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NCT04094610PHASE1, PHASE2Recruiting

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

Turning Point Therapeutics, Inc.

Start Date

3/12/2020

Completion Date

9/30/2027

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.

Eligibility Criteria

Age Range: No minimum to 25 years

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.

Interventions

DRUG

Oral repotrectinib (TPX-0005)

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Conditions

Locally Advanced Solid TumorsMetastatic Solid TumorsLymphomaPrimary CNS Tumors

Locations

Children's Hospital Los Angeles

Los Angeles, California 90027-6062

United States

University of California at Los Angeles

Los Angeles, California 90095

United States

Children's Hospital Colorado - Anschutz Medical Campus

Aurora, Colorado 80045

United States

Local Institution - 2105

Orlando, Florida 32806

United States

Local Institution - 2120

Orlando, Florida 32827

United States

Children's Healthcare of Atlanta - Egleston Hospital

Atlanta, Georgia 30329

United States

Maine Medical Center

Scarborough, Maine 04074

United States

Dana Farber Cancer Institute.

Boston, Massachusetts 02215

United States

Washington University School of Medicine in St. Louis

St Louis, Missouri 63110

United States

Local Institution - 2110

New Brunswick, New Jersey 08901

United States

Local Institution - 2102

New York, New York 10065

United States

Levine Children's Hospital- Pediatric Neuro-Oncology

Charlotte, North Carolina 28203

United States

Local Institution - 2112

Cleveland, Ohio 44195

United States

Local Institution - 2114

Hershey, Pennsylvania 17033

United States

Children's Hospital of Philadelphia-Center for Childhood Cancer Research

Philadelphia, Pennsylvania 19104

United States

St. Jude Children's Research Hospital

Memphis, Tennessee 38015

United States

The University of Texas Southwestern Medical Center - Harold C Simmons Comprehensive Cancer Center

Dallas, Texas 75390

United States

Baylor College of Medicine

Houston, Texas 77030

United States

Local Institution - 2104

Houston, Texas 77030

United States

Children's Hospital of Richmond at VCU

Richmond, Virginia 23219

United States

Local Institution - 6104

Randwick, New South Wales 2031

Australia

Local Institution - 6103

Westmead, New South Wales 0

Australia

Children's Health Queensland Hospital and Health Service

South Brisbane, Queensland 4101

Australia

Perth Childrens Hospital

Nedlands, Western Australia 6009

Australia

University Of Calgary

Calgary, Alberta T3B 6A8

Canada

Stollery Children'S Hospital

Edmonton, Alberta T6G 2B7

Canada

Children'S Hospital Of Eastern Ontario

Ottawa, Ontario K1H 8L1

Canada

St Justine Hospital

Montreal, Quebec H3T 1C5

Canada

Rigshospitalet - Glostrup

Copenhagen, 2100

Denmark

Local Institution - 6111

Lyon, Rhone 69008

France

Centre Hospitalier Universitaire D'Angers

Angers, 49933

France

Centre Hospitalier Universitaire de Bordeaux - Groupe Hospitalier Pellegrin

Bordeaux, 33076

France

Institut d Hematologie et d Oncologie Pediatriques

Lyon, 69373

France

Hôpitaux Universitaires de Marseille Timone

Marseille, 13385

France

Local Institution - 6110

Marseille, 13385

France

Local Institution - 6112

Nantes, 44093

France

Local Institution - 6109

Paris, 75005

France

Institut Gustave-Roussy

Villejuif, 94805

France

Local Institution - 6108

Villejuif, 94805

France

Fondazione IRCCS - Istituto Nazionale dei Tumori

Milan, 20133

Italy

Local Institution - 6113

Padova, 35128

Italy

Local Institution - 4302

Rome, 00165

Italy

Local Institution - 6114

Torino, 10126

Italy

National University Hospital

Singapore, 119228

Singapore

KK Women's and Children's Hospital

Singapore, 229899

Singapore

Local Institution - 6303

Seoul, Seodaemun-gu 03722

South Korea

Seoul National University Hospital

Seoul, 03080

South Korea

Asan Medical Center

Seoul, 05505

South Korea

Local Institution - 6304

Seoul, 06351

South Korea

Hospital Sant Joan De Deu

Esplugues de Llobregat, Barcelona 08950

Spain

Clínica Universidad de navarra

Pamplona, Navarre 31008

Spain

Local Institution - 6105

Barcelona, 08014

Spain

Hospital Universitari Vall d'Hebron

Barcelona, 8035

Spain

Hospital Infantil Universitario Nino Jesus

Madrid, 28009

Spain

Local Institution - 6106

Madrid, 28009

Spain

Clinica Universidad de Navarra

Madrid, 28022

Spain

HM Sanchinarro University Hospital

Madrid, 28050

Spain

Hospital Universitario Virgen del Rocio

Seville, 41013

Spain

Hospital Universitario Y Politecnico La Fe

Valencia, 46026

Spain

Local Institution - 6107

Valencia, 46026

Spain

National Taiwan University Hospital

Taipei, 100225

Taiwan

Taipei Medical University Hospital

Taipei, 11031

Taiwan

Alder Hey Children's NHS Foundation Trust

Liverpool, England L12 2AP

United Kingdom

Local Institution - 4403

Birmingham, B4 6DH

United Kingdom

University Hospital of Wales

Cardiff, CF14 4XW

United Kingdom

Royal Hosp. for Children

Glasgow, G51 4TF

United Kingdom

The Royal Marsden NHS Foundation Trust

London, SW3 6JJ

United Kingdom

Great Ormond Street Hospital For Children NHS Foundation Trust

London, WC1N 3JH

United Kingdom