Clinical Trials Register

Summary
EudraCT Number:	2020-005492-12
Sponsor's Protocol Code Number:	BDTX-189-01
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2021-06-15
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

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A. Protocol Information

A.1

Member State Concerned

Netherlands - Competent Authority

A.2

EudraCT number

2020-005492-12

A.3

Full 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

MasterKey-01: een fase 1/2, open-label, tweedelig, multicenter onderzoek ter beoordeling van de veiligheid, verdraagbaarheid, farmacokinetiek en antitumoractiviteit van BDTX-189, een remmer van allosterische ErbB-mutaties, bij patiënten met gevorderde solide maligniteiten

A.3.1

Title 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.3.2

Name or abbreviated title of the trial where available

MasterKey-01

A.4.1

Sponsor's protocol code number

BDTX-189-01

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT04209465

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Black Diamond Therapeutics, Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Black Diamond Therapeutics, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Black Diamond Therapeutics, Inc.
B.5.2	Functional name of contact point	Senior Vice President Clinical Deve
B.5.3	Address:
B.5.3.1	Street Address	One Main Street, 10th Floor
B.5.3.2	Town/ city	Cambridge
B.5.3.3	Post code	MA 02142
B.5.3.4	Country	United States
B.5.4	Telephone number	17203521426

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	BDTX-189
D.3.2	Product code	BDTX-189
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	BDTX-189
D.3.9.3	Other descriptive name	BDTX-189
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	200
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another 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.1.1

Medical condition(s) being investigated

Lung cancer, breast cancer, any other solid tumors with specific gene mutations

Longkanker, borstkanker, andere solide tumoren met specifieke genmutaties

E.1.1.1

Medical condition in easily understood language

Lung cancer, breast cancer, any other solid tumors with specific gene mutations

Longkanker, borstkanker, andere solide tumoren met specifieke genmutaties

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10065252
E.1.2	Term	Solid tumor
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Assess the antitumor activity of BDTX-189 as a single agent by evaluation of objective response as determined by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in patients with allosteric human epidermal growth factor receptor 2 (HER2) mutations, including epidermal growth factor receptor(EGFR)/HER2 exon 20 insertion mutations

Het beoordelen van de antitumoractiviteit van BDTX-189 als monotherapie door evaluatie van de objectieve respons zoals bepaald aan de hand van de Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 bij patiënten met allosterische humane epidermale groeifactorreceptor 2 (HER2)-mutaties, inclusief epidermale groeifactorreceptor (EGFR)/HER2 exon 20-insertiemutaties

E.2.2

Secondary objectives of the trial

- Assess the safety and tolerability of BDTX-189 as an oral single agent
- Investigate the PK of BDTX-189 using population PK (PopPK) methods and explore correlations between PK, response, and/or safety findings
- Assess additional measures of antitumor activity of BDTX-189 as a single agent by evaluation of DOR, disease control and PFS as determined by RECIST v1.1, and overall survival (OS)

- Het beoordelen van de veiligheid en verdraagbaarheid van BDTX-189 als een orale monotherapie
- Het onderzoeken van de farmacokinetiek van BDTX-189 met behulp van populatie-farmacokinetische (PopPK) -methoden en het verkennen van de correlaties tussen farmacokinetiek, respons en/of veiligheidsbevindingen
- Het beoordelen van aanvullende maatstaven van antitumoractiviteit van BDTX-189 als monotherapie, door evaluatie van DOR, ziektebeheersing en PFS zoals bepaald aan de hand van RECIST v1.1, en algehele overleving (OS)

E.2.3

Trial contains a sub-study

E.3

Principal 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;
Patients with a solid tumor harboring an:
a. Allosteric HER2 mutation
b. EGFR or HER2 exon 20 insertion mutation
as determined by a validated next-generation sequencing (NGS) test routinely used by each institution using tissue and/or plasma. Eligible mutations are summarized in Appendix I.
Eligible patients will be assigned to one of the 4 following cohorts:
Cohort 1: NSCLC with EGFR or HER2 exon 20 insertion mutation
Cohort 2: Breast cancer with an allosteric HER2 mutation and EGFR/HER2 exon 20 insertion mutations
Cohort 3: Any tumor (except breast) with an S310F/Y mutation
Cohort 4: Any other allosteric HER2 mutation and EGFR/HER2 exon 20 insertion mutations not assigned to Cohorts 1-3;
Adequate archival tumor tissue or willing to undergo pretreatment biopsy;
Measurable disease according to RECIST version 1.1.

- Histologisch of cytologisch bevestigde lokaal gevorderde of gemetastaseerde solide tumor met gedocumenteerd recidief of ziekteprogressie op standaard antikankertherapie in de gevorderde/gemetastaseerde setting
- Geen standaardtherapie beschikbaar of standaardtherapie wordt als ongeschikt of ondraaglijk beschouwd volgens de Onderzoeker en in overleg met de Medische Monitor
- Patiënten met een solide tumor met een:
a. Allosterische HER2-mutatie
b. EGFR-of HER2-exon 20-insertiemutatie
zoals bepaald door een gevalideerde next-generation sequencing (NGS)-test die routinematig door elke instelling wordt gebruikt met behulp van weefsel en/of plasma. In aanmerking komende mutaties worden samengevat in Bijlage I van het protocol.
In aanmerking komende patiënten worden toegewezen aan een van de volgende 4 cohorten:
Cohort 1: NSCLC met EGFR-of HER2-exon 20-insertiemutatie
Cohort 2: Borstkanker met een allosterische HER2-mutatie en EGFR/HER2-exon 20-insertiemutaties
Cohort 3: Elke andere tumor (behalve borstkanker) met een S310F/Y-mutatie
Cohort 4: Elke andere allosterische HER2-mutatie en EGFR/HER2-exon 20-insertiemutaties die niet zijn toegewezen aan Cohorten 1-3
Voldoende gearchiveerd tumorweefsel of bereid om een biopsie te ondergaan vóór de behandeling

E.4

Principal exclusion criteria

Clinical laboratory values meeting the following criteria within 4 weeks (28 days) prior to baseline:
a. Serum creatinine ≥1.5 × upper limit of normal (ULN) or calculated creatinine clearance ≤60 mL/min using Cockcroft-Gault equation
b. Total bilirubin ≥1.5 × ULN or ≥3.0 × ULN in the presence of documented Gilbert’s syndrome
c. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥2.5 × ULN, or AST or ALT ≥5.0 × ULN in the presence of liver metastases
d. Hematologic function:
i. Absolute neutrophil count (ANC) ≤1000 cells/μL
ii. Hemoglobin ≤8.5 g/dL or 5.28 mmol/L
iii. Platelet count ≤75,000/μL
Significant cardiovascular disease, including:
a. 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
b. Myocardial infarction, severe or unstable angina within 6 months prior to baseline
c. Significant thrombotic or embolic events within 3 months prior to baseline, including, but not limited to, stroke or transient ischemic attack. Catheter-related thrombosis and deep vein thrombosis are not a cause for exclusion
d. History or presence of any uncontrolled cardiovascular disease
e. 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:
a. Evidence of second- or third-degree atrioventricular block
b. Clinically significant arrhythmia (as determined by the Investigator)
c. QTc interval of >470 msec as calculated according to Fridericia’s formula (QTcF = QT/R to R interval0.33)
Leptomeningeal or untreated and/or symptomatic central nervous system (CNS) malignancies (primary or metastatic); patients with asymptomatic CNS metastases who have undergone surgery or radiotherapy and who have been on a stable or tapering dose of corticosteroids for at least 2 weeks prior to the first scheduled day of dosing will be eligible for the trial
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
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)
a. 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

Klinische laboratoriumwaarden die binnen 4 weken (28 dagen) vóór baseline voldoen aan de volgende criteria:
a. Serumcreatinine ≥ 1,5 × de bovengrens van normaal (ULN) of berekende creatinineklaring ≤ 60 ml/min, met behulp van de Cockcroft-Gault-vergelijking
b. Totaal bilirubine ≥ 1,5 × ULN of ≥ 3,0 × ULN in aanwezigheid van gedocumenteerd Syndroom van Gilbert
c. Aspartaataminotransferase (ASAT) of alanine-aminotransferase (ALAT) ≥ 2,5 × ULN, of ASAT of ALT ≥ 5,0 × ULN in aanwezigheid van levermetastasen
d. Hematologische functie:
i. Absoluut aantal neutrofielen (ANC) ≤ 1000 cellen/μl
ii. Hemoglobine ≤ 8,5 g/dl or 5,28 mmol/l
iii. Aantal bloedplaatjes ≤ 75.000/μl
Significante cardiovasculaire ziekte, waaronder:
a. Hartfalen Klasse III of IV volgens de definitie van de New York Heart Association, of linkerventrikelejectiefractie (LVEF) < 50% of onder de ondergrens van het normale bereik van de Instelling
b. Myocardinfarct, ernstige of instabiele angina pectoris binnen 6 maanden voorafgaand aan de baseline
c. Significante trombotische of embolische voorvallen binnen 3 maanden voorafgaand aan de baseline, inclusief, maar niet beperkt tot, beroerte of voorbijgaande ischemische aanval. Kathetergerelateerde trombose en diepe veneuze trombose zijn geen reden voor exclusie
d. Geschiedenis of aanwezigheid van een ongecontroleerde hart- en vaatziekte
e. Persoonlijke of familiegeschiedenis van lange QT-syndroom
Elektrocardiogram (ECG) bevindingen, verkregen met behulp van de ECG-machine van de onderzoekslocatie en daaruit afgeleide metingen, die voldoen aan een van de volgende criteria:
a. Bewijs van tweede- of derdegraads atrioventriculair blok
b. Klinisch significante aritmie (zoals bepaald door de Onderzoeker)
c. QTc-interval van > 470 msec zoals berekend volgens de formule van Fridericia (QTcF = QT/R tot R- interval 0,33)
Leptomeningeale of onbehandelde en/of symptomatische maligniteiten van het centrale zenuwstelsel (CZS) (primair of gemetastaseerd); patiënten met asymptomatische CZS-metastasen die een operatie of radiotherapie hebben ondergaan en die gedurende ten minste 2 weken voorafgaand aan de eerste geplande toedieningsdag een stabiele dosis corticosteroïden hebben gebruikt of deze afbouwden, komen in aanmerking voor het onderzoek
Vrouwen die zwanger zijn of borstvoeding geven
Protonpompremmers gebruiken of daarmee niet kunnen stoppen binnen 1 week voorafgaand aan de baseline
Bekende gelijktijdige KRAS-mutatie
Bekende tumor met resistentiemutaties, waaronder EGFR-T790M- of C797S-mutaties of HER2-C805S-mutatie
Eerder gedocumenteerde behandelingsrespons (d.w.z. complete respons [CR], gedeeltelijke respons [PR] of stabiele ziekte [SD] die ≥ 24 weken duurt volgens RECIST v1.1) op goedgekeurde of experimentele HER2- of EGFR-therapieën (bijv. afatinib, lapatinib, dacomitinib, neratinib, trastuzumab deruxtecan, poziotinib, mobocertinib, amivantamab)
a. Patiënten met of zonder tumorrespons die na 8 weken therapie (of minder) stoppen vanwege toxiciteit kunnen worden overwogen na overleg met de Medische Monitor van de opdrachtgever.

E.5 End points

E.5.1

Primary end point(s)

Confirmed objective response rate (ORR) defined as either a complete response (CR) or partial response (PR) by RECIST version 1.1 as determined by the Investigator based on computed tomography (CT) or magnetic resonance imaging (MRI) scans

Bevestigd objectief responspercentage (ORR) gedefinieerd als een volledige respons (CR) of gedeeltelijke respons (PR) door RECIST versie 1.1 zoals bepaald door de onderzoeker op basis van computertomografie (CT) of magnetische resonantie beeldvorming (MRI) -scans

E.5.1.1

Timepoint(s) of evaluation of this end point

Patients will be evaluated for response to treatment after 2 cycles of treatment. Response will be assessed at 6-week intervals (±3 days) during the first 24 weeks (8 cycles) of study treatment. Thereafter, patients will be evaluated for response to treatment every 12 weeks (±7 days), at the EOT visit (if not performed within the previous 4 weeks), and at the discretion of the Investigator.

Patiënten zullen na 2 behandelingscycli worden beoordeeld op hun respons op de behandeling. De respons zal worden beoordeeld met tussenpozen van 6 weken (± 3 dagen) gedurende de eerste 24 weken (8 cycli) van de studiebehandeling. Daarna zullen patiënten elke 12 weken (± 7 dagen) worden beoordeeld op hun respons op de behandeling, tijdens het EOT-bezoek (indien niet uitgevoerd in de voorgaande 4 weken), en naar keuze van de onderzoeker.

E.5.2

Secondary end point(s)

Incidence of TEAEs; changes in clinical laboratory parameters, vital signs, and electrocardiogram (ECG) parameters, cardiac function; and physical examination results PopPK parameters oral clearance (Cl/F), oral volume of distribution (Vd/F), and first-order absorption rate constant (Ka) for BDTX-189. Cl/F will be used to generate estimates of BDTX-189 area under the concentration time curve (AUC). Possible PK/safety, PK/efficacy correlations, and covariate analysis of intrinsic/extrinsic factors. Additional measures of antitumor activity including
DOR, DCR, PFS, and OS.

E.5.2.1

Timepoint(s) of evaluation of this end point

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Safety Expansion portion

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If 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

Poland

Portugal

United Kingdom

Netherlands

Spain

E.8.7

Trial has a data monitoring committee

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.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

100

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2021-06-15

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-12-17

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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