Clinical Trials

Inclusion Criteria:

• Patients ≥ 18 years of age at the time of informed consent.
• Histologic diagnosis of GIST and must be able to provide an archival tumor tissue sample, otherwise, a fresh biopsy is required.
• Molecular pathology report with mutational status of KIT/PDGFRA must be available. Mutation status must be identified using a PCR or sequencing based assay. Molecular pathology report with mutation status of KIT/PDGFRA must be provided to the Sponsor for review prior to randomization. If the molecular pathology report is not available or insufficient, an archival tumor tissue sample or fresh biopsy is required for mutation status confirmation by the central laboratory prior to randomization.
• Patients must have progressed on imatinib or have documented intolerance to imatinib. Imatinib treatment must have been discontinued 10 days prior to the first dose of study drug. All prior imatinib treatment will count as one line of therapy (e.g., adjuvant imatinib and dose escalation of imatinib).
• Eastern Cooperative Oncology Group (ECOG) PS of ≤ 2 at screening.
• Female patients of childbearing potential must have a negative serum beta-human chorionic gonadotrophin (β-hCG) pregnancy test at screening and negative pregnancy test at Cycle 1 Day 1 prior to the first dose of study drug.
• Patients of reproductive potential must agree to follow contraception requirements outlined in Section 6.11.9.
• Patients must have at least 1 measurable lesion according to mRECIST Version 1.1 (non-nodal lesions must be ≥ 1.0 cm in the long axis or ≥ double the slide thickness in the long axis) within 21 days prior to the first dose of study drug.
• Adequate organ function and bone marrow reserve as indicated by the following central laboratory assessments performed at screening:
  • Absolute Neutrophil Count (ANC) ≥1000/μ;
  • Hemoglobin ≥ 8 g/dL;
  • Platelet count ≥ 75,000/μ;
  • Total bilirubin ≤ 1.5 x the upper limit of normal (ULN);
  • Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 x ULN (≤ 5x ULN in the presence of hepatic metastases);
  • Creatinine clearance ≥50 ml/min based on Cockcroft Gault estimation;
  • Prothrombin time (PT), international normalized ratio (INR) and partial thromboplastin time (PTT) ≤1.5 x ULN. Patients on a stable regimen of anticoagulant therapy for at least one month prior to the first dose of study drug may have PT/INR measurements > 1.5 x ULN if, in the opinion of the Investigator, the patient is suitable for the study. An adequate rationale must be provided to the Sponsor prior to randomization.
• Resolution of all toxicities from prior therapy to ≤ Grade 1 (or patient baseline) within 1 week prior to the first dose of study drug (excluding alopecia and ≤ Grade 3 clinically asymptomatic lipase, amylase, and creatine phosphokinase (CPK) laboratory abnormalities).
• The patient is capable of understanding and complying with the protocol and has signed the informed consent document. Signed informed consent form (ICF) must be obtained before any study-specific procedures are performed.

 Exclusion Criteria:

• Treatment with any other line of therapy in addition to imatinib for advanced GIST.
• Patients with a prior or concurrent malignancy whose natural history or treatment have the potential to interfere with the safety or efficacy assessment of this clinical trial are not eligible. For example, patients receiving adjuvant cancer treatment are not eligible if those medications are potentially active against GIST or excluded per protocol.
  • NOTE: Patients with a history of breast cancer, requiring continued hormonal treatment (e.g. anti-estrogen or an aromatase inhibitor) may continue treatment. Patients with a history of prostate cancer, requiring continued support with luteinizing hormone-releasing hormone (LHRH) agonists, with or without androgens, may continue treatment.
• Patient has known active central nervous system metastases.
• New York Heart Association class II-IV heart disease, myocardial infarction within 6 months of cycle 1 day 1, active ischemia or any other uncontrolled cardiac condition such as angina pectoris, clinically significant cardiac arrhythmia requiring therapy, uncontrolled hypertension or congestive heart failure.
• Left ventricular ejection fraction (LVEF) < 50% at screening.
• Arterial thrombotic or embolic events such as cerebrovascular accident (including ischemic attacks) or hemoptysis within 6 months before the first dose of study drug.
• Venous thrombotic events (e.g., deep vein thrombosis) or pulmonary arterial events (e.g., pulmonary embolism) within 1 month before the first dose of study drug. Patients on stable anticoagulation therapy for at least one month are eligible.
• 12-lead electrocardiogram (ECG) demonstrating QT interval corrected (QTc) by Fridericia's formula > 450 ms in males or > 470 ms in females at screening or history of long QTc syndrome.
• Use of strong or moderate inhibitors or inducers of cytochrome P450 (CYP) 3A4, including certain herbal medications (e.g., St. John’s Wort) within 14 days or 5 x the half-life (whichever is longer) prior to the first dose of study drug, and consumption of grapefruit or grapefruit juice within 14 days prior to the first dose of study drug. Please refer to the Indiana University Department of Medicine website (http://medicine.iupui.edu/clinpharm/ddis/main-table/) for guidance on medications that inhibit/induce CYP3A4 enzymes.
• Use of known substrates or inhibitors of BCRP transporters within 14 days or 5 x the half-life (whichever is longer) prior to the first dose of study drug. Please refer to the US Food and Drug Administration’s (FDA) website for inhibitors and substrates (https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm).
• Major surgeries (e.g. abdominal laparotomy) within 4 weeks of the first dose of study drug. All major surgical wounds must be healed and free of infection or dehiscence before the first dose of study drug.
• Any other clinically significant comorbidities, such as uncontrolled pulmonary disease, active infection, or any other condition, which in the judgment of the Investigator, could compromise compliance with the protocol, interfere with interpretation of the study results, or predispose the patient to safety risks.
• Known human immunodeficiency virus or hepatitis C infection only if the patient is taking medications that are excluded per protocol, active hepatitis B, or active hepatitis C infection.
• If female, the patient is pregnant or lactating.
• Known allergy or hypersensitivity to any component of the study drug. Patients with history of Stevens-Johnson syndrome on a prior tyrosine kinase inhibitor (TKI) are excluded.
• Gastrointestinal abnormalities including, but not limited to:
  • inability to take oral medication;
  • malabsorption syndromes;
  • requirement for intravenous (IV) alimentation.
• Any active bleeding excluding hemorrhoidal or gum bleeding.