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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04094610
Recruitment Status : Recruiting
First Posted : September 19, 2019
Last Update Posted : December 14, 2020
Sponsor:
Information provided by (Responsible Party):
Turning Point Therapeutics, Inc.

Tracking Information
First Submitted Date  ICMJE September 12, 2019
First Posted Date  ICMJE September 19, 2019
Last Update Posted Date December 14, 2020
Actual Study Start Date  ICMJE March 20, 2020
Estimated Primary Completion Date December 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 29, 2020)
  • Dose limiting toxicities (DLTs) (Phase 1) [ Time Frame: Within 28 days of the first repotrectinib dose ]
    Define the dose limiting toxicities (DLTs) (Phase 1)
  • Pediatric Recommended Phase 2 Dose (RP2D) (Phase 1) [ Time Frame: Within 28 days of the last patient dosed in escalation ]
    To determine the pediatric RP2D (Phase 1)
  • Overall Response Rate (ORR) (Phase 2) [ Time Frame: 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)
Original Primary Outcome Measures  ICMJE
 (submitted: September 17, 2019)
  • Dose limiting toxicities (DLTs) (Phase 1) [ Time Frame: Within 28 days of the first repotrectinib dose ]
    Define the dose limiting toxicities (DLTs) (Phase 1)
  • Pediatric Recommended Phase 2 Dose (RP2D) (Phase 1) [ Time Frame: Within 28 days of the last patient dosed in escalation ]
    To determine the pediatric RP2D (Phase 1)
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 29, 2020)
  • Overall Response Rate (ORR) (Phase 1) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: Approximately three years ]
    CNS-PFS in subjects with measurable brain metastases (Phase 2)
  • Progression-free survival (PFS) (Phase 2) [ Time Frame: Approximately three years ]
    To determine the PFS (Phase 2)
  • Overall survival (OS) (Phase 2) [ Time Frame: Approximately three years ]
    To determine the OS (Phase 2)
  • Maximum concentration of repotrectinib in plasma (Cmax) [ Time Frame: 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) [ Time Frame: 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
Original Secondary Outcome Measures  ICMJE
 (submitted: September 17, 2019)
  • Overall Response Rate (ORR) (Phase 1) [ Time Frame: Approximately three years ]
    To determine the overall response rate (ORR) by Blinded Independent Central Review (BICR) (Phase 1)
  • Clinical Benefit Rate (CBR) (Phase 1) [ Time Frame: Approximately three years ]
    To determine the CBR of repotrectinib (TPX-0005) (Phase 1)
  • Time to response (TTR) (Phase 1) [ Time Frame: Approximately three years ]
    To determine the TTR of reprotrectinib (TPX-005) (Phase 1)
  • Duration of response (DOR) (Phase 1) [ Time Frame: Approximately three years ]
    To determine the DOR of repotrectinib (TPX-0005) (Phase 1)
  • Intracranial objective response rate (IC-ORR) (Phase 1) [ Time Frame: Approximately three years ]
    To determine the IC-ORR of repotrectinib (TPX-005) (Phase 1)
  • Maximum concentration of repotrectinib in plasma (Cmax) [ Time Frame: 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) [ Time Frame: 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
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of Repotrectinib in Pediatric and Young Adult Subjects Harboring ALK, ROS1, OR NTRK1-3 Alterations
Official Title  ICMJE 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
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.

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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Locally Advanced Solid Tumors
  • Metastatic Solid Tumors
  • Lymphoma
  • Primary CNS Tumors
Intervention  ICMJE Drug: Oral repotrectinib (TPX-0005)
Oral repotrectinib (TPX-0005)
Other Names:
  • Oral repotrectinib (TPX-0005) capsules
  • Oral repotrectinib (TPX-0005) oral suspension
  • repotrectinib
Study Arms  ICMJE 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

Intervention: Drug: Oral repotrectinib (TPX-0005)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 29, 2020)
75
Original Estimated Enrollment  ICMJE
 (submitted: September 17, 2019)
12
Estimated Study Completion Date  ICMJE December 2023
Estimated Primary Completion Date December 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Key Inclusion Criteria:

  1. 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.
  2. Age <12 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 Criteria (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 14 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.
  10. Adequate hematologic, renal and hepatic function.

Phase 2 Inclusion Criteria:

  1. Age 12 to <25 years
  2. 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.
  3. 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 (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) > 470 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 25 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Zachary Zimmerman, M.D. (858) 276-0005 clinical@tptherapeutics.com
Listed Location Countries  ICMJE Australia,   Korea, Republic of,   Singapore,   Taiwan,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04094610
Other Study ID Numbers  ICMJE TPX-0005-07
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: There are no plans to share individual participant data with other researchers.
Responsible Party Turning Point Therapeutics, Inc.
Study Sponsor  ICMJE Turning Point Therapeutics, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Zachary Zimmerman, M.D. Turning Point Therapeutics
PRS Account Turning Point Therapeutics, Inc.
Verification Date December 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP