E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10065252 |
E.1.2 | Term | Solid tumor |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main 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. |
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E.2.2 | Secondary objectives of the trial |
To determine the Duration of Response (DOR), time to response (TTR), and clinical benefit rate (CBR) of repotrectinib, as assessed by BICR. • 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 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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. 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 ROS1+ NSCLC (n=120). • Disease progression, unresponsive, 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). • Up to one prior line of chemotherapy OR immunotherapy before or after a ROS1 TKI is allowed (chemo- or immunotherapy-based ombination regimen is considered as one line of treatment).
EXP-3: 2 Prior ROS1 TKIs and NO Chemotherapy or Immunotherapy ROS1+ NSCLC (n=80). • Disease progression, unresponsive, 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. • Up to 2 prior lines of chemo or immunotherapy are allowed (chemo- or immunotherapy-based combination regimen is considered as one line of treatment). EXP-5: TRK TKI-naïve NTRK+ solid tumors (n=110). • No prior exposure to a TRK TKI is allowed. • Any number of prior lines of chemo or immunotherapy is allowed. EXP-6: TRK TKI-pretreated NTRK+ solid tumors (n=80). • Disease progression, unresponsive, 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.
please see protocol page 83 for the full inclusion criteria. |
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E.4 | Principal 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 Turning Point Therapeutics. 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Endpoint for Phase 2: • Objective Response Rate (ORR) assessed by BICR using RECIST v1.1. |
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E.5.1.1 | Timepoint(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. For the EXP-4 cohort using Simon’s two -stage design, the confidence interval will be calculated using exact confidence interval based on method proposed by Shan (Shan, 2018).
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E.5.2 | Secondary end point(s) |
Secondary Endpoints for Phase 2: • Duration of Response (DOR), Time to Response (TTR), and Clinical Benefit Rate (CBR) • Intracranial tumor response in subjects with measurable brain metastases, as determined by BICR using modified RECIST v1.1 • CNS Progression-Free Survival (CNS-PFS) in subjects with measurable brain metastases using modified RECIST v1.1 • Progression-Free Survival (PFS), and OS • Type, incidence, severity, timing, seriousness, and relatedness of AEs and laboratory abnormalities • Pharmacokinetic parameters of repotrectinib • Pharmacokinetic parameters of midazolam (midazolam DDI sub-study only) • Changes in Quality-of-life and health status during repotrectinib treatment |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
13.2.2.2.1 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 who have not died within 28 days of the last dose of study treatment. 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.
see protocol page 185-186 for more details. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 41 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Canada |
China |
Hong Kong |
Japan |
Korea, Republic of |
Singapore |
Taiwan |
United States |
France |
Poland |
Netherlands |
Spain |
Germany |
Italy |
Belgium |
Denmark |
Hungary |
United Kingdom |
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E.8.7 | Trial 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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |