An Open-Label Early Access Phase 3b Study of Ivosidenib in Patients With a Pretreated Locally Advanced or Metastatic Cholangiocarcinoma

Trial ID: 2022-501463-40-01
Protocol: DIM-95031-002
Sponsor: Servier Affaires Medicales

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Diseases & Conditions

Cholangiocarcinoma

Objectives

The primary objective of this study is to evaluate the **safety** of ivosidenib in patients with pretreated locally advanced or metastatic **cholangiocarcinoma**. This is clinically relevant as it aims to determine the tolerability and potential adverse effects of ivosidenib, which is crucial for ensuring patient safety and guiding treatment decisions in this patient population.

Secondary objectives include:

Efficacy in daily clinical practice, which assesses the real-world effectiveness of ivosidenib in managing the disease.
Quality of life (HRQOL), focusing on the impact of treatment on patients' overall well-being and daily functioning.
Utilization of medical resources, which examines the healthcare resources required during treatment, providing insights into the economic implications of therapy.

Participants

The clinical trial involves a total of **78 participants** diagnosed with **locally advanced or metastatic cholangiocarcinoma**. The study population includes both male and female subjects, aged 18 years and older, who have been pretreated and are not eligible for curative-intent resection, transplantation, or ablative therapies. Participants were selected based on specific criteria, including a histopathological diagnosis of cholangiocarcinoma with documented IDH1 gene mutations and an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1. The trial includes individuals who have recovered from prior anticancer therapy toxicities and possess adequate bone marrow, hepatic, and renal function. The study does not specify particular lifestyle considerations such as diet or physical activity. The trial population also includes vulnerable groups, ensuring a comprehensive evaluation of the safety of ivosidenib in this patient cohort.

Plans and Procedures

The clinical trial is designed to evaluate the **safety** of **ivosidenib** in patients with pretreated locally advanced or metastatic **cholangiocarcinoma**. This is an open-label, Phase 3b study, which involves the administration of **ivosidenib** in the form of film-coated tablets, taken orally. The trial is expected to run until December 31, 2025, with recruitment having commenced on August 23, 2023. Participants will be involved in the study for a maximum treatment period of 24 months, during which they will receive a daily dose of up to 500 mg of **ivosidenib**.

The trial follows a structured sequence of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age, diagnosis, and previous treatment history. Participants must be at least 18 years old, have a histopathological diagnosis of nonresectable or metastatic **cholangiocarcinoma**, and have documented IDH1 gene mutations. They must also have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 and adequate bone marrow, hepatic, and renal function. Follow-up visits will be conducted regularly to monitor safety and efficacy, including assessments of adverse events (AEs), serious adverse events (SAEs), and other safety parameters such as laboratory tests, ECGs, and vital signs. The end-of-study visit will conclude the participant's involvement, with a comprehensive evaluation of their response to treatment.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they choose to withdraw consent. The primary endpoints focus on the safety profile of **ivosidenib**, while secondary endpoints include treatment response, progression-free survival, overall survival, and health-related quality of life (HRQOL) assessments. The study aims to provide valuable data on the therapeutic potential of **ivosidenib** in this patient population, contributing to the understanding of its role in managing advanced **cholangiocarcinoma**.

Treatment

The clinical trial involves the administration of **Ivosidenib**, a chemical compound, as the experimental medication. Ivosidenib is provided in the form of a film-coated tablet. The active substance, Ivosidenib, is administered orally. The dosage is set at a maximum of 500 mg per day, with the total daily dose not exceeding 500 mg. The treatment period is capped at 24 months. The study-specific packaging and labeling are utilized to ensure proper administration and compliance. The medication is identified by the sponsor product code AG-120 and is designated as an orphan drug under the number EU/3/18/1994.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on evaluating the safety of Ivosidenib in patients with pretreated locally advanced or metastatic cholangiocarcinoma. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen.

Efficacy

Efficacy in this clinical trial will be assessed through a series of secondary endpoints. These include the response to treatment based on tumor assessments conducted by the investigator according to local clinical practice. Key parameters for evaluating efficacy will include **progression-free survival (PFS)**, overall survival (OS), duration of response (DOR), and time to response (TTR). Additionally, health-related quality of life (HRQOL) will be measured using the validated European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Cholangiocarcinoma and Gallbladder Cancer Module (QLQ-BIL21). Health economic outcomes will be evaluated using the 5-level EuroQol 5-dimensional questionnaire (EQ-5D-5L). The proportion of days spent at home or in the hospital and the use of concomitant medications will also be recorded as part of the efficacy assessment.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Be ≥18 years of age
Have a histopathological diagnosis of CCA consistent with nonresectable or metastatic CCA and are not eligible for curative-intent resection, transplantation, or ablative therapies
Have documented IDH1 R132C, R132L, R132G, R132H, or R132S gene-mutated disease based on a local validated biomolecular profiling method
Have documented locally advanced or metastatic CCA following at least 1 prior line of systemic therapy
Have an ECOG PS score of 0 or 1
Have recovered from toxicities associated with prior anticancer therapy to baseline or have stabilized under medical management
Have adequate bone marrow function as described in the protocol.
Have adequate hepatic function as described in the protocol.
Have adequate renal function as described in the protocol.
Be able to understand and willing to sign the informed consent form (ICF) and to comply with the study procedures.
Willingness to comply with contraception guidelines of this study.

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Exclusion Criteria

Received a prior IDH1 inhibitor
Had a prior transplantation
Received systemic anticancer therapy <2 weeks prior to first dose of study treatment on C1D1, immune based anticancer therapy <4 weeks prior to C1D1, or an investigational agent <5 half-lives of this agent prior to C1D1
Received radiotherapy to metastatic sites of disease <2 weeks prior to C1D1
Underwent hepatic radiation, chemoembolization, and radiofrequency ablation <4 weeks prior to C1D1
Have known symptomatic brain metastases requiring steroids.
Have a history of another primary cancer, with the exception of: a) curatively resected non-melanoma skin cancer; b) curatively treated cervical carcinoma in situ; or c) other primary solid or liquid tumor with no known active disease present that, in the opinion of the Investigator, will not affect patient outcome in the setting of current CCA diagnosis.
Underwent major surgery <4 weeks prior to C1D1 or have not recovered from post-surgery toxicities
Are pregnant or breastfeeding
Are taking known strong cytochrome P450 (CYP) 3A4 inducers or inhibitors or sensitive CYP3A4 substrate medications, unless they can be transferred to other medications.
Are taking P-glycoprotein (P-gp) transporter-sensitive substrate medications or inhibitors unless they can be transferred to other medications.
Have an active infection requiring systemic anti-infective therapy or with an unexplained fever >38.5°C within 7 days of Day 1.
Have any known hypersensitivity to any of the components of ivosidenib
Have significant active cardiac disease within 6 months prior to the start of study treatment.
Have known active hepatitis B (HBV) or hepatitis C (HCV) infections, known positive human immunodeficiency virus (HIV) antibody results, or acquired immunodeficiency syndrome (AIDS) related illness.
Have any gastrointestinal medical condition which would limit ingestion or gastrointestinal absorption according to investigator’s judgment

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Austria	Not Recruiting	23 Aug 2023	2
Belgium	Not Recruiting	23 Aug 2023	25
France	Not Recruiting	23 Aug 2023	20
Germany	Not Recruiting	23 Aug 2023	13
Ireland	Not Recruiting	23 Aug 2023	12
Italy	Not Recruiting	23 Aug 2023	47
The Netherlands	Not Recruiting	23 Aug 2023	—
Romania	Recruiting	23 Aug 2023	10
Spain	Not Recruiting	23 Aug 2023	45
Sweden	Not Recruiting	23 Aug 2023	10