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    Summary
    EudraCT Number:2016-003616-13
    Sponsor's Protocol Code Number:TPX-0005-01
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2020-07-06
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedDenmark - DHMA
    A.2EudraCT number2016-003616-13
    A.3Full title of the trial
    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)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase 1/2 Open Label solid tumour Safety and Tolerability study.
    A.4.1Sponsor's protocol code numberTPX-0005-01
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03093116
    A.5.4Other Identifiers
    Name:Other Study IdentifierNumber:CA127-1024
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/542/2021
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorTurning Point Therapeutics, Inc. (a wholly owned subsidiary of Bristol Myers Squibb company)
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportTurning Point Therapeutics, Inc. (a wholly owned subsidiary of Bristol Myers Squibb company)
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBristol Myers Squibb International Corporation
    B.5.2Functional name of contact pointGSM-CT
    B.5.3 Address:
    B.5.3.1Street AddressParc de l´Alliance - Avenue de Filande, 4
    B.5.3.2Town/ cityBraine-l'Allerud
    B.5.3.3Post code1420
    B.5.3.4CountryBelgium
    B.5.6E-mailmg-gsm-ct@bms.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameRepotrectinib
    D.3.2Product code TPX-0005, BMS-986472
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRepotrectinib
    D.3.9.1CAS number 1802220-02-5
    D.3.9.2Current sponsor codeTPX-0005, BMS-986472
    D.3.9.3Other descriptive nameTP-01067, CML-478, FP-247
    D.3.10 Strength
    D.3.10.1Concentration unit mg/g milligram(s)/gram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    advanced solid tumors
    E.1.1.1Medical condition in easily understood language
    Cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10065252
    E.1.2Term Solid tumor
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Phase 2 Study
    • To determine the confirmed Objective 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 ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement.
    E.2.2Secondary objectives of the trial
    Phase 2 study
    • To determine the Duration of Response (DOR), time to response (TTR), and clinical benefit rate (CBR) of repotrectinib, as assessed by BICR, in each subject population expansion cohort.
    • To estimate the progression-free survival (PFS) and overall survival (OS) of subjects treated with repotrectinib with advanced solid tumors that harbor a ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement.
    • To evaluate the safety and tolerability of repotrectinib when administered at the RP2D in subjects with advanced solid tumors that harbor a ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement.
    • To determine the intracranial objective response rate (IC-ORR) of repotrectinib and Central Nervous System PFS (CNS-PFS) in subjects presenting with measurable brain metastases at baseline, using modified RECIST v1.1 assessment.
    • To confirm PK of repotrectinib at the RP2D.
    • To assess treatment-related symptoms and general health status using validated instruments
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Histologically or cytologically confirmed diagnosis of locally advanced, or metastatic solid tumor (including primary CNS tumors) that harbors a ROS1 or NTRK1-3 gene fusion. Note: Locally advanced disease is defined as Stage III when a subject is not a candidate for surgery, radiation, or multi-modality therapy and metastatic disease is defined as Stage IV per the American Joint Committee on Cancer Eighth Edition Cancer Staging Manual guidelines (Rami-Porta 2017).
    - Subject must have a documented ROS1 or NTRK1-3 gene fusion determined by tissue-based local testing using either:-
    a) a next-generation sequencing (NGS) or quantitative polymerase chain reaction (qPCR) test will be accepted to determine molecular eligibility.

    b) a fluorescence in situ hybridization (FISH) test AND prospective confirmation of fusion status by a central diagnostic laboratory test
    selected by the Sponsor PRIOR to enrollment will be accepted to determine molecular eligibility.
    - At least 1 measurable target lesion according to RECIST (version 1.1)
    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 (version 1.1) are eligible.
    - Subjects with advanced solid tumors harboring ROS1, NTRK1, NTRK2, or NTRK3 rearrangement will be assigned into 6 distinct expansion (EXP) cohorts provided all inclusion and exclusion criteria are met:
    EXP-1: ROS1 TKI-naïve ROS1+ NSCLC (n=110).
    • No prior exposure to a ROS1 TKI is allowed.
    • Up to one prior line of chemotherapy OR immunotherapy is allowed (chemo- or immunotherapy-based combination regimen is considered as one line of treatment).
    EXP-2: 1 Prior ROS1 TKI and 1 Platinum-based Chemotherapy ROS1+ NSCLC (n=120).
    • Disease progression, or intolerant to one prior line of a ROS1 TKI.
    • ROS1 TKIs used in a prior line of treatment are limited to crizotinib, ceritinib, entrectinib, or lorlatinib. Note: Any previous exposure to a ROS1 TKI is considered as one prior line of TKI treatment (e.g., if the same ROS1 TKI was given before and after a chemotherapy or other systemic therapy, it is considered as 2 prior TKIs and the subject would not be eligible for EXP-2).

    • In addition, the subject must have received one prior line of platinum-based chemotherapy OR one prior line of platinum-based chemotherapy in combination with immunotherapy before or after a ROS1 TKI (Note: Subject is not eligible if he/she has been treated with more than one line of chemotherapy OR has received immunotherapy alone).

    EXP-3: 2 Prior ROS1 TKIs and NO Chemotherapy or Immunotherapy ROS1+ NSCLC (n=80).
    • Disease progression, or intolerant to 2 prior lines of a ROS1 TKI treatment.
    • ROS1 TKIs used in prior lines of treatment are limited to crizotinib, ceritinib, entrectinib, lorlatinib, brigatinib, ensartinib, or cabozantinib. Other prior ROS1 TKI agents that are not listed may be allowed after discussion with the Sponsor Medical Monitor. Note: Any previous exposure to a ROS1 TKI is considered as one prior line of TKI treatment (e.g., if 2 different ROS1 TKIs are utilized, or the same ROS1 TKI was given before and after a chemotherapy or other systemic therapy, it is considered as 2 prior TKIs and the subject would be eligible).
    • No prior lines of chemotherapy or immunotherapy are allowed.
    EXP-4: Prior ROS1 TKI and NO Chemotherapy or Immunotherapy ROS1+ NSCLC (n=120).
    • No prior exposure to a ROS1 or TKI is allowed.
    • Note: No prior lines of chemotherapy or immunotherapy are allowed
    EXP-5: TRK TKI-naïve NTRK+ solid tumors (n=80).
    • No prior exposure to a TRK TKI is allowed.
    • Any number of prior lines of chemo or immunotherapy is allowed.
    • Subjects with NSCLC are not allowed.
    EXP-6: TRK TKI-pretreated NTRK+ solid tumors (n=120).
    • Disease progression, or intolerant to 1 or 2 prior TRK TKIs.
    • TRK TKIs used in prior lines of treatment are limited to entrectinib, larotrectinib, or selitrectinib (LOXO-195) and carbozantinib. Other prior TRK TKIs that are not listed may be allowed after discussion with the Sponsor Medical Monitor. Note: Any previous exposure of a TRK TKI is considered as one prior line of TKI treatment, (e.g., if 2 different TRK TKIs are utilized or the same TRK TKI was used before and after a chemo- or other systemic therapy, it is counted as 2 prior TKIs and the subject would be eligible).
    • Any number of prior lines of chemo- or immunotherapy are allowed.
    • Subjects with NSCLC are not allowed.
    please see protocol page 83-88 for the full inclusion criteria.
    E.4Principal 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 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 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 requiring ongoing treatment (bacterial, fungal, viral including human immunodeficiency virus positivity).
    8. Gastrointestinal disease (e.g., Crohn’s disease, ulcerative colitis, short gut syndrome) or other malabsorption syndromes that would impact on drug absorption.
    9. Peripheral neuropathy, paresthesia, dizziness, dysgeusia, muscle weakness, ataxia 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.
    11. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or that may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the subject inappropriate for entry into this study, or could compromise protocol objectives in the opinion of the Investigator and/or Sponsor.
    12. Current use or anticipated need for drugs that are known to be strong CYP3A inhibitors or inducers as listed in Appendix 5 of the protocol.
    13. Hypersensitivity to the active substance or to any of the excipients.
    E.5 End points
    E.5.1Primary end point(s)
    Primary Endpoint for Phase 2:
    • Objective Response Rate (ORR) assessed by BICR using RECIST version 1.1, in each subject population expansion cohort of solid tumors that harbor a ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The ORR will be defined as the proportion of subjects with a confirmed complete response (CR) or partial response (PR). A confirmed response is a response that persists on a repeat-imaging performed at least 4 weeks after initial documentation of response. Subjects with a confirmed objective response (CR or PR) will be referred to as responders. Non-responders will include subjects without a confirmed objective response, SD, or PD.
    The ORR will be reported as the proportion of responders along with the corresponding 2-sided 95% Clopper-Pearson exact CI.
    Subgroup analyses of primary endpoint ORR may be performed by
    demographic and baseline risk factors in each expansion cohort if data permit.
    E.5.2Secondary end point(s)
    Secondary Endpoints for Phase 2:
    • Duration of Response (DOR)
    • Time to Response (TTR)
    • Clinical Benefit Rate (CBR)
    • Intracranial Objective Response Rate
    • CNS Progression-Free Survival (CNS-PFS)
    • Progression-Free Survival (PFS)
    • Overall Survival (OS)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Duration of Response (DOR)
    The DOR will be defined from the first date of objective response (either CR or PR) to first documentation of radiographic disease progression, as assessed by RECIST v1.1. The DOR will be censored at the last tumor assessment date for subjects without disease progression. The DOR will only be calculated for the subgroup of subjects with a confirmed objective tumor response. The DOR will be summarized in the populations of subjects with a confirmed CR or PR using the Kaplan-Meier method and will be displayed graphically where appropriate. The median event time (if appropriate) and 2-sided 95% CI for the median will be provided. The number and % of subjects with actual DOR ≥6, 12, and 18 months will also be tabulated.

    See Protocol pages 179-180 for details.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA35
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Singapore
    Hong Kong
    Taiwan
    Australia
    Canada
    China
    Japan
    Korea, Republic of
    United Kingdom
    United States
    Belgium
    Denmark
    France
    Germany
    Hungary
    Italy
    Netherlands
    Poland
    Spain
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    English End of trial in all participating countries will be defined as the time at which the secondary endpoint of OS has been met in each expansion cohort.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years8
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years8
    E.8.9.2In all countries concerned by the trial months3
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 20
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 20
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 410
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 200
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state3
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 255
    F.4.2.2In the whole clinical trial 630
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Standard clinical practice
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-08-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-09-21
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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