Testing Oral repotrectinib for locally advanced solid tumors

Inclusion

• +ECOG PS 0-1.
• +Age ≥18 (or age ≥ 20 of age as required by local regulation).
• +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.
• +Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1.
• +Age ≥12 (or age ≥ 20 as required by local regulation).
• +Willing and able to provide written institutional review boardResearch Ethics Board (REB)The independent committee that must approve a study before it can run.Read more → (IRB)/institutional ethics committee-approved Informed ConsentInformed consentThe process of being told what taking part involves, then choosing freely.Read more → or an Assent signed by a parent or legal guardian for subjects age 12 to 17.
• +Subject must have a documented ROS1 or NTRK1-3 gene fusion determined by tissue-based local testing using either:
• +Patients with asymptomatic CNS metastases (treated or untreated) and/or asymptomatic leptomeningeal carcinomatosis are eligible to enroll if they satisfy the protocolProtocolThe detailed plan a study must follow.Read more → specified criteria.
• +Subjects with asymptomatic CNS metastases (treated or untreated) and/or asymptomatic leptomeningeal carcinomatosis are eligible to enroll if they satisfy the protocol specified criteria.
• +Symptomatic brain metastases or leptomeningeal involvement.
• +Known active infections (bacterial, fungal, viral including HIV positivity).
• +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.
• +Capability to swallow capsules intact (without chewing, crushing, or opening).
• +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.
• +Resolution of all acute toxic effects (excluding alopecia) of any prior anti-cancer therapy to National Cancer Institute Common Terminology Criteria for Adverse EventsAdverse eventAny medical problem that happens during a study, whether or not the treatment caused it.Read more → (NCI CTCAE) Version 4.03 Grade less than or equal to 1.
• +BaselineBaselineYour starting measurements, taken before treatment begins.Read more → 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
• +Life expectancy ≥ 3 months.
• +PHASE 2Phase 2A middle-stage study looking at what a treatment does and watching for side effects.Read more → Key Inclusion CriteriaInclusion criteriaThe things you must have or be for a study to consider you.Read more →
• +a next-generation sequencing (NGS) or quantitative polymerase chain reaction (qPCR) test will be accepted to determine molecular eligibilityEligibility criteriaThe full list of requirements for taking part in a study.Read more →.
• +Adequate tumor tissue needs to be sent to the SponsorSponsorThe organisation responsible for the study overall.Read more → designated central diagnostic laboratory for retrospective confirmation by a central diagnostic laboratory test selected by the Sponsor.
• +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 enrollmentEnrolmentThe number of participants a study plans to include, or has included.Read more → will be accepted to determine molecular eligibility.
• +Adequate tumor tissue must be sent to the Sponsor designated central diagnostic laboratory for prospective confirmation by a central diagnostic laboratory test selected by the Sponsor PRIOR to enrollment.
• +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.
• +Subjects with advanced solid tumors harboring ROS1, NTRK1, NTRK2, or NTRK3 rearrangement will be assigned into 6 distinct expansion (EXP) cohortsCohortA group of participants sharing a characteristic, followed together.Read more → provided all inclusion and exclusion criteriaExclusion criteriaThe things that would prevent someone from taking part.Read more → are met.
• +i. EXP-1: ROS1 TKI-naïve ROS1+ NSCLC ii. EXP-2: 1 Prior ROS1 TKI and 1 Platinum based chemo ROS1+ NSCLC iii. EXP-3: 2 Prior ROS1 TKIs ROS1+ NSCLC (No Chemo or IO) iv. EXP-4: 1 Prior ROS1 TKI ROS1+ NSCLC (No Chemo or IO) v. EXP-5: TRK TKI-naïve NTRK+ solid tumors vi. EXP-6: TRK TKI-pretreated NTRK+ solid tumors
• +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 \> 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
• +Life expectancy ≥ 3 months.
• +Key Exclusion Criteria PHASE 1Phase 1The earliest stage of human testing, in a small group, focused on safety.Read more → and PHASE 2
• +Concurrent participation in another therapeutic clinical trialInterventional studyA study where participants are given something to see what happens.Read more →.
• +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.
• +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
• +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 screeningScreeningThe checks done before joining, to see whether a study fits.Read more → 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.
• +Gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gut syndrome) or other malabsorption syndromes that would impact drug absorption.
• +Peripheral neuropathy of CTCAE ≥grade 2.
• +Prior cytotoxic chemotherapy is allowed.
• +Prior immunotherapy is allowed.
• +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
• +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.