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

• ClinicalTrials.gov Identifier: NCT04094610
• Recruitment Status: Recruiting
• First Posted: September 19, 2019
• Last Update Posted: April 10, 2024
• Sponsor: Turning Point Therapeutics, Inc.
• Information provided by (Responsible Party): Turning Point Therapeutics, Inc.

Tracking Information

• First Submitted Date: September 12, 2019
• First Posted Date: September 19, 2019
• Last Update Posted Date: April 10, 2024
• Actual Study Start Date: March 12, 2020
• Estimated Primary Completion Date: September 30, 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 29, 2020)

• Dose limiting toxicities (DLTs) (Phase 1) [ Time Frame: Within 28 days of the first repotrectinib dose ]
  Define the dose limiting toxicities (DLTs) (Phase 1)
• Pediatric Recommended Phase 2 Dose (RP2D) (Phase 1) [ Time Frame: Within 28 days of the last patient dosed in escalation ]
  To determine the pediatric RP2D (Phase 1)
• Overall Response Rate (ORR) (Phase 2) [ Time Frame: Two to three years after first dose of repotrectinib ]
  To determine the confirmed ORR of repotrectinib (TPX-0005) as assessed by Blinded Independent Central Review (Phase 2)

Original Primary Outcome Measures (submitted: September 17, 2019)

• Dose limiting toxicities (DLTs) (Phase 1) [ Time Frame: Within 28 days of the first repotrectinib dose ]
  Define the dose limiting toxicities (DLTs) (Phase 1)
• Pediatric Recommended Phase 2 Dose (RP2D) (Phase 1) [ Time Frame: Within 28 days of the last patient dosed in escalation ]
  To determine the pediatric RP2D (Phase 1)

Current Secondary Outcome Measures (submitted: May 29, 2020)

• Overall Response Rate (ORR) (Phase 1) [ Time Frame: Approximately three years ]
  To determine the overall response rate (ORR) by Blinded Independent Central Review (BICR) (Phase 1)
• Clinical Benefit Rate (CBR) (Phase 1 and Phase 2) [ Time Frame: Approximately three years ]
  To determine the CBR of repotrectinib (TPX-0005) (Phase 1 and Phase 2)
• Time to response (TTR) (Phase 1 and Phase 2) [ Time Frame: Approximately three years ]
  To determine the TTR of reprotrectinib (TPX-005) (Phase 1 and Phase 2)
• Duration of response (DOR) (Phase 1 and Phase 2) [ Time Frame: Approximately three years ]
  To determine the DOR of repotrectinib (TPX-0005) (Phase 1 and Phase 2)
• Intracranial objective response rate (IC-ORR) (Phase 1 and Phase 2) [ Time Frame: Approximately three years ]
  To determine the IC-ORR of repotrectinib (TPX-005) (Phase 1 and Phase 2)
• Central Nervous System Progression-Free Survival (CNS-PFS) (Phase 2) [ Time Frame: Approximately three years ]
  CNS-PFS in subjects with measurable brain metastases (Phase 2)
• Progression-free survival (PFS) (Phase 2) [ Time Frame: Approximately three years ]
  To determine the PFS (Phase 2)
• Overall survival (OS) (Phase 2) [ Time Frame: Approximately three years ]
  To determine the OS (Phase 2)
• Maximum concentration of repotrectinib in plasma (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) ]
  To determine the Cmax
• Area under the concentration versus time curve of repotrectinib in plasma (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) ]
  To determine the AUC

Original Secondary Outcome Measures (submitted: September 17, 2019)

• Overall Response Rate (ORR) (Phase 1) [ Time Frame: Approximately three years ]
  To determine the overall response rate (ORR) by Blinded Independent Central Review (BICR) (Phase 1)
• Clinical Benefit Rate (CBR) (Phase 1) [ Time Frame: Approximately three years ]
  To determine the CBR of repotrectinib (TPX-0005) (Phase 1)
• Time to response (TTR) (Phase 1) [ Time Frame: Approximately three years ]
  To determine the TTR of reprotrectinib (TPX-005) (Phase 1)
• Duration of response (DOR) (Phase 1) [ Time Frame: Approximately three years ]
  To determine the DOR of repotrectinib (TPX-0005) (Phase 1)
• Intracranial objective response rate (IC-ORR) (Phase 1) [ Time Frame: Approximately three years ]
  To determine the IC-ORR of repotrectinib (TPX-005) (Phase 1)
• Maximum concentration of repotrectinib in plasma (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) ]
  To determine the Cmax
• Area under the concentration versus time curve of repotrectinib in plasma (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) ]
  To determine the AUC

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Repotrectinib in Pediatric and Young Adult Subjects Harboring ALK, ROS1, OR NTRK1-3 Alterations
• Official Title: 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

Brief Summary

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.

Detailed Description

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
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Locally Advanced Solid Tumors
• Metastatic Solid Tumors
• Lymphoma
• Primary CNS Tumors

Intervention

Drug: Oral repotrectinib (TPX-0005)

Oral repotrectinib (TPX-0005)

Other Names:

• Oral repotrectinib (TPX-0005) capsules
• Oral repotrectinib (TPX-0005) oral suspension
• repotrectinib

Study Arms

Experimental: Repotrectinib (TPX-0005)

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: ROS1 gene fusions or other ROS1 aberrations

Intervention: Drug: Oral repotrectinib (TPX-0005)

• Publications *: Wachter F, Al-Ibraheemi A, Trissal MC, Hollowell M, DuBois SG, Collins NB, Church AJ, Janeway KA. Molecular Characterization of Inflammatory Tumors Facilitates Initiation of Effective Therapy. Pediatrics. 2021 Dec 1;148(6):e2021050990. doi: 10.1542/peds.2021-050990.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: May 29, 2020): 75
• Original Estimated Enrollment (submitted: September 17, 2019): 12
• Estimated Study Completion Date: September 30, 2027
• Estimated Primary Completion Date: September 30, 2026 (Final data collection date for primary outcome measure)

Eligibility Criteria

Key Inclusion Criteria:

1. Documented genetic ROS1 point mutation, fusion, or amplification or NTRK1-3 fusion 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.
2. Phase 1: Age <12 years; Phase 2: Age 12- 25 years
3. Prior cytotoxic chemotherapy is allowed.
4. Prior immunotherapy is allowed.
5. 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.
6. All subjects must have measurable disease by RECIST v1.1 or Response Assessment in Neuro-Oncology (RANO) criteria at time of enrollment.
7. Subjects with a primary CNS tumor or CNS metastases must be neurologically stable on a stable or decreasing dose of steroids for at least 7 days prior to enrollment.
8. Subjects must have a Lansky (< 16 years) or Karnofsky (≥ 16 years) score of at least 50.
9. Life expectancy greater than or equal to 12 weeks, in the investigator's opinion.
10. Adequate hematologic, renal and hepatic function.

Phase 2 Inclusion Criteria:

1. 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 advanced solid tumors with ROS1 gene fusions or other ROS1 aberrations (including amplifications and point mutations) with measurable disease.
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):

1. Subjects with neuroblastoma with only bone marrow disease evaluable by bone marrow aspiration only.
2. 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.
3. Known active infections requiring ongoing treatment (bacterial, fungal, viral including HIV positivity).
4. Gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gut syndrome) or other malabsorption syndromes that would impact drug absorption.

5. 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
6. Peripheral neuropathy of CTCAE ≥grade 2.
7. Subjects being treated with or anticipating the need for treatment with strong CYP3A4 inhibitors or inducers.
8. Any potential allergies to repotrectinib and/or its excipients.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: up to 25 Years (Child, Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: BMS Study Connect Contact Center www.BMSStudyConnect.com; 855-907-3286; Clinical.Trials@bms.com

Contact: First line of the email MUST contain the NCT# and Site #.

• Listed Location Countries: Australia, Canada, Denmark, France, Italy, Korea, Republic of, Singapore, Spain, Taiwan, United Kingdom, United States

Administrative Information

• NCT Number: NCT04094610
• Other Study ID Numbers: CA127-1029; CA127-1029 ( Other Identifier: BMS Protocol ID ); TPX-0005-07 ( Other Identifier: Turning Point Therapeutics Protocol ID )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No
• Plan Description: There are no plans to share individual participant data with other researchers.

• Current Responsible Party: Turning Point Therapeutics, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Turning Point Therapeutics, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Bristol-Myers Squibb; Bristol-Myers Squibb

• PRS Account: Turning Point Therapeutics, Inc.
• Verification Date: April 2024