1363TiP - A phase I/II study of TPX-0131, a novel oral ALK tyrosine kinase inhibitor, in patients with ALK+ advanced/metastatic NSCLC

Background

TPX-0131 is a next-generation ALK tyrosine kinase inhibitor (TKI) designed to overcome a broad array of mutations that can limit the effectiveness of previous generation ALK TKIs. In cellular assays, TPX-0131 potently inhibits wild-type ALK (IC₅₀ = 0.4 nM) and many clinically observed resistance mutations, including the G1202R solvent front mutation (IC₅₀ = 0.2 nM), L1196M gatekeeper mutation (IC₅₀ = 0.5 nM) and multiple compound mutations (IC₅₀ < 1 nM). In vivo studies show brain tissue penetration.

Trial design

This phase I/II multicenter, single-arm, open-label study (FORGE-1; NCT04849273) will evaluate the safety, tolerability, pharmacokinetics (PK), and efficacy of TPX-0131 in pretreated patients with ALK+ advanced/metastatic NSCLC. Key eligibility criteria include: ALK fusion confirmed by approved FISH, IHC, NGS or qPCR; ≥18 years; ECOG PS ≤1; ≥1 measurable target lesion. Phase I dose escalation will follow a 3+3 design with TPX-0131 starting at a dose of 1 mg once daily; escalation will proceed via a modified Fibonacci method. Phase II will include 3 specified expansion cohorts (n = 60 each): EXP-1 requires 1 prior ALK TKI (2^nd or 3^rd generation) and no chemotherapy (CTX) or immunotherapy (IO); EXP-2 requires 2 prior ALK TKIs (at least one as 2^nd or 3^rd generation) and no CTX or IO; EXP-3 requires 2 prior ALK TKIs (at least one as 2^nd or 3^rd generation) and no more than 1 line of prior CTX and/or IO. Radiographic efficacy assessments will be based on blinded independent central review (BICR) using RECIST v1.1. Phase I primary endpoints include dose-limiting toxicities to determine maximum tolerated dose and/or recommended phase II dose; secondary endpoints include PK and objective response rate (ORR) by BICR. Phase II primary endpoint is ORR by BICR; secondary endpoints include duration of response, time to response, clinical benefit rate, intracranial tumor response, progression-free survival (PFS), overall survival, adverse events, central nervous system (CNS) PFS, PK, and quality-of-life. CNS endpoints will be assessed in patients with measurable brain metastases. Phase I will be enrolling in Australia, USA, and South Korea.

Clinical trial identification

NCT04849273.

Editorial acknowledgement

Lee Miller, Miller Medical Communications.

Legal entity responsible for the study

Turning Point Therapeutics Inc.

Funding

Turning Point Therapeutics Inc.

Disclosure

B.J. Solomon: Financial Interests, Personal, Other, Consulting; Honoraria: Bristol Myers Squibb; Financial Interests, Personal, Advisory Role: Bristol Myers Squibb; Financial Interests, Personal, Other, Consulting; Honoraria: Merck Sharp & Dohme; Financial Interests, Personal, Advisory Role: Merck Sharp & Dohme; Financial Interests, Personal, Other, Consulting; Honoraria: AstraZeneca; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Other, Consulting; Honoraria: Pfizer; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Other, Consulting; Honoraria: Roche/Genentech; Financial Interests, Personal, Advisory Role: Roche/Genentech; Financial Interests, Personal, Other, Consulting: Amgen; Financial Interests, Personal, Advisory Role: Amgen; Financial Interests, Personal, Other, Consulting: Lilly; Financial Interests, Personal, Advisory Role: Lilly; Financial Interests, Personal, Royalties: Veristrat (Biodesix); Financial Interests, Personal, Royalties: UpToDate; Financial Interests, Institutional, Research Grant: Sanofi-Regeneron; Financial Interests, Institutional, Principal Investigator: Turning Point Therapeutics Inc. M. Millward: Financial Interests, Personal, Advisory Board: Merck, Sharp & Dohme; Financial Interests, Personal, Invited Speaker: Merck, Sharp & Dohme; Financial Interests, Personal, Advisory Board: Takeda; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Financial Interests, Personal, Sponsor/Funding: Bristol Myers Squibb; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Sponsor/Funding: AstraZeneca; Financial Interests, Personal, Advisory Board: AstraZeneca. D. Kim: Financial Interests, Personal, Advisory Role: Health Insurance Review & Assessment Service, Korea; Financial Interests, Personal, Invited Speaker: Korean Association for Lung Cancer; Financial Interests, Personal, Invited Speaker: Korean Cancer Association; Financial Interests, Personal, Invited Speaker: Korean Society of Medical Oncology; Financial Interests, Personal, Invited Speaker: Taiwan Lung Cancer Society; Financial Interests, Personal, Other, Travel support for advisory board meeting attendance: Amgen; Financial Interests, Personal, Other, Travel support for advisory board meeting attendance: Daiichi Sankyo; Financial Interests, Institutional, Other, Local PI, Clinical Trial Funding: Alpha Biopharma; Financial Interests, Institutional, Other, Local PI, Clinical Trial Funding: Amgen; Financial Interests, Institutional, Other, Local PI, Clinical Trial Funding: AstraZeneca/MedImmune; Financial Interests, Institutional, Other, Local PI, Clinical Trial Funding: Boehringer Ingelheim; Financial Interests, Institutional, Other, Local PI, Clinical Trial Funding: Bridge Bio Therapeutics; Financial Interests, Institutional, Other, Coordinating PI, Clinical Trial Funding: Chong Keun Dang; Financial Interests, Institutional, Other, Local PI, Clinical Trial Funding: Daiichi Sankyo; Financial Interests, Institutional, Other, Local PI, Clinical Trial Funding: GlaxoSmithKline; Financial Interests, Institutional, Other, Local PI, Clinical Trial Funding: Hanmi; Financial Interests, Institutional, Other, Local PI, Clinical Trial Funding: Janssen; Financial Interests, Institutional, Other, Local PI, Clinical Trial Funding: Merus; Financial Interests, Institutional, Other, Local PI, Clinical Trial Funding: Mirati Therapeutics; Financial Interests, Institutional, Other, Local PI, Clinical Trial Funding: Merck, Sharp & Dohme; Financial Interests, Institutional, Other, Local PI, Clinical Trial Funding: Novartis; Financial Interests, Institutional, Other, Local PI, Clinical Trial Funding: Ono Pharmaceuticals; Financial Interests, Institutional, Other, Local PI, Clinical Trial Funding: Pfizer; Financial Interests, Institutional, Other, Local PI, Clinical Trial Funding: Roche/Genentech; Financial Interests, Institutional, Other, Local PI, Clinical Trial Funding: Takeda; Financial Interests, Institutional, Other, Local PI, Clinical Trial Funding: Turning Point Therapeutics Inc.; Financial Interests, Institutional, Other, Local PI, Clinical Trial Funding: Xcovery; Non-Financial Interests, Personal, Advisory Role: Amgen; Non-Financial Interests, Personal, Member of the Board of Directors: Asian Thoracic Oncology Research Group; Non-Financial Interests, Personal, Advisory Role: AstraZeneca; Non-Financial Interests, Personal, Advisory Role: Bristol Myers Squibb; Non-Financial Interests, Personal, Advisory Role: Ono Pharmaceuticals; Non-Financial Interests, Personal, Advisory Role: Daiichi Sankyo; Non-Financial Interests, Personal, Advisory Role: GlaxoSmithKline; Non-Financial Interests, Personal, Advisory Role: Janssen; Non-Financial Interests, Personal, Member of the Board of Directors: Korean Association for Lung Cancer; Non-Financial Interests, Personal, Member of the Board of Directors: Korean Cancer Association; Non-Financial Interests, Personal, Member of the Board of Directors: Korean Society of Medical Oncology; Non-Financial Interests, Personal, Advisory Role: Pfizer; Non-Financial Interests, Personal, Advisory Role: SK BioPharm; Non-Financial Interests, Personal, Advisory Role: Takeda; Non-Financial Interests, Personal, Advisory Role: Yuhan. E.K. Park: Financial Interests, Personal, Full or part-time Employment: Turning Point Therapeutics, Inc. J.J. Lin: Financial Interests, Personal, Other, Consultant: Boehringer Ingelheim; Financial Interests, Personal and Institutional, Other, Consultant, Travel: Pfizer; Financial Interests, Personal and Institutional, Research Grant: Pfizer; Financial Interests, Personal, Other, Consultant: C4 Therapeutics; Financial Interests, Personal, Other, Consultant: Nuvalent; Financial Interests, Personal and Institutional, Other, Consultant: Turning Point Therapeutics Inc.; Financial Interests, Personal and Institutional, Research Grant: Turning Point Therapeutics Inc.; Financial Interests, Personal, Other, Consultant: Blueprint Medicines; Financial Interests, Personal and Institutional, Other, Consultant: Elevation Oncology; Financial Interests, Personal and Institutional, Research Grant: Elevation Oncology; Financial Interests, Personal and Institutional, Other, Consultant: Roche/Genentech; Financial Interests, Personal and Institutional, Research Grant: Roche/Genentech; Financial Interests, Institutional, Research Grant: Hengrui Therapeutics; Financial Interests, Institutional, Research Grant: Neon Therapeutics; Financial Interests, Institutional, Research Grant: Relay Therapeutics; Financial Interests, Institutional, Research Grant: Bayer; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Personal, Other, CME Funding: OncLive; Financial Interests, Personal, Other, CME Funding: Northwell Health; Financial Interests, Personal, Other, CME Funding: MedStar Health.