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

Phase 1

Recruiting

• Conditions: Metastatic Solid Tumors; Lymphoma; Primary CNS Tumors; Locally Advanced Solid Tumors
• Interventions: Drug: Oral repotrectinib (TPX-0005)

• Registration Number: NCT04094610
• Lead Sponsor: Turning Point Therapeutics, Inc.

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 Timeline

• Study First Submitted: 2019-09-12
• Study First Submitted QC: 2019-09-17
• Study First Posted: 2019-09-19
• Study Start: 2020-03-12
• Status Verified: 2025-02
• Last Update Submitted: 2025-02-12
• Last Update Posted: 2025-02-14
• Primary Completion: 2026-09-30
• Study Completion: 2027-09-30

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 75

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.

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Repotrectinib (TPX-0005)	Oral 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

Primary Outcome Measures

Name	Time	Method
Dose limiting toxicities (DLTs) (Phase 1)	Within 28 days of the first repotrectinib dose	Define the dose limiting toxicities (DLTs) (Phase 1)
Pediatric Recommended Phase 2 Dose (RP2D) (Phase 1)	Within 28 days of the last patient dosed in escalation	To determine the pediatric RP2D (Phase 1)
Overall Response Rate (ORR) (Phase 2)	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)

Secondary Outcome Measures

Name	Time	Method
Time to response (TTR) (Phase 1 and Phase 2)	Approximately three years	To determine the TTR of reprotrectinib (TPX-005) (Phase 1 and Phase 2)
Central Nervous System Progression-Free Survival (CNS-PFS) (Phase 2)	Approximately three years	CNS-PFS in subjects with measurable brain metastases (Phase 2)
Overall Response Rate (ORR) (Phase 1)	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)	Approximately three years	To determine the CBR of repotrectinib (TPX-0005) (Phase 1 and Phase 2)
Duration of response (DOR) (Phase 1 and Phase 2)	Approximately three years	To determine the DOR of repotrectinib (TPX-0005) (Phase 1 and Phase 2)
Progression-free survival (PFS) (Phase 2)	Approximately three years	To determine the PFS (Phase 2)
Intracranial objective response rate (IC-ORR) (Phase 1 and Phase 2)	Approximately three years	To determine the IC-ORR of repotrectinib (TPX-005) (Phase 1 and Phase 2)
Overall survival (OS) (Phase 2)	Approximately three years	To determine the OS (Phase 2)
Maximum concentration of repotrectinib in plasma (Cmax)	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)	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

Trial Locations

Locations (68)

Children's Hospital Los Angeles; 🇺🇸 Los Angeles, California, United States

University of California at Los Angeles; 🇺🇸 Los Angeles, California, United States

Children's Hospital Colorado - Anschutz Medical Campus; 🇺🇸 Aurora, Colorado, United States

Arnold Palmer Hospital For Children; 🇺🇸 Orlando, Florida, United States

Local Institution - 2120; 🇺🇸 Orlando, Florida, United States

Local Institution - 2119; 🇺🇸 Atlanta, Georgia, United States

Maine Medical Center; 🇺🇸 Scarborough, Maine, United States

Dana Farber Cancer Institute.; 🇺🇸 Boston, Massachusetts, United States

Washington University School of Medicine in St. Louis; 🇺🇸 Saint Louis, Missouri, United States

Local Institution - 2110; 🇺🇸 New Brunswick, New Jersey, United States

Memorial Sloan-Kettering Cancer Center.; 🇺🇸 New York, New York, United States

Local Institution - 2121; 🇺🇸 Charlotte, North Carolina, United States

Local Institution - 2112; 🇺🇸 Cleveland, Ohio, United States

Penn State Milton S. Hershey Medical Center; 🇺🇸 Hershey, Pennsylvania, United States

Children'S Hospital Of Philadelphia; 🇺🇸 Philadelphia, Pennsylvania, United States

Children's Hospital of Richmond at VCU; 🇺🇸 Richmond, Virginia, United States

Local Institution - 6104; 🇦🇺 Randwick, New South Wales, Australia

Local Institution - 6103; 🇦🇺 Westmead, New South Wales, Australia

St. Jude Children's Research Hospital; 🇺🇸 Memphis, Tennessee, United States

The University of Texas Southwestern Medical Center - Harold C Simmons Comprehensive Cancer Center; 🇺🇸 Dallas, Texas, United States

Local Institution - 2118; 🇺🇸 Houston, Texas, United States

The University of Texas MD Anderson Cancer Center.; 🇺🇸 Houston, Texas, United States

Children's Health Queensland Hospital and Health Service; 🇦🇺 South Brisbane, Queensland, Australia

Perth Childrens Hospital; 🇦🇺 Nedlands, Western Australia, Australia

University Of Calgary; 🇨🇦 Calgary, Alberta, Canada

Stollery Children'S Hospital; 🇨🇦 Edmonton, Alberta, Canada

Local Institution - 2203; 🇨🇦 Ottawa, Ontario, Canada

Local Institution - 2205; 🇨🇦 Montreal, Quebec, Canada

Rigshospitalet - Glostrup; 🇩🇰 Copenhagen, Denmark

Local Institution - 6111; 🇫🇷 Lyon, Rhone, France

Centre Hospitalier Universitaire D'Angers; 🇫🇷 Angers, France

Institut d Hematologie et d Oncologie Pediatriques; 🇫🇷 Lyon Cedex 08, France

Centre Hospitalier Universitaire de Bordeaux - Groupe Hospitalier Pellegrin; 🇫🇷 Bordeaux, France

Hôpitaux Universitaires de Marseille Timone; 🇫🇷 Marseille Cedex 5, France

Local Institution - 6110; 🇫🇷 Marseille Cedex 5, France

Local Institution - 6112; 🇫🇷 Nantes, France

Local Institution - 6109; 🇫🇷 Paris, France

Institut Gustave-Roussy; 🇫🇷 Villejuif, France

Local Institution - 6108; 🇫🇷 Villejuif, France

Fondazione IRCCS - Istituto Nazionale dei Tumori; 🇮🇹 Milano, Italy

Local Institution - 6113; 🇮🇹 Padova, Italy

National University Hospital; 🇸🇬 Singapore, Singapore

KK Women's and Children's Hospital; 🇸🇬 Singapore, Singapore

Hospital Sant Joan De Deu; 🇪🇸 Esplugues de Llobregat, Barcelona, Spain

Clínica Universidad de navarra; 🇪🇸 Pamplona, Navarra, Spain

Local Institution - 6105; 🇪🇸 Barcelona, Spain

Hospital Universitari Vall d'Hebron; 🇪🇸 Barcelona, Spain

Local Institution - 4302; 🇮🇹 Rome, Italy

Local Institution - 6114; 🇮🇹 Torino, Italy

Yonsei Universtidy Health System; 🇰🇷 Seoul, Seodaemun-gu, Korea, Republic of

Asan Medical Center; 🇰🇷 Seoul, Korea, Republic of

Samsung Medical Center; 🇰🇷 Seoul, Korea, Republic of

Seoul National University Hospital; 🇰🇷 Seoul, Korea, Republic of

Hospital Infantil Universitario Nino Jesus; 🇪🇸 Madrid, Spain

Local Institution - 6106; 🇪🇸 Madrid, Spain

Clinica Universidad de Navarra; 🇪🇸 Madrid, Spain

HM Sanchinarro University Hospital; 🇪🇸 Madrid, Spain

Local Institution - 4108; 🇪🇸 Sevilla, Spain

Hospital Universitario Y Politecnico La Fe; 🇪🇸 Valencia, Spain

Local Institution - 6107; 🇪🇸 Valencia, Spain

National Taiwan University Hospital; 🇨🇳 Taipei, Taiwan

Taipei Medical University Hospital; 🇨🇳 Taipei, Taiwan

Local Institution - 4404; 🇬🇧 Liverpool, England, United Kingdom

Local Institution - 4403; 🇬🇧 Birmingham, United Kingdom

Local Institution - 4401; 🇬🇧 Cardiff, United Kingdom

Local Institution - 4406; 🇬🇧 Glasgow, United Kingdom

Local Institution - 4405; 🇬🇧 London, United Kingdom

Local Institution - 4402; 🇬🇧 London, United Kingdom