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

This was a clinical study with an orally administered drug, BDTX-189 in participants with advanced solid tumors that had 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 were 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 preliminary antitumor activity of BDTX-189 in participants with select allosteric ErbB gene mutations

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 was a first-in-human study that evaluated BDTX-189 orally administered daily as a single agent in patients with solid tumors harboring select mutations or alterations. The Phase 1 portion was 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 focused on patients with a solid tumor and 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

Eligible mutations must have been determined by a validated next-generation sequencing (NGS) test routinely used by each institution and performed in a CLIA-certified or equivalent laboratory.

The Phase 2 portion was not initiated.

Eligibility Criteria:
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

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:

  1. Serum creatinine ≥1.5 × upper limit of normal (ULN) or calculated creatinine clearance ≤60 mL/min using Cockcroft-Gault equation
  2. Total bilirubin ≥1.5 × ULN or ≥3.0 × ULN in the presence of documented Gilbert's syndrome
  3. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥2.5 × ULN, or AST or ALT ≥5.0 × ULN in the presence of liver metastases
  4. Hematologic function:

     1. Absolute neutrophil count (ANC) ≤1000 cells/μL
     2. Hemoglobin ≤8.5 g/dL or 5.28 mmol/L
     3. Platelet count ≤75,000/μL
* Significant cardiovascular disease, including:

  1. 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
  2. Myocardial infarction, severe or unstable angina within 6 months prior to baseline
  3. Significant thrombotic or embolic events within 3 months prior to baseline
  4. History or presence of any uncontrolled cardiovascular disease
  5. Personal or family history of long QT syndrome
* ECG findings meeting any of the following criteria:

  1. 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