A Study to Assess DCC-2618 and Sunitinib in Patients With Advanced GIST After Treatment With Imatinib

Inclusion criteria

• Male or female patients ≥18 years of age.
• Histological diagnosis of advanced GIST and capability of providing tumor tissue sample (the interval between tumor tissue collection and signing of informed consent form should be less than 3 years). Otherwise, biopsy is required.
• Provide molecular test report with KIT/PDGFRA mutation status prior to randomization.
• Patients must have progressed on imatinib or have documented intolerance to imatinib. Subjects must have discontinued imatinib treatment 10 days prior to the first dose of the study drug. All prior imatinib treatments will be considered as first-line (such as imatinib adjuvant therapy and imatinib dose increase).
• ECOG PS of 0-2.
• Female patients of childbearing potential must have a negative serum beta-human chorionic gonadotropin (β-hCG) pregnancy test at screening.
• Patients of reproductive potential must agree to follow the contraception requirements.
• At least 1 measurable lesion according to the "RECIST v1.1-GIST-specific Criteria" (non-nodal lesions must be ≥1.0 cm in the long axis or ≥ double the slide thickness in the long axis) ; obtaining radiographic image results within 28 days prior to the first dose of study drug.
• Good organ function and bone marrow reserve function, including:

• Neutrophil count ≥ 1,000/µL
• Hemoglobin ≥ 8 g/dL
• Platelet count ≥ 75,000/µL
• Total bilirubin ≤ 1.5 × the upper limit of normal (ULN)
• AST and ALT ≤ 3×ULN, and AST and ALT≤ 5×ULN in the presence of hepatic metastases
• Creatinine clearance ≥ 50 mL/min (based on Cockcroft-Gault estimation Formulas for calculation)
• Prothrombin time (PT), international normalized ratio (INR) or partial thromboplastin time ≤ 1.5 × ULN. Patients on a stable, maintenance regimen of anticoagulant therapy for at least 30 days prior to study drug administration may have PT/INR measurements >1.5 × 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 baseline) within 1 week prior to the first dose of study drug (excluding alopecia and ≤ Grade 3 clinically asymptomatic lipase, amylase, and creatine phosphokinase laboratory abnormalities).
• Patient is capable of understanding and complying with the protocol. Subjects should sign the written informed consent before any study-related procedures were performed.

Exclusion criteria

• Treatment with any other line of therapy in addition to imatinib for advanced GIST. Imatinib-containing combination therapy in the first-line treatment should not be enrolled.
• 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.
• Patient has known active central nervous system metastases.
• New York Heart Association class II - IV heart disease, myocardial infarct, active ischemia or any other uncontrolled cardiac condition within the first 6 months of the first dose of study drug such as angina pectoris, clinically significant cardiac arrhythmia requiring therapy, uncontrolled hypertension or congestive heart failure.
• Left ventricular ejection fraction (LVEF) < 50%.
• 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 by Fridericia's formula > 450 ms in males or > 470 ms in females at screening or history of long QT interval syndrome.
• Use of strong or moderate inhibitors and/or inducers of cytochrome P450 (CYP) 3A4 within 14 days or 5 x the half-life (whichever is longer) prior to the first dose of study drug, including certain herbal medications (eg, St. John's Wort) and consumption of grapefruit or grapefruit juice within 14 days prior to the first dose of study drug.
• Use of known substrates or inhibitors of breast cancer resistance protein (BCRP) transporters within 14 days or 5 x the half-life (whichever is longer) prior to the first dose of study drug.
• 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, hepatitis B virus (HBV) DNA > 2000 IU/ml or > 104 copies/ml.
• Female patients who are pregnant or lactating or who plan to become pregnant during the study treatment period.
• Known hypersensitivity to any component of the study drug. Patients with Stevenson Johnson syndrome in previous TKI treatment need to be excluded.
• Gastrointestinal abnormalities including but not limited to:

• inability to take oral medication
• malabsorption syndrome
• Requiring intravenous nutrition
• Any active hemorrhages, excluding hemorrhoids or gum bleeding.