Clinical trial NCT04094610: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Locally Advanced Solid Tumors
Metastatic Solid Tumors
Lymphoma
Primary CNS Tumors
Keywords: ALK
ROS1
NTRK1-3
Primary CNS tumor
anaplastic large cell lymphoma
metastatic solid tumor
advanced solid tumor
sarcoma
infantile fibrosarcoma
glioblastoma
soft tissue schwannoma
solitary fibrous tumor
glioma
inflammatory myofibroblastic tumor
pediatric
Lead sponsor: Turning Point Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2019-09-19
Enrollment: 75
Sex: ALL
Maximum age (years): 25
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Dose limiting toxicities (DLTs) (Phase 1)
timeFrame: Within 28 days of the first repotrectinib dose
measure: Pediatric Recommended Phase 2 Dose (RP2D) (Phase 1)
timeFrame: Within 28 days of the last patient dosed in escalation
measure: Overall Response Rate (ORR) (Phase 2)
timeFrame: Two to three years after first dose of repotrectinib
Secondary outcomes:
measure: Overall Response Rate (ORR) (Phase 1)
timeFrame: Approximately three years
measure: Clinical Benefit Rate (CBR) (Phase 1 and Phase 2)
timeFrame: Approximately three years
measure: Time to response (TTR) (Phase 1 and Phase 2)
timeFrame: Approximately three years
measure: Duration of response (DOR) (Phase 1 and Phase 2)
timeFrame: Approximately three years
measure: Intracranial objective response rate (IC-ORR) (Phase 1 and Phase 2)
timeFrame: Approximately three years
measure: Central Nervous System Progression-Free Survival (CNS-PFS) (Phase 2)
timeFrame: Approximately three years
measure: Progression-free survival (PFS) (Phase 2)
timeFrame: Approximately three years
measure: Overall survival (OS) (Phase 2)
timeFrame: Approximately three years
measure: Maximum concentration of repotrectinib in plasma (Cmax)
timeFrame: Pre-dose and up to 24 hours post-dose on Day 1 and Day 15 in Cycle 1 (each cycle is 28 days)
measure: Area under the concentration versus time curve of repotrectinib in plasma (AUC)
timeFrame: Pre-dose and up to 24 hours post-dose on Day 1 and Day 15 in Cycle 1 (each cycle is 28 days)
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Los Angeles
country: United States
facility: University of California at Los Angeles
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado - Anschutz Medical Campus
state: Colorado
city: Orlando
country: United States
facility: Arnold Palmer Hospital For Children
state: Florida
city: Orlando
country: United States
facility: Local Institution - 2120
state: Florida
city: Atlanta
country: United States
facility: Local Institution - 2119
state: Georgia
city: Scarborough
country: United States
facility: Maine Medical Center
state: Maine
city: Boston
country: United States
facility: Dana Farber Cancer Institute.
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University School of Medicine in St. Louis
state: Missouri
city: New Brunswick
country: United States
facility: Local Institution - 2110
state: New Jersey
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center.
state: New York
city: Charlotte
country: United States
facility: Local Institution - 2121
state: North Carolina
city: Cleveland
country: United States
facility: Local Institution - 2112
state: Ohio
city: Hershey
country: United States
facility: Penn State Milton S. Hershey Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Children'S Hospital Of Philadelphia
state: Pennsylvania
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
city: Dallas
country: United States
facility: The University of Texas Southwestern Medical Center - Harold C Simmons Comprehensive Cancer Center
state: Texas
city: Houston
country: United States
facility: Local Institution - 2118
state: Texas
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center.
state: Texas
city: Richmond
country: United States
facility: Children's Hospital of Richmond at VCU
state: Virginia
city: Randwick
country: Australia
facility: Local Institution - 6104
state: New South Wales
city: Westmead
country: Australia
facility: Local Institution - 6103
state: New South Wales
city: South Brisbane
country: Australia
facility: Children's Health Queensland Hospital and Health Service
state: Queensland
city: Nedlands
country: Australia
facility: Perth Childrens Hospital
state: Western Australia
city: Calgary
country: Canada
facility: University Of Calgary
state: Alberta
city: Edmonton
country: Canada
facility: Stollery Children'S Hospital
state: Alberta
city: Ottawa
country: Canada
facility: Local Institution - 2203
state: Ontario
city: Montreal
country: Canada
facility: Local Institution - 2205
state: Quebec
city: Copenhagen
country: Denmark
facility: Rigshospitalet - Glostrup
city: Lyon
country: France
facility: Local Institution - 6111
state: Rhone
city: Angers
country: France
facility: Centre Hospitalier Universitaire D'Angers
city: Bordeaux
country: France
facility: Centre Hospitalier Universitaire de Bordeaux - Groupe Hospitalier Pellegrin
city: Lyon Cedex 08
country: France
facility: Institut d Hematologie et d Oncologie Pediatriques
city: Marseille Cedex 5
country: France
facility: Hôpitaux Universitaires de Marseille Timone
city: Marseille Cedex 5
country: France
facility: Local Institution - 6110
city: Nantes
country: France
facility: Local Institution - 6112
city: Paris
country: France
facility: Local Institution - 6109
city: Villejuif
country: France
facility: Institut Gustave-Roussy
city: Villejuif
country: France
facility: Local Institution - 6108
city: Milano
country: Italy
facility: Fondazione IRCCS - Istituto Nazionale dei Tumori
city: Padova
country: Italy
facility: Local Institution - 6113
city: Rome
country: Italy
facility: Local Institution - 4302
city: Torino
country: Italy
facility: Local Institution - 6114
city: Seoul
country: Korea, Republic of
facility: Yonsei Universtidy Health System
state: Seodaemun-gu
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Singapore
country: Singapore
facility: National University Hospital
city: Singapore
country: Singapore
facility: KK Women's and Children's Hospital
city: Esplugues de Llobregat
country: Spain
facility: Hospital Sant Joan De Deu
state: Barcelona
city: Pamplona
country: Spain
facility: Clínica Universidad de navarra
state: Navarra
city: Barcelona
country: Spain
facility: Local Institution - 6105
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital Infantil Universitario Nino Jesus
city: Madrid
country: Spain
facility: Local Institution - 6106
city: Madrid
country: Spain
facility: Clinica Universidad de Navarra
city: Madrid
country: Spain
facility: HM Sanchinarro University Hospital
city: Sevilla
country: Spain
facility: Local Institution - 4108
city: Valencia
country: Spain
facility: Hospital Universitario Y Politecnico La Fe
city: Valencia
country: Spain
facility: Local Institution - 6107
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Taipei
country: Taiwan
facility: Taipei Medical University Hospital
city: Liverpool
country: United Kingdom
facility: Local Institution - 4404
state: England
city: Birmingham
country: United Kingdom
facility: Local Institution - 4403
city: Cardiff
country: United Kingdom
facility: Local Institution - 4401
city: Glasgow
country: United Kingdom
facility: Local Institution - 4406
city: London
country: United Kingdom
facility: Local Institution - 4405
city: London
country: United Kingdom
facility: Local Institution - 4402
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References:
citation: 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.