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

Lymphoma Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04094610
• Other study ID #: CA127-1029
• Secondary ID: CA127-1029TPX-00
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: March 12, 2020
• Est. completion date: September 30, 2027

Study information

• Verified date: April 2024
• Source: Turning Point Therapeutics, Inc.
• Contact: BMS Study Connect Contact Center www.BMSStudyConnect.com
• Phone: 855-907-3286
• Email: Clinical.Trials[@]bms.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 75
• Est. completion date: September 30, 2027
• Est. primary completion date: September 30, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 25 Years

Eligibility

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.

Related Conditions & MeSH terms

• Central Nervous System Neoplasms
• Locally Advanced Solid Tumors
• Lymphoma
• Metastatic Solid Tumors
• Neoplasms
• Primary CNS Tumors

Intervention

Drug:
• Oral repotrectinib (TPX-0005)
Oral repotrectinib (TPX-0005)

Locations

Country	Name	City	State
Australia	Perth Childrens Hospital	Perth	Western Australia
Australia	Local Institution - 6104	Randwick	New South Wales
Australia	Children's Health Queensland Hospital and Health Service	South Brisbane	Queensland
Australia	Local Institution - 6103	Westmead	New South Wales
Canada	Local Institution - 2202	Calgary	Alberta
Canada	Local Institution - 2201	Edmonton	Alberta
Denmark	Rigshospitalet - Glostrup	Copenhagen
France	Local Institution - 4203	Angers Cedex 1
France	Local Institution - 4201	Bordeaux
France	Local Institution - 6111	Lyon	Rhone
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
Italy	Fondazione IRCCS - Istituto Nazionale dei Tumori	Milano
Italy	Local Institution - 6113	Padova
Italy	Local Institution - 4302	Rome
Italy	Local Institution - 6114	Torino
Korea, Republic of	Local Institution - 6302	Seoul
Korea, Republic of	Local Institution - 6304	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Yonsei Universtidy Health System	Seoul	Seodaemun-gu
Singapore	KK Women's and Children's Hospital	Singapore
Singapore	National University Hospital	Singapore
Spain	Local Institution - 4103	Barcelona
Spain	Local Institution - 6105	Barcelona
Spain	Hospital Infantil Universitario Nino Jesus	Madrid
Spain	Local Institution - 4101	Madrid
Spain	Local Institution - 4104	Madrid	Boadilla Del Monte
Spain	Local Institution - 6106	Madrid
Spain	Local Institution - 4102	Pamplona
Spain	Local Institution - 6107	Valencia
Taiwan	National Taiwan University Hospital	Taipei
Taiwan	Taipei Medical University Hospital	Taipei
United Kingdom	Local Institution - 4403	Birmingham
United Kingdom	Local Institution - 4401	Cardiff
United Kingdom	Local Institution - 4406	Glasgow
United Kingdom	Local Institution - 4404	Liverpool	England
United Kingdom	Local Institution - 4402	London
United Kingdom	Local Institution - 4405	London
United States	Children's Hospital Colorado - Anschutz Medical Campus	Aurora	Colorado
United States	Dana Farber Cancer Institute.	Boston	Massachusetts
United States	Local Institution - 2112	Cleveland	Ohio
United States	The University of Texas Southwestern Medical Center - Harold C Simmons Comprehensive Cancer Center	Dallas	Texas
United States	Penn State Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	The University of Texas MD Anderson Cancer Center.	Houston	Texas
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	University of California at Los Angeles	Los Angeles	California
United States	St. Jude Children's Research Hospital	Memphis	Tennessee
United States	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey
United States	Memorial Sloan-Kettering Cancer Center.	New York	New York
United States	Arnold Palmer Hospital For Children	Orlando	Florida
United States	Children'S Hospital Of Philadelphia	Philadelphia	Pennsylvania
United States	Children's Hospital of Richmond at VCU	Richmond	Virginia
United States	Washington University School of Medicine in St. Louis	Saint Louis	Missouri
United States	Maine Medical Center	Scarborough	Maine

Sponsors (1)

Lead Sponsor	Collaborator
Turning Point Therapeutics, Inc.

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Denmark,  France,  Italy,  Korea, Republic of,  Singapore,  Spain,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Dose limiting toxicities (DLTs) (Phase 1)	Define the dose limiting toxicities (DLTs) (Phase 1)	Within 28 days of the first repotrectinib dose
Primary	Pediatric Recommended Phase 2 Dose (RP2D) (Phase 1)	To determine the pediatric RP2D (Phase 1)	Within 28 days of the last patient dosed in escalation
Primary	Overall Response Rate (ORR) (Phase 2)	To determine the confirmed ORR of repotrectinib (TPX-0005) as assessed by Blinded Independent Central Review (Phase 2)	Two to three years after first dose of repotrectinib
Secondary	Overall Response Rate (ORR) (Phase 1)	To determine the overall response rate (ORR) by Blinded Independent Central Review (BICR) (Phase 1)	Approximately three years
Secondary	Clinical Benefit Rate (CBR) (Phase 1 and Phase 2)	To determine the CBR of repotrectinib (TPX-0005) (Phase 1 and Phase 2)	Approximately three years
Secondary	Time to response (TTR) (Phase 1 and Phase 2)	To determine the TTR of reprotrectinib (TPX-005) (Phase 1 and Phase 2)	Approximately three years
Secondary	Duration of response (DOR) (Phase 1 and Phase 2)	To determine the DOR of repotrectinib (TPX-0005) (Phase 1 and Phase 2)	Approximately three years
Secondary	Intracranial objective response rate (IC-ORR) (Phase 1 and Phase 2)	To determine the IC-ORR of repotrectinib (TPX-005) (Phase 1 and Phase 2)	Approximately three years
Secondary	Central Nervous System Progression-Free Survival (CNS-PFS) (Phase 2)	CNS-PFS in subjects with measurable brain metastases (Phase 2)	Approximately three years
Secondary	Progression-free survival (PFS) (Phase 2)	To determine the PFS (Phase 2)	Approximately three years
Secondary	Overall survival (OS) (Phase 2)	To determine the OS (Phase 2)	Approximately three years
Secondary	Maximum concentration of repotrectinib in plasma (Cmax)	To determine the Cmax	Pre-dose and up to 24 hours post-dose on Day 1 and Day 15 in Cycle 1 (each cycle is 28 days)
Secondary	Area under the concentration versus time curve of repotrectinib in plasma (AUC)	To determine the AUC	Pre-dose and up to 24 hours post-dose on Day 1 and Day 15 in Cycle 1 (each cycle is 28 days)

External Links

•   BMS Clinical Trial Information
•   BMS Clinical Trial Patient Recruiting