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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Institut De Recherches Internationales Servier IRIS

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

24 Mar 2025 → ongoing

Decision date (initial)

2025-03-03

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Laboratorios Servier, S. L · ADIR France

External identifiers

EU CT number

2024-514261-19-00

ClinicalTrials.gov

NCT06501625

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Efficacy, Pharmacodynamic, Others

Safety Lead-in Phase:
To assess the safety and tolerability of ivosidenib in combination with durvalumab and gemcitabine/cisplatin as first-line therapy in participants with locally advanced, unresectable or metastatic CCA harboring on isocitrate deshydrogenase 1 (IDH1) mutation.
To determine the recommended combination dose (RCD) of ivosidenib in combination with durvalumab and gemcitabine/cisplatin as first-line therapy.
Expansion Phase:
To assess the clinical activity of ivosidenib in combination with durvalumab and gemcitabine/cisplatin as first-line therapy using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1

Secondary objectives 4

1. Safety Lead-in Phase and Expansion phase: To evaluate the pharmacokinetics (PK) and pharmacodynamic (PD) effect of ivosidenib when given in combination with durvalumab and gemcitabine/ cisplatin as first-line therapy
2. Safety Lead-in Phase and Expansion Phase: To investigate the immunogenicity of durvalumab
3. Expansion Phase: To confirm the safety and tolerability of the RCD of ivosidenib with durvalumab and gemcitabine/cisplatin
4. Expansion Phase: To evaluate additional efficacy parameters to assess the anti-tumor activity of ivosidenib in combination with durvalumab and gemcitabine/ cisplatin as first-line therapy

Conditions and MedDRA coding

Locally advanced, unresectable or metastatic cholangiocarcinoma with an IDH1 mutation

Study design 2 periods

Regulatory references

Plan to share IPD

Yes

IPD plan description

Servier’s Data Sharing Policy is available at https://clinicaltrials.servier.com/data-request-portal/. Researchers can ask for a study protocol, patient-level and/or study-level clinical study data including clinical study reports. They can ask for all interventional clinical studies in patients:Submitted for new medicines and new indications approved after 1 January 2014 in the European Economic Area(EEA) or the United States(US).Where Servier or an affiliate are the Marketing Authorisation Holders (MAH). The date of the first MA of the new medicine (or the new indication) in one of the EEA Member States will be considered within this scope. In addition, Servier’s data sharing policy includes all interventional clinical studies in patients: sponsored by Servier, with a first patient enrolled as of 1 January 2004 onwards, for New Chemical Entity or New Biological Entity (new pharmaceutical form excluded) for which development has been terminated before any MA approval.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Have a histopathological confirmed diagnosis consistent with locally advanced unresectable or metastatic cholangiocarcinoma
2. Have documented IDH1 gene-mutated CCA based on local testing (R132C/L/G/H/S mutation variants tested).
3. Have at least one evaluable and measurable lesion as defined by RECIST v1.1.
4. 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
5. 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
6. 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 8

1. 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).
2. 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.
3. 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
4. Participation in another interventional study at the same time or within 14 days prior to the first study medication (triple combination treatment) administration.
5. 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.
6. 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
7. 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.
8. 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)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 4

1. 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
2. Safety Lead-in Phase: Incidence and severity of adverse events (AEs), adverse events of special interest (AESIs), and serious adverse events (SAEs)
3. Safety Lead-in Phase: Dose reductions, delays, interruptions, and discontinuation.
4. 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

Secondary endpoints 9

1. 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)
2. Safety Lead-in Phase: PD parameters including plasma 2-hydroxygluturate (2-HG) concentrations
3. Safety Lead-in Phase and Expansion Phase: Presence of ADAs for durvalumab (confirmatory results: positive or negative, titres)
4. Expansion Phase: Incidence and severity of AEs, AESIs, and SAEs
5. Expansion Phase: Dose reductions, delays, interruptions, and discontinuation
6. Expansion Phase: Overall survival (OS)
7. 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
8. 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
9. Expansion Phase: Plasma 2-hydroxygluturate (2-HG) concentration

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Institut De Recherches Internationales Servier IRIS

Sponsor organisation

Institut De Recherches Internationales Servier IRIS

Address

22 Route 128

City

Gif Sur Yvette

Postcode

91190

Country

France

Scientific contact point

Organisation

Institut De Recherches Internationales Servier IRIS

Contact name

Clinical Studies Department

Public contact point

Organisation

Institut De Recherches Internationales Servier IRIS

Contact name

Clinical Studies Department

Third parties 9

Locations

3 EU/EEA countries · 13 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 33 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

8 submissions — initial application plus substantial / non-substantial modifications