Gemcitabine and Cisplatin with or without Devimistat as First Line Therapy for the Treatment of Advanced Unresectable Biliary Tract Cancer, BilT-04 Trial

Inclusion Criteria

• Patients must have a pathologically or cytologically confirmed carcinoma (except neuroendocrine) of the biliary tract (intra-hepatic, extra-hepatic [hilar, distal] or gallbladder) that is not eligible for curative resection, transplantation, or ablative therapies. Tumors of mixed cholangiocarcinoma/hepatocellular carcinoma histology are excluded
• Patients may not have received prior systemic treatment (chemotherapy or targeted therapy) for advanced BTC. Prior peri-operative chemotherapy is permitted provided it was completed > 6 months from enrollment
• Patients may have received prior radiation, chemoembolization, radioembolization or other local ablative therapies or hepatic resection if completed >= 4 weeks prior to enrollment AND if patient has recovered to =< grade 1 toxicity. Extrahepatic palliative radiation is permitted if completed >= 2 weeks prior to enrollment AND if patient has recovered to =< grade 1 toxicity
• Patients must have radiographically measurable disease (as per Response Evaluation Criteria in Solid Tumors [RECIST] version [v]1.1) in at least one site not previously treated with radiation or liver directed therapy (including bland, chemo- or radio-embolization, or ablation) either within the liver or in a metastatic site
• Must be >= 18 years of age
• Must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
• Ability to understand and willingness to sign Institutional Review Board (IRB)-approved informed consent
• Willing to provide archived tissue, if available, from a previous diagnostic biopsy or surgery
• Must be able to tolerate computed tomography (CT) and/or magnetic resonance imaging (MRI) with contrast
• Absolute neutrophil count >= 1500/mm^3 (obtained =< 2 weeks prior to enrollment)
• Hemoglobin >= 9 g/dL (obtained =< 2 weeks prior to enrollment)
• Platelets >= 100,000/mm^3 (obtained =< 2 weeks prior to enrollment)
• Serum creatinine =< 1.5 x upper limit of normal (ULN) (obtained =< 2 weeks prior to enrollment)
• Creatinine clearance >= 50 mL/min (obtained =< 2 weeks prior to enrollment)
• Albumin >= 3.0 g/dL (obtained =< 2 weeks prior to enrollment)
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3.0 x ULN (=< 5 x ULN if liver tumor or metastasis) (obtained =< 2 weeks prior to enrollment)
• Total bilirubin =< 1.5 x ULN (obtained =< 2 weeks prior to enrollment)
• International normalized ratio (INR) =< 1.5 x ULN (obtained =< 2 weeks prior to enrollment)
• Women of child-bearing potential and men must agree to use 2 methods of adequate contraception (hormonal plus barrier or 2 barrier forms) OR abstinence prior to study entry, for the duration of study participation and for 6 months (for men and women) following completion of study therapy

Exclusion Criteria

• Must not have prior history of brain metastasis (unless previously treated, asymptomatic and stable for at least 3 months), or organ transplantation
• Must not have undergone a major surgical procedure < 4 weeks prior to enrollment
• Must not have an active second malignancy other than in situ cancer or localized prostate cancer (Gleason score < 8). Patients with a history of other malignancy are eligible provided primary treatment of that cancer was completed > 1 year prior to enrollment and the patient is free of clinical or radiologic evidence of recurrent or progressive malignancy
• Must have no ongoing active, uncontrolled infections (afebrile for > 48 hours off antibiotics)
• Must not have a psychiatric illness, other significant medical illness, or social situation which, in the investigator’s opinion, would limit compliance or ability to comply with study requirements
• Women must not be pregnant or breastfeeding since study drugs may harm the fetus or child. All females of childbearing potential (not surgically sterilized and between menarche and 1 year post menopause) must have a negative screening pregnancy test
• Must not have active heart disease including symptomatic heart failure (New York Heart Association [NYHA] class 3 or 4), unstable angina pectoris, uncontrolled cardiac arrhythmia or interstitial lung disease
• Prisoners or subjects who are involuntarily incarcerated, or compulsorily detained for treatment of either a psychiatric or physical (e.g. infectious disease) illness would be excluded
• Must not have prolonged QT interval corrected by Fridericia's Formula (QTcF) interval > 480 msec
• Patients with known hypersensitivity to cisplatin, gemcitabine or CPI-613, or its inactive components would be excluded