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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04209465
Recruitment Status : Recruiting
First Posted : December 24, 2019
Last Update Posted : October 19, 2020
Sponsor:
Information provided by (Responsible Party):
Black Diamond Therapeutics, Inc.

Brief Summary:

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

Condition or disease Intervention/treatment Phase
Solid Tumor Drug: BDTX-189 Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : December 19, 2019
Estimated Primary Completion Date : June 2023
Estimated Study Completion Date : December 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Phase 1 - Dose escalation
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
Participants will receive a daily, oral dose of BDTX-189 as part of a 3 week cycle.

Experimental: Phase 2 - Dose expansion
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
Participants will receive a daily, oral dose of BDTX-189 as part of a 3 week cycle.




Primary Outcome Measures :
  1. 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. ]
    Certain toxicities will be considered dose-limiting unless clearly attributable to an extraneous cause, such as underlying disease.

  2. Phase 2: Objective response rate as a measure of antitumor activity [ Time Frame: Assessed until disease progression or death for up to 12 months ]
    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.


Secondary Outcome Measures :
  1. 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 ]
    Adverse events will be assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.

  2. 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) ]
    Blood samples will be taken to measure the plasma concentrations of BDTX-189 in both a fed and fasted state.

  3. 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 ]
    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.

  4. 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 ]
    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.

  5. 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 ]
    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.

  6. 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 ]
    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.

  7. Phase 2: Overall survival as a measure of clinical activity [ Time Frame: Assessed every 12 weeks after treatment discontinuation for up to 1 year ]
    Overall survival is the time from first study dose until death from any cause or study discontinuation.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 >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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04209465


Contacts
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Contact: Carl Cook 1-302-743-7938 ccook@bdtherapeutics.com

Locations
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United States, Arizona
HonorHealth Recruiting
Scottsdale, Arizona, United States, 85258
Principal Investigator: Jasgit Sachdev, MD         
United States, California
University of California at Irvine Medical Center Recruiting
Orange, California, United States, 92868
Principal Investigator: Viola Zhu, MD, PhD         
United States, Connecticut
Yale University, Yale Cancer Center Recruiting
New Haven, Connecticut, United States, 06520
Contact: Patricia LoRusso, DO         
United States, Florida
Florida Cancer Specialists Recruiting
Lake Mary, Florida, United States, 32746
Principal Investigator: Shekeab Jauhari, MD         
Florida Cancer Specialists Recruiting
Sarasota, Florida, United States, 34232
Principal Investigator: Manish Patel, MD         
United States, Massachusetts
Dana-Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Principal Investigator: Pasi Janne, MD,PhD         
United States, New York
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Principal Investigator: Alison Schram, MD         
United States, Tennessee
Tennessee Oncology Recruiting
Nashville, Tennessee, United States, 37203
Principal Investigator: Erika Hamilton, MD         
United States, Texas
MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Principal Investigator: Jordi Ahnert, MD, PhD         
Sponsors and Collaborators
Black Diamond Therapeutics, Inc.
Investigators
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Study Director: Carl Cook Black Diamond Therapeutics, Inc.
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)

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Responsible Party: Black Diamond Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT04209465    
Other Study ID Numbers: BDTX-189-01
First Posted: December 24, 2019    Key Record Dates
Last Update Posted: October 19, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Black Diamond Therapeutics, Inc.:
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