Clinical Trials /

A Study of Repotrectinib (TPX-0005) in Patients With Advanced Solid Tumors Harboring ALK, ROS1, or NTRK1-3 Rearrangements

NCT03093116

Description:

Phase 1 dose escalation will determine the first cycle dose-limiting toxicities (DLTs), the maximum tolerated dose (MTD), the biologically effective dose and recommended Phase 2 dose (RP2D) of repotrectinib given to adult subjects with advanced solid malignancies harboring an ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement. Phase 2 will determine the confirmed Overall response Rate (ORR) as assessed by Blinded Independent Central Review (BICR) of repotrectinib in each subject population expansion cohort of advanced solid tumors that harbor an ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement. The secondary objective will include the duration of response (DOR), time to response (TTR), progression-free survival (PFS) overall survival (OS) and clinical benefit rate (CBR) of repotrectinib in each expansion cohort of advanced solid tumors that harbor an ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement.

Related Conditions:
  • Malignant Solid Tumor
  • Non-Hodgkin Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study of Repotrectinib (TPX-0005) in Patients With Advanced Solid Tumors Harboring ALK, ROS1, or NTRK1-3 Rearrangements
  • Official Title: A Phase 1/2, Open-Label, Multi-Center, First-in-Human Study of the Safety, Tolerability, Pharmacokinetics, and Anti-Tumor Activity of TPX-0005 in Patients With Advanced Solid Tumors Harboring ALK, ROS1, or NTRK1-3 Rearrangements (TRIDENT-1)

Clinical Trial IDs

  • ORG STUDY ID: TPX-0005-01
  • NCT ID: NCT03093116

Conditions

  • Locally Advanced Solid Tumors
  • Metastatic Solid Tumors

Interventions

DrugSynonymsArms
Oral repotrectinib (TPX-0005)repotrectinibPhase1 repotrectinib (TPX-0005)

Purpose

Phase 1 dose escalation will determine the first cycle dose-limiting toxicities (DLTs), the maximum tolerated dose (MTD), the biologically effective dose and recommended Phase 2 dose (RP2D) of repotrectinib given to adult subjects with advanced solid malignancies harboring an ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement. Phase 2 will determine the confirmed Overall response Rate (ORR) as assessed by Blinded Independent Central Review (BICR) of repotrectinib in each subject population expansion cohort of advanced solid tumors that harbor an ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement. The secondary objective will include the duration of response (DOR), time to response (TTR), progression-free survival (PFS) overall survival (OS) and clinical benefit rate (CBR) of repotrectinib in each expansion cohort of advanced solid tumors that harbor an ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement.

Detailed Description

      In Phase 2, study subjects will be enrolled into 6 distinct expansion (EXP) cohorts:

        -  EXP-1: ROS1+ NSCLC. No prior ROS1TKI allowed. Any prior lines of chemotherapy or
           immunotherapy are allowed.

        -  EXP-2: ROS1+ NSCLC. Disease progression on one prior ROS1 TKI only. Any prior lines of
           chemotherapy or immunotherapy are allowed.

        -  EXP-3: ROS1+ NSCLC. Disease progression on two prior ROS1 TKIs only. Any prior lines of
           chemotherapy or immunotherapy allowed.

        -  EXP-4: ROS1+ or ALK+ non-NSCLC advanced solid tumors. No prior ROS1 or ALK TKIs allowed.
           Any prior lines of chemotherapy or immunotherapy allowed.

      NTRK Advanced Solid Tumors:

        -  EXP-5: NTRK+ advanced solid tumors. No prior TRK TKI is allowed.

        -  EXP-6: NTRK+ advanced solid tumors. No more than 2 prior TRK TKIs are allowed. Prior
           lines of chemotherapy or immunotherapy allowed.
    

Trial Arms

NameTypeDescriptionInterventions
Phase1 repotrectinib (TPX-0005)ExperimentalPhase 1 Oral repotrectinib (TPX-0005): Phase 1a dose escalation, Phase 1b food-effect sub-study, and Phase 1c dose escalation with food Phase 2 Oral repotrectinib (TPX-0005): EXP-1 Cohort : ROS1+ NSCLC. No prior ROS1TKI allowed. Any prior lines of chemotherapy or immunotherapy are allowed. EXP-2 Cohort: ROS1+ NSCLC. Disease progression on one prior ROS1 TKI only. Any prior lines of chemotherapy or immunotherapy are allowed. EXP-3 Cohort: ROS1+ NSCLC. Disease progression on two prior ROS1 TKIs only. Any prior lines of chemotherapy or immunotherapy allowed. EXP-4 Cohort: ROS1+ or ALK+ non-NSCLC advanced solid tumors. No prior ROS1 or ALK TKIs allowed. Any prior lines of chemotherapy or immunotherapy allowed. EXP-5 Cohort: NTRK+ advanced solid tumors. No prior TRK TKI is allowed. EXP-6 Cohort: NTRK+ advanced solid tumors. No more than 2 prior TRK TKIs are allowed. Prior lines of chemotherapy or immunotherapy allowed.
  • Oral repotrectinib (TPX-0005)

Eligibility Criteria

        Key Inclusion Criteria:

          1. Histologically or cytologically confirmed diagnosis of locally advanced, or metastatic
             solid tumor (including primary CNS tumors) (Stage IV, American Joint Committee on
             Cancer v.7) that harbors an ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement by
             protocol specified tests.

          2. ECOG PS 0-1.

          3. Age ≥18 (or age ≥ 20 of age as required by local regulation). In Phase 2, Age ≥12 is
             allowed.

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

          5. At least 1 measurable target lesion according to RECIST version 1.1. CNS-only
             measurable disease as defined by RECIST version 1.1 is allowed.

          6. Prior cytotoxic chemotherapy is allowed.

          7. Prior immunotherapy is allowed.

          8. 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.

          9. Patients with asymptomatic CNS metastases (treated or untreated) and/or asymptomatic
             leptomeningeal carcinomatosis are eligible to enroll if they satisfy the protocol
             specified criteria.

         10. Life expectancy ≥ 3 months.

        Key Exclusion Criteria:

          1. Concurrent participation in another therapeutic clinical trial.

          2. Symptomatic brain metastases or leptomeningeal involvement.

          3. History of previous cancer, except for squamous cell or basal-cell carcinoma of the
             skin, or any in situ carcinoma that has been completely resected, requiring therapy
             within the previous 2 years.

          4. Major surgery within 4 weeks of start of treatment

          5. Clinically significant cardiovascular disease (either active or within 6 months prior
             to enrollment): myocardial infarction, unstable angina, coronary/peripheral artery
             bypass graft, symptomatic congestive heart failure (New York Heart Association
             Classification Class ≥ II), cerebrovascular accident or transient ischemic attack,
             symptomatic bradycardia, requirement for anti-arrhythmic medication. Ongoing cardiac
             dysrhythmias of NCI CTCAE grade ≥2

          6. 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 (QTcF) > 470 msec obtained
                  from 3 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, hypokalemia, congenital long QT syndrome, family
                  history of long QT syndrome, or any concomitant medication known to prolong the
                  QT interval.

          7. Known active infections (bacterial, fungal, viral including HIV positivity).

          8. Gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gut
             syndrome) or other malabsorption syndromes that would impact drug absorption.

          9. Peripheral neuropathy of CTCAE ≥grade 2.

         10. History of extensive, disseminated, bilateral, or presence of CTCAE grade 3 or 4
             interstitial fibrosis or interstitial lung disease including a history of pneumonitis,
             hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease,
             obliterative bronchiolitis, and pulmonary fibrosis. Subjects with history of prior
             radiation pneumonitis are not excluded.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Define the Maximum Tolerated Dose (MTD)
Time Frame:Within 28 days of the first repotrectinib (TPX-0005) dose for each patient.
Safety Issue:
Description:To determine the MTD (Phase 1)

Secondary Outcome Measures

Measure:To determine the effect of food on the AUC of repotrectinib (TPX-0005). (Phase 1)
Time Frame:Two to three months after starting treatment for each patient.
Safety Issue:
Description:o determine the effect of food on the AUC of repotrectinib (TPX-0005).
Measure:To determine the preliminary objective response rate (ORR)
Time Frame:Approximately three years.
Safety Issue:
Description:To determine the preliminary objective response rate (ORR) by Blinded Independent Central Review (BICR) and clinical benefit rate (CBR) of repotrectinib (Phase 1)
Measure:To determine the duration of response (DOR)
Time Frame:Approximately three years.
Safety Issue:
Description:To determine the DOR of repotrectinib (TPX-0005) (Phase 2)
Measure:To determine the clinical benefit rate (CBR)
Time Frame:Approximately three years.
Safety Issue:
Description:To determine the CBR of repotrectinib (TPX-0005) (Phase 2)
Measure:To determine the progression free survival (PFS).
Time Frame:Approximately three years.
Safety Issue:
Description:To determine the PFS (Phase 2)
Measure:To determine the overall survival (OS).
Time Frame:Approximately three years.
Safety Issue:
Description:To determine the OS (Phase 2)
Measure:To determine the intracranial objective response rate.
Time Frame:Approximately three years.
Safety Issue:
Description:To determine the intracranial objective response rate (Phase 2)

Details

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

Trial Keywords

  • ALK Gene Rearrangement
  • ROS1 Gene Rearrangement
  • NTRK 1/2/3 Gene Rearrangement

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