A Study of BDTX-189, an Orally Available Allosteric ErbB Inhibitor, in Patients With Advanced Solid Tumors. (MasterKey-01)

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 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

Study Overview

• Status: Terminated
• Conditions: Solid Tumor
• Intervention / Treatment: Drug: BDTX-189

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 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.

• Study Type: Interventional
• Enrollment (Actual): 91
• Phase: Phase 1

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark
    • 9500
• France
  • Bordeau, France, 33000
    • 9501
  • Lille, France, 59000
    • 9525
  • Lyon, France, 69008
    • 9373
  • Poitiers, France, 86021
    • 9512
  • Rennes, France, 44229
    • 9476
• Spain
  • Barcelona, Spain, 08028
    • 9496
  • Barcelona, Spain, 08035
    • 9363
  • Barcelona, Spain, 08036
    • 9508
  • Madrid, Spain, 28007
    • 9429
  • Madrid, Spain, 28040
    • 9495
  • Madrid, Spain, 28041
    • 9383
  • Madrid, Spain, 28050
    • 9382
  • Valencia, Spain, 46010
    • 9510
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85258
      • 9250
  • California
    • Long Beach, California, United States, 90813
      • 9405
    • Orange, California, United States, 92868
      • 9474
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • 7141
  • Florida
    • Lake Mary, Florida, United States, 32746
      • 4080
    • Orlando, Florida, United States, 32827
      • 4100
    • Plantation, Florida, United States, 33322
      • 9535
    • Sarasota, Florida, United States, 34232
      • 4060
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • 9035
  • Illinois
    • Rolling Meadows, Illinois, United States, 60008
      • 9530
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • 9092
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • 9203
  • New York
    • Buffalo, New York, United States, 14263
      • 9209
    • New York, New York, United States, 10016
      • 9215
    • New York, New York, United States, 10065
      • 9236
  • Oregon
    • Portland, Oregon, United States, 97213
      • 9264
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • 7122
  • Tennessee
    • Chattanooga, Tennessee, United States, 37404
      • 4107
    • Nashville, Tennessee, United States, 37203
      • 3000
  • Texas
    • Dallas, Texas, United States, 75390
      • 9003
    • Houston, Texas, United States, 77030
      • 9117
    • Webster, Texas, United States, 77598
      • 9538
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • 9112
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • 9173

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 1 - Dose escalation; In Part A, cohorts of patients with select HER2, HER3, or EGFR alterations received increasing doses of BDTX-189.	Drug: BDTX-189; Participants received a daily, oral dose of BDTX-189 as part of a 3 week cycle.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number 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.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1: 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: 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: 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

Collaborators and Investigators

• Sponsor: Black Diamond Therapeutics, Inc.

Publications and helpful links

General Publications

• Erika Paige Hamilton, Manish R. Patel, Jordi Rodon, David S. Hong, Alison M. Schram, Pasi A. Janne, Patricia LoRusso, Jasgit C. Sachdev, Sai Hong Ou, Elizabeth A Buck, Matthew O'Connor, Nigel Waters, Karsten Witt, Carl Cook. Masterkey-01: Phase I/II, open-label multicenter study to assess safety, tolerability, pharmacokinetics, and antitumor activity of BDTX-189, an inhibitor of allosteric ErbB mutations, in patients with advanced solid malignancies. J Clin Oncol 38: 2020 (suppl; abstr TPS3665)

Study record dates

Study Major Dates

• Study Start (Actual): December 19, 2019
• Primary Completion (Actual): September 2, 2022
• Study Completion (Actual): September 16, 2022

Study Registration Dates

• First Submitted: December 19, 2019
• First Submitted That Met QC Criteria: December 20, 2019
• First Posted (Actual): December 24, 2019

Study Record Updates

• Last Update Posted (Actual): April 17, 2025
• Last Update Submitted That Met QC Criteria: March 30, 2025
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: colorectal cancer; breast cancer; lung cancer; endometrial cancer; non-small cell lung cancer; colon cancer; bladder cancer; gastric cancer; solid tumor; biliary tract cancer; HER2 positive; HER2 overexpression; Genes, HER2; HER2 mutation; exon 20 insertion mutation; Genes, erbb2; HER2 amplification; genes, exon 20 insertion
• Other Study ID Numbers: BDTX-189-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No