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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 : April 12, 2019
Sponsor:
Information provided by (Responsible Party):
Turning Point Therapeutics, Inc.

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.


Condition or disease Intervention/treatment Phase
Locally Advanced Solid Tumors Metastatic Solid Tumors Drug: Oral repotrectinib (TPX-0005) Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 450 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : February 27, 2017
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : March 2022

Arm Intervention/treatment
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.

Drug: Oral repotrectinib (TPX-0005)
Oral repotrectinib (TPX-0005) capsules.
Other Name: repotrectinib




Primary Outcome Measures :
  1. 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)

  2. 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)

  3. Overall Response Rate (ORR) [ Time Frame: Two to three months after starting treatment for each patient. ]
    To determine the ORR of repotrectinib (TPX-0005) as assessed by Blinded Independent Central Review (Phase 2)


Secondary Outcome Measures :
  1. 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).

  2. 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)

  3. To determine the duration of response (DOR) [ Time Frame: Approximately three years. ]
    To determine the DOR of repotrectinib (TPX-0005) (Phase 2)

  4. To determine the clinical benefit rate (CBR) [ Time Frame: Approximately three years. ]
    To determine the CBR of repotrectinib (TPX-0005) (Phase 2)

  5. To determine the progression free survival (PFS). [ Time Frame: Approximately three years. ]
    To determine the PFS (Phase 2)

  6. To determine the overall survival (OS). [ Time Frame: Approximately three years. ]
    To determine the OS (Phase 2)

  7. To determine the intracranial objective response rate. [ Time Frame: Approximately three years. ]
    To determine the intracranial objective response rate (Phase 2)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03093116


Contacts
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Contact: Shanna Stopatschinskaja, M.D. (858) 926-5251 clinical@tptherapeutics.com

Locations
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United States, California
UC Irvine Health, Chao Family Comprehensive Cancer Center Recruiting
Orange, California, United States, 92868
Contact: Susanna Searcy    877-827-8839    ucstudy@uci.edu   
United States, Colorado
University of Colorado Denver Recruiting
Aurora, Colorado, United States, 80045
Contact: Paula Fisk    720-848-0676    paula.fisk@ucdenver.edu   
United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
Contact: Alice T Shaw, M.D., Ph.D.    617-724-4000    ashaw1@partners.org   
United States, New York
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Deepa Ramaswami    646-888-4425    ramaswad@mskcc.org   
Contact: Judy Nguyen    (646) 888-4425    Nguyenj2@mskcc.org   
Korea, Republic of
Seoul National University Hospital Recruiting
Seoul, Korea, Republic of, 110-744
Contact: Dong-Wan Kim, M.D., Ph.D.    +82-2-2072-2995    kimdw@snu.ac.kr   
Yonsei Cancer Center, Severance Hospital Recruiting
Seoul, Korea, Republic of, 120-752
Contact: Byoung Chul Cho, M.D., Ph.D.    +82-2-2228-8126    cbc1971@yuhs.ac   
Samsung Medical Center Recruiting
Seoul, Korea, Republic of, 135-710
Contact: Jeeyun Lee, M.D., Ph.D.    +82-2-3410-3459    jyun.lee@samsung.com   
Sponsors and Collaborators
Turning Point Therapeutics, Inc.
Investigators
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Study Director: Shanna Stopatschinskaja, M.D. Turning Point Therapeutics, Inc.

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Responsible Party: Turning Point Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT03093116     History of Changes
Other Study ID Numbers: TPX-0005-01
First Posted: March 28, 2017    Key Record Dates
Last Update Posted: April 12, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: There are no plans to share individual participant data with other researchers.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Turning Point Therapeutics, Inc.:
ALK Gene Rearrangement
ROS1 Gene Rearrangement
NTRK 1/2/3 Gene Rearrangement

Additional relevant MeSH terms:
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Neoplasms