NCT04772235

Phase I Study of Repotrectinib and Osimertinib in NSCLC Patients

Phase I Clinical Study to Assess Safety and Efficacy of Repotrectinib Combined With Osimertinib in Patients With Advanced, Metastatic EGFR Mutant NSCLC (TOTEM).

• Status: Recruiting
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 32 (estimated)
• Sponsor: Instituto Oncológico Dr Rosell · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

This is a Phase I study of repotrectinib in combination with osimertinib in patients with advanced or metastatic EGFR mutant non small cell lung cancer (NSCLC). The study will be conducted in 2 parts, Part Ia and Part Ib, and its purpose will be to find the incidence of dose-limiting toxicities (DLTs) as defined by the primary safety and tolerability endpoint. The Phase Ia study will also determine the impact of repotrectinib on osimertinib pharmacokinetics (PK) and the maximum tolerated dose (MTD), if reached, of repotrectinib given in combination with osimertinib and the recommended Phase II dose (RP2D). Dose escalation will be conducted according to a 'Rolling-6' based study design with 3 dose levels for repotrectinib: 80 mg once a day (QD), 160 mg QD or 160 mf QD during 14 days followed by 160 mg twice a day (BID); in combination with 80 mg QD of osimertinib. A total of 6 patients will be enrolled in each dose level cohort. In addition, this Phase Ib study will test early drug activity (efficacy) of the proposed combination treatment in an expansion cohort at the RP2D.

Detailed description

Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) designed to inhibit activating EGFR mutations (exon 19 deletion and L858R) and resistant T790M mutations with low activity against wild type EGFR. Repotrectinib, potently inhibits Anaplastic Lymphoma Kinase (ALK), Ros proto-oncogene 1 (ROS1), and Tropomyosin receptor kinases (TRK) family kinases; this novel target drug also inhibits Janus kinase 2 (JAK2), sarcoma (SRC), and focal adhesion (FAK), which have shown to be important targets associated with EGFR TKI resistance. This is a Phase I study of repotrectinib in combination with osimertinib in patients with advanced or metastatic EGFR mutant NSCLC. The study will be conducted in 2 parts, Part Ia and Part Ib: Part A: of the Phase I study will enroll approximately 9-18 patients in up to 3 dose levels of 3-6 patients each: 80 mg once a day (QD), 160 mg QD or 160 mf QD during 14 days followed by 160 mg twice a day (BID); in combination with 80 mg QD of osimertinib. Patients will receive the combination treatment daily in 3-week cycles until disease progression occurs. Part B: of the Phase I study is a dose expansion to assess additional PK and safety parameters. Part B will enroll between 20 and 30 patients in 2 cohorts of at least 10 patients each. The 2 cohorts are defined by treatment history: Cohort I, those who have progressed on osimertinib; Cohort II, those who progressed on any first or second generation TKI. The phase 1A portion of this study will test the safety, tolerability, PK effects, and preliminary efficacy of the EGFR TKI inhibitor osimertinib in combination with repotrectinib in adult patients with advanced/metastatic EGFR mutant NSCLC. The phase 1B (expansion cohort) of this study will test the efficacy of the combination of osimertinib and repotrectinib in terms of progression-free survival and response rate in EGFR TKI-naïve patients with EGFR mutant NSCLC.

Conditions

• Nsclc

Interventions

Type	Name	Description
DRUG	Repotrectinib	Repotrectinib will be taken orally once daily with or without food Part A: Dose escalation phase, with 3 dose levels for repotrectinib: (1) 80 mg QD, (2) 160 mg QD and (3) 160 mg QD for 14 days followed by 160 mg BID; in combination with 80 mg QD of osimertinib Part B: at the RP2D for all patients in combination with osimertinib.
DRUG	Osimertinib	Osimertinib will be taken orally at 80 mg once daily with or without food. Part A: lead in dose in monotherapy at 80 mg QD during 14 days. In combination with repotrectinib afterwards. Depending on the safety and PK/ dose dependent interactions (DDIs) readout during the DLT assessment period, osimertinib dose may be adjusted. Part B: at the RP2D level in combination with repotrectinib

Timeline

• Start date: 2022-02-11
• Primary completion: 2026-04-01
• Completion: 2026-06-01
• First posted: 2021-02-26
• Last updated: 2024-04-03

Locations

4 sites across 1 country: Spain