A Study of Repotrectinib (TPX-0005) in Patients With Advanced Solid Tumours Harboring ALK, ROS1, or NTRK1-3 Rearrangements

Official Title

A Phase 1/2, Open-Label, Multi-Centre, First-in-Human Study of the Safety, Tolerability, Pharmacokinetics, and Anti-Tumour Activity of TPX-0005 in Patients With Advanced Solid Tumours Harboring ALK, ROS1, or NTRK1-3 Rearrangements (TRIDENT-1)

Summary:

Phase 1 dose escalation will determine the first cycle dose-limiting toxicities (DLTs), the maximum tolerated dose (MTD), the biologically effective dose and recommended Phase 2 dose (RP2D) of repotrectinib given to adult subjects with advanced solid malignancies harboring an ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement.

Midazolam DDI substudy will examine effect of of repotrectinib on CYP3A induction.

Phase 2 will determine the confirmed Overall Response Rate (ORR) as assessed by Blinded Independent Central Review (BICR) of repotrectinib in each subject population expansion cohort of advanced solid tumours that harbor a ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement. The secondary objective will include the duration of response (DOR), time to response (TTR), progression-free survival (PFS), overall survival (OS) and clinical benefit rate (CBR) of repotrectinib in each expansion cohort of advanced solid tumours that harbor a ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement.

Trial Description

Primary Outcome:

• Dose limiting toxicities (DLTs) (Phase 1)
• Recommended Phase 2 Dose (RP2D) (Phase 1)
• Overall Response Rate (ORR) Phase 2

Secondary Outcome:

• Maximum plasma concentration (CMAX) of repotrectinib (TPX-0005) (Phase 1)
• Area under the plasma concentration time curve (AUC) of repotrectinib (TPX-0005) (Phase 1)
• Area under the plasma concentration time curve (AUC) of repotrectinib under different food intake conditions(TPX-0005) (Phase 1)
• Maximum plasma concentration (CMAX) of repotrectinib under different food intake conditions(TPX-0005) (Phase 1)
• Area under the plasma concentration time curve (AUC) of midazolam(TPX-0005) (Phase 1)
• Maximum plasma concentration (CMAX) of midazolam(TPX-0005) (Phase 1)
• Plasma concentration of repotrectinib following administration at RP2D (Phase 2)
• Preliminary objective response rate (ORR) (Phase 1)
• Duration of response (DOR) (Phase 2)
• Clinical benefit rate (CBR) (Phase 2)
• Progression free survival (PFS) (Phase 2)
• Overall survival (OS) (Phase 2)
• Intracranial objective response rate (Phase 2)

In Phase 2, study subjects will be enrolled into 6 distinct expansion (EXP) cohorts:

• EXP-1: ROS1 TKI-naïve ROS1+ NSCLC. Up to one prior line of chemotherapy OR immunotherapy is allowed

• EXP-2: 1 Prior ROS1 TKI AND 1 Platinum-based Chemotherapy ROS1+ NSCLC. Disease progression, or intolerant to one prior line of a ROS1 TKI. Must have received one prior line of platinum based chemotherapy OR one prior line of platinum based chemotherapy in combination with immunotherapy before or after a ROS1 TKI

• EXP-3: 2 Prior ROS1 TKIs AND NO Chemotherapy ROS1+ NSCLC. Disease progression, or intolerant to 2 prior lines of a ROS1 TKI treatment. No prior lines of chemotherapy or immunotherapy are allowed.

• EXP-4: 1 Prior ROS1 TKI and NO Chemotherapy or Immunotherapy. Disease progression or intolerant to one prior line of a ROS1 TKI. No prior lines of chemotherapy or immunotherapy are allowed.

• EXP-5: TRK TKI-naïve NTRK+ solid tumours. Any number of prior lines of chemo or immunotherapy is allowed.

• EXP-6: TRK TKI-pretreated NTRK+ solid tumours. Disease progression, or intolerant to 1 or 2 prior TRK TKIs. Any number of prior lines of chemo- or immunotherapy are allowed.

View this trial on ClinicalTrials.gov