A Study to Test the Safety of the Investigational Drug Larotrectinib in 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 drug larotrectinib in adult cancer patients. The drug may be used to treat cancer with a change in a particular gene (NTRK1, NTRK2 or NTRK3), because it blocks the action of these genes in cancer cells. The study also investigates how the drug is absorbed and processed in the human body. This is the first study to test larotrectinib in humans with cancer, for whom no other effective therapy exists.

Detailed Description
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The trial will be conducted in 2 parts: an initial dose escalation phase of larotrectinib in subjects with advanced solid tumors will be followed by an expansion phase in subjects with solid tumors having a NTRK fusion. The objectives of the study are to determine the safety, pharmacokinetic profile, recommended dose and efficacy of orally administered larotrectinib in patients with NTRK fusions.

Official Title
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A Phase 1 Study of the Oral TRK Inhibitor Larotrectinib in Adult Patients With Solid Tumors

Conditions
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Solid Tumors Harboring NTRK Fusion

Intervention / Treatment
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* Drug: Larotrectinib (Vitrakvi, BAY2757556)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients with a locally advanced or metastatic solid tumor that has progressed or was nonresponsive to available therapies, are unfit for standard chemotherapy or for which no standard or available curative therapy exists Proof of a malignancy harboring a NTRK fusion Eastern Cooperative Oncology Group (ECOG) score of 0, 1 or 2 and a life expectancy of at least 3 months Adequate hematologic, hepatic, and renal function Exclusion Criteria: Patients with unstable primary central-nervous-system tumors or metastasis, exceptions possible Clinically significant active cardiovascular disease or history of myocardial infarction Active uncontrolled systemic bacterial, viral, or fungal infection Current treatment with a strong CYP3A4 inhibitor or inducer Pregnancy or lactation

Ages Eligible for Study
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Minimum Age: 18 Years

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: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tumor patients_Dose 1<br>Adult patients with solid tumors receiving 50 mg of BAY2757556 once daily (dose escalation cohort). | Drug: Larotrectinib (Vitrakvi, BAY2757556)<br>* BAY2757556 will be administered orally as capsule or in liquid form over continuous 28-day cycles.<br>* Other names: LOXO-101;|
| Experimental: Tumor patients_Dose 2<br>Adult patients with solid tumors receiving 100 mg of BAY2757556 once daily (dose escalation cohort). | Drug: Larotrectinib (Vitrakvi, BAY2757556)<br>* BAY2757556 will be administered orally as capsule or in liquid form over continuous 28-day cycles.<br>* Other names: LOXO-101;|
| Experimental: Tumor patients_Dose 3<br>Adult patients with solid tumors receiving 100 mg of BAY2757556 twice daily (dose escalation cohort). | Drug: Larotrectinib (Vitrakvi, BAY2757556)<br>* BAY2757556 will be administered orally as capsule or in liquid form over continuous 28-day cycles.<br>* Other names: LOXO-101;|
| Experimental: Tumor patients_Dose 4<br>Adult patients with solid tumors receiving 200 mg of BAY2757556 once daily (dose escalation cohort). | Drug: Larotrectinib (Vitrakvi, BAY2757556)<br>* BAY2757556 will be administered orally as capsule or in liquid form over continuous 28-day cycles.<br>* Other names: LOXO-101;|
| Experimental: Tumor patients_Dose 5<br>Adult patients with solid tumors receiving 150 mg of BAY2757556 twice daily (dose escalation cohort). | Drug: Larotrectinib (Vitrakvi, BAY2757556)<br>* BAY2757556 will be administered orally as capsule or in liquid form over continuous 28-day cycles.<br>* Other names: LOXO-101;|
| Experimental: Tumor patients_Dose 6<br>Adult patients with solid tumors receiving 200 mg of BAY2757556 twice daily (dose escalation cohort). | Drug: Larotrectinib (Vitrakvi, BAY2757556)<br>* BAY2757556 will be administered orally as capsule or in liquid form over continuous 28-day cycles.<br>* Other names: LOXO-101;|
| Experimental: Tumor patients_Expansion<br>Adults patients with solid tumors and neurotrophic tyrosine kinase (NTRK) genes or proteins of types 1 - 3 (dose expansion cohort). Patients receive either the recommended or maximum tolerated dose of BAY2757556 as determined in the dose escalation part. | Drug: Larotrectinib (Vitrakvi, BAY2757556)<br>* BAY2757556 will be administered orally as capsule or in liquid form over continuous 28-day cycles.<br>* Other names: LOXO-101;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events |  | 25 months | 
| Severity of adverse events | The severity of adverse events will be assesssed according to the NCI CTCAE version 4.03. | 25 months | 
| Maximum tolerated dose (MTD) |  | 25 months | 
| Recommended dose for dose expansion |  | 25 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum concentration of larotrectinib in plasma (Cmax) |  | Predose and 0.25, 0.5, 1, 2, 4, 6 and 8 hours after drug administration on Days 1 and 8 of Cycle 1 | 
| Time to maximum concentration of larotrectinib in plasma (Tmax) |  | Predose and 0.25, 0.5, 1, 2, 4, 6 and 8 hours after drug administration on Days 1 and 8 of Cycle 1 | 
| Half-life of larotrectinib in plasma (t1/2) |  | Predose and 0.25, 0.5, 1, 2, 4, 6 and 8 hours after drug administration on Days 1 and 8 of Cycle 1 | 
| Area under the concentration versus time curve of larotrectinib in plasma (AUC) |  | Predose and 0.25, 0.5, 1, 2, 4, 6 and 8 hours after drug administration on Days 1 and 8 of Cycle 1 | 
| Overall Response Rate (ORR) | Assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or Response Assessment in Neuro-Oncology (RANO) as appropriate | Up to 60 months | 
| Duration of Response (DOR) |  | Up to 60 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced solid tumors, Neurotrophic tyrosine receptor kinase (NTRK), NTRK1, NTRK2, NTRK3, Fusion Positive, TRK fusion, TRKA, TRKB, TRKC, ETV6