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A Study of Repotrectinib (TPX-0005) in Patients With Advanced Solid Tumors Harboring ALK, ROS1, or NTRK1-3 Rearrangements (TRIDENT-1)

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ClinicalTrials.gov Identifier: NCT03093116
Recruitment Status : Recruiting
First Posted : March 28, 2017
Last Update Posted : May 30, 2019
Sponsor:
Information provided by (Responsible Party):
Turning Point Therapeutics, Inc.

Tracking Information
First Submitted Date  ICMJE March 6, 2017
First Posted Date  ICMJE March 28, 2017
Last Update Posted Date May 30, 2019
Actual Study Start Date  ICMJE February 27, 2017
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 28, 2019)
  • Define the Maximum Tolerated Dose (MTD) [ Time Frame: Within 28 days of the first repotrectinib (TPX-0005) dose for each patient. ]
    To determine the MTD (Phase 1)
  • Define the Recommended Phase 2 Dose (RP2D) [ Time Frame: Within 28 days of the first repotrectinib (TPX-0005) dose for each patient. ]
    To determine the RP2D (Phase 1)
  • Overall Response Rate (ORR) [ Time Frame: Two to three years after starting treatment for each patient. ]
    To determine the ORR of repotrectinib (TPX-0005) as assessed by Blinded Independent Central Review (Phase 2)
Original Primary Outcome Measures  ICMJE
 (submitted: March 21, 2017)
  • Define the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) [ Time Frame: Within 28 days of the first TPX-0005 dose for each patient. ]
    To determine the MTD and RP2D.
  • Overall Response Rate (ORR) [ Time Frame: Two to three months after starting treatment for each patient. ]
    To determine the ORR of TPX-0005 as assessed by Blinded Independent Central Review.
Change History Complete list of historical versions of study NCT03093116 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: April 9, 2019)
  • 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. ]
    o determine the effect of food on the AUC of repotrectinib (TPX-0005).
  • To determine the preliminary objective response rate (ORR) [ Time Frame: Approximately three years. ]
    To determine the preliminary objective response rate (ORR) by Blinded Independent Central Review (BICR) and clinical benefit rate (CBR) of repotrectinib (Phase 1)
  • To determine the duration of response (DOR) [ Time Frame: Approximately three years. ]
    To determine the DOR of repotrectinib (TPX-0005) (Phase 2)
  • To determine the clinical benefit rate (CBR) [ Time Frame: Approximately three years. ]
    To determine the CBR of repotrectinib (TPX-0005) (Phase 2)
  • To determine the progression free survival (PFS). [ Time Frame: Approximately three years. ]
    To determine the PFS (Phase 2)
  • To determine the overall survival (OS). [ Time Frame: Approximately three years. ]
    To determine the OS (Phase 2)
  • To determine the intracranial objective response rate. [ Time Frame: Approximately three years. ]
    To determine the intracranial objective response rate (Phase 2)
Original Secondary Outcome Measures  ICMJE
 (submitted: March 21, 2017)
  • To determine the effect of food on the AUC of TPX-0005. [ Time Frame: Two to three months after starting treatment for each patient. ]
    To determine the effect of food on the AUC of TPX-0005.
  • To determine the time to response (TTR) [ Time Frame: Approximately three years. ]
    • To determine the TTR of TPX-0005.
  • To determine the duration of response (DOR) [ Time Frame: Approximately three years. ]
    • To determine the DOR of TPX-0005.
  • To determine the clinical benefit rate (CBR) [ Time Frame: Approximately three years. ]
    • To determine the CBR of TPX-0005.
  • To determine the progression free survival (PFS). [ Time Frame: Approximately three years. ]
    • To determine the PFS.
  • To determine the overall survival (OS). [ Time Frame: Approximately three years. ]
    • To determine the OS.
  • To determine the intracranial objective response rate. [ Time Frame: Approximately three years. ]
    • To determine the intracranial objective response rate.
  • To determine the CNS progression-free survival. [ Time Frame: Approximately three years. ]
    • To determine the CNS progression-free survival.
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 (TPX-0005) in Patients With Advanced Solid Tumors Harboring ALK, ROS1, or NTRK1-3 Rearrangements
Official Title  ICMJE 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)
Brief Summary

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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Locally Advanced Solid Tumors
  • Metastatic Solid Tumors
Intervention  ICMJE Drug: Oral repotrectinib (TPX-0005)
Oral repotrectinib (TPX-0005) capsules.
Other Name: repotrectinib
Study Arms  ICMJE Experimental: Phase1 repotrectinib (TPX-0005)

Phase 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.

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: March 21, 2017)
450
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 2022
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Shanna Stopatschinskaja, M.D. (858) 926-5251 clinical@tptherapeutics.com
Listed Location Countries  ICMJE Korea, Republic of,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03093116
Other Study ID Numbers  ICMJE TPX-0005-01
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: Shanna Stopatschinskaja, M.D. Turning Point Therapeutics, Inc.
PRS Account Turning Point Therapeutics, Inc.
Verification Date May 2019

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