IVOSIDENIB for Cholangiocarcinoma | Cholangiocarcinoma with IDH1 mutation

Inclusion criteria

• {"criterion_text":"- Have a histopathological confirmed diagnosis consistent with locally advanced unresectable or metastatic cholangiocarcinoma"}
• {"criterion_text":"- Have documented IDH1 gene-mutated CCA based on local testing (R132C/L/G/H/S mutation variants tested)."}
• {"criterion_text":"- Have at least one evaluable and measurable lesion as defined by RECIST v1.1."}
• {"criterion_text":"- 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"}
• {"criterion_text":"- Have adequate hepatic function as evidenced by: - Serum bilirubin ≤ 1.5 × the upper limit of normal (ULN); this will not apply to participants with confirmed Gilbert’s syndrome. Any clinically significant biliary obstruction should be resolved before randomization - Aspartate aminotransferase (AST), and alanine aminotransferase (ALT) ≤ 2.5 × ULN; for participants with hepatic metastases, ALT and AST ≤ 5.0 × ULN"}
• {"criterion_text":"- Have adequate renal function, defined as: creatinine clearance > 50 mL/min as calculated by Cockcroft-Gault formula (using actual body weight): Creatine CL (mL/min)= (140 − Age) × (weight in kg) × (0.85 if female)/72 × serum creatinine (mg/dL)"}

Exclusion criteria

• {"criterion_text":"- Received treatment for locally advanced, unresectable or metastatic disease with the following exceptions: - Treatment with up to one cycle of durvalumab plus gemcitabine/cisplatin treatment is permitted before initiation of study treatment (Cycle 1 Day 1) and if 1 cycle of durvalumab plus gemcitabine/cisplatin was given prior to C1D1, participants may receive up to 7 cycles of durvalumab/gemcitabine/cisplatin with ivosidenib on study. 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. - Participants 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)."}
• {"criterion_text":"- 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, or one prior cycle allowance in aforementioned criteria."}
• {"criterion_text":"- Unresolved Grade ≥2 adverse events from a previous anticancer therapy (e.g. neuropathy), with the exception of alopecia and vitiligo and the laboratory values listed in the inclusion criteria. - Participants with irreversible toxicity not reasonably expected to be exacerbated by treatment with ivosidenib may be included only after consultation with the medical monitor"}
• {"criterion_text":"- Participation in another interventional study at the same time or within 14 days prior to the first study medication (triple combination treatment) administration."}
• {"criterion_text":"- 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, rheumatoid arthritis, 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."}
• {"criterion_text":"- 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 replacement therapy - unmedicated celiac disease that is controlled by diet"}
• {"criterion_text":"- Have heart rate-corrected QT interval using Fridericia’s formula (QTcF) of ≥ 450 msec or with other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome/sudden death, polymorphic ventricular arrhythmia). The Sponsor should review participants with bundle branch block and prolonged QTcF for potential inclusion."}
• {"criterion_text":"- Have an active , severe, or uncontrolled active, or acute or chronic infection, are not eligible : - Known co-infection with HBV and HCV, or co-infection with HBV and HDV. HBV, HCV, or HDV positivity is defined as: * HBV positive (presence of HBsAg and/or anti-HBcAb with detectable HBV DNA or HBV RNA) * HCV positive (presence of anti-HCV antibodies or HCV RNA) * HDV positive (presence of anti-HDV antibodies or HDV RNA) - Known Tuberculosis (clinical evaluation includes: clinical history, physical examination and/or radiographic findings, and tuberculosis testing as per local practice) - Known human immunodeficiency virus (clinical evaluation includes: positive HIV 1/2 antibodies)"}

Primary endpoints

• {"endpoint_text":"- Safety Lead-in Phase: Dose-limiting toxicities (DLTs) associated with ivosidenib in combination with durvalumab and gemcitabine/ cisplatin as first-line therapy during the first cycle of treatment","definition_or_measurement_approach":"DLTs assessed during first cycle of treatment in Safety Lead-in Phase (per protocol-defined DLT criteria)."}
• {"endpoint_text":"- Safety Lead-in Phase: Incidence and severity of adverse events (AEs), adverse events of special interest (AESIs), and serious adverse events (SAEs)","definition_or_measurement_approach":"Standard AE reporting including grading of severity and classification of AESIs and SAEs according to protocol-defined criteria."}
• {"endpoint_text":"- Safety Lead-in Phase: Dose reductions, delays, interruptions, and discontinuation.","definition_or_measurement_approach":"Recording of dose modifications, delays, interruptions and treatment discontinuations during Safety Lead-in Phase."}
• {"endpoint_text":"- Expansion phase: Objective response (confirmed complete response ([CR] or confirmed partial response [PR]) of anti-tumor activity of ivosidenib in combination with durvalumab and gemcitabine/cisplatin as first-line therapy using RECIST v1.1","definition_or_measurement_approach":"Objective response evaluated and confirmed per RECIST v1.1 (CR or PR confirmed)."}

Secondary endpoints

• {"endpoint_text":"- Safety Lead-in Phase: Ivosidenib plasma concentrations and PK parameters including, but not limited to: • Area under the concentration-versus-time curve (AUC) from time 0 to time of last measurable concentration (AUC0-t) • AUC over 1 dosing interval at steady state (AUCtau,ss) • Time to maximum concentration (Tmax) • Maximum concentration (Cmax) • Trough concentration (Ctrough) • Apparent volume of distribution (Vd/F) • Apparent clearance (CL/F)","definition_or_measurement_approach":"Pharmacokinetic sampling and calculation of standard PK parameters (AUC0-t, AUCtau,ss, Tmax, Cmax, Ctrough, Vd/F, CL/F)."}
• {"endpoint_text":"- Safety Lead-in Phase: PD parameters including plasma 2-hydroxygluturate (2-HG) concentrations","definition_or_measurement_approach":"Measurement of plasma 2-HG concentrations as PD biomarker."}
• {"endpoint_text":"- Safety Lead-in Phase and Expansion Phase: Presence of ADAs for durvalumab (confirmatory results: positive or negative, titres)","definition_or_measurement_approach":"Assessment of anti-drug antibodies (ADAs) for durvalumab with confirmatory testing and titre reporting."}
• {"endpoint_text":"- Expansion Phase: Incidence and severity of AEs, AESIs, and SAEs","definition_or_measurement_approach":"Standard AE reporting during Expansion Phase with grading and classification."}
• {"endpoint_text":"- Expansion Phase: Dose reductions, delays, interruptions, and discontinuation","definition_or_measurement_approach":"Recording of dose modifications, delays, interruptions and treatment discontinuations during Expansion Phase."}
• {"endpoint_text":"- Expansion Phase: Overall survival (OS)","definition_or_measurement_approach":"Overall survival measured from randomization/enrollment to death from any cause."}
• {"endpoint_text":"- Expansion Phase: Duration of response (DOR), progression-free survival (PFS), disease control (i.e., confirmed CR, confirmed PR, or stable disease [SD]), and time to response (TTR) according to RECIST v1.1","definition_or_measurement_approach":"Tumor response and time-to-event endpoints assessed per RECIST v1.1 (DOR, PFS, disease control rate, TTR)."}
• {"endpoint_text":"- Expansion Phase: Ivosidenib plasma concentrations and PK parameters including, but not limited to, AUC0-t, AUCtau,ss, Tmax, Cmax, Ctrough, Vd/F, and CL/F","definition_or_measurement_approach":"PK sampling and analysis as per PK endpoints (see Safety Lead-in PK endpoints)."}
• {"endpoint_text":"- Expansion Phase: Plasma 2-hydroxygluturate (2-HG) concentration","definition_or_measurement_approach":"Measurement of plasma 2-HG concentration as PD marker."}

France

Earliest CTIS Part Ii Submission Date

17-02-2025

Latest Decision Or Authorization Date

24-02-2026

Processing Time Days

372

Number Of Sites

3

Number Of Participants

3

Spain

Earliest CTIS Part Ii Submission Date

12-02-2025

Latest Decision Or Authorization Date

20-03-2026

Processing Time Days

401

Number Of Sites

5

Number Of Participants

8

Germany

Earliest CTIS Part Ii Submission Date

21-02-2025

Latest Decision Or Authorization Date

01-04-2026

Processing Time Days

404

Number Of Sites

5

Number Of Participants

5

Primary sponsor

Full Name

Institut De Recherches Internationales Servier IRIS

Organisation Type

Pharmaceutical company

Country Of Registered Address

France

Contract research organisations

Name

IQVIA Limited

Name

Ppd Inc.

Responsibilities

PK of study drug Tibsovo in plasma, PD-2HG in plasma

Name

PPD Global Central Labs

Responsibilities

Central Lab and Logistics Platform

Third parties

• {"country":"France","full_name":"Median Technologies","duties_or_roles":"Blinded Independent Central Reviewer of Imaging","organisation_type":"Pharmaceutical company"}
• {"country":"Belgium","full_name":"PPD Global Central Labs","duties_or_roles":"Central Lab and Logistics Platform","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"IQVIA Limited","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Life Technologies Clinical Services Lab Inc.","duties_or_roles":"DNA sequencing including IDH1 mutation status","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"France","full_name":"Firalis","duties_or_roles":"Analysis of plasma cytokine (Mechanism of Action and Predictor of Response)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Bioagilytix Labs LLC","duties_or_roles":"PK/ADA for durvalumab","organisation_type":"Pharmaceutical company"}
• {"country":"Spain","full_name":"Vall D Hebron Institute Of Oncology","duties_or_roles":"IDH1 mutation status (alternative option)","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Azenta US Inc.","duties_or_roles":"Long Term Storage / Biobank","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Ppd Inc.","duties_or_roles":"PK of study drug Tibsovo in plasma, PD-2HG in plasma","organisation_type":"Pharmaceutical company"}