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

Sponsor

Black Diamond Therapeutics, Inc. (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT04209465

Collaborator

(none)

Enrollment

Locations

Arms

47.4

Anticipated Duration (Months)

2.4

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

91 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 :

Dec 19, 2019

Anticipated Primary Completion Date :

Jun 1, 2023

Anticipated Study Completion Date :

Dec 1, 2023

Arms and Interventions

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.

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.

Outcome Measures

Primary Outcome Measures

Incidence 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.
Phase 2: Objective response rate as a measure of antitumor activity [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

Phase 1 and Phase 2: 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 and Phase 2: 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 and Phase 2: Duration of response as a measure of antitumor activity [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.
Phase 1 and Phase 2: Disease control rate as a measure of antitumor activity [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.
Phase 1 and Phase 2: 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.
Phase 2: Overall survival as a measure of clinical activity [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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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:

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

Phase 2 Only:

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.

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:

Serum creatinine ≥1.5 × upper limit of normal (ULN) or calculated creatinine clearance ≤60 mL/min using Cockcroft-Gault equation
Total bilirubin ≥1.5 × ULN or ≥3.0 × ULN in the presence of documented Gilbert's syndrome
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥2.5 × ULN, or AST or ALT ≥5.0 × ULN in the presence of liver metastases
Hematologic function:
Absolute neutrophil count (ANC) ≤1000 cells/μL
Hemoglobin ≤8.5 g/dL or 5.28 mmol/L
Platelet count ≤75,000/μL

Significant cardiovascular disease, including:

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
Myocardial infarction, severe or unstable angina within 6 months prior to baseline
Significant thrombotic or embolic events within 3 months prior to baseline
History or presence of any uncontrolled cardiovascular disease
Personal or family history of long QT syndrome

ECG findings meeting any of the following criteria:

Evidence of second- or third-degree atrioventricular block
Clinically significant arrhythmia (as determined by the Investigator)
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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	9250	Scottsdale	Arizona	United States	85258
2	9405	Long Beach	California	United States	90813
3	9474	Orange	California	United States	92868
4	7141	New Haven	Connecticut	United States	06520
5	4080	Lake Mary	Florida	United States	32746
6	4100	Orlando	Florida	United States	32827
7	9535	Plantation	Florida	United States	33322
8	4060	Sarasota	Florida	United States	34232
9	9035	Atlanta	Georgia	United States	30322
10	9530	Rolling Meadows	Illinois	United States	60008
11	9092	New Orleans	Louisiana	United States	70112
12	9203	Boston	Massachusetts	United States	02215
13	9209	Buffalo	New York	United States	14263
14	9215	New York	New York	United States	10016
15	9236	New York	New York	United States	10065
16	9264	Portland	Oregon	United States	97213
17	7122	Pittsburgh	Pennsylvania	United States	15232
18	4107	Chattanooga	Tennessee	United States	37404
19	3000	Nashville	Tennessee	United States	37203
20	9003	Dallas	Texas	United States	75390
21	9117	Houston	Texas	United States	77030
22	9538	Webster	Texas	United States	77598
23	9112	Fairfax	Virginia	United States	22031
24	9173	Milwaukee	Wisconsin	United States	53226
25	9500	Copenhagen		Denmark
26	9501	Bordeau		France	33000
27	9525	Lille		France	59000
28	9373	Lyon		France	69008
29	9512	Poitiers		France	86021
30	9476	Rennes		France	44229
31	9496	Barcelona		Spain	08028
32	9363	Barcelona		Spain	08035
33	9508	Barcelona		Spain	08036
34	9429	Madrid		Spain	28007
35	9495	Madrid		Spain	28040
36	9383	Madrid		Spain	28041
37	9382	Madrid		Spain	28050
38	9510	Valencia		Spain	46010