Clinical Trials /

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

NCT04209465

Description:

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

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: BDTX-189-01
  • NCT ID: NCT04209465

Conditions

  • Solid Tumor

Interventions

DrugSynonymsArms
BDTX-189Phase 1 - Dose escalation

Purpose

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

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Phase 1 - Dose escalationExperimentalIn 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 50 patients will be enrolled in this dose escalation arm, though up to 24 additional patients may be enrolled if an alternative schedule is explored.
  • BDTX-189
Phase 2 - Dose expansionExperimentalIn 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 up to 100 participants will be enrolled in this phase 2 portion.
  • BDTX-189

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

        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.

          -  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 >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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of dose limiting toxicities as a determinant of the Recommended Phase 2 Dose (RP2D)
Time Frame:After the first dose of treatment for up to 21 days.
Safety Issue:
Description:Certain toxicities will be considered dose-limiting unless clearly attributable to an extraneous cause, such as underlying disease.

Secondary Outcome Measures

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

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Black Diamond Therapeutics, Inc.

Trial Keywords

  • 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

Last Updated

December 20, 2019