The objective of this study is to investigate the safety, tolerability and preliminary activity of ivosidenib in combination with durvalumab and gemcitabine/cisplatin as first-line therapy in participants with locally advanced, unresectable or metastatic cholangiocarcinoma with an IDH1 mutation. The study will begin with a safety lead-in phase (Phase 1b study) to determine the recommended combination dose (RDC) and then will transition to an expansion phase (Phase 2 study) to assess the clinical activity of ivosidenib in combination with durvalumab and gemcitabine/cisplatin at the RCD. During the treatment period participants will have study visits on days 1, 8, and 15 of Cycle 1, on days 1 and 8 of Cycle 2 to 8, and on day 1 of each additional cycle. Cycles 1 through 8 are 21 day cycles, and each following cycle is 28 days. Approximately 30 days and 90 days after treatment has ended, safety follow-up visits will occur and then participants will be followed for survival every 3 months. Study visits may include blood tests, ECG, vital signs, and a physical examination.
Have a histopathological confirmed diagnosis consistent with locally advanced unresectable or metastatic cholangiocarcinoma.
Have documented IDH1 gene-mutated cholangiocarcinoma based on local or central laboratory testing (R132C/L/G/H/S mutation variants tested).
Have at least one evaluable and measurable lesion as defined by RECIST v1.1.
Absolute neutrophil count ≥ 1,500/mm3 or 1.5 ×109/L
Treatment with up to one cycle of durvalumab plus gemcitabine/cisplatin treatment is permitted before study participation. Note: For the Safety Lead-In Phase, participants who received one prior cycle of durvalumab plus gemcitabine/cisplatin and required dose modifications for treatment-related toxicity are excluded.
Patients who developed recurrent disease > 6 months after surgery with curative intent, and, if given, > 6 months after the completion of adjuvant (chemotherapy and/or radiation).
Prior exposure to immune-mediated therapy, including, but not limited to, anti-PD-1or other anti-PD-L1, and anti-PD-L2, anti-CTLA-4 antibodies, excluding therapeutic anticancer vaccines.
Unresolved Grade ≥2 adverse events from a previous anticancer therapy, with the exception of alopecia and vitiligo and the laboratory values listed in the inclusion criteria.
Sequential
Ivosidenib
DrugTwo 250 mg tablets, totaling 500 mg, administered orally once daily, taken continuously throughout treatment duration
Durvalumab (for the first 8, 21-day, cycles)
Drug1500mg intravenous (IV) infusion every 3 weeks, for a maximum of 8 (21-day) cycles
Gemcitabine (for the first 8, 21-day, cycles)
Drug1000 mg/m2 IV infusion on days 1 and 8 of every 21-day cycle, for a maximum of 8 cycles
Cisplatin (for the first 8, 21-day, cycles)
Drug25 mg/m\^2 IV infusion on days 1 and 8 of every 21-day cycle, for a maximum of 8 cycles
Durvalumab (starting from cycle 9)
Drug1500mg intravenous (IV) infusion every 4 weeks, starting from cycle 9. Cycles are 28 days long, starting Cycle 9.
Ivosidenib Recommended Combination Dose (RCD)
DrugRCD administered orally once daily, taken continuously throughout treatment duration
Safety Lead-in Phase: Number of Dose-limiting toxicities (DLTs)
Safety Lead-in Phase: Number of adverse events (AEs), adverse events of special interest (AESIs), and serious adverse events (SAEs)
Expansion Phase: Objective response rate (ORR)
Confirmed complete response (CR) or confirmed partial response (PR) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
Safety Lead-in Phase: Ivosidenib Area under the concentration-versus-time curve (AUC) from time 0 to time of last measurable concentration (AUC0-t)
Safety Lead-in Phase: Ivosidenib AUC over 1 dosing interval at steady state (AUCtau,ss)
Safety Lead-in Phase: Ivosidenib time to maximum concentration (Tmax)
Safety Lead-in Phase: Ivosidenib maximum concentration (Cmax)
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