriptive statistics will be provided for drug adherence and participant demographics.

Measure: Adherence, as defined by pill count

Time: Up to 48 months

Description: Will be measured and descriptive statistics provided. Generalized linear models and graphical methods will be used to explore factors as identified by serum biomarkers that may be predictive of toxicity dose reductions, dose holds or hospitalizations.

Measure: IL-6, CRP, and D-dimer analysis

Time: Baseline to up to 48 months

Purpose: Treatment

Allocation: N/A

Single Group Assignment


There are 23 SNPs

SNPs


1 D769H

Generalized linear models and graphical methods will be used to explore factors as identified by serum biomarkers that may be predictive of toxicity dose reductions, dose holds or hospitalizations.. Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance 0-2 - Life expectancy of greater than 12 weeks - Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) - Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies - HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines - If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) - Both measurable as well as non-measurable disease will be allowed - Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration - Total bilirubin within normal institutional limits within 4 weeks of pre-registration - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration - Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration - Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) - All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement - Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib - Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study - Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: - Prior treatment with neratinib - Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) - Any major surgery =< 28 days prior to the initiation of investigational products - Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib - Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia - Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes - Inability to take oral medication - Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas - Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.0 diarrhea of any etiology at baseline) - Known clinically active infection with hepatitis B or hepatitis C virus - Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s --- G309A --- --- G309E --- --- S310F --- --- S310Y --- --- S653C --- --- V659E --- --- R678Q --- --- V697L --- --- T733I --- --- L755S --- --- L755P --- --- E757A --- --- D769H ---

judgment, makes the patient inappropriate for this study Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance 0-2 - Life expectancy of greater than 12 weeks - Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) - Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies - HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines - If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) - Both measurable as well as non-measurable disease will be allowed - Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration - Total bilirubin within normal institutional limits within 4 weeks of pre-registration - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration - Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration - Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) - All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement - Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib - Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study - Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: - Prior treatment with neratinib - Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) - Any major surgery =< 28 days prior to the initiation of investigational products - Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib - Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia - Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes - Inability to take oral medication - Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas - Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.0 diarrhea of any etiology at baseline) - Known clinically active infection with hepatitis B or hepatitis C virus - Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s --- G309A --- --- G309E --- --- S310F --- --- S310Y --- --- S653C --- --- V659E --- --- R678Q --- --- V697L --- --- T733I --- --- L755S --- --- L755P --- --- E757A --- --- D769H ---


2 D769N

Generalized linear models and graphical methods will be used to explore factors as identified by serum biomarkers that may be predictive of toxicity dose reductions, dose holds or hospitalizations.. Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance 0-2 - Life expectancy of greater than 12 weeks - Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) - Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies - HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines - If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) - Both measurable as well as non-measurable disease will be allowed - Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration - Total bilirubin within normal institutional limits within 4 weeks of pre-registration - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration - Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration - Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) - All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement - Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib - Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study - Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: - Prior treatment with neratinib - Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) - Any major surgery =< 28 days prior to the initiation of investigational products - Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib - Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia - Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes - Inability to take oral medication - Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas - Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.0 diarrhea of any etiology at baseline) - Known clinically active infection with hepatitis B or hepatitis C virus - Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s --- G309A --- --- G309E --- --- S310F --- --- S310Y --- --- S653C --- --- V659E --- --- R678Q --- --- V697L --- --- T733I --- --- L755S --- --- L755P --- --- E757A --- --- D769H --- --- D769Y --- --- D769N ---

judgment, makes the patient inappropriate for this study Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance 0-2 - Life expectancy of greater than 12 weeks - Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) - Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies - HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines - If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) - Both measurable as well as non-measurable disease will be allowed - Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration - Total bilirubin within normal institutional limits within 4 weeks of pre-registration - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration - Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration - Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) - All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement - Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib - Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study - Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: - Prior treatment with neratinib - Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) - Any major surgery =< 28 days prior to the initiation of investigational products - Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib - Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia - Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes - Inability to take oral medication - Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas - Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.0 diarrhea of any etiology at baseline) - Known clinically active infection with hepatitis B or hepatitis C virus - Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s --- G309A --- --- G309E --- --- S310F --- --- S310Y --- --- S653C --- --- V659E --- --- R678Q --- --- V697L --- --- T733I --- --- L755S --- --- L755P --- --- E757A --- --- D769H --- --- D769Y --- --- D769N ---


3 D769Y

Generalized linear models and graphical methods will be used to explore factors as identified by serum biomarkers that may be predictive of toxicity dose reductions, dose holds or hospitalizations.. Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance 0-2 - Life expectancy of greater than 12 weeks - Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) - Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies - HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines - If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) - Both measurable as well as non-measurable disease will be allowed - Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration - Total bilirubin within normal institutional limits within 4 weeks of pre-registration - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration - Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration - Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) - All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement - Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib - Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study - Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: - Prior treatment with neratinib - Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) - Any major surgery =< 28 days prior to the initiation of investigational products - Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib - Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia - Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes - Inability to take oral medication - Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas - Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.0 diarrhea of any etiology at baseline) - Known clinically active infection with hepatitis B or hepatitis C virus - Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s --- G309A --- --- G309E --- --- S310F --- --- S310Y --- --- S653C --- --- V659E --- --- R678Q --- --- V697L --- --- T733I --- --- L755S --- --- L755P --- --- E757A --- --- D769H --- --- D769Y ---

judgment, makes the patient inappropriate for this study Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance 0-2 - Life expectancy of greater than 12 weeks - Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) - Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies - HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines - If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) - Both measurable as well as non-measurable disease will be allowed - Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration - Total bilirubin within normal institutional limits within 4 weeks of pre-registration - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration - Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration - Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) - All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement - Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib - Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study - Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: - Prior treatment with neratinib - Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) - Any major surgery =< 28 days prior to the initiation of investigational products - Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib - Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia - Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes - Inability to take oral medication - Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas - Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.0 diarrhea of any etiology at baseline) - Known clinically active infection with hepatitis B or hepatitis C virus - Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s --- G309A --- --- G309E --- --- S310F --- --- S310Y --- --- S653C --- --- V659E --- --- R678Q --- --- V697L --- --- T733I --- --- L755S --- --- L755P --- --- E757A --- --- D769H --- --- D769Y ---


4 E757A

Generalized linear models and graphical methods will be used to explore factors as identified by serum biomarkers that may be predictive of toxicity dose reductions, dose holds or hospitalizations.. Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance 0-2 - Life expectancy of greater than 12 weeks - Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) - Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies - HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines - If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) - Both measurable as well as non-measurable disease will be allowed - Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration - Total bilirubin within normal institutional limits within 4 weeks of pre-registration - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration - Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration - Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) - All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement - Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib - Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study - Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: - Prior treatment with neratinib - Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) - Any major surgery =< 28 days prior to the initiation of investigational products - Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib - Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia - Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes - Inability to take oral medication - Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas - Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.0 diarrhea of any etiology at baseline) - Known clinically active infection with hepatitis B or hepatitis C virus - Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s --- G309A --- --- G309E --- --- S310F --- --- S310Y --- --- S653C --- --- V659E --- --- R678Q --- --- V697L --- --- T733I --- --- L755S --- --- L755P --- --- E757A ---

judgment, makes the patient inappropriate for this study Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance 0-2 - Life expectancy of greater than 12 weeks - Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) - Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies - HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines - If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) - Both measurable as well as non-measurable disease will be allowed - Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration - Total bilirubin within normal institutional limits within 4 weeks of pre-registration - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration - Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration - Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) - All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement - Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib - Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study - Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: - Prior treatment with neratinib - Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) - Any major surgery =< 28 days prior to the initiation of investigational products - Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib - Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia - Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes - Inability to take oral medication - Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas - Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.0 diarrhea of any etiology at baseline) - Known clinically active infection with hepatitis B or hepatitis C virus - Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s --- G309A --- --- G309E --- --- S310F --- --- S310Y --- --- S653C --- --- V659E --- --- R678Q --- --- V697L --- --- T733I --- --- L755S --- --- L755P --- --- E757A ---


5 G309A

Generalized linear models and graphical methods will be used to explore factors as identified by serum biomarkers that may be predictive of toxicity dose reductions, dose holds or hospitalizations.. Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance 0-2 - Life expectancy of greater than 12 weeks - Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) - Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies - HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines - If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) - Both measurable as well as non-measurable disease will be allowed - Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration - Total bilirubin within normal institutional limits within 4 weeks of pre-registration - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration - Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration - Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) - All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement - Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib - Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study - Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: - Prior treatment with neratinib - Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) - Any major surgery =< 28 days prior to the initiation of investigational products - Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib - Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia - Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes - Inability to take oral medication - Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas - Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.0 diarrhea of any etiology at baseline) - Known clinically active infection with hepatitis B or hepatitis C virus - Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s --- G309A ---

judgment, makes the patient inappropriate for this study Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance 0-2 - Life expectancy of greater than 12 weeks - Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) - Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies - HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines - If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) - Both measurable as well as non-measurable disease will be allowed - Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration - Total bilirubin within normal institutional limits within 4 weeks of pre-registration - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration - Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration - Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) - All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement - Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib - Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study - Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: - Prior treatment with neratinib - Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) - Any major surgery =< 28 days prior to the initiation of investigational products - Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib - Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia - Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes - Inability to take oral medication - Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas - Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.0 diarrhea of any etiology at baseline) - Known clinically active infection with hepatitis B or hepatitis C virus - Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s --- G309A ---


6 G309E

Generalized linear models and graphical methods will be used to explore factors as identified by serum biomarkers that may be predictive of toxicity dose reductions, dose holds or hospitalizations.. Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance 0-2 - Life expectancy of greater than 12 weeks - Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) - Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies - HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines - If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) - Both measurable as well as non-measurable disease will be allowed - Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration - Total bilirubin within normal institutional limits within 4 weeks of pre-registration - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration - Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration - Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) - All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement - Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib - Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study - Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: - Prior treatment with neratinib - Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) - Any major surgery =< 28 days prior to the initiation of investigational products - Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib - Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia - Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes - Inability to take oral medication - Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas - Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.0 diarrhea of any etiology at baseline) - Known clinically active infection with hepatitis B or hepatitis C virus - Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s --- G309A --- --- G309E ---

judgment, makes the patient inappropriate for this study Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance 0-2 - Life expectancy of greater than 12 weeks - Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) - Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies - HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines - If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) - Both measurable as well as non-measurable disease will be allowed - Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration - Total bilirubin within normal institutional limits within 4 weeks of pre-registration - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration - Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration - Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) - All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement - Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib - Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study - Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: - Prior treatment with neratinib - Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) - Any major surgery =< 28 days prior to the initiation of investigational products - Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib - Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia - Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes - Inability to take oral medication - Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas - Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.0 diarrhea of any etiology at baseline) - Known clinically active infection with hepatitis B or hepatitis C virus - Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s --- G309A --- --- G309E ---


7 G776C

Generalized linear models and graphical methods will be used to explore factors as identified by serum biomarkers that may be predictive of toxicity dose reductions, dose holds or hospitalizations.. Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance 0-2 - Life expectancy of greater than 12 weeks - Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) - Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies - HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines - If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) - Both measurable as well as non-measurable disease will be allowed - Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration - Total bilirubin within normal institutional limits within 4 weeks of pre-registration - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration - Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration - Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) - All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement - Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib - Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study - Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: - Prior treatment with neratinib - Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) - Any major surgery =< 28 days prior to the initiation of investigational products - Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib - Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia - Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes - Inability to take oral medication - Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas - Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.0 diarrhea of any etiology at baseline) - Known clinically active infection with hepatitis B or hepatitis C virus - Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s --- G309A --- --- G309E --- --- S310F --- --- S310Y --- --- S653C --- --- V659E --- --- R678Q --- --- V697L --- --- T733I --- --- L755S --- --- L755P --- --- E757A --- --- D769H --- --- D769Y --- --- D769N --- --- G776V --- --- G776C ---

judgment, makes the patient inappropriate for this study Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance 0-2 - Life expectancy of greater than 12 weeks - Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) - Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies - HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines - If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) - Both measurable as well as non-measurable disease will be allowed - Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration - Total bilirubin within normal institutional limits within 4 weeks of pre-registration - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration - Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration - Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) - All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement - Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib - Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study - Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: - Prior treatment with neratinib - Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) - Any major surgery =< 28 days prior to the initiation of investigational products - Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib - Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia - Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes - Inability to take oral medication - Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas - Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.0 diarrhea of any etiology at baseline) - Known clinically active infection with hepatitis B or hepatitis C virus - Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s --- G309A --- --- G309E --- --- S310F --- --- S310Y --- --- S653C --- --- V659E --- --- R678Q --- --- V697L --- --- T733I --- --- L755S --- --- L755P --- --- E757A --- --- D769H --- --- D769Y --- --- D769N --- --- G776V --- --- G776C ---


8 G776V

Generalized linear models and graphical methods will be used to explore factors as identified by serum biomarkers that may be predictive of toxicity dose reductions, dose holds or hospitalizations.. Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance 0-2 - Life expectancy of greater than 12 weeks - Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) - Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies - HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines - If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) - Both measurable as well as non-measurable disease will be allowed - Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration - Total bilirubin within normal institutional limits within 4 weeks of pre-registration - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration - Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration - Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) - All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement - Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib - Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study - Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: - Prior treatment with neratinib - Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) - Any major surgery =< 28 days prior to the initiation of investigational products - Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib - Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia - Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes - Inability to take oral medication - Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas - Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.0 diarrhea of any etiology at baseline) - Known clinically active infection with hepatitis B or hepatitis C virus - Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s --- G309A --- --- G309E --- --- S310F --- --- S310Y --- --- S653C --- --- V659E --- --- R678Q --- --- V697L --- --- T733I --- --- L755S --- --- L755P --- --- E757A --- --- D769H --- --- D769Y --- --- D769N --- --- G776V ---

judgment, makes the patient inappropriate for this study Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance 0-2 - Life expectancy of greater than 12 weeks - Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) - Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies - HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines - If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) - Both measurable as well as non-measurable disease will be allowed - Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration - Total bilirubin within normal institutional limits within 4 weeks of pre-registration - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration - Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration - Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) - All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement - Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib - Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study - Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: - Prior treatment with neratinib - Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) - Any major surgery =< 28 days prior to the initiation of investigational products - Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib - Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia - Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes - Inability to take oral medication - Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas - Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.0 diarrhea of any etiology at baseline) - Known clinically active infection with hepatitis B or hepatitis C virus - Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s --- G309A --- --- G309E --- --- S310F --- --- S310Y --- --- S653C --- --- V659E --- --- R678Q --- --- V697L --- --- T733I --- --- L755S --- --- L755P --- --- E757A --- --- D769H --- --- D769Y --- --- D769N --- --- G776V ---


9 L755P

Generalized linear models and graphical methods will be used to explore factors as identified by serum biomarkers that may be predictive of toxicity dose reductions, dose holds or hospitalizations.. Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance 0-2 - Life expectancy of greater than 12 weeks - Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) - Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies - HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines - If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) - Both measurable as well as non-measurable disease will be allowed - Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration - Total bilirubin within normal institutional limits within 4 weeks of pre-registration - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration - Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration - Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) - All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement - Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib - Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study - Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: - Prior treatment with neratinib - Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) - Any major surgery =< 28 days prior to the initiation of investigational products - Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib - Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia - Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes - Inability to take oral medication - Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas - Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.0 diarrhea of any etiology at baseline) - Known clinically active infection with hepatitis B or hepatitis C virus - Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s --- G309A --- --- G309E --- --- S310F --- --- S310Y --- --- S653C --- --- V659E --- --- R678Q --- --- V697L --- --- T733I --- --- L755S --- --- L755P ---

judgment, makes the patient inappropriate for this study Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance 0-2 - Life expectancy of greater than 12 weeks - Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) - Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies - HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines - If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) - Both measurable as well as non-measurable disease will be allowed - Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration - Total bilirubin within normal institutional limits within 4 weeks of pre-registration - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration - Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration - Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) - All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement - Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib - Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study - Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: - Prior treatment with neratinib - Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) - Any major surgery =< 28 days prior to the initiation of investigational products - Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib - Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia - Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes - Inability to take oral medication - Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas - Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.0 diarrhea of any etiology at baseline) - Known clinically active infection with hepatitis B or hepatitis C virus - Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s --- G309A --- --- G309E --- --- S310F --- --- S310Y --- --- S653C --- --- V659E --- --- R678Q --- --- V697L --- --- T733I --- --- L755S --- --- L755P ---


10 L755S

Generalized linear models and graphical methods will be used to explore factors as identified by serum biomarkers that may be predictive of toxicity dose reductions, dose holds or hospitalizations.. Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance 0-2 - Life expectancy of greater than 12 weeks - Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) - Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies - HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines - If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) - Both measurable as well as non-measurable disease will be allowed - Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration - Total bilirubin within normal institutional limits within 4 weeks of pre-registration - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration - Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration - Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) - All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement - Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib - Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study - Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: - Prior treatment with neratinib - Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) - Any major surgery =< 28 days prior to the initiation of investigational products - Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib - Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia - Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes - Inability to take oral medication - Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas - Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.0 diarrhea of any etiology at baseline) - Known clinically active infection with hepatitis B or hepatitis C virus - Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s --- G309A --- --- G309E --- --- S310F --- --- S310Y --- --- S653C --- --- V659E --- --- R678Q --- --- V697L --- --- T733I --- --- L755S ---

judgment, makes the patient inappropriate for this study Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance 0-2 - Life expectancy of greater than 12 weeks - Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) - Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies - HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines - If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) - Both measurable as well as non-measurable disease will be allowed - Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration - Total bilirubin within normal institutional limits within 4 weeks of pre-registration - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration - Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration - Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) - All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement - Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib - Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study - Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: - Prior treatment with neratinib - Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) - Any major surgery =< 28 days prior to the initiation of investigational products - Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib - Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia - Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes - Inability to take oral medication - Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas - Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.0 diarrhea of any etiology at baseline) - Known clinically active infection with hepatitis B or hepatitis C virus - Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s --- G309A --- --- G309E --- --- S310F --- --- S310Y --- --- S653C --- --- V659E --- --- R678Q --- --- V697L --- --- T733I --- --- L755S ---


11 L841V

Generalized linear models and graphical methods will be used to explore factors as identified by serum biomarkers that may be predictive of toxicity dose reductions, dose holds or hospitalizations.. Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance 0-2 - Life expectancy of greater than 12 weeks - Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) - Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies - HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines - If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) - Both measurable as well as non-measurable disease will be allowed - Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration - Total bilirubin within normal institutional limits within 4 weeks of pre-registration - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration - Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration - Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) - All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement - Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib - Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study - Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: - Prior treatment with neratinib - Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) - Any major surgery =< 28 days prior to the initiation of investigational products - Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib - Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia - Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes - Inability to take oral medication - Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas - Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.0 diarrhea of any etiology at baseline) - Known clinically active infection with hepatitis B or hepatitis C virus - Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s --- G309A --- --- G309E --- --- S310F --- --- S310Y --- --- S653C --- --- V659E --- --- R678Q --- --- V697L --- --- T733I --- --- L755S --- --- L755P --- --- E757A --- --- D769H --- --- D769Y --- --- D769N --- --- G776V --- --- G776C --- --- V777L --- --- L841V ---

judgment, makes the patient inappropriate for this study Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance 0-2 - Life expectancy of greater than 12 weeks - Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) - Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies - HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines - If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) - Both measurable as well as non-measurable disease will be allowed - Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration - Total bilirubin within normal institutional limits within 4 weeks of pre-registration - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration - Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration - Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) - All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement - Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib - Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study - Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: - Prior treatment with neratinib - Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) - Any major surgery =< 28 days prior to the initiation of investigational products - Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib - Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia - Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes - Inability to take oral medication - Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas - Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.0 diarrhea of any etiology at baseline) - Known clinically active infection with hepatitis B or hepatitis C virus - Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s --- G309A --- --- G309E --- --- S310F --- --- S310Y --- --- S653C --- --- V659E --- --- R678Q --- --- V697L --- --- T733I --- --- L755S --- --- L755P --- --- E757A --- --- D769H --- --- D769Y --- --- D769N --- --- G776V --- --- G776C --- --- V777L --- --- L841V ---


12 L869R

Generalized linear models and graphical methods will be used to explore factors as identified by serum biomarkers that may be predictive of toxicity dose reductions, dose holds or hospitalizations.. Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance 0-2 - Life expectancy of greater than 12 weeks - Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) - Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies - HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines - If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) - Both measurable as well as non-measurable disease will be allowed - Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration - Total bilirubin within normal institutional limits within 4 weeks of pre-registration - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration - Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration - Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) - All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement - Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib - Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study - Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: - Prior treatment with neratinib - Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) - Any major surgery =< 28 days prior to the initiation of investigational products - Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib - Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia - Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes - Inability to take oral medication - Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas - Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.0 diarrhea of any etiology at baseline) - Known clinically active infection with hepatitis B or hepatitis C virus - Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s --- G309A --- --- G309E --- --- S310F --- --- S310Y --- --- S653C --- --- V659E --- --- R678Q --- --- V697L --- --- T733I --- --- L755S --- --- L755P --- --- E757A --- --- D769H --- --- D769Y --- --- D769N --- --- G776V --- --- G776C --- --- V777L --- --- L841V --- --- V842I --- --- R849W --- --- L869R ---

judgment, makes the patient inappropriate for this study Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance 0-2 - Life expectancy of greater than 12 weeks - Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) - Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies - HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines - If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) - Both measurable as well as non-measurable disease will be allowed - Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration - Total bilirubin within normal institutional limits within 4 weeks of pre-registration - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration - Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration - Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) - All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement - Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib - Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study - Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: - Prior treatment with neratinib - Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) - Any major surgery =< 28 days prior to the initiation of investigational products - Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib - Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia - Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes - Inability to take oral medication - Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas - Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.0 diarrhea of any etiology at baseline) - Known clinically active infection with hepatitis B or hepatitis C virus - Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s --- G309A --- --- G309E --- --- S310F --- --- S310Y --- --- S653C --- --- V659E --- --- R678Q --- --- V697L --- --- T733I --- --- L755S --- --- L755P --- --- E757A --- --- D769H --- --- D769Y --- --- D769N --- --- G776V --- --- G776C --- --- V777L --- --- L841V --- --- V842I --- --- R849W --- --- L869R ---


13 R678Q

Generalized linear models and graphical methods will be used to explore factors as identified by serum biomarkers that may be predictive of toxicity dose reductions, dose holds or hospitalizations.. Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance 0-2 - Life expectancy of greater than 12 weeks - Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) - Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies - HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines - If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) - Both measurable as well as non-measurable disease will be allowed - Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration - Total bilirubin within normal institutional limits within 4 weeks of pre-registration - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration - Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration - Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) - All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement - Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib - Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study - Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: - Prior treatment with neratinib - Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) - Any major surgery =< 28 days prior to the initiation of investigational products - Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib - Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia - Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes - Inability to take oral medication - Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas - Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.0 diarrhea of any etiology at baseline) - Known clinically active infection with hepatitis B or hepatitis C virus - Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s --- G309A --- --- G309E --- --- S310F --- --- S310Y --- --- S653C --- --- V659E --- --- R678Q ---

judgment, makes the patient inappropriate for this study Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance 0-2 - Life expectancy of greater than 12 weeks - Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) - Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies - HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines - If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) - Both measurable as well as non-measurable disease will be allowed - Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration - Total bilirubin within normal institutional limits within 4 weeks of pre-registration - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration - Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration - Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) - All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement - Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib - Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study - Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: - Prior treatment with neratinib - Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) - Any major surgery =< 28 days prior to the initiation of investigational products - Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib - Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia - Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes - Inability to take oral medication - Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas - Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.0 diarrhea of any etiology at baseline) - Known clinically active infection with hepatitis B or hepatitis C virus - Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s --- G309A --- --- G309E --- --- S310F --- --- S310Y --- --- S653C --- --- V659E --- --- R678Q ---


14 R849W

Generalized linear models and graphical methods will be used to explore factors as identified by serum biomarkers that may be predictive of toxicity dose reductions, dose holds or hospitalizations.. Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance 0-2 - Life expectancy of greater than 12 weeks - Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) - Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies - HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines - If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) - Both measurable as well as non-measurable disease will be allowed - Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration - Total bilirubin within normal institutional limits within 4 weeks of pre-registration - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration - Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration - Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) - All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement - Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib - Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study - Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: - Prior treatment with neratinib - Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) - Any major surgery =< 28 days prior to the initiation of investigational products - Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib - Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia - Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes - Inability to take oral medication - Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas - Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.0 diarrhea of any etiology at baseline) - Known clinically active infection with hepatitis B or hepatitis C virus - Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s --- G309A --- --- G309E --- --- S310F --- --- S310Y --- --- S653C --- --- V659E --- --- R678Q --- --- V697L --- --- T733I --- --- L755S --- --- L755P --- --- E757A --- --- D769H --- --- D769Y --- --- D769N --- --- G776V --- --- G776C --- --- V777L --- --- L841V --- --- V842I --- --- R849W ---

judgment, makes the patient inappropriate for this study Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance 0-2 - Life expectancy of greater than 12 weeks - Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) - Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies - HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines - If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) - Both measurable as well as non-measurable disease will be allowed - Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration - Total bilirubin within normal institutional limits within 4 weeks of pre-registration - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration - Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration - Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) - All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement - Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib - Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study - Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: - Prior treatment with neratinib - Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) - Any major surgery =< 28 days prior to the initiation of investigational products - Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib - Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia - Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes - Inability to take oral medication - Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas - Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.0 diarrhea of any etiology at baseline) - Known clinically active infection with hepatitis B or hepatitis C virus - Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s --- G309A --- --- G309E --- --- S310F --- --- S310Y --- --- S653C --- --- V659E --- --- R678Q --- --- V697L --- --- T733I --- --- L755S --- --- L755P --- --- E757A --- --- D769H --- --- D769Y --- --- D769N --- --- G776V --- --- G776C --- --- V777L --- --- L841V --- --- V842I --- --- R849W ---


15 R896C

Generalized linear models and graphical methods will be used to explore factors as identified by serum biomarkers that may be predictive of toxicity dose reductions, dose holds or hospitalizations.. Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance 0-2 - Life expectancy of greater than 12 weeks - Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) - Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies - HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines - If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) - Both measurable as well as non-measurable disease will be allowed - Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration - Total bilirubin within normal institutional limits within 4 weeks of pre-registration - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration - Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration - Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) - All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement - Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib - Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study - Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: - Prior treatment with neratinib - Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) - Any major surgery =< 28 days prior to the initiation of investigational products - Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib - Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia - Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes - Inability to take oral medication - Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas - Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.0 diarrhea of any etiology at baseline) - Known clinically active infection with hepatitis B or hepatitis C virus - Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s --- G309A --- --- G309E --- --- S310F --- --- S310Y --- --- S653C --- --- V659E --- --- R678Q --- --- V697L --- --- T733I --- --- L755S --- --- L755P --- --- E757A --- --- D769H --- --- D769Y --- --- D769N --- --- G776V --- --- G776C --- --- V777L --- --- L841V --- --- V842I --- --- R849W --- --- L869R --- --- R896C ---

judgment, makes the patient inappropriate for this study Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance 0-2 - Life expectancy of greater than 12 weeks - Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) - Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies - HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines - If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) - Both measurable as well as non-measurable disease will be allowed - Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration - Total bilirubin within normal institutional limits within 4 weeks of pre-registration - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration - Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration - Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) - All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement - Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib - Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study - Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: - Prior treatment with neratinib - Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) - Any major surgery =< 28 days prior to the initiation of investigational products - Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib - Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia - Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes - Inability to take oral medication - Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas - Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.0 diarrhea of any etiology at baseline) - Known clinically active infection with hepatitis B or hepatitis C virus - Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s --- G309A --- --- G309E --- --- S310F --- --- S310Y --- --- S653C --- --- V659E --- --- R678Q --- --- V697L --- --- T733I --- --- L755S --- --- L755P --- --- E757A --- --- D769H --- --- D769Y --- --- D769N --- --- G776V --- --- G776C --- --- V777L --- --- L841V --- --- V842I --- --- R849W --- --- L869R --- --- R896C ---


16 S310F

Generalized linear models and graphical methods will be used to explore factors as identified by serum biomarkers that may be predictive of toxicity dose reductions, dose holds or hospitalizations.. Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance 0-2 - Life expectancy of greater than 12 weeks - Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) - Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies - HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines - If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) - Both measurable as well as non-measurable disease will be allowed - Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration - Total bilirubin within normal institutional limits within 4 weeks of pre-registration - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration - Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration - Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) - All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement - Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib - Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study - Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: - Prior treatment with neratinib - Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) - Any major surgery =< 28 days prior to the initiation of investigational products - Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib - Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia - Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes - Inability to take oral medication - Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas - Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.0 diarrhea of any etiology at baseline) - Known clinically active infection with hepatitis B or hepatitis C virus - Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s --- G309A --- --- G309E --- --- S310F ---

judgment, makes the patient inappropriate for this study Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance 0-2 - Life expectancy of greater than 12 weeks - Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) - Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies - HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines - If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) - Both measurable as well as non-measurable disease will be allowed - Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration - Total bilirubin within normal institutional limits within 4 weeks of pre-registration - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration - Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration - Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) - All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement - Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib - Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study - Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: - Prior treatment with neratinib - Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) - Any major surgery =< 28 days prior to the initiation of investigational products - Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib - Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia - Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes - Inability to take oral medication - Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas - Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.0 diarrhea of any etiology at baseline) - Known clinically active infection with hepatitis B or hepatitis C virus - Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s --- G309A --- --- G309E --- --- S310F ---


17 S310Y

Generalized linear models and graphical methods will be used to explore factors as identified by serum biomarkers that may be predictive of toxicity dose reductions, dose holds or hospitalizations.. Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance 0-2 - Life expectancy of greater than 12 weeks - Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) - Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies - HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines - If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) - Both measurable as well as non-measurable disease will be allowed - Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration - Total bilirubin within normal institutional limits within 4 weeks of pre-registration - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration - Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration - Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) - All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement - Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib - Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study - Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: - Prior treatment with neratinib - Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) - Any major surgery =< 28 days prior to the initiation of investigational products - Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib - Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia - Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes - Inability to take oral medication - Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas - Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.0 diarrhea of any etiology at baseline) - Known clinically active infection with hepatitis B or hepatitis C virus - Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s --- G309A --- --- G309E --- --- S310F --- --- S310Y ---

judgment, makes the patient inappropriate for this study Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance 0-2 - Life expectancy of greater than 12 weeks - Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) - Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies - HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines - If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) - Both measurable as well as non-measurable disease will be allowed - Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration - Total bilirubin within normal institutional limits within 4 weeks of pre-registration - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration - Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration - Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) - All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement - Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib - Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study - Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: - Prior treatment with neratinib - Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) - Any major surgery =< 28 days prior to the initiation of investigational products - Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib - Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia - Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes - Inability to take oral medication - Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas - Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.0 diarrhea of any etiology at baseline) - Known clinically active infection with hepatitis B or hepatitis C virus - Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s --- G309A --- --- G309E --- --- S310F --- --- S310Y ---


18 S653C

Generalized linear models and graphical methods will be used to explore factors as identified by serum biomarkers that may be predictive of toxicity dose reductions, dose holds or hospitalizations.. Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance 0-2 - Life expectancy of greater than 12 weeks - Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) - Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies - HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines - If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) - Both measurable as well as non-measurable disease will be allowed - Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration - Total bilirubin within normal institutional limits within 4 weeks of pre-registration - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration - Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration - Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) - All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement - Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib - Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study - Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: - Prior treatment with neratinib - Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) - Any major surgery =< 28 days prior to the initiation of investigational products - Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib - Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia - Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes - Inability to take oral medication - Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas - Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.0 diarrhea of any etiology at baseline) - Known clinically active infection with hepatitis B or hepatitis C virus - Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s --- G309A --- --- G309E --- --- S310F --- --- S310Y --- --- S653C ---

judgment, makes the patient inappropriate for this study Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance 0-2 - Life expectancy of greater than 12 weeks - Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) - Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies - HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines - If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) - Both measurable as well as non-measurable disease will be allowed - Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration - Total bilirubin within normal institutional limits within 4 weeks of pre-registration - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration - Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration - Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) - All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement - Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib - Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study - Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: - Prior treatment with neratinib - Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) - Any major surgery =< 28 days prior to the initiation of investigational products - Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib - Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia - Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes - Inability to take oral medication - Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas - Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.0 diarrhea of any etiology at baseline) - Known clinically active infection with hepatitis B or hepatitis C virus - Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s --- G309A --- --- G309E --- --- S310F --- --- S310Y --- --- S653C ---


19 T733I

Generalized linear models and graphical methods will be used to explore factors as identified by serum biomarkers that may be predictive of toxicity dose reductions, dose holds or hospitalizations.. Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance 0-2 - Life expectancy of greater than 12 weeks - Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) - Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies - HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines - If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) - Both measurable as well as non-measurable disease will be allowed - Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration - Total bilirubin within normal institutional limits within 4 weeks of pre-registration - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration - Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration - Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) - All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement - Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib - Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study - Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: - Prior treatment with neratinib - Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) - Any major surgery =< 28 days prior to the initiation of investigational products - Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib - Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia - Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes - Inability to take oral medication - Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas - Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.0 diarrhea of any etiology at baseline) - Known clinically active infection with hepatitis B or hepatitis C virus - Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s --- G309A --- --- G309E --- --- S310F --- --- S310Y --- --- S653C --- --- V659E --- --- R678Q --- --- V697L --- --- T733I ---

judgment, makes the patient inappropriate for this study Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance 0-2 - Life expectancy of greater than 12 weeks - Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) - Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies - HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines - If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) - Both measurable as well as non-measurable disease will be allowed - Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration - Total bilirubin within normal institutional limits within 4 weeks of pre-registration - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration - Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration - Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) - All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement - Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib - Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study - Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: - Prior treatment with neratinib - Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) - Any major surgery =< 28 days prior to the initiation of investigational products - Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib - Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia - Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes - Inability to take oral medication - Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas - Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.0 diarrhea of any etiology at baseline) - Known clinically active infection with hepatitis B or hepatitis C virus - Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s --- G309A --- --- G309E --- --- S310F --- --- S310Y --- --- S653C --- --- V659E --- --- R678Q --- --- V697L --- --- T733I ---


20 V659E

Generalized linear models and graphical methods will be used to explore factors as identified by serum biomarkers that may be predictive of toxicity dose reductions, dose holds or hospitalizations.. Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance 0-2 - Life expectancy of greater than 12 weeks - Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) - Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies - HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines - If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) - Both measurable as well as non-measurable disease will be allowed - Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration - Total bilirubin within normal institutional limits within 4 weeks of pre-registration - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration - Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration - Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) - All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement - Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib - Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study - Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: - Prior treatment with neratinib - Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) - Any major surgery =< 28 days prior to the initiation of investigational products - Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib - Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia - Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes - Inability to take oral medication - Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas - Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.0 diarrhea of any etiology at baseline) - Known clinically active infection with hepatitis B or hepatitis C virus - Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s --- G309A --- --- G309E --- --- S310F --- --- S310Y --- --- S653C --- --- V659E ---

judgment, makes the patient inappropriate for this study Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance 0-2 - Life expectancy of greater than 12 weeks - Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) - Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies - HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines - If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) - Both measurable as well as non-measurable disease will be allowed - Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration - Total bilirubin within normal institutional limits within 4 weeks of pre-registration - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration - Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration - Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) - All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement - Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib - Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study - Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: - Prior treatment with neratinib - Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) - Any major surgery =< 28 days prior to the initiation of investigational products - Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib - Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia - Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes - Inability to take oral medication - Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas - Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.0 diarrhea of any etiology at baseline) - Known clinically active infection with hepatitis B or hepatitis C virus - Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s --- G309A --- --- G309E --- --- S310F --- --- S310Y --- --- S653C --- --- V659E ---


21 V697L

Generalized linear models and graphical methods will be used to explore factors as identified by serum biomarkers that may be predictive of toxicity dose reductions, dose holds or hospitalizations.. Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance 0-2 - Life expectancy of greater than 12 weeks - Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) - Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies - HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines - If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) - Both measurable as well as non-measurable disease will be allowed - Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration - Total bilirubin within normal institutional limits within 4 weeks of pre-registration - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration - Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration - Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) - All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement - Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib - Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study - Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: - Prior treatment with neratinib - Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) - Any major surgery =< 28 days prior to the initiation of investigational products - Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib - Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia - Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes - Inability to take oral medication - Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas - Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.0 diarrhea of any etiology at baseline) - Known clinically active infection with hepatitis B or hepatitis C virus - Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s --- G309A --- --- G309E --- --- S310F --- --- S310Y --- --- S653C --- --- V659E --- --- R678Q --- --- V697L ---

judgment, makes the patient inappropriate for this study Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance 0-2 - Life expectancy of greater than 12 weeks - Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) - Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies - HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines - If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) - Both measurable as well as non-measurable disease will be allowed - Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration - Total bilirubin within normal institutional limits within 4 weeks of pre-registration - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration - Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration - Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) - All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement - Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib - Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study - Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: - Prior treatment with neratinib - Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) - Any major surgery =< 28 days prior to the initiation of investigational products - Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib - Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia - Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes - Inability to take oral medication - Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas - Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.0 diarrhea of any etiology at baseline) - Known clinically active infection with hepatitis B or hepatitis C virus - Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s --- G309A --- --- G309E --- --- S310F --- --- S310Y --- --- S653C --- --- V659E --- --- R678Q --- --- V697L ---


22 V777L

Generalized linear models and graphical methods will be used to explore factors as identified by serum biomarkers that may be predictive of toxicity dose reductions, dose holds or hospitalizations.. Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance 0-2 - Life expectancy of greater than 12 weeks - Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) - Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies - HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines - If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) - Both measurable as well as non-measurable disease will be allowed - Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration - Total bilirubin within normal institutional limits within 4 weeks of pre-registration - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration - Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration - Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) - All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement - Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib - Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study - Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: - Prior treatment with neratinib - Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) - Any major surgery =< 28 days prior to the initiation of investigational products - Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib - Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia - Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes - Inability to take oral medication - Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas - Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.0 diarrhea of any etiology at baseline) - Known clinically active infection with hepatitis B or hepatitis C virus - Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s --- G309A --- --- G309E --- --- S310F --- --- S310Y --- --- S653C --- --- V659E --- --- R678Q --- --- V697L --- --- T733I --- --- L755S --- --- L755P --- --- E757A --- --- D769H --- --- D769Y --- --- D769N --- --- G776V --- --- G776C --- --- V777L ---

judgment, makes the patient inappropriate for this study Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance 0-2 - Life expectancy of greater than 12 weeks - Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) - Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies - HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines - If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) - Both measurable as well as non-measurable disease will be allowed - Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration - Total bilirubin within normal institutional limits within 4 weeks of pre-registration - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration - Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration - Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) - All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement - Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib - Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study - Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: - Prior treatment with neratinib - Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) - Any major surgery =< 28 days prior to the initiation of investigational products - Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib - Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia - Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes - Inability to take oral medication - Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas - Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.0 diarrhea of any etiology at baseline) - Known clinically active infection with hepatitis B or hepatitis C virus - Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s --- G309A --- --- G309E --- --- S310F --- --- S310Y --- --- S653C --- --- V659E --- --- R678Q --- --- V697L --- --- T733I --- --- L755S --- --- L755P --- --- E757A --- --- D769H --- --- D769Y --- --- D769N --- --- G776V --- --- G776C --- --- V777L ---


23 V842I

Generalized linear models and graphical methods will be used to explore factors as identified by serum biomarkers that may be predictive of toxicity dose reductions, dose holds or hospitalizations.. Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance 0-2 - Life expectancy of greater than 12 weeks - Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) - Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies - HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines - If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) - Both measurable as well as non-measurable disease will be allowed - Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration - Total bilirubin within normal institutional limits within 4 weeks of pre-registration - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration - Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration - Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) - All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement - Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib - Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study - Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: - Prior treatment with neratinib - Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) - Any major surgery =< 28 days prior to the initiation of investigational products - Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib - Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia - Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes - Inability to take oral medication - Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas - Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.0 diarrhea of any etiology at baseline) - Known clinically active infection with hepatitis B or hepatitis C virus - Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s --- G309A --- --- G309E --- --- S310F --- --- S310Y --- --- S653C --- --- V659E --- --- R678Q --- --- V697L --- --- T733I --- --- L755S --- --- L755P --- --- E757A --- --- D769H --- --- D769Y --- --- D769N --- --- G776V --- --- G776C --- --- V777L --- --- L841V --- --- V842I ---

judgment, makes the patient inappropriate for this study Inclusion Criteria: - Eastern Cooperative Oncology Group (ECOG) performance 0-2 - Life expectancy of greater than 12 weeks - Histologically or cytologically proven metastatic breast cancer (metastases can be proven with imaging results in certain circumstances provided that the initial tumor was demonstrated histologically) - Stage IV HER2/Neu positive breast cancer patients who failed previous anti-HER2 targeted therapies - HER2 positivity as defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines - If HER2 negative by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but activating somatic mutations of HER2 gene identified through genomic sequencing including but not limited to the following (Clinical Laboratory Improvement Act [CLIA] certified lab test): missense substitutions (G309A, G309E, S310F, S310Y, S653C, V659E, R678Q, V697L, T733I, L755S, L755P, E757A, D769H, D769Y, D769N, G776V, G776C, V777L, L841V, V842I, R849W, L869R, R896C); insertions/deletions (A775_G776insYVMA aka Y772_A755dup, G776VinsC, G776AinsVGC, G776 insertions, G778_S779insCPG, P780_781insGSP aka G778_P780dup, L755_T759del) and/or HER3 activating mutations; there is no limitation on the number of prior lines of systemic therapy or HER2-targeted therapies (prior neratinib not allowed) - Both measurable as well as non-measurable disease will be allowed - Hemoglobin >= 9 g/dL (after transfusion, if necessary) within 4 weeks of pre-registration - Total bilirubin within normal institutional limits within 4 weeks of pre-registration - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal within 4 weeks of pre-registration - Creatinine clearance >= 30 mL/min as calculated by Cockcroft-Gault formula within 4 weeks of pre-registration - Baseline left ventricular ejection fraction LVEF >= 50% as evaluated by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) - All grade >= 2 toxicities other than alopecia from prior therapy have resolved by the time of study commencement - Patient must have completed radiation therapy with adequate recovery of bone marrow and organ functions, before starting neratinib - Patient with stable or treated brain metastases are eligible; asymptomatic patients with metastatic brain disease who have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days are eligible to participate in the study - Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: - Prior treatment with neratinib - Concurrent usage of other investigational agents, chemotherapy, or hormone therapy; prior chemotherapy, hormonal therapy, targeted therapy, and investigational agents are allowed but all toxicities grade >= 2 must have resolved by the time of study commencement (except alopecia) - Any major surgery =< 28 days prior to the initiation of investigational products - Received chemotherapy or biologic therapy =< 3 weeks prior to the start of neratinib - Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2, including individuals who currently use digitalis specifically for congestive heart failure), unstable angina, myocardial infarction within 12 month of enrollment or ventricular arrhythmia - Concurrent use of digoxin due to cardiac disease; corrected QT (QTc) interval >= 450 milliseconds in men and >= 470 milliseconds in women within 2 weeks of registration or known history of QTc prolongation or Torsades de Pointes - Inability to take oral medication - Other malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) cervix or vulva carcinoma in situ; c) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, or benign tumors of the adrenal or pancreas - Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn?s disease, malabsorption, or grade >= 2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.0 diarrhea of any etiology at baseline) - Known clinically active infection with hepatitis B or hepatitis C virus - Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situations that would, in the investigator?s --- G309A --- --- G309E --- --- S310F --- --- S310Y --- --- S653C --- --- V659E --- --- R678Q --- --- V697L --- --- T733I --- --- L755S --- --- L755P --- --- E757A --- --- D769H --- --- D769Y --- --- D769N --- --- G776V --- --- G776C --- --- V777L --- --- L841V --- --- V842I ---



HPO Nodes


HPO:
Protein Mutations 0
SNP 0