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

Conditions

1. Solid Tumor

Interventions

1. 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 >470 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 - Known concurrent KRAS mutation - Known tumor-harboring resistance mutations including EGFR T790M or C797S mutations or HER2 C805S mutation Phase 2 Only: - Prior documented treatment response to approved or investigational HER2 or EGFR tyrosine kinase inhibitor therapies 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 ---

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

Conditions

1. Non Small Cell Lung Cancer Metastatic
2. Non Small Cell Lung Cancer Stage III
3. HER2 Gene Mutation

Interventions

1. 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 ---

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

Conditions

1. HER2 Positive Breast Carcinoma
2. Stage IV Breast Cancer AJCC v6 and v7

Interventions

1. Other: Comprehensive Geriatric Assessment
2. Other: Laboratory Biomarker Analysis
3. Drug: Neratinib
4. 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 ---

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

Conditions

1. Solid Tumor Cancers
2. Lung Cancer
3. Bladder Cancer
4. Urinary Tract Cancers

Interventions

1. Drug: ado-trastuzumab emtansine

MeSH:Urologic 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 ---

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

Conditions

1. EGFR Exon 20 Mutation
2. ERBB2 Gene Mutation
3. Recurrent Lung Non-Small Cell Carcinoma
4. Stage IV Non-Small Cell Lung Cancer AJCC v7

Interventions

1. 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 ---