E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
NSCLC, breast cancer, biliary tract cancer, or cervical cancer, any other solid tumors with specific gene mutations |
|
E.1.1.1 | Medical condition in easily understood language |
Lung cancer, breast cancer, biliary tract cancer, or cervical cancer, any other solid tumors with specific gene mutations |
|
E.1.1.2 | 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 | No |
E.2 Objective of the trial |
E.2.1 | Main 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.2.2 | Secondary 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.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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.4 | Principal 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.5.1 | Primary 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.5.1.1 | Timepoint(s) of evaluation of this end point |
Several timepoints throughout the study and at the end of the study |
|
E.5.2 | Secondary 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.5.2.1 | Timepoint(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.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
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 | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | Yes |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
EU Safety Expansion portion |
|
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | 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.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 55 |
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 | No |
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 |
Netherlands |
Poland |
Portugal |
Spain |
United Kingdom |
|
E.8.7 | Trial 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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 5 |