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Report for Mutation G776V

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

There are 2 clinical trials

Clinical Trials


1 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 Other: Comprehensive Geriatric Assessment Other: Laboratory Biomarker Analysis Drug: Neratinib Other: Pharmacological Study
MeSH: Breast Neoplasms
HPO: Breast carcinoma Neoplasm of the breast

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 ---

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

2 A Phase II Study of Poziotinib in EGFR in Exon 20 Mutant Advanced Non Small Cell Lung Cancer (NSCLC)

This phase II trial studies how well poziotinib works in treating patients with non-small lung cancer with EGFR or HER2 exon 20 mutation that is stage IV or has come back. Poziotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT03066206 EGFR Exon 20 Mutation ERBB2 Gene Mutation Recurrent Lung Non-Small Cell Carcinoma Stage IV Non-Small Cell Lung Cancer AJCC v7 Drug: Poziotinib
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

Toxicity data will be summarized by frequency tables.. Inclusion Criteria: - Histologically or cytologically confirmed stage IV or recurrent solid tumor not amenable to curative intent therapy - Cohort 1 specific inclusion criteria: Documented EGFR exon 20 mutation by one of the following Clinical Laboratory Improvement Act (CLIA) certified tests: OncoMine Comprehensive Assay (OCA), Guardant360 Assay (using plasma), or FoundationOne Assay or by a Food and Drug Administration (FDA) approved device using cobas EGFR mutation test version (v)2 or therascreen EGFR RGQ PCt kit; eligible mutations include D770_N771insSVD, D770_N771insNPG, V769_D770insASV, H773_V774insNPH, or any other exon 20 in-frame insertion or point mutation excluding T790M - Patients must be previously treated with one or more regimens of systemic therapy for locally advanced or metastatic disease; previously untreated patients are eligible only if EGFR Exon 20 mutation is confirmed using an FDA approved device: cobas EGFR mutation test v2 or therascreen EGFR RGQ polymerase chain reaction (PCR) Kit prior to study enrollment - Cohort 2 specific inclusion criteria: documented HER2 exon 20 mutation by a CLIA certified laboratory; eligible mutations include A775_G776insYVMA, G776_V777insVC, or P780_Y781insGSP, or any other in-frame exon 20 insertion mutation or point mutation including, but not limited to, L755S, G776V, and V777L - Measurable disease by RECIST 1.1 - Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 - Ability to take pills by mouth - Leukocytes >= 3,000/mcL - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Hemoglobin >= 9.0 g/dL - Total bilirubin =< 2 x upper limit of normal (ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 institutional upper limit of normal of =< 5 x ULN if liver metastases are present - Alkaline phosphatase =< 2.5 institutional upper limit of normal of =< 5 x ULN if liver metastases are present - Creatinine clearance > 50 mL/min/1.73 --- T790M --- --- L755S --- --- G776V ---

Inclusion Criteria: - Histologically or cytologically confirmed stage IV or recurrent solid tumor not amenable to curative intent therapy - Cohort 1 specific inclusion criteria: Documented EGFR exon 20 mutation by one of the following Clinical Laboratory Improvement Act (CLIA) certified tests: OncoMine Comprehensive Assay (OCA), Guardant360 Assay (using plasma), or FoundationOne Assay or by a Food and Drug Administration (FDA) approved device using cobas EGFR mutation test version (v)2 or therascreen EGFR RGQ PCt kit; eligible mutations include D770_N771insSVD, D770_N771insNPG, V769_D770insASV, H773_V774insNPH, or any other exon 20 in-frame insertion or point mutation excluding T790M - Patients must be previously treated with one or more regimens of systemic therapy for locally advanced or metastatic disease; previously untreated patients are eligible only if EGFR Exon 20 mutation is confirmed using an FDA approved device: cobas EGFR mutation test v2 or therascreen EGFR RGQ polymerase chain reaction (PCR) Kit prior to study enrollment - Cohort 2 specific inclusion criteria: documented HER2 exon 20 mutation by a CLIA certified laboratory; eligible mutations include A775_G776insYVMA, G776_V777insVC, or P780_Y781insGSP, or any other in-frame exon 20 insertion mutation or point mutation including, but not limited to, L755S, G776V, and V777L - Measurable disease by RECIST 1.1 - Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 - Ability to take pills by mouth - Leukocytes >= 3,000/mcL - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Hemoglobin >= 9.0 g/dL - Total bilirubin =< 2 x upper limit of normal (ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 institutional upper limit of normal of =< 5 x ULN if liver metastases are present - Alkaline phosphatase =< 2.5 institutional upper limit of normal of =< 5 x ULN if liver metastases are present - Creatinine clearance > 50 mL/min/1.73 --- T790M --- --- L755S --- --- G776V ---

Primary Outcomes

Description: According to Response Evaluation Criteria in Solid Tumors 1.1 criteria.

Measure: Objective response rate a in patients with estimated glomerular filtration rate (EGFR) exon 20 mutant non-small Cell Lung Cancer (NSCLC) (Cohort 1)

Time: Up to 4 years

Description: According to Response Evaluation Criteria in Solid Tumors 1.1 criteria.

Measure: Objective response rate a in patients with human epidermal growth factor receptor 2 (HER2) exon 20 mutant non-small Cell Lung Cancer (NSCLC) (Cohort 2)

Time: Up to 4 years

Secondary Outcomes

Description: Will be estimated along with 95% confidence intervals.

Measure: Disease control rate (complete response + partial response + stable disease) of poziotinb in cohort 1 and 2, analyzed independently

Time: Up to 4 years

Description: Will be estimated using the Kaplan-Meier method and the comparison between or among patient's characteristic groups will be evaluated by log-rank test. The Cox regression model may be applied to assess the effect of covariates of interest on progression free survival.

Measure: Progression free survival of poziotinb in cohort 1 and 2, analyzed independently

Time: Up to 4 years

Description: Will be estimated using the Kaplan-Meier method and the comparison between or among patient's characteristic groups will be evaluated by log-rank test. The Cox regression model may be applied to assess the effect of covariates of interest on overall survival.

Measure: Overall survival of poziotinb in cohort 1 and 2, analyzed independently

Time: Up to 4 years

Description: Duration of response will be measured.

Measure: Duration of response of poziotinb in cohort 1 and 2, analyzed independently

Time: Up to 4 years

Description: Assessed by Common Terminology Criteria for Adverse Events version 4.03. Toxicity data will be summarized by frequency tables.

Measure: Incidence of adverse events

Time: Up to 4 years


HPO Nodes


Non-small cell lung carcinoma
Genes 3
TP53 TP53 BAP1
Breast carcinoma
Genes 95
TP53 PPM1D CTNNB1 TP53 COL14A1 AKT1 AKT1 OPCML MDM2 BRCA1 SLC22A18 POLE BRCA2 BRCA1 SDHC NTHL1 PTEN XRCC3 MSH6 IDH1 RAD51C RAD51C CASP8 RB1CC1 PIK3CA PALLD KRAS PIK3CA CHEK2 BRIP1 MRE11 NTHL1 ATM TP53 RAD51D STK11 PRKN ESR1 PIK3CA KLLN MSH2 SDHD KRAS SEC23B HMMR PTEN POLD1 PIK3CA IDH2 BRCA1 PALB2 BRIP1 TP53 RAD51 RNF43 BARD1 BARD1 AAGAB AKT1 SMAD4 RAD50 STK11 CHEK2 RAD54L NBN CDKN2A SEC23B CDH1 WRN NQO2 PALB2 ATR PALB2 TWIST1 SDHB MSH2 BRCA2 BRCA1 RAD51 CHEK2 MLH1 BRCA1 FGFR2 TP53 PHB BRCA2 CDH1 PTEN BRCA2 CHEK2 CDKN2A APC MLH1 AKT1 APC
Neoplasm of the lung
Genes 61
REST GPC3 WT1 HPGD BRAF PIK3CA TP53 TRIM28 RB1 TRIP13 SLCO2A1 AKT1 CASP8 KRAS TSC1 POU6F2 EWSR1 PRKN LMNA NAB2 TERT TSC2 SLC22A18 BRCA2 PPP2R1B STAT6 STK11 MUC5B ERBB2 TSC2 MBTPS2 BAP1 TSC2 DICER1 PDGFRB PERP EGFR TSC1 DIS3L2 NOTCH3 KEAP1 DICER1 DICER1 WT1 TSC1 C11ORF95 IRF1 CYP2A6 WRN RELA WT1 PTEN SFTPC SFTPA2 ERCC6 TRPV3 TP53 H19 TRIM28 FASLG MAP3K8