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

Phase 1

Terminated

Conditions: Solid Tumor

Interventions: Drug: BDTX-189

Registration Number: NCT04209465

Lead Sponsor: Black Diamond Therapeutics, Inc.

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 91

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 & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Phase 1 - Dose escalation	BDTX-189	In Part A, cohorts of patients with select HER2, HER3, or EGFR alterations received increasing doses of BDTX-189.

Primary Outcome Measures

Name	Time	Method
Number of Dose Limiting Toxicities as a Determinant of the Recommended Phase 2 Dose (RP2D)	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.

Secondary Outcome Measures

Name	Time	Method
Phase 1: Incidence of Treatment-emergent Adverse Events as a Measure of Safety and Tolerability of BDTX-189	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.
Phase 1: Plasma Concentration of BDTX-189 as a Measure of Pharmacokinetics	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.
Phase 1: Objective Response Rate as a Preliminary Measure of Antitumor Activity	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.
Phase 1: Progression-free Survival as a Measure of Antitumor Activity	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.

Trial Locations

Locations (38): 9250
🇺🇸
Scottsdale, Arizona, United States
9512
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Poitiers, France
9474
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Orange, California, United States
9405
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Long Beach, California, United States
4060
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Sarasota, Florida, United States
7122
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Pittsburgh, Pennsylvania, United States
4107
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Chattanooga, Tennessee, United States
9530
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Rolling Meadows, Illinois, United States
9035
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Atlanta, Georgia, United States
9117
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Houston, Texas, United States
4080
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Lake Mary, Florida, United States
9215
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New York, New York, United States
9382
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Madrid, Spain
9510
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Valencia, Spain
7141
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New Haven, Connecticut, United States
4100
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Orlando, Florida, United States
9535
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Plantation, Florida, United States
9209
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Buffalo, New York, United States
9203
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Boston, Massachusetts, United States
9236
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New York, New York, United States
9264
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Portland, Oregon, United States
3000
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Nashville, Tennessee, United States
9003
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Dallas, Texas, United States
9112
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Fairfax, Virginia, United States
9501
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Bordeau, France
9500
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Copenhagen, Denmark
9173
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Milwaukee, Wisconsin, United States
9538
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Webster, Texas, United States
9525
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Lille, France
9373
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Lyon, France
9476
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Rennes, France
9496
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Barcelona, Spain
9508
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Barcelona, Spain
9363
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Barcelona, Spain
9429
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Madrid, Spain
9495
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Madrid, Spain
9383
🇪🇸
Madrid, Spain
9092
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New Orleans, Louisiana, United States