A Study of Repotrectinib in Pediatric and Young Adult Subjects Harboring ALK, ROS1, OR NTRK1-3 Alterations

Study Overview
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Brief Summary
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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 subjects with advanced or metastatic malignancies harboring ALK, ROS1, or NTRK1-3 alterations.

Detailed Description
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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.

Official Title
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A Phase 1/2, Open-Label, Safety, Tolerability, Pharmacokinetics, and Anti-Tumor Activity Study of Repotrectinib in Pediatric and Young Adult Subjects With Advanced or Metastatic Malignancies Harboring ALK, ROS1, NTRK1-3 Alterations

Conditions
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Primary CNS Tumors, Locally Advanced Solid Tumors, Metastatic Solid Tumors, Lymphoma

Intervention / Treatment
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* Drug: Oral repotrectinib (TPX-0005)


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Documented genetic ALK, ROS1, or NTRK1-3 alteration (point mutation, fusion, amplification) as identified by local testing in a Clinical Laboratory Improvement Amendments (CLIA) laboratory in the US or equivalently accredited diagnostic lab outside the United States (US) is required. Phase 1: Age <12 years; Phase 2: Age 12- 25 years Prior cytotoxic chemotherapy is allowed. Prior immunotherapy is allowed. Resolution of all acute toxic effects (excluding alopecia) of any prior anti-cancer therapy to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03 Grade less than or equal to 1. All subjects must have measurable disease by RECIST v1.1 or Response Assessment in Neuro-Oncology Criteria (RANO) criteria at time of enrollment. Subjects with a primary CNS tumor or CNS metastases must be neurologically stable on a stable or decreasing dose of steroids for at least 14 days prior to enrollment. Subjects must have a Lansky (< 16 years) or Karnofsky (≥ 16 years) score of at least 50. Life expectancy greater than or equal to 12 weeks. Adequate hematologic, renal and hepatic function. Phase 2 Inclusion Criteria: Cohort Specific Inclusion Criteria: Cohort 1: Subjects with NTRK fusion gene positive (NTRK+) advanced solid tumors (including primary CNS tumors), that are tropomyosin receptor kinase (TRK) TKI naïve; Cohort 2: subjects with NTRK+ advanced solid tumors (including primary CNS tumors), that are TRK TKI pre-treated; Cohort 3: subjects with tumors or ALCL characterized by other ALK/ROS1/NTRK alterations or NTRK fusions without centrally confirmed measurable disease or not otherwise eligible for Cohort 1 or 2. Subjects in Cohorts 1 and 2 must have prospectively confirmed measurable disease by BICR prior to enrollment. Key Exclusion Criteria (Phase 1 and Phase 2): Subjects with neuroblastoma with only bone marrow disease evaluable by bone marrow aspiration only. Major surgery within 14 days (2 weeks) of start of repotrectinib treatment. Central venous access (Broviac, Mediport, etc.) placement does not meet criteria for major surgery. Known active infections (bacterial, fungal, viral including HIV positivity). Gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gut syndrome) or other malabsorption syndromes that would impact drug absorption. Any of the following cardiac criteria: Mean resting corrected QT interval (ECG interval measured from the onset of the QRS complex to the end of the T wave) for heart rate (QTc) > 480 msec obtained from three ECGs, using the screening clinic ECG machine-derived QTc value Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block, second degree heart block, PR interval > 250 msec) Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, congenital long QT syndrome, family history of long QT syndrome, or any concomitant medication known to prolong the QT interval Peripheral neuropathy of CTCAE ≥grade 2. Subjects being treated with or anticipating the need for treatment with strong CYP3A4 inhibitors or inducers.

Ages Eligible for Study
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Maximum Age: 25 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Repotrectinib (TPX-0005)<br>Phase 1 Oral repotrectinib (TPX-0005): Safety and tolerability at different dose levels Phase 2 Oral repotrectinib (TPX-0005): 3 cohorts Cohort 1: TKI-naive NTRK fusion Cohort 2: Prior TKI NTRK fusion Cohort 3: ALK/ROS1/NTRK alterations or fusions in tumors and ALCL | Drug: Oral repotrectinib (TPX-0005)<br>* Oral repotrectinib (TPX-0005)<br>* Other names: repotrectinib;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose limiting toxicities (DLTs) (Phase 1) | Define the dose limiting toxicities (DLTs) (Phase 1) | Within 28 days of the first repotrectinib dose | 
| Pediatric Recommended Phase 2 Dose (RP2D) (Phase 1) | To determine the pediatric RP2D (Phase 1) | 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) | Two to three years after first dose of repotrectinib | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) (Phase 1) | To determine the overall response rate (ORR) by Blinded Independent Central Review (BICR) (Phase 1) | 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) | 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) | 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) | 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) | Approximately three years | 
| Central Nervous System Progression-Free Survival (CNS-PFS) (Phase 2) | CNS-PFS in subjects with measurable brain metastases (Phase 2) | Approximately three years | 
| Progression-free survival (PFS) (Phase 2) | To determine the PFS (Phase 2) | Approximately three years | 
| Overall survival (OS) (Phase 2) | To determine the OS (Phase 2) | Approximately three years | 
| Maximum concentration of repotrectinib in plasma (Cmax) | To determine the Cmax | 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 | Pre-dose and up to 24 hours post-dose on Day 1 and Day 15 in Cycle 1 (each cycle is 28 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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glioma, pediatric, ALK, ROS1, NTRK1-3, Primary CNS tumor, anaplastic large cell lymphoma, metastatic solid tumor, advanced solid tumor, sarcoma, infantile fibrosarcoma, glioblastoma, soft tissue schwannoma, solitary fibrous tumor, inflammatory myofibroblastic tumor