SNPMiner Trials by Shray Alag


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Report for Mutation L755S

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

There are 5 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 ---

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 ---

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 2 Trial of Ado-Trastuzumab Emtansine for Patients With HER2 Amplified or Mutant Cancers

The purpose of this study is to find out what effects, a drug called ado-trastuzumab emtansine has on the patient and their cancer which is thought to be controlled by the abnormal HER2 gene.

NCT02675829 Solid Tumor Cancers Lung Cancer Bladder Cancer Urinary Tract Cancers Drug: ado-trastuzumab emtansine
MeSH:Urologic Neoplasms
HPO:Urinary tract neoplasm

- Pathologically confirmed advanced solid tumor cancers - For Cohort 1, documented activating HER2 mutation in lung cancer by CLIA laboratory, specifically exon 20 insYVMA (Y772_A775dup), insGSP (G778_P780dup), insTGT (G776delinsVC), single base pair substitutions L755A, L755S, V777L, V659E, S310F, or another HER2 mutation approved by the Principal Investigator - For Cohorts 2, 3, 4, documented HER2 amplification identified through next generation sequencing by MSK-IMPACT or at another Clinical Laboratory Improvement Amendments (CLIA) laboratory, or documented HER2 amplification by in-situ hybridization (ISH) with HER2/CEP17 ratio ≥2.0 at a CLIA laboratory. --- L755A --- --- L755S ---

Primary Outcomes

Description: As soon as evaluations for each tumor assessment are completed, the Investigator should assess the patient's overall response (target plus non- target lesions) based on criteria and overall response algorithms as defined in RECIST version 1.1. Scans must be assessable for all evaluations.

Measure: best overall response (ORR)

Time: 2 years

3 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 ---

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 ---

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

4 Phase II Trial of Trastuzumab in Combination With Pertuzumab in Pretreated Patients With Non-small Cell Lung Cancer (NSCLC) Harboring a Her2 Mutation and Receiving Docetaxel

HER2 (erbB-2/neu) is a member of the erbB receptor tyrosine kinase family. ERBB2 gene which encodes human epidermal growth factor 2 (HER2) is a major proliferative driver activating downstream signaling through PI3K-AKT and MEK-ERK. HER2 overexpression or gene amplification is associated with sensitivity to trastuzumab and lapatinib in breast cancer. Among actual lung cancer biomarker, HER2 remains apart. HER2 involvement is known for a long time but clinical research has been stopped for many years since the first clinical trials in unselected patients were negative. Recently trastuzumab + pertuzumab + docetaxel has been tested for first-line treatment of HER2-positive metastatic breast cancer (CLEOPATRA trial). Analysis of the primary end point showed that patients who received pertuzumab, trastuzumab, and docetaxel (pertuzumab group) had a significantly longer median progression-free survival, as assessed by independent reviewers an did those who received placebo, trastuzumab, and docetaxel (control group) (hazard ratio favoring the pertuzumab group, 0.62). There is thus a strong rational for treating HER2 mutated lung cancer patient with these drugs.

NCT03845270 Non Small Cell Lung Cancer Metastatic Non Small Cell Lung Cancer Stage III HER2 Gene Mutation Drug: pertuzumab + trastuzumab + docetaxel
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Not suitable for radiation, inoperable stage III or stage IV 4. HER2 exon 20 mutation or insertion among which: in-frame insertions in exon 20 between codons 775 and 881 including the 12bp insertion with a duplication / insertion of 4 amino acids (YVMA) at codon 775, the 3bp insertion with a complex insertion-substitution G776>VC and point mutations L755S and G776C. --- L755S ---

Primary Outcomes

Description: Percentage of patient with confirmed objective response rate with RECIST 1.1

Measure: Objective Response Rate

Time: 6 weeks (confirmation needed at 12 weeks)

Secondary Outcomes

Description: Time from enrollment until death due to any cause

Measure: Overall Survival

Time: About 24 months

Description: time from enrollment to first observation of progression (according to RECIST v1.1) or date of death (from any cause)

Measure: Progression-free survival

Time: About 24 months

Description: Time from documentation of tumor response to disease progression.

Measure: Duration of response

Time: About 24 months

Measure: Incidence, type and severity of non-serious and serious adverse event

Time: About 24 months

Other Outcomes

Measure: Correlation between OR, PFS, and HER2 mutation kinetic on cfDNA

Time: About 24 months

5 MasterKey-01: A Phase 1/2, Open-label, Two-part, Multicenter Study to Assess the Safety, Tolerability, Pharmacokinetics & Antitumor Activity of BDTX-189, an Inhibitor of Allosteric ErbB Mutations, in Patients w/ Advanced Solid Malignancies

This is a clinical study with an orally administered drug, BDTX-189 in participants with advanced solid tumors that have select mutations or alterations in human epidermal growth factor receptor 2 (HER2/ErbB2) genes or epidermal growth factor receptor (EGFR/ErbB1). The main goals of this study are to: - Find the recommended dose of BDTX-189 that can be given safely to participants - Learn more about the side effects of BDTX-189 - Learn what the body does to BDTX-189 after it has been taken (pharmacokinetics or PK) - Determine the antitumor activity of BDTX-189 in participants with select allosteric ErbB gene mutations

NCT04209465 Solid Tumor Drug: BDTX-189

Overall survival is the time from first study dose until death from any cause or study discontinuation.. Main Inclusion Criteria: - Histologically- or cytologically-confirmed locally advanced or metastatic solid tumor with documented recurrence or disease progression from standard anticancer therapy in the advanced/metastatic setting - No standard therapy available or standard therapy is considered unsuitable or intolerable according to the Investigator and consultation with the Medical Monitor Phase 1 Only: - Solid tumor patients with alterations that may be associated with antitumor activity based on preclinical data for BDTX-189 such as: 1. Allosteric HER2 or HER3 mutation(s) 2. EGFR or HER2 exon 20 insertion mutation(s) 3. HER2 amplified or overexpressing tumors 4. EGFR exon 19 deletion or L858R mutation Phase 2 Only: - Patients with a solid tumor harboring an: 1. Allosteric HER2 mutation (including but not limited to S310F/Y, R678Q, L755S/P, V777L, V842I) 2. EGFR or HER2 exon 20 insertion mutation Eligible mutations must be determined by a validated next-generation sequencing (NGS) test routinely used by each institution and performed in a CLIA-certified or equivalent laboratory. --- L858R --- --- S310F --- --- R678Q --- --- L755S ---

Evidence of second- or third-degree atrioventricular block 2. Clinically significant arrhythmia (as determined by the Investigator) 3. QTcF interval of >480 msec - Leptomeningeal or untreated and/or symptomatic CNS malignancies (primary or metastatic) - Women who are pregnant or breast-feeding - Taking or unable to discontinue proton pump inhibitors within 1 week prior to baseline Phase 2 Only: - Prior documented treatment response to approved or investigational HER2 or EGFR tyrosine kinase inhibitor therapies - Known concurrent KRAS mutation - Known tumor-harboring resistance mutations including EGFR T790M or C797S mutations or HER2 C805S mutation Main Inclusion Criteria: - Histologically- or cytologically-confirmed locally advanced or metastatic solid tumor with documented recurrence or disease progression from standard anticancer therapy in the advanced/metastatic setting - No standard therapy available or standard therapy is considered unsuitable or intolerable according to the Investigator and consultation with the Medical Monitor Phase 1 Only: - Solid tumor patients with alterations that may be associated with antitumor activity based on preclinical data for BDTX-189 such as: 1. Allosteric HER2 or HER3 mutation(s) 2. EGFR or HER2 exon 20 insertion mutation(s) 3. HER2 amplified or overexpressing tumors 4. EGFR exon 19 deletion or L858R mutation Phase 2 Only: - Patients with a solid tumor harboring an: 1. Allosteric HER2 mutation (including but not limited to S310F/Y, R678Q, L755S/P, V777L, V842I) 2. EGFR or HER2 exon 20 insertion mutation Eligible mutations must be determined by a validated next-generation sequencing (NGS) test routinely used by each institution and performed in a CLIA-certified or equivalent laboratory. --- T790M --- --- C797S --- --- C805S --- --- L858R --- --- S310F --- --- R678Q --- --- L755S ---

Phase 2 will focus on patients with a solid tumor harboring an: - Allosteric HER2 mutation (including but not limited to S310F/Y, R678Q, L755S/P, V777L, V842I) - EGFR or HER2 exon 20 insertion mutation Eligible mutations must be determined by a validated next-generation sequencing (NGS) test routinely used by each institution and performed in a CLIA-certified or equivalent laboratory. --- S310F --- --- R678Q --- --- L755S ---

Primary Outcomes

Description: Certain toxicities will be considered dose-limiting unless clearly attributable to an extraneous cause, such as underlying disease.

Measure: Incidence of dose limiting toxicities as a determinant of the Recommended Phase 2 Dose (RP2D)

Time: After the first dose of treatment for up to 21 days.

Description: Objective response rate is defined as the proportion of participants who achieve a confirmed complete response (CR; disappearance of all target and non-target lesions) or partial response (PR; at least a 30% decrease from baseline in the sum of diameters of target lesions) per RECIST version 1.1.

Measure: Phase 2: Objective response rate as a measure of antitumor activity

Time: Assessed until disease progression or death for up to 12 months

Secondary Outcomes

Description: Adverse events will be assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.

Measure: Phase 1 and Phase 2: Incidence of treatment-emergent adverse events as a measure of safety and tolerability of BDTX-189

Time: From Cycle 1 Day 1 (each cycle is 21 days) until 30 days post last dose

Description: Blood samples will be taken to measure the plasma concentrations of BDTX-189 in both a fed and fasted state.

Measure: Phase 1 and Phase 2: Plasma concentration of BDTX-189 as a measure of pharmacokinetics

Time: Multiple time points during Cycles 1-4 (each cycle is 21 days)

Description: Objective response is defined as the proportion of participants who achieved a complete response (CR; disappearance of all target and non-target lesions) or partial response (PR; at least a 30% decrease from baseline in the sum of diameters of target lesions) per RECIST version 1.1.

Measure: Phase 1: Objective response rate as a preliminary measure of antitumor activity

Time: Assessed until disease progression or death for up to 12 months

Description: Duration of response is the time from first documentation of a response to first evidence of progressive disease per RECIST version 1.1 or death. A response is defined as either a complete response (CR; disappearance of all target lesions and non-target lesions) or partial response (PR; at least a 30% decrease in the sum of diameters of target lesions). Progressive disease is defined by a target lesion increase of 20% and at least 5mm from smallest on-study lesion sum, the appearance of new lesions, or unequivocal progression of non-target lesions.

Measure: Phase 1 and Phase 2: Duration of response as a measure of antitumor activity

Time: Assessed until disease progression or death for up to 12 months

Description: Disease control rate is defined as the proportion of participants achieving: a complete response (CR; disappearance of all target and non-target lesions), partial response (PR; at least a 30% decrease in the sum of diameters of target lesions), or stable disease (SD; neither sufficient shrinkage to qualify for a PR nor sufficient increase in lesions) per RECIST version 1.1.

Measure: Phase 1 and Phase 2: Disease control rate as a measure of antitumor activity

Time: Assessed until disease progression or death for up to 12 months

Description: Progression-free survival is the time from first study dose until disease progression (PD; target lesion increase of 20% and at least 5mm from smallest on-study lesion sum, the appearance of new lesions, or unequivocal progression of non-target lesions) per RECIST v1.1.

Measure: Phase 1 and Phase 2: Progression-free survival as a measure of antitumor activity

Time: Assessed until disease progression or death for up to 12 months

Description: Overall survival is the time from first study dose until death from any cause or study discontinuation.

Measure: Phase 2: Overall survival as a measure of clinical activity

Time: Assessed every 12 weeks after treatment discontinuation for up to 1 year


HPO Nodes