Clinical trial NCT04209465: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Solid Tumor
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
Lead sponsor: Black Diamond Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2019-12-24
Enrollment: 91
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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

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.

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

Primary outcomes:
measure: Number of Dose Limiting Toxicities as a Determinant of the Recommended Phase 2 Dose (RP2D)
timeFrame: After the first dose of treatment for up to 21 days.
Secondary outcomes:
measure: Phase 1: Incidence of Treatment-emergent Adverse Events as a Measure of Safety and Tolerability of BDTX-189
timeFrame: From Cycle 1 Day 1 (each cycle is 21 days) until 30 days post last dose
measure: Phase 1: Plasma Concentration of BDTX-189 as a Measure of Pharmacokinetics
timeFrame: Multiple time points during Cycles 1-4 (each cycle is 21 days)
measure: Phase 1: Objective Response Rate as a Preliminary Measure of Antitumor Activity
timeFrame: Assessed until disease progression or death for up to 12 months
measure: Phase 1: Progression-free Survival as a Measure of Antitumor Activity
timeFrame: Assessed until disease progression or death for up to 12 months
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: 9250
state: Arizona
city: Long Beach
country: United States
facility: 9405
state: California
city: Orange
country: United States
facility: 9474
state: California
city: New Haven
country: United States
facility: 7141
state: Connecticut
city: Lake Mary
country: United States
facility: 4080
state: Florida
city: Orlando
country: United States
facility: 4100
state: Florida
city: Plantation
country: United States
facility: 9535
state: Florida
city: Sarasota
country: United States
facility: 4060
state: Florida
city: Atlanta
country: United States
facility: 9035
state: Georgia
city: Rolling Meadows
country: United States
facility: 9530
state: Illinois
city: New Orleans
country: United States
facility: 9092
state: Louisiana
city: Boston
country: United States
facility: 9203
state: Massachusetts
city: Buffalo
country: United States
facility: 9209
state: New York
city: New York
country: United States
facility: 9215
state: New York
city: New York
country: United States
facility: 9236
state: New York
city: Portland
country: United States
facility: 9264
state: Oregon
city: Pittsburgh
country: United States
facility: 7122
state: Pennsylvania
city: Chattanooga
country: United States
facility: 4107
state: Tennessee
city: Nashville
country: United States
facility: 3000
state: Tennessee
city: Dallas
country: United States
facility: 9003
state: Texas
city: Houston
country: United States
facility: 9117
state: Texas
city: Webster
country: United States
facility: 9538
state: Texas
city: Fairfax
country: United States
facility: 9112
state: Virginia
city: Milwaukee
country: United States
facility: 9173
state: Wisconsin
city: Copenhagen
country: Denmark
facility: 9500
city: Bordeau
country: France
facility: 9501
city: Lille
country: France
facility: 9525
city: Lyon
country: France
facility: 9373
city: Poitiers
country: France
facility: 9512
city: Rennes
country: France
facility: 9476
city: Barcelona
country: Spain
facility: 9496
city: Barcelona
country: Spain
facility: 9363
city: Barcelona
country: Spain
facility: 9508
city: Madrid
country: Spain
facility: 9429
city: Madrid
country: Spain
facility: 9495
city: Madrid
country: Spain
facility: 9383
city: Madrid
country: Spain
facility: 9382
city: Valencia
country: Spain
facility: 9510
Study officials:
References:
citation: 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)