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

NCT04094610

Description:

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).

Related Conditions:
  • Anaplastic Large Cell Lymphoma
  • Malignant Central Nervous System Neoplasm
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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

Clinical Trial IDs

  • ORG STUDY ID: TPX-0005-07
  • NCT ID: NCT04094610

Conditions

  • Locally Advanced Solid Tumors
  • Metastatic Solid Tumors
  • Lymphoma
  • Primary CNS Tumors

Interventions

DrugSynonymsArms
Oral repotrectinib (TPX-0005)Oral repotrectinib (TPX-0005) capsules, repotrectinibRepotrectinib (TPX-0005)

Purpose

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).

Detailed Description

      Enrollment of subjects into Phase 1 will proceed concurrently by age as follows:

      • Subjects 4 to <12 years old will initially be enrolled in the Phase 1 part to determine the
      pediatric RP2D for this age group.

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Repotrectinib (TPX-0005)ExperimentalPhase 1 Oral repotrectinib (TPX-0005): Safety and tolerability at different dose levels
  • Oral repotrectinib (TPX-0005)

Eligibility Criteria

        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 4 to <12 years.

          3. Capability to swallow capsules intact (without chewing, crushing, or opening).

          4. Prior cytotoxic chemotherapy is allowed.

          5. Prior immunotherapy is allowed.

          6. 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.

          7. All subjects must have measurable disease by RECIST v1.1 or Response Assessment in
             Neuro-Oncology Criteria (RANO) criteria at time of enrollment.

          8. 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.

          9. Subjects must have a Lansky (< 16 years) score of at least 50.

         10. Life expectancy greater than or equal to 12 weeks.

         11. Adequate hematologic, renal and hepatic function.

        Key Exclusion Criteria:

          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.
      
Maximum Eligible Age:12 Years
Minimum Eligible Age:4 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose limiting toxicities (DLTs) (Phase 1)
Time Frame:Within 28 days of the first repotrectinib dose
Safety Issue:
Description:Define the dose limiting toxicities (DLTs) (Phase 1)

Secondary Outcome Measures

Measure:Overall Response Rate (ORR) (Phase 1)
Time Frame:Approximately three years
Safety Issue:
Description:To determine the overall response rate (ORR) by Blinded Independent Central Review (BICR) (Phase 1)
Measure:Clinical Benefit Rate (CBR) (Phase 1)
Time Frame:Approximately three years
Safety Issue:
Description:To determine the CBR of repotrectinib (TPX-0005) (Phase 1)
Measure:Time to response (TTR) (Phase 1)
Time Frame:Approximately three years
Safety Issue:
Description:To determine the TTR of reprotrectinib (TPX-005) (Phase 1)
Measure:Duration of response (DOR) (Phase 1)
Time Frame:Approximately three years
Safety Issue:
Description:To determine the DOR of repotrectinib (TPX-0005) (Phase 1)
Measure:Intracranial objective response rate (IC-ORR) (Phase 1)
Time Frame:Approximately three years
Safety Issue:
Description:To determine the IC-ORR of repotrectinib (TPX-005) (Phase 1)
Measure: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)
Safety Issue:
Description:To determine the Cmax
Measure: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)
Safety Issue:
Description:To determine the AUC

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Turning Point Therapeutics, Inc.

Trial 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

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