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    Summary
    EudraCT Number:2020-005492-12
    Sponsor's Protocol Code Number:BDTX-189-01
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2021-04-12
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedDenmark - DHMA
    A.2EudraCT number2020-005492-12
    A.3Full title of the trial
    MasterKey-01: A Phase 1/2, Open-label, Two-part, Multicenter Study to Assess the Safety, Tolerability, Pharmacokinetics, and Antitumor Activity of BDTX-189, an Inhibitor of Allosteric ErbB Mutations, in Patients with Advanced Solid Malignancies
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 1/2 Study to Assess the Safety and Antitumor Activity of BDTX-189 in Patients with Advanced Solid Malignancies
    A.3.2Name or abbreviated title of the trial where available
    MasterKey-01
    A.4.1Sponsor's protocol code numberBDTX-189-01
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04209465
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorBlack Diamond Therapeutics, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportBlack Diamond Therapeutics, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBlack Diamond Therapeutics, Inc.
    B.5.2Functional name of contact pointChief Medical Officer
    B.5.3 Address:
    B.5.3.1Street AddressOne Main Street, 10th Floor
    B.5.3.2Town/ cityCambridge
    B.5.3.3Post code MA 02142
    B.5.3.4CountryUnited States
    B.5.4Telephone number12034352152
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameBDTX-189
    D.3.2Product code BDTX-189
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBDTX-189
    D.3.9.3Other descriptive nameBDTX-189
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    NSCLC, breast cancer, biliary tract cancer, or cervical cancer, any other solid tumors with specific gene mutations
    E.1.1.1Medical condition in easily understood language
    Lung cancer, breast cancer, biliary tract cancer, or cervical cancer, any other solid tumors with specific gene mutations
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10065252
    E.1.2Term Solid tumor
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Part A:
    • Determine the recommended Phase 2 dose (RP2D) and schedule of BDTX-189 as a single agent administered orally (PO) in patients with advanced solid malignancies

    Part B:
    • Assess the antitumor activity of BDTX-189 as a single agent in patients with allosteric human epidermal growth factor receptor 2 (HER2) mutations, including epidermal growth factor receptor (EGFR)/HER2 exon 20 insertion mutations
    E.2.2Secondary objectives of the trial
    Part A and B:
    • Assess the safety and tolerability of BDTX-189
    • Investigate the pharmacokinetics (PK) of BDTX-189 using population PK (PopPK) methods and explore correlations between PK, response, and/or safety findings

    Part A:
    • Establish the PK of BDTX-189 and circulating metabolite profile after a single dose and at steady state
    • Assess the preliminary efficacy and antitumor activity of BDTX-189 as a sin
    • Assess the effect of food on the PK of BDTX-189

    Part B:
    • Assess additional measures of efficacy and antitumor activity of BDTX-189.
    • Assess patient outcome by evaluation of electronic patient reported outcomes (ePRO)

    Exploratory Objectives:
    Part A and B: Evaluate allosteric ErbB mutations, gene amplifications, and possible markers of drug sensitivity and resistance in plasma using circulating tumor deoxyribonucleic acid (ctDNA)
    Part A: Evaluate the pharmacodynamic (PDx) effects of BDTX-189 in tumor tissue as determined by ErbB signaling pathway proteins

    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Part A and Part B:
    • 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

    Part A Dose Escalation Only:
    • No standard therapy available according to the Investigator
    • Patients with solid tumor 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
    - HER2 amplified or overexpressing tumor
    - EGFR exon 19 deletion or L858R mutation
    Mutations must have been determined by a validated next-generation sequencing (NGS) test routinely used by each institution using tissue and/or plasma and performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified or equivalent laboratory. A list of eligible validated oncogenic mutations from 1 of the 7 MTCs is provided in Appendix I.

    Part A Safety Expansion Only:
    • No standard therapy available according to the Investigator
    • Patients with one of the following mutations and tumor pairs:
    - Allosteric HER2 mutation in patients with NSCLC, breast cancer, biliary tract cancer, or cervical cancer
    - EGFR or HER2 exon 20 insertion mutation in patients with NSCLC
    - HER2 amplified or overexpressing tumor from the following cancer types: breast, gastric, gastroesophageal, colorectal, endometrial, biliary tract, cancer of unknown primary (CUP), and NSCLC
    Mutations must have been determined by a validated NGS test routinely used by each institution using tissue and/or plasma and performed in a CLIA-certified or equivalent laboratory. A list of eligible validated oncogenic mutations from 1 of the 7 MTCs are provided in Appendix I.
    Note: The Sponsor reserves the right to prioritize tumor/genomic alteration pairs and o cap enrollment for any of these based on the Sponsor’s portfolio decision-making process.
    • Mandatory archival tumor tissue or willing to undergo pretreatment biopsy if no archival tissue available (Section 5.7.1).
    • Measurable disease according to RECIST version 1.1 (Appendix B).

    Part B Only:
    • Patients with locally advanced or metastatic:
    - NSCLC who have received at least one prior platinum-containing regimen (with or without an anti-programmed death-ligand 1 [PD-(L)1] antibody) and no more 2 prior regimens for advanced NSCLC. Patients with no prior therapy who refuse standard therapy may also be eligible following discussion and approval by the Sponsor’s Medical Monitor.
    - Solid tumor other than NSCLC who have received at least one and no more than 3 prior regimens for advanced cancer.
    • Patients with solid tumor(s) harboring an:
    - Allosteric HER2 mutation
    - EGFR exon 20 insertion mutation or HER2 exon 20 insertion or point mutation
    Mutations must have been determined by a validated NGS test routinely used by each institution using tissue and/or plasma and performed in a CLIA-certified or equivalent laboratory. A list of eligible validated oncogenic mutations from 1 of the 7 MTCs is provided in Appendix I.
    Eligible patients will be assigned to one of the 5 following cohorts:
    Cohort 1: NSCLC with an allosteric EGFR exon 20 insertion mutation from MTC-A
    Cohort 2: NSCLC with an allosteric HER2 exon 20 insertion mutation from MTC-B or point mutation from MTC-C
    Cohort 3: Breast cancer with an allosteric HER2 mutation from MTC-B, MTC-C, MTC-D, MTC-E, or MTC-F
    Cohort 4: NSCLC, biliary tract cancer, or cervical cancer with an allosteric HER2 mutation from MTC-D
    Cohort 5: Any solid tumor type with any allosteric ErbB mutation from any of the 7 MTCs (MTC-A to MTC-G), excluding patients who are otherwise eligible for Cohorts 1-4.
    Note: The Sponsor reserves the right to prioritize Cohorts (ie, tumor/mutation pairs) and to cap enrollment for any Cohort based on the Sponsor’s portfolio decision-making process.
    • Mandatory archival tumor tissue or willing to undergo pretreatment biopsy if no archival tissue available (Section 5.7.1).
    • Measurable disease according to RECIST version 1.1 (Appendix B)
    E.4Principal exclusion criteria
    Part A and Part B:
    • Clinical laboratory values meeting the following criteria within 4 weeks (28 days) prior to baseline:
    - Serum creatinine ≥1.5 × upper limit of normal (ULN) AND 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:
    a. Absolute neutrophil count ≤1000 cells/μL
    b. Hemoglobin ≤8.5 g/dL or 5.28 mmol/L
    c. Platelet count ≤75,000/μL
    • Significant cardiovascular disease, including:
    - Cardiac failure New York Heart Association Class III or IV (Appendix D), 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, including, but not limited to, stroke or transient ischemic attack. Catheterrelated thrombosis and deep vein thrombosis are not a cause for exclusion
    - History or presence of any uncontrolled cardiovascular disease
    - Personal or family history of long QT syndrome
    • Electrocardiogram (ECG) findings obtained using the study site’s ECG machine-derived measurements, meeting any of the following criteria:
    - Evidence of second- or third-degree atrioventricular block
    - Clinically significant arrhythmia (as determined by the Investigator)
    - QTc interval of >470 msec as calculated according to Fridericia’s formula (QTcF = QT/R to R interval0.33)
    • Leptomeningeal or untreated central nervous system (CNS) malignancies (primary or metastatic); patients with asymptomatic CNS metastases who have undergone surgery or radiotherapy 4 weeks prior to Cycle 1 Day 1 and who are on a dose of prednisone of no more than 10 mg or equivalent will be eligible for Part A of the trial.
    • 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, T798I, or T862A mutations
    • Prior documented treatment response (i.e., complete response [CR], partial response [PR], or stable disease [SD] lasting ≥24 weeks by RECIST v1.1) to approved or investigational HER2 or EGFR therapies (e.g., afatinib, lapatinib, dacomitinib, neratinib, trastuzumab deruxtecan, poziotinib, mobocertinib, amivantamab)
    - Patients with or without tumor response discontinuing after 8 weeks or less of therapy due to toxicity may be considered after discussion with the Sponsor Medical Monitor
    - Patients with an NGS test (tissue or plasma) obtained within 8 weeks of Baseline which does not include any mutations listed in exclusion criteria #7
    or #8 may be considered after discussion with the Sponsor Medical Monitor.
    • Women who are pregnant or breast-feeding
    E.5 End points
    E.5.1Primary end point(s)
    Part A: Incidence and severity of TEAEs, including DLTs, graded according to NCI CTCAE, Version 5.0

    Part B: Objective response defined as either a CR or PR, as determined by BICR and per RECIST version 1.1 based on CT or MRI scans
    E.5.1.1Timepoint(s) of evaluation of this end point
    Several timepoints throughout the study and at the end of the study
    E.5.2Secondary end point(s)
    Part A and B:
    - Incidence of TEAEs; changes in clinical laboratory parameters, vital signs, ECG parameters, cardiac function, and physical examination results
    - PopPK parameters: Cl/F, Vd/F, and Ka for BDTX-189. Cl/F will be used to generate estimates of BDTX-189 AUC. Possible PK/safety and PK/efficacy correlations, and covariate analysis of intrinsic/extrinsic factors

    Part A:
    - PK parameter estimates of BDTX-189 generated from plasma concentration-time data (e.g., Cmax, Tmax, AUC, and t1/2)
    - Investigator-assessed objective response, DOR, DCR, PFS as determined by RECIST v1.1, and OS (for Safety Expansion portion).
    - PK parameter estimates of BDTX-189 generated from plasma concentration-time data (e.g., Cmax, Tmax, AUC, t1/2, Cl/F, and Vd/F). Fed/fasted geometric least squares mean ratio and 90% CI for BDTX-189 Cmax and AUC

    Part B:
    - Objective response (Investigator assessed), DOR (Investigator and BICR assessed), DCR (Investigator and BICR assessed), PFS (Investigator and BICR assessed) per RECIST v1.1, and OS
    - Change from baseline in the FACT-G subscales, NCCN-FACT FBSI-16 subscales, NCCN-FACT FLSI-17 subscales, EQ-5D-5L, PROMIS physical function score, and NCI-CTCAE scores

    Exploratory objectives
    - Part A and B: Presence and/or disappearance of circulating ErbB mutations and other activating mutations, and other markers of drug sensitivity and resistance
    - Part A: ErbB signaling pathway proteins in tumor tissue, such as pERK

    E.5.2.1Timepoint(s) of evaluation of this end point
    Several timepoints throughout the study and at the end of the study
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans Yes
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    EU Safety Expansion portion
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA55
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Canada
    Israel
    United States
    Denmark
    France
    Germany
    Italy
    Netherlands
    Poland
    Portugal
    Spain
    United Kingdom
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months5
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 300
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 319
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 210
    F.4.2.2In the whole clinical trial 619
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2021-05-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-05-05
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2022-09-02
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