A Study to Test the Safety of the Investigational Drug Selitrectinib in Children and Adults That May Treat Cancer

Study Overview
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Brief Summary
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This research study is done to test the safety of the new drug selitrectinib in children and adults with cancer having a change in a particular gene (NTRK1, NTRK2 or NTRK3). The drug may treat cancer by interfering with the effect of the NTRK genes on cancer growth. The study also investigates how the drug is absorbed and processed in the human body, and how well and for how long the cancer responds to the drug. This is the first study to test selitrectinib in humans with cancer, for whom no other effective therapy exists.

Detailed Description
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The primary objective is to determine the recommended dose for further study of oral selitrectinib with previously treated neurotrophic tyrosine kinase (NTRK) cancers in 2 patient groups: a) aged 12 years and older and b) younger than 12 years. Secondary objectives of Phase I are to characterize the pharmakokinetic properties of the test drug, its safety and tolerability, and to assess the objective response rate (ORR) of NTRK-tumors.

Official Title
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A Phase 1 Study of the TRK Inhibitor Selitrectinib (BAY 2731954) in Adult and Pediatric Subjects With Previously Treated NTRK Fusion Cancers

Conditions
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Solid Tumors Harboring NTRK Fusion

Intervention / Treatment
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* Drug: Selitrectinib (BAY2731954)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Advanced solid tumor for which, in the opinion of the investigator, no other standard therapy offers greater benefit. A solid tumor diagnosis in the setting of: a) a documented NTRK fusion and a clinical history of relapse following a response to a prior TRK inhibitor b) a documented NTRK fusion unresponsive to a prior TRK inhibitor c) a documented NTRK fusion and a clinical history of intolerance to a prior TRK inhibitor NTRK gene fusions will be identified in a CLIA-certified (or equivalently-accredited diagnostic) laboratory. If such a report cannot be provided, other available certifications/accreditations are required and need to be documented. Patients with infantile fibrosarcoma (IFS) or congenital mesoblastic nephroma (CMN) may be enrolled based on an ETV6+ FISH test without identifying NTRK3. Performance Status: Eastern Cooperative Oncology Group (ECOG) score ≤ 2 in adults or Karnofsky Performance Status (KPS) Score≥50% (age ≥ 16 years) or Lansky Performance Score (LPS) ≥ 40% (age < 16 years). Life expectancy of at least 3 months. Adequate hematologic, hepatic and renal function. Patients with stable central nervous system (CNS) primary tumor, brain metastases, or treated spinal cord compression are eligible if neurological symptoms have been stable for 7 days prior to the first dose of selitrectinib. Ability to receive study drug orally or by enteral administration Exclusion Criteria: Prior exposure to second generation TRK inhibitor (e.g. selitrectinib, repotrectinib [TPX-0005]), taletrectinib [DS-6501b/AB-106]). Exception is in case patient presented intolerance to the second generation TRK inhibitor agent and the duration of exposure was less than 28 days. No previous treatment with selitrectinib is allowed. Concurrent treatment with a strong CYP3A4 inhibitor or inducer, consumption of grapefruit juice or Seville oranges, or drugs associated with QT prolongation. Clinically significant active cardiovascular disease or history of myocardial infarction within 3 months prior to planned start of selitrectinib, or prolongation of QT interval corrected for heart rate (QTc interval) >480 milliseconds within past 6 months Major surgery within 7 days of enrollment Uncontrolled systemic bacterial, fungal or viral infection. Pregnancy or lactation. Known hypersensitivity to selitrectinib or Ora-Sweet® SF and OraPlus® for patients receiving liquid formulation.

Ages Eligible for Study
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Minimum Age: 1 Month

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cancer participants <12 years<br>A Rolling-6 dose escalation design will be used. The starting dose for participants age < 12 years will be 25% below the highest dose level cohort divided by 1.73 m^2 cleared by the Safety Review Committee (SRC) for subjects age 12 years and older. | Drug: Selitrectinib (BAY2731954)<br>* Selitrectinib is administered as capsules or liquid formulation.<br>* Other names: Loxo-195;|
| Experimental: Cancer participants ≥12 years<br>A 3+3 dose escalation design will be used to determine the maximum tolerated dose (MTD)/recommended dose for further study, enrolling 3 to 6 participants per cohort with a starting dose level of 100 mg twice daily (BID). | Drug: Selitrectinib (BAY2731954)<br>* Selitrectinib is administered as capsules or liquid formulation.<br>* Other names: Loxo-195;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) |  | Up to 42 days | 
| Recommended dose |  | Up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events |  | Up to 56 months | 
| Severity of adverse events | Severity is assessed using CTCAE version 4.03 | Up to 56 months | 
| Duration of adverse events |  | Up to 56 months | 
| Number of subjects with safety-relevant changes in clinical parameters or vital signs after drug administration |  | Up to 56 months | 
| Severity of safety-relevant changes in clinical parameters or vital signs after drug administration |  | Up to 56 months | 
| Overall response rate (ORR) in subjects with NTRK fusion cancer previously treated with TRK inhibitor determined by investigator | ORR is determined by the investigator using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. | Up to 56 months | 
| Overall response rate (ORR) in subjects with primary central nervous system (CNS) malignancies determined by investigator | ORR is determined by the treating investigator using the Response Assessment in Neuro-Oncology (RANO) criteria. | Up to 56 months | 
| Maximum concentration (Cmax) of BAY2731954 in plasma |  | Predose, 0.25, 0.5, 1, 2, 4, 6, 8 hours post-dose on Day 1, predose, 0.5, 1, 2, 4 post-dose on Day 8 of Cycle 1 (cycle length 28 days) | 
| Area under the concentration versus time curve of BAY2731954 in plasma (AUC (0-10), AUC(0-12) for BID dosing and AUC(0-24) for QD dosing) |  | At defined time points for different cohort, up to 10 hours post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Solid Tumor, Metastatic cancer, Advanced cancer, Neurotrophic tyrosine receptor kinase (NTRK), NTRK1, NTRK2, NTRK3, Fusion Positive, Children