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

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.

Interventions

• Oral repotrectinib (TPX-0005) · DRUG

  Oral repotrectinib (TPX-0005)

Published eligibility criteria

Verbatim from the registry. Only the site can decide how these apply to a specific patient.

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.

Sites (68)

• Children's Hospital Los Angeles, Los Angeles, California · RECRUITING
• University of California at Los Angeles, Los Angeles, California · RECRUITING
• Children's Hospital Colorado - Anschutz Medical Campus, Aurora, Colorado · RECRUITING
• Local Institution - 2105, Orlando, Florida · COMPLETED
• Local Institution - 2120, Orlando, Florida · COMPLETED
• Children's Healthcare of Atlanta - Egleston Hospital, Atlanta, Georgia · RECRUITING
• Maine Medical Center, Scarborough, Maine · RECRUITING
• Dana Farber Cancer Institute., Boston, Massachusetts · RECRUITING
• Washington University School of Medicine in St. Louis, St Louis, Missouri · RECRUITING
• Local Institution - 2110, New Brunswick, New Jersey · COMPLETED
• Local Institution - 2102, New York, New York · COMPLETED
• Levine Children's Hospital- Pediatric Neuro-Oncology, Charlotte, North Carolina · RECRUITING
• Local Institution - 2112, Cleveland, Ohio · COMPLETED
• Local Institution - 2114, Hershey, Pennsylvania · COMPLETED
• Children's Hospital of Philadelphia-Center for Childhood Cancer Research, Philadelphia, Pennsylvania · RECRUITING
• St. Jude Children's Research Hospital, Memphis, Tennessee · RECRUITING
• The University of Texas Southwestern Medical Center - Harold C Simmons Comprehensive Cancer Center, Dallas, Texas · RECRUITING
• Baylor College of Medicine, Houston, Texas · RECRUITING
• Local Institution - 2104, Houston, Texas · COMPLETED
• Children's Hospital of Richmond at VCU, Richmond, Virginia · WITHDRAWN
• Local Institution - 6104, Randwick, New South Wales, Australia · RECRUITING
• Local Institution - 6103, Westmead, New South Wales, Australia · COMPLETED
• Children's Health Queensland Hospital and Health Service, South Brisbane, Queensland, Australia · RECRUITING
• Perth Childrens Hospital, Nedlands, Western Australia, Australia · RECRUITING
• University Of Calgary, Calgary, Alberta, Canada · RECRUITING
• Stollery Children'S Hospital, Edmonton, Alberta, Canada · RECRUITING
• Children'S Hospital Of Eastern Ontario, Ottawa, Ontario, Canada · RECRUITING
• St Justine Hospital, Montreal, Quebec, Canada · RECRUITING
• Rigshospitalet - Glostrup, Copenhagen, Denmark · RECRUITING
• Local Institution - 6111, Lyon, Rhone, France · NOT_YET_RECRUITING
• Centre Hospitalier Universitaire D'Angers, Angers, France · RECRUITING
• Centre Hospitalier Universitaire de Bordeaux - Groupe Hospitalier Pellegrin, Bordeaux, France · RECRUITING
• Institut d Hematologie et d Oncologie Pediatriques, Lyon, France · RECRUITING
• Hôpitaux Universitaires de Marseille Timone, Marseille, France · RECRUITING
• Local Institution - 6110, Marseille, France · NOT_YET_RECRUITING
• Local Institution - 6112, Nantes, France · NOT_YET_RECRUITING
• Local Institution - 6109, Paris, France · NOT_YET_RECRUITING
• Institut Gustave-Roussy, Villejuif, France · RECRUITING
• Local Institution - 6108, Villejuif, France · NOT_YET_RECRUITING
• Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy · RECRUITING
• Local Institution - 6113, Padova, Italy · WITHDRAWN
• Local Institution - 4302, Rome, Italy · NOT_YET_RECRUITING
• Local Institution - 6114, Torino, Italy · WITHDRAWN
• National University Hospital, Singapore, Singapore · RECRUITING
• KK Women's and Children's Hospital, Singapore, Singapore · RECRUITING
• Local Institution - 6303, Seoul, Seodaemun-gu, South Korea · COMPLETED
• Seoul National University Hospital, Seoul, South Korea · RECRUITING
• Asan Medical Center, Seoul, South Korea · RECRUITING
• Local Institution - 6304, Seoul, South Korea · COMPLETED
• Hospital Sant Joan De Deu, Esplugues de Llobregat, Barcelona, Spain · RECRUITING
• Clínica Universidad de navarra, Pamplona, Navarre, Spain · RECRUITING
• Local Institution - 6105, Barcelona, Spain · NOT_YET_RECRUITING
• Hospital Universitari Vall d'Hebron, Barcelona, Spain · RECRUITING
• Hospital Infantil Universitario Nino Jesus, Madrid, Spain · RECRUITING
• Local Institution - 6106, Madrid, Spain · NOT_YET_RECRUITING
• Clinica Universidad de Navarra, Madrid, Spain · RECRUITING
• HM Sanchinarro University Hospital, Madrid, Spain · RECRUITING
• Hospital Universitario Virgen del Rocio, Seville, Spain · RECRUITING
• Hospital Universitario Y Politecnico La Fe, Valencia, Spain · RECRUITING
• Local Institution - 6107, Valencia, Spain · NOT_YET_RECRUITING
• National Taiwan University Hospital, Taipei, Taiwan · RECRUITING
• Taipei Medical University Hospital, Taipei, Taiwan · RECRUITING
• Alder Hey Children's NHS Foundation Trust, Liverpool, England, United Kingdom · RECRUITING
• Local Institution - 4403, Birmingham, United Kingdom · COMPLETED
• University Hospital of Wales, Cardiff, United Kingdom · RECRUITING
• Royal Hosp. for Children, Glasgow, United Kingdom · RECRUITING
• The Royal Marsden NHS Foundation Trust, London, United Kingdom · RECRUITING
• Great Ormond Street Hospital For Children NHS Foundation Trust, London, United Kingdom · RECRUITING