Gemcitabine and Cisplatin With or Without CPI-613 as First Line Therapy for Patients With Advanced Unresectable Biliary Tract Cancer (BilT-04)

A Multi-Center Randomized Phase IB/II Study of Gemcitabine and Cisplatin With or Without CPI-613 as First Line Therapy for Patients With Advanced Unresectable Biliary Tract Cancer (BilT-04)

The purpose of this research study is to determine the safety and efficacy of CPI-613 (devimistat) in the treatment of advanced biliary tract cancer when used in combination with standard of care chemotherapy (gemcitabine plus cisplatin) compared to gemcitabine plus cisplatin alone.

This research study has two parts:

In the phase 1 portion of this study, patients will receive a combination of CPI-613 and standard of care chemotherapy. Dose levels of CPI-613 will be adjusted to find the best dose, which will be the recommended phase 2 dose level.

In the phase 2 portion of this study, patients will be randomized into two arms. Patients in Arm A will receive the combination of the recommended dose level of CPI-613 and standard of care chemotherapy. Patients in Arm B will receive standard of care chemotherapy.

At the end of the study, researchers will compare the health outcomes of the patients that received CPI-613 + standard care to the outcomes of patients that received only standard care.

Inclusion:

• 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 RECISTv1.1) 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 ECOG performance status of 0-1.
• Ability to understand and willingness to sign IRB-approved informed consent.
• Willing to provide archived tissue, if available, from a previous diagnostic biopsy or surgery.
• Must be able to tolerate CT and/or MRI with contrast.
• Adequate organ function (per protocol) 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.

Exclusions:

• Prior history of brain metastasis (unless previously treated, asymptomatic and stable for at least 3 months) or organ transplant.
• Underwent a major surgical procedure < 4 weeks prior to enrollment.
• Active second malignancy other than in situ cancer or localized prostate cancer (Gleason score <8). Patients with 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.
• Ongoing active, uncontrolled infection (must be afebrile for > 48 hours off antibiotics) .
• 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.
• Pregnancy or breastfeeding. (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.)
• Active heart disease including symptomatic heart failure (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.
• Prolonged QTcF interval >480 msec.
• Known hypersensitivity to cisplatin, gemcitabine or CPI-613, or its inactive components.