Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

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: NCT03093116
Recruitment Status : Recruiting
First Posted : March 28, 2017
Last Update Posted : October 16, 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 October 16, 2019
Actual Study Start Date  ICMJE February 27, 2017
Estimated Primary Completion Date March 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 24, 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)
  • Recommended Phase 2 Dose (RP2D) (Phase 1) [ Time Frame: Within 28 days of the last patient dosed in escalation ]
    To determine the RP2D (Phase 1)
  • Overall Response Rate (ORR) Phase 2 [ Time Frame: Two to three years after first dose of repotrectinib dose ]
    To determine the confirmed 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: June 24, 2019)
  • Maximum plasma concentration (CMAX) of repotrectinib (TPX-0005) (Phase 1) [ Time Frame: Up to 72 hours post dose ]
    To determine the maximum plasma concentration (CMAX) of repotrectinib (TPX-0005)
  • Area under the plasma concentration time curve (AUC) of repotrectinib (TPX-0005) (Phase 1) [ Time Frame: Up to 72 hours post dose ]
    To determine the area under the plasma concentration time curve (AUC) of repotrectinib
  • Area under the plasma concentration time curve (AUC) of repotrectinib under different food intake conditions(TPX-0005) (Phase 1) [ Time Frame: Up to 72 hours post dose ]
    To determine the area under the plasma concentration time curve (AUC) of repotrectinib under different food intake conditions(TPX-0005) (Phase 1)
  • Maximum plasma concentration (CMAX) of repotrectinib under different food intake conditions(TPX-0005) (Phase 1) [ Time Frame: Up to 72 hours post dose ]
    To determine the maximum plasma concentration (CMAX) of repotrectinib under different food intake conditions(TPX-0005) (Phase 1)
  • Area under the plasma concentration time curve (AUC) of midazolam(TPX-0005) (Phase 1) [ Time Frame: Up to 24 hours post dose ]
    To determine the area under the plasma concentration time curve (AUC) of midazolam(TPX-0005) (Phase 1)
  • Maximum plasma concentration (CMAX) of midazolam(TPX-0005) (Phase 1) [ Time Frame: Up to 24 hours post dose ]
    To determine the maximum plasma concentration (CMAX) of midazolam(TPX-0005) (Phase 1)
  • Plasma concentration of repotrectinib following administration at RP2D (Phase 2) [ Time Frame: Pre dose and 4 hours post dose ]
    To evaluate the plasma concentration of repotrectinib following administration at RP2D (Phase 2)
  • Preliminary objective response rate (ORR) (Phase 1) [ Time Frame: Approximately three years ]
    To determine the preliminary objective response rate (ORR) by Blinded Independent Central Review (BICR) (Phase 1)
  • Duration of response (DOR) (Phase 2) [ Time Frame: Approximately three years ]
    To determine the DOR of repotrectinib (TPX-0005) (Phase 2)
  • Clinical benefit rate (CBR) (Phase 2) [ Time Frame: Approximately three years ]
    To determine the CBR of repotrectinib (TPX-0005) (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)
  • Intracranial objective response rate (Phase 2) [ 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.

Midazolam DDI substudy will examine effect of of repotrectinib on CYP3A induction.

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 TKI-naïve ROS1+ NSCLC. Up to one prior line of chemotherapy OR immunotherapy is allowed
  • EXP-2: 1 Prior ROS1 TKI ROS1+ NSCLC. Disease progression, unresponsive, or intolerant to one prior line of a ROS1 TKI. Up to one prior line of chemotherapy OR immunotherapy before or after a ROS1 TKI is allowed
  • EXP-3: 2 Prior ROS1 TKIs ROS1+ NSCLC. Disease progression, unresponsive, or intolerant to 2 prior lines of a ROS1 TKI treatment. Up to one prior line of chemotherapy OR immunotherapy pre-TKI or post-TKI is allowed
  • EXP-4: ROS1 or ALK TKI-naïve ROS1+ or ALK+ solid tumors (non-NSCLC). No prior ROS1 or ALK TKIs allowed. Up to 2 prior lines of chemo or immunotherapy are allowed
  • EXP-5: TRK TKI-naïve NTRK+ solid tumors. Any number of prior lines of chemo or immunotherapy is allowed.
  • EXP-6: TRK TKI-pretreated NTRK+ solid tumors. Disease progression, unresponsive, or intolerant to 1 or 2 prior TRK TKIs. Any number of prior lines of chemo- or immunotherapy are 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: 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, and Midazolam drug-drug interaction sub-study.

Phase 2

Oral repotrectinib (TPX-0005): 6 distinct expansion cohorts

  • EXP-1: ROS1 TKI-naïve ROS1+ NSCLC
  • EXP-2: 1 Prior ROS1 TKI ROS1+ NSCLC
  • EXP-3: 2 Prior ROS1 TKIs ROS1+ NSCLC
  • EXP-4: ROS1 or ALK TKI-naïve ROS1+ or ALK+ solid tumors (non-NSCLC)
  • EXP-5: TRK TKI-naïve NTRK+ solid tumors
  • EXP-6: TRK TKI-pretreated NTRK+ solid tumors
Intervention: Drug: Oral repotrectinib (TPX-0005)
Publications * Drilon A, Ou SI, Cho BC, Kim DW, Lee J, Lin JJ, Zhu VW, Ahn MJ, Camidge DR, Nguyen J, Zhai D, Deng W, Huang Z, Rogers E, Liu J, Whitten J, Lim JK, Stopatschinskaja S, Hyman DM, Doebele RC, Cui JJ, Shaw AT. Repotrectinib (TPX-0005) Is a Next-Generation ROS1/TRK/ALK Inhibitor That Potently Inhibits ROS1/TRK/ALK Solvent- Front Mutations. Cancer Discov. 2018 Oct;8(10):1227-1236. doi: 10.1158/2159-8290.CD-18-0484. Epub 2018 Aug 9.

*   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 December 2022
Estimated Primary Completion Date March 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

PHASE 1

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).
  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. Baseline laboratory values fulfilling the following requirements:Absolute neutrophils count (ANC) ≥1500/mm3 (1.5 × 109/L); Platelets (PLTs) ≥100,000/mm3 (100 × 109/L); Hemoglobin ≥ 9.0 g/dL transfusions are allowed; Serum creatinine or creatinine clearance Within normal limits or > 40 mL/min; Total serum bilirubin < 1.5 × ULN; Liver transaminases (ASTs/ALTs) < 2.5 × ULN; < 5 × ULN if liver metastases are present Alkaline phosphatase (ALP); < 2.5 × ULN; < 5 × ULN if liver and/or bone metastasis are present; Serum calcium, magnesium, and potassium Normal or CTCAE grade ≤ 1 with or without supplementation
  11. Life expectancy ≥ 3 months.

PHASE 2 Key Inclusion Criteria

  1. Histologically or cytologically confirmed diagnosis of locally advanced, or metastatic solid tumor (including primary CNS tumors) that harbors a ROS1, ALK or NTRK1-3 gene fusion.
  2. Subjects must have a documented ROS1, ALK or NTRK1-3 gene fusion that has been identified by local testing AND that has been prospectively confirmed by a central diagnostic laboratory selected by the Sponsor to determine molecular eligibility PRIOR to enrollment.
  3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1.
  4. Age ≥12 (or age ≥ 20 as required by local regulation).
  5. Willing and able to provide written institutional review board (IRB)/institutional ethics committee-approved Informed Consent or an Assent signed by a parent or legal guardian for subjects age 12 to 17.
  6. At least 1 measurable target lesion according to RECIST (v1.1) prospectively confirmed by Blinded Independent Central Radiology Review (BICR), selected by Sponsor, PRIOR to enrollment. Subjects with CNS-only measurable disease ≥10 mm as defined by RECIST (v1.1) are eligible.
  7. Subjects with advanced solid tumors harboring ALK, ROS1, NTRK1, NTRK2, or NTRK3 rearrangement will be assigned into 6 distinct expansion (EXP) cohorts provided all inclusion and exclusion criteria are met.

    i. EXP-1: ROS1 TKI-naïve ROS1+ NSCLC ii. EXP-2: 1 Prior ROS1 TKI ROS1+ NSCLC iii. EXP-3: 2 Prior ROS1 TKIs ROS1+ NSCLC iv. EXP-4: ROS1 or ALK TKI-naïve ROS1+ or ALK+ solid tumors (non-NSCLC) v. EXP-5: TRK TKI-naïve NTRK+ solid tumors vi. EXP-6: TRK TKI-pretreated NTRK+ solid tumors

  8. Subjects with asymptomatic CNS metastases (treated or untreated) and/or asymptomatic leptomeningeal carcinomatosis are eligible to enroll if they satisfy the protocol specified criteria.
  9. Baseline laboratory values fulfilling the following requirements:Absolute neutrophils count (ANC) ≥1500/mm3 (1.5 × 109/L); Platelets (PLTs) ≥100,000/mm3 (100 × 109/L); Hemoglobin ≥ 9.0 g/dL transfusions are allowed; Serum creatinine or creatinine clearance Within normal limits or > 40 mL/min; Total serum bilirubin < 1.5 × ULN; Liver transaminases (ASTs/ALTs) < 2.5 × ULN; < 5 × ULN if liver metastases are present Alkaline phosphatase (ALP); < 2.5 × ULN; < 5 × ULN if liver and/or bone metastasis are present; Serum calcium, magnesium, and potassium Normal or CTCAE grade ≤ 1 with or without supplementation
  10. Life expectancy ≥ 3 months.

Key Exclusion Criteria PHASE 1 and PHASE 2

  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 repotrectinib treatment. Radiation therapy (except palliative to relieve bone pain) within 2 weeks of study entry. Palliative radiation (≤10 fractions) must have been completed at least 48 hours prior to study entry
  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 12 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Shanna Stopatschinskaja, M.D. (858) 276-0005 clinical@tptherapeutics.com
Listed Location Countries  ICMJE Australia,   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 September 2019

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