A Study to Test the Safety of the Investigational Drug Loxo-195 in Children and Adults That May Treat Cancer

This research study is done to test the safety of the new drug Loxo-195 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 Loxo-195 in humans with cancer, for whom no other effective therapy exists.

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 equivalent) laboratory. 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 ≤ 3 (age ≥ 16 years) or Lansky Performance Score (LPS) ≥ 40% (age < 16 years). If enrolled with primary CNS tumor to be assessed by RANO, Karnofsky Performance Score (KPS) (age ≥ 16 years) or LPS (age < 16 years) ≥ 50%.
• Life expectancy > 4 weeks.
• Adequate hematologic, hepatic and renal function.
• Patients with stable 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 LOXO-195
• Ability to receive study drug orally or by enteral administration

Exclusion Criteria

• Concurrent treatment with a strong CYP3A4 inhibitor or inducer or drugs associated with QT prolongation.
• Clinically significant active cardiovascular disease or history of myocardial infarction within 3 months prior to planned start of LOXO-195, 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 LOXO-195 or Ora-Sweet® SF and OraPlus® for patients receiving liquid formulation.

The trial will be conducted in 2 parts: dose escalation (Phase I ) and dose expansion (Phase 2) . The primary objective of Phase 1 is to establish the recommended dose of Loxo-195 to treat neurotrophic tyrosine kinase (NTRK) fusion cancers in patients a) aged 12 years and older and b) younger than 12 years. Secondary objectives of Phase 1 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. The primary objective of Phase 2 is to assess the overall response rate in NTRK fusion cancer patients as determined by an independent review committee (IRC). Secondary objectives of Phase 2 comprise the safety and efficacy of Loxo-195 at the recommended dose.

Lead Organization
Bayer Corporation