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

Официальное название

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

Обзор

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.

Подробное описание

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.

Вмешательства

• Препарат Oral repotrectinib (TPX-0005)
  Oral repotrectinib (TPX-0005)

Первичные конечные точки

• Dose limiting toxicities (DLTs) (Phase 1) [Срок оценки: Within 28 days of the first repotrectinib dose]
• Pediatric Recommended Phase 2 Dose (RP2D) (Phase 1) [Срок оценки: Within 28 days of the last patient dosed in escalation]
• Overall Response Rate (ORR) (Phase 2) [Срок оценки: Two to three years after first dose of repotrectinib]

Вторичные конечные точки (10)

• Overall Response Rate (ORR) (Phase 1) [Срок оценки: Approximately three years]
• Clinical Benefit Rate (CBR) (Phase 1 and Phase 2) [Срок оценки: Approximately three years]
• Time to response (TTR) (Phase 1 and Phase 2) [Срок оценки: Approximately three years]
• Duration of response (DOR) (Phase 1 and Phase 2) [Срок оценки: Approximately three years]
• Intracranial objective response rate (IC-ORR) (Phase 1 and Phase 2) [Срок оценки: Approximately three years]
• Central Nervous System Progression-Free Survival (CNS-PFS) (Phase 2) [Срок оценки: Approximately three years]
• Progression-free survival (PFS) (Phase 2) [Срок оценки: Approximately three years]
• Overall survival (OS) (Phase 2) [Срок оценки: Approximately three years]
• Maximum concentration of repotrectinib in plasma (Cmax) [Срок оценки: 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) [Срок оценки: Pre-dose and up to 24 hours post-dose on Day 1 and Day 15 in Cycle 1 (each cycle is 28 days)]

Критерии участия

Критерии включения

• 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.
• 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 (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 7 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, in the investigator's opinion.
• 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 advanced solid tumors with ROS1 gene fusions or other ROS1 aberrations (including amplifications and point mutations) with measurable disease.
• 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 requiring ongoing treatment (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.
• Any potential allergies to repotrectinib and/or its excipients.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 20 центров

• Children's Hospital Los Angeles — Los Angeles
• University of California at Los Angeles — Los Angeles
• Children's Hospital Colorado - Anschutz Medical Campus — Aurora
• Local Institution - 2105 — Orlando
• Local Institution - 2120 — Orlando
• Children's Healthcare of Atlanta - Egleston Hospital — Atlanta
• Maine Medical Center — Scarborough
• Dana Farber Cancer Institute. — Boston
• … и ещё 12 центров

Испания · 11 центров

• Hospital Sant Joan De Deu — Esplugues de Llobregat
• Clínica Universidad de navarra — Pamplona
• Local Institution - 6105 — Barcelona
• Hospital Universitari Vall d'Hebron — Barcelona
• Hospital Infantil Universitario Nino Jesus — Madrid
• Local Institution - 6106 — Madrid
• Clinica Universidad de Navarra — Madrid
• HM Sanchinarro University Hospital — Madrid
• … и ещё 3 центра

Франция · 10 центров

• Local Institution - 6111 — Lyon
• Centre Hospitalier Universitaire D'Angers — Angers
• Centre Hospitalier Universitaire de Bordeaux - Groupe Hospitalier Pellegrin — Bordeaux
• Institut d Hematologie et d Oncologie Pediatriques — Lyon
• Hôpitaux Universitaires de Marseille Timone — Marseille
• Local Institution - 6110 — Marseille
• Local Institution - 6112 — Nantes
• Local Institution - 6109 — Paris
• … и ещё 2 центра

Великобритания · 6 центров

• Alder Hey Children's NHS Foundation Trust — Liverpool
• Local Institution - 4403 — Birmingham
• University Hospital of Wales — Cardiff
• Royal Hosp. for Children — Glasgow
• The Royal Marsden NHS Foundation Trust — London
• Great Ormond Street Hospital For Children NHS Foundation Trust — London

Австралия · 4 центра

• Local Institution - 6104 — Randwick
• Local Institution - 6103 — Westmead
• Children's Health Queensland Hospital and Health Service — South Brisbane
• Perth Childrens Hospital — Nedlands

Канада · 4 центра

• University Of Calgary — Calgary
• Stollery Children'S Hospital — Edmonton
• Children'S Hospital Of Eastern Ontario — Ottawa
• St Justine Hospital — Montreal

Италия · 4 центра

• Fondazione IRCCS - Istituto Nazionale dei Tumori — Milan
• Local Institution - 6113 — Padova
• Local Institution - 4302 — Rome
• Local Institution - 6114 — Torino

South Korea · 4 центра

• Local Institution - 6303 — Seoul
• Seoul National University Hospital — Seoul
• Asan Medical Center — Seoul
• Local Institution - 6304 — Seoul

Сингапур · 2 центра

• National University Hospital — Singapore
• KK Women's and Children's Hospital — Singapore

Тайвань · 2 центра

• National Taiwan University Hospital — Taipei
• Taipei Medical University Hospital — Taipei

Дания · 1 центр

• Rigshospitalet - Glostrup — Copenhagen

Публикации

• 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. PMID 34814185

Идентификаторы

NCT: NCT04094610 · CA127-1029 · CA127-1029 · TPX-0005-07

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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