Ivosidenib Plus Durvalumab and Gemcitabine/Cisplatin as First-Line Therapy in Participants With Locally Advanced or Metastatic Cholangiocarcinoma With an IDH1 Mutation

Inclusion Criteria:

• Have a histopathological confirmed diagnosis consistent with locally advancedunresectable or metastatic cholangiocarcinoma.

• Have documented IDH1 gene-mutated cholangiocarcinoma based on local or centrallaboratory testing (R132C/L/G/H/S mutation variants tested).

• Have at least one evaluable and measurable lesion as defined by RECIST v1.1.

• Have adequate bone marrow function as evidenced by:

• Absolute neutrophil count ≥ 1,500/mm3 or 1.5 ×109/L

• Hemoglobin ≥ 9 g/dL

• Platelet count ≥ 100,000/mm3 or 100 × 109/L

• Have adequate hepatic function as evidenced by:

• Serum bilirubin ≤ 2.0 × the upper limit of normal (ULN); this will not apply topatients with confirmed Gilbert's syndrome. Any clinically significant biliaryobstruction should be resolved before randomization

• Aspartate aminotransferase (AST), and alanine aminotransferase (ALT) ≤ 2.5 × ULN;for patients with hepatic metastases, ALT and AST ≤ 5.0 × ULN

• Have adequate renal function, defined as: creatinine clearance > 60 mL/min per 24hour urine or as calculated on the Cockcroft-Gault formula (using actual bodyweight):

Creatine CL (mL/min)= (140 - Age) × (weight in kg) × (0.85 if female)/72 × serum creatinine (mg/dL)

Exclusion Criteria:

• Received treatment for locally advanced, unresectable or metastatic disease with thefollowing exceptions:

• Treatment with up to one cycle of durvalumab plus gemcitabine/cisplatin treatment ispermitted before study participation. Note: For the Safety Lead-In Phase,participants who received one prior cycle of durvalumab plus gemcitabine/cisplatinand required dose modifications for treatment-related toxicity are excluded.

• Patients who developed recurrent disease > 6 months after surgery with curativeintent, and, if given, > 6 months after the completion of adjuvant (chemotherapyand/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, excludingtherapeutic anticancer vaccines.

• Unresolved Grade ≥2 adverse events from a previous anticancer therapy, with theexception of alopecia and vitiligo and the laboratory values listed in the inclusioncriteria.

• Patients with Grade ≥2 neuropathy to be evaluated on a case-by-case basis afterconsultation with the medical monitor

• Patients with irreversible toxicity not reasonably expected to be exacerbated bytreatment with ivosidenib may be included only after consultation with the medicalmonitor

• Participation in another interventional study at the same time or within 14 daysprior to the first study medication (triple combination treatment) administration.For patients having participated to another prior interventional study, the firstdose of ivosidenib should occur after a period greater than or equal to 5 half-livesor 28 days, whichever is shorter of the last dose of the prior investigationalproduct.

• Active or prior documented autoimmune or inflammatory disorders including:

• inflammatory bowel disease (e.g., colitis or Crohn's disease)

• diverticulitis (with the exception of diverticulosis)

• systemic lupus erythematosus

• Sarcoidosis syndrome

• Wegener syndrome (granulomatosis with polyangiitis, Graves' disease, rheumatoidarthritis, hypophysitis, uveitis, etc.)

Note: in cases with no active disease for ≥ 5 years, patients may be considered for inclusion if approved by the Medical Monitor. Participants with the following conditions are eligible for the study:

• chronic skin condition that does not require systemic therapy

• vitiligo

• alopecia

• hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacementtherapy

• unmedicated celiac disease that is controlled by diet

• Have heart rate-corrected QT interval using Fridericia's formula (QTcF) of ≥ 450msec or with other factors that increase the risk of QT prolongation or arrhythmicevents (e.g., heart failure, hypokalemia, family history of long QT intervalsyndrome/sudden death, polymorphic ventricular arrhythmia). The Sponsor shouldreview participants with bundle branch block and prolonged QTcF for potentialinclusion.

• Have an active infection, including:

• Hepatitis B (clinical evaluation includes: presence of hepatitis B surface antigen [HBsAg] and/or anti-HBcAb with detectable hepatitis B virus [HBV] DNA ≥ 10 IU/mL)

• Hepatitis C

• Tuberculosis (clinical evaluation includes: clinical history, physical examinationand/or radiographic findings, and tuberculosis testing as per local practice)

• Human immunodeficiency virus (clinical evaluation includes: positive HIV 1/2antibodies) Note: Patients with a resolved or past HBV infection (i.e., presence ofhepatitis B core antibody [anti-HBc] and absence of HBsAg) do not need to beexcluded from the study. Patients positive for hepatitis C (HCV) antibody areeligible only if the polymerase chain reaction is negative for HCV RNA.