A Study of BDTX-189, an Orally Available Allosteric ErbB Inhibitor, in Patients With Advanced Solid Tumors.

Study Overview
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Brief Summary
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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

Detailed Description
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BDTX-189 is an irreversible, small molecular inhibitor that is highly selective versus wild-type EGFR and potent for cancer driver mutations of the ErbB family, including extracellular, transmembrane, and kinase domain allosteric mutations of HER2, as well as EGFR and HER2 exon 20 insertion mutations. These allosteric ErbB mutations are found in 1 - 2 % of most solid tumors and enriched in some cancers with a prevalence of about 2 - 7% such as in non-small cell lung cancer, breast cancer, colorectal cancer, bladder cancer, and endometrial cancer. Currently approved HER2 and EGFR directed therapies are not active against the spectrum of allosteric mutations at relevant and tolerated exposure levels. This Phase 1/2 multi-center, open-label trial is a first-in-human study that will evaluate BDTX-189 orally administered daily as a single agent in patients with solid tumors harboring select mutations or alterations. The Phase 1 portion is a dose escalation primarily designed to assess the safety and tolerability of BDTX-189 and to determine a recommended Phase 2 dose (RP2D). Phase 1 will focus on patients with a solid tumor with alterations such as: Allosteric HER2 or HER3 mutation(s) EGFR or HER2 exon 20 insertion mutation(s) HER2 amplified or overexpressing tumors EGFR exon 19 deletion or L858R mutation Following selection of the RP2D, a Phase 2 portion will be initiated to further evaluate the clinical activity of BDTX-189. 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.

Official Title
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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

Conditions
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Solid Tumor

Intervention / Treatment
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* Drug: BDTX-189


Participation Criteria
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Eligibility Criteria
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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: Allosteric HER2 or HER3 mutation(s) EGFR or HER2 exon 20 insertion mutation(s) HER2 amplified or overexpressing tumors EGFR exon 19 deletion or L858R mutation Phase 2 Only: 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. Adequate archival tumor tissue or willing to undergo pretreatment biopsy Measurable disease according to RECIST version 1.1 Main Exclusion Criteria: Clinical laboratory values meeting the following criteria within 4 weeks (28 days) prior to baseline: Serum creatinine ≥1.5 × upper limit of normal (ULN) or calculated creatinine clearance ≤60 mL/min using Cockcroft-Gault equation Total bilirubin ≥1.5 × ULN or ≥3.0 × ULN in the presence of documented Gilbert's syndrome Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥2.5 × ULN, or AST or ALT ≥5.0 × ULN in the presence of liver metastases Hematologic function: Absolute neutrophil count (ANC) ≤1000 cells/μL Hemoglobin ≤8.5 g/dL or 5.28 mmol/L Platelet count ≤75,000/μL Significant cardiovascular disease, including: Cardiac failure New York Heart Association Class III or IV, or left ventricular ejection fraction (LVEF) <50% or below the lower limit of the Institution's normal range Myocardial infarction, severe or unstable angina within 6 months prior to baseline Significant thrombotic or embolic events within 3 months prior to baseline History or presence of any uncontrolled cardiovascular disease Personal or family history of long QT syndrome ECG findings meeting any of the following criteria: Evidence of second- or third-degree atrioventricular block Clinically significant arrhythmia (as determined by the Investigator) 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 - Dose escalation<br>In Part A, cohorts of patients with select HER2, HER3, or EGFR alterations will receive increasing doses of BDTX-189. It is expected that up to approximately 70 patients will be enrolled in this dose escalation arm. If an alternative schedule is explored, up to 24 additional patients may be enrolled. | Drug: BDTX-189<br>* Participants will receive a daily, oral dose of BDTX-189 as part of a 3 week cycle.<br>|
| Experimental: Phase 2 - Dose expansion<br>In Part B, patients with a solid tumor harboring specific allosteric HER2 mutations or an HER2 or EGFR exon 20 insertion mutation will receive the recommended Phase 2 dose of BDTX-189. It is expected that approximately 100 participants will be enrolled in this phase 2 portion. | Drug: BDTX-189<br>* Participants will receive a daily, oral dose of BDTX-189 as part of a 3 week cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose limiting toxicities as a determinant of the Recommended Phase 2 Dose (RP2D) | Certain toxicities will be considered dose-limiting unless clearly attributable to an extraneous cause, such as underlying disease. | After the first dose of treatment for up to 21 days. | 
| Phase 2: Objective response rate as a measure of antitumor activity | 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. | Assessed until disease progression or death for up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1 and Phase 2: Incidence of treatment-emergent adverse events as a measure of safety and tolerability of BDTX-189 | Adverse events will be assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5. | From Cycle 1 Day 1 (each cycle is 21 days) until 30 days post last dose | 
| Phase 1 and Phase 2: Plasma concentration of BDTX-189 as a measure of pharmacokinetics | Blood samples will be taken to measure the plasma concentrations of BDTX-189 in both a fed and fasted state. | Multiple time points during Cycles 1-4 (each cycle is 21 days) | 
| Phase 1: Objective response rate as a preliminary measure of antitumor activity | 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. | Assessed until disease progression or death for up to 12 months | 
| Phase 1 and Phase 2: Duration of response as a measure of antitumor activity | 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. | Assessed until disease progression or death for up to 12 months | 
| Phase 1 and Phase 2: Disease control rate as a measure of antitumor activity | 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. | Assessed until disease progression or death for up to 12 months | 
| Phase 1 and Phase 2: Progression-free survival as a measure of antitumor activity | 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. | Assessed until disease progression or death for up to 12 months | 
| Phase 2: Overall survival as a measure of clinical activity | Overall survival is the time from first study dose until death from any cause or study discontinuation. | Assessed every 12 weeks after treatment discontinuation for up to 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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solid tumor, HER2 mutation, exon 20 insertion mutation, HER2 positive, Genes, HER2, Genes, erbb2, HER2 amplification, HER2 overexpression, genes, exon 20 insertion, lung cancer, non-small cell lung cancer, breast cancer, colon cancer, colorectal cancer, bladder cancer, endometrial cancer, gastric cancer, biliary tract cancer