(P 316) FIRST-IN-HUMAN PHASE 1/1B STUDY OF IDRX-42, A NOVEL ORAL TYROSINE KINASE KIT INHIBITOR, IN PARTICIPANTS WITH METASTATIC AND/OR UNRESECTABLE GASTROINTESTINAL STROMAL TUMORS

Objective: The majority of gastrointestinal stromal tumors (GISTs) are driven by constitutively activated kinases, either KIT or PDGFRA, and respond to treatment with tyrosine kinase inhibitors (TKI) such as imatinib, sunitinib, regorafenib, and ripretinib. During treatment, most GISTs develop heterogeneous resistance to TKI, which is usually driven by secondary mutations in the primary kinase oncogene (KIT or platelet-derived growth factor-alpha [PDGFRA]). Therefore, novel therapies are needed to prevent the emergence of resistant subclones or to treat TKI-resistant GISTs. IDRX-42 (formerly M4205) is a potent, highly selective, orally administered, small-molecule TKI targeting disease-specific oncogenic drivers and a range of clinically relevant resistance mutations of KIT. Nonclinical studies of IDRX-42 have demonstrated robust antitumor activity in patient- and cell line-derived GIST xenograft models, including models with relevant KIT mutations, including TKI resistance mutations (De Sutter L, et al. AACR 2022).

Methods: IDRX-42-001 is a phase 1/1b, first-in-human, open-label, multicenter study to evaluate single-agent IDRX-42 in participants with metastatic and/or surgically unresectable GISTs. The phase 1 dose escalation will utilize a 3+3 design to evaluate safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of IDRX-42 to establish the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Phase 1b will consist of exploratory cohorts of participants with selected lines of prior therapy to assess the antitumor activity of IDRX-42 and to further characterize the safety profile of IDRX-42 at the RP2D. Eligible participants are aged ≥18 years with Eastern Cooperative Oncology Group performance status of 0–1, have documented pathogenic mutation in KIT or any PDGFRA mutation other than exon 18 mutations, and at least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors version 1.1 modified for participants with GIST (mRECIST v1.1) per investigator assessment. Phase 1 dose-escalation participants must have documented progression on at least imatinib. For the phase 1b exploratory cohorts, participants in cohort 1 must have progressed on imatinib only (2nd-line therapy), participants in cohort 2 must have progressed on both imatinib and sunitinib (3rd-line therapy) or progressed on imatinib, sunitinib, and an additional agent (ie, regorafenib or ripretinib) (4th-line therapy), and participants in cohort 3 must have progressed on imatinib, sunitinib, regorafenib, and ripretinib (5th-line or greater therapy). IDRX-42 will be administered starting at 120 mg orally daily (QD) in 28-day cycles until disease progression, unacceptable toxicity, or other reason for discontinuation. The primary endpoints are to determine the nature, incidence, and severity of IDRX-42 treatment-emergent adverse events and dose-limiting toxicities (phase 1), and to continue to evaluate safety and determine the objective response rate per Investigator assessed mRECIST v1.1 (phase 1b). Secondary endpoints include PK parameters, duration of response, progression-free survival, and time to response related to IDRX-42 treatment. Exploratory endpoints will evaluate potential predictive and pharmacodynamic markers using ctDNA, as well as changes in KIT, PDGFRA, and other relevant gene mutant allele fractions and their correlation with clinical outcomes.

Results: Not applicable

Conclusion: Not applicable