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

Sponsor

Turning Point Therapeutics, Inc. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04094610

Collaborator

(none)

Enrollment

Locations

Arm

44.4

Anticipated Duration (Months)

2.7

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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 subjects with advanced or metastatic malignancies harboring ALK, ROS1, or NTRK1-3 alterations.

Condition or Disease	Intervention/Treatment	Phase
Locally Advanced Solid Tumors Metastatic Solid Tumors Lymphoma Primary CNS Tumors	Drug: Oral repotrectinib (TPX-0005)	Phase 1/Phase 2

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

75 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Mar 20, 2020

Anticipated Primary Completion Date :

Dec 1, 2022

Anticipated Study Completion Date :

Dec 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Repotrectinib (TPX-0005) Phase 1 Oral repotrectinib (TPX-0005): Safety and tolerability at different dose levels Phase 2 Oral repotrectinib (TPX-0005): 3 cohorts Cohort 1: TKI-naive NTRK fusion Cohort 2: Prior TKI NTRK fusion Cohort 3: ALK/ROS1/NTRK alterations or fusions in tumors and ALCL	Drug: Oral repotrectinib (TPX-0005) Oral repotrectinib (TPX-0005) Other Names: Oral repotrectinib (TPX-0005) capsules Oral repotrectinib (TPX-0005) oral suspension repotrectinib

Arm

Intervention/Treatment

Experimental: Repotrectinib (TPX-0005)

Phase 1 Oral repotrectinib (TPX-0005): Safety and tolerability at different dose levels Phase 2 Oral repotrectinib (TPX-0005): 3 cohorts Cohort 1: TKI-naive NTRK fusion Cohort 2: Prior TKI NTRK fusion Cohort 3: ALK/ROS1/NTRK alterations or fusions in tumors and ALCL

Drug: Oral repotrectinib (TPX-0005)

Oral repotrectinib (TPX-0005)

Other Names:

Oral repotrectinib (TPX-0005) capsules

Oral repotrectinib (TPX-0005) oral suspension

repotrectinib

Outcome Measures

Primary Outcome Measures

Dose limiting toxicities (DLTs) (Phase 1) [Within 28 days of the first repotrectinib dose]
Define the dose limiting toxicities (DLTs) (Phase 1)
Pediatric Recommended Phase 2 Dose (RP2D) (Phase 1) [Within 28 days of the last patient dosed in escalation]
To determine the pediatric RP2D (Phase 1)
Overall Response Rate (ORR) (Phase 2) [Two to three years after first dose of repotrectinib]
To determine the confirmed ORR of repotrectinib (TPX-0005) as assessed by Blinded Independent Central Review (Phase 2)

Secondary Outcome Measures

Overall Response Rate (ORR) (Phase 1) [Approximately three years]
To determine the overall response rate (ORR) by Blinded Independent Central Review (BICR) (Phase 1)
Clinical Benefit Rate (CBR) (Phase 1 and Phase 2) [Approximately three years]
To determine the CBR of repotrectinib (TPX-0005) (Phase 1 and Phase 2)
Time to response (TTR) (Phase 1 and Phase 2) [Approximately three years]
To determine the TTR of reprotrectinib (TPX-005) (Phase 1 and Phase 2)
Duration of response (DOR) (Phase 1 and Phase 2) [Approximately three years]
To determine the DOR of repotrectinib (TPX-0005) (Phase 1 and Phase 2)
Intracranial objective response rate (IC-ORR) (Phase 1 and Phase 2) [Approximately three years]
To determine the IC-ORR of repotrectinib (TPX-005) (Phase 1 and Phase 2)
Central Nervous System Progression-Free Survival (CNS-PFS) (Phase 2) [Approximately three years]
CNS-PFS in subjects with measurable brain metastases (Phase 2)
Progression-free survival (PFS) (Phase 2) [Approximately three years]
To determine the PFS (Phase 2)
Overall survival (OS) (Phase 2) [Approximately three years]
To determine the OS (Phase 2)
Maximum concentration of repotrectinib in plasma (Cmax) [Pre-dose and up to 24 hours post-dose on Day 1 and Day 15 in Cycle 1 (each cycle is 28 days)]
To determine the Cmax
Area under the concentration versus time curve of repotrectinib in plasma (AUC) [Pre-dose and up to 24 hours post-dose on Day 1 and Day 15 in Cycle 1 (each cycle is 28 days)]
To determine the AUC

Eligibility Criteria

Criteria

Ages Eligible for Study:

0 Years to 25 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Key Inclusion Criteria:

Documented genetic ALK, ROS1, or NTRK1-3 alteration (point mutation, fusion, amplification) 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 Criteria (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 14 days prior to enrollment.
Subjects must have a Lansky (< 16 years) or Karnofsky (≥ 16 years) score of at least
Life expectancy greater than or equal to 12 weeks.
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 tumors or ALCL characterized by other ALK/ROS1/NTRK alterations or NTRK fusions without centrally confirmed measurable disease or not otherwise eligible for Cohort 1 or 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):

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 (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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital Los Angeles	Los Angeles	California	United States	90027
2	University of California, Los Angeles	Los Angeles	California	United States	90095
3	Children's Hospital Colorado	Aurora	Colorado	United States	80045
4	Arnold Palmer Hospital for Children	Orlando	Florida	United States	32806
5	Maine Children's Cancer Program	Scarborough	Maine	United States	04074
6	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
7	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
8	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey	United States	08901
9	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
10	Cleveland Clinic	Cleveland	Ohio	United States	44195
11	Penn State Children's Hospital at Penn State Health Milton S. Hershey Medical Center	Hershey	Pennsylvania	United States	17033
12	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
13	St. Jude Children's Research Hospital	Memphis	Tennessee	United States	38105
14	The University of Texas Southwestern Medical Center, Children's Medical Center of Dallas	Dallas	Texas	United States	75235
15	MD Anderson Cancer Center	Houston	Texas	United States	77030
16	Sydney Children's Hospital	Sydney	New South Wales	Australia	2031
17	The Children's Hospital at Westmead	Westmead	New South Wales	Australia	2145
18	Queensland Children's Hospital	South Brisbane	Queensland	Australia	4101
19	Perth Children's Hospital	Nedlands	Western Australia	Australia	6009
20	Stollery Children's Hospital	Edmonton	Alberta	Canada	T6G 2B7
21	Seoul National University Hospital	Seoul		Korea, Republic of	03080
22	Yonsei University Health System, Severance Hospital	Seoul		Korea, Republic of	03722
23	Asan Medical Center	Seoul		Korea, Republic of	05505
24	Samsung Medical Center	Seoul		Korea, Republic of	06351
25	National University Hospital	Singapore		Singapore	119074
26	KK Women's and Children's Hospital	Singapore		Singapore	229899
27	National Taiwan University Hospital	Taipei City		Taiwan	100225
28	Taipei Medical University Hospital	Taipei		Taiwan	11031