Phase 1 will evaluate the safety and tolerability at different dose levels of repotrectinib in pediatric and young adult subjects with advanced or metastatic malignancies harboring anaplastic lymphoma kinase (ALK), receptor tyrosine kinase encoded by the gene ROS1 (ROS1), or neurotrophic receptor kinase genes encoding TRK kinase family (NTRK1-3) alterations to estimate the Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) and select the Pediatric Recommended Phase 2 Dose (RP2D). Phase 2 will determine the anti-tumor activity of repotrectinib in pediatric and young adult subjects with advanced or metastatic malignancies harboring ROS1 or NTRK1-3 alterations.
Enrollment of subjects into Phase 1 will proceed concurrently by age as follows: * Subjects \<12 years old will initially be enrolled in the Phase 1 part to determine the pediatric RP2D for this age group; once the pediatric RP2D is determined, subjects age \<12 years old may be enrolled into the Phase 2 part of the study. * Subjects 12 to 25 years old will be directly enrolled into the Phase 2 part concurrent with Phase 1 enrollment. Phase 1: Approximately 12 pediatric subjects with locally advanced or metastatic solid tumors, including a primary central nervous system (CNS) tumor, or anaplastic large cell lymphoma (ALCL), with disease progression or who are non-responsive or intolerant to available therapies and for which no standard or available curative therapy exists. Phase 2: Subjects will be enrolled in one of 3 cohorts as follows: Cohort 1: approximately 10-20 subjects with solid tumors characterized by NTRK fusion, TRK tyrosine kinase inhibitor (TKI)-naïve, and centrally confirmed measurable disease at baseline. Cohort 2: approximately 23 subjects with solid tumors characterized by NTRK fusion, TRK TKI-pretreated, and centrally confirmed measurable disease at baseline. Cohort 3: approximately 20 subjects with solid tumors or ALCL characterized by other ALK/ROS1/NTRK alterations or NTRK fusions without centrally confirmed measurable disease not otherwise eligible for Cohort 1 or 2. As of the current protocol amendment, only patients with ROS1 alterations will be enrolled to this cohort.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
75
Oral repotrectinib (TPX-0005)
Children's Hospital Los Angeles
Los Angeles, California, United States
RECRUITINGUniversity of California at Los Angeles
Los Angeles, California, United States
RECRUITINGChildren's Hospital Colorado - Anschutz Medical Campus
Aurora, Colorado, United States
RECRUITINGLocal Institution - 2105
Orlando, Florida, United States
Dose limiting toxicities (DLTs) (Phase 1)
Define the dose limiting toxicities (DLTs) (Phase 1)
Time frame: Within 28 days of the first repotrectinib dose
Pediatric Recommended Phase 2 Dose (RP2D) (Phase 1)
To determine the pediatric RP2D (Phase 1)
Time frame: Within 28 days of the last patient dosed in escalation
Overall Response Rate (ORR) (Phase 2)
To determine the confirmed ORR of repotrectinib (TPX-0005) as assessed by Blinded Independent Central Review (Phase 2)
Time frame: Two to three years after first dose of repotrectinib
Overall Response Rate (ORR) (Phase 1)
To determine the overall response rate (ORR) by Blinded Independent Central Review (BICR) (Phase 1)
Time frame: Approximately three years
Clinical Benefit Rate (CBR) (Phase 1 and Phase 2)
To determine the CBR of repotrectinib (TPX-0005) (Phase 1 and Phase 2)
Time frame: Approximately three years
Time to response (TTR) (Phase 1 and Phase 2)
To determine the TTR of reprotrectinib (TPX-005) (Phase 1 and Phase 2)
Time frame: Approximately three years
Duration of response (DOR) (Phase 1 and Phase 2)
To determine the DOR of repotrectinib (TPX-0005) (Phase 1 and Phase 2)
Time frame: Approximately three years
Intracranial objective response rate (IC-ORR) (Phase 1 and Phase 2)
To determine the IC-ORR of repotrectinib (TPX-005) (Phase 1 and Phase 2)
Time frame: Approximately three years
Central Nervous System Progression-Free Survival (CNS-PFS) (Phase 2)
CNS-PFS in subjects with measurable brain metastases (Phase 2)
Time frame: Approximately three years
Progression-free survival (PFS) (Phase 2)
To determine the PFS (Phase 2)
Time frame: Approximately three years
Overall survival (OS) (Phase 2)
To determine the OS (Phase 2)
Time frame: Approximately three years
Maximum concentration of repotrectinib in plasma (Cmax)
To determine the Cmax
Time frame: Pre-dose and up to 24 hours post-dose on Day 1 and Day 15 in Cycle 1 (each cycle is 28 days)
Area under the concentration versus time curve of repotrectinib in plasma (AUC)
To determine the AUC
Time frame: Pre-dose and up to 24 hours post-dose on Day 1 and Day 15 in Cycle 1 (each cycle is 28 days)
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CONTACT
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Local Institution - 2120
Orlando, Florida, United States
COMPLETEDChildren's Healthcare of Atlanta - Egleston Hospital
Atlanta, Georgia, United States
RECRUITINGMaine Medical Center
Scarborough, Maine, United States
RECRUITINGDana Farber Cancer Institute.
Boston, Massachusetts, United States
RECRUITINGWashington University School of Medicine in St. Louis
St Louis, Missouri, United States
RECRUITINGLocal Institution - 2110
New Brunswick, New Jersey, United States
COMPLETED...and 58 more locations