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

Solid Tumor Clinical Trial

— MasterKey-01  

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 Details — Status: Terminated

Administrative data

• NCT number: NCT04209465
• Other study ID #: BDTX-189-01
• Status: Terminated
• Phase: Phase 1/Phase 2
• Start date: December 19, 2019
• Est. completion date: September 16, 2022

Study information

• Verified date: October 2022
• Source: Black Diamond Therapeutics, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 91
• Est. completion date: September 16, 2022
• Est. primary completion date: September 2, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Solid Tumor

Intervention

Drug:
• BDTX-189
Participants will receive a daily, oral dose of BDTX-189 as part of a 3 week cycle.

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Black Diamond Therapeutics, Inc.

Countries where clinical trial is conducted

United States,  Denmark,  France,  Spain, 

References & Publications (1)

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)

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence 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.
Primary	Phase 2: Objective response rate as a measure of antitumor activity	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.	Assessed until disease progression or death for up to 12 months
Secondary	Phase 1 and Phase 2: 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
Secondary	Phase 1 and Phase 2: 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)
Secondary	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
Secondary	Phase 1 and Phase 2: Duration of response as a measure of antitumor activity	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.	Assessed until disease progression or death for up to 12 months
Secondary	Phase 1 and Phase 2: Disease control rate as a measure of antitumor activity	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.	Assessed until disease progression or death for up to 12 months
Secondary	Phase 1 and Phase 2: 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
Secondary	Phase 2: Overall survival as a measure of clinical activity	Overall survival is the time from first study dose until death from any cause or study discontinuation.	Assessed every 12 weeks after treatment discontinuation for up to 1 year