Safety Study of Ivosidenib in Patients with Pretreated Locally Advanced or Metastatic Cholangiocarcinoma

Trial ID: 2022-501463-40-00
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 in a population that has already undergone prior treatments, providing critical safety data for this therapeutic option.

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 and logistical aspects of therapy management.

Participants

The clinical trial involves a total of **44 participants** diagnosed with **locally advanced or metastatic cholangiocarcinoma**. The study population includes both male and female subjects, aged 18 years and older, who have previously undergone at least one line of systemic therapy. Participants were selected based on specific criteria, including a histopathological diagnosis of cholangiocarcinoma that is nonresectable or metastatic, and the presence of an IDH1 gene mutation. The trial includes individuals with an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants must have recovered from prior therapy-related toxicities and possess adequate bone marrow, hepatic, and renal function. The trial population is characterized by a willingness to comply with study procedures and contraception guidelines. The study also considers vulnerable populations, ensuring ethical standards are maintained throughout the trial.

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 a Phase IIIb, open-label study, which means that both the researchers and participants know which treatment is being administered. The trial is expected to run from January 30, 2023, to December 31, 2024. Participants will be involved in the study for a maximum treatment period of 24 months, during which they will receive **ivosidenib** orally, with a maximum daily dose of 500 mg.

The trial includes several key visits. The initial visit is the inclusion (screening) visit, where eligibility is assessed based on criteria such as age (≥18 years), a confirmed diagnosis of nonresectable or metastatic **cholangiocarcinoma**, and documented IDH1 gene mutation. Participants must also have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 and adequate bone marrow, hepatic, and renal function. Following the screening, eligible participants will proceed to the treatment phase, where they will receive the investigational product.

Throughout the study, participants will attend regular follow-up visits to monitor safety and efficacy outcomes. These visits will include assessments of adverse events (AEs), serious adverse events (SAEs), and other safety parameters such as laboratory tests, 12-lead ECG, vital signs, and ECOG performance status. Secondary endpoints will evaluate treatment response, progression-free survival, overall survival, duration of response, and health-related quality of life using validated questionnaires.

The end-of-study visit will occur after the completion of the treatment period or upon early termination. Conditions that may lead to early termination include the occurrence of unacceptable toxicity, disease progression, or withdrawal of consent by the participant. The study aims to provide comprehensive data on the safety and potential benefits of **ivosidenib** in this patient population.

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, also named Ivosidenib, is administered orally. The dosage regimen for this trial specifies a maximum daily dose of 500 mg, with the total dose not exceeding 500 mg per day. The treatment period is set for a maximum of 24 months. The medication is identified by the sponsor product code AG-120 and has been designated as an orphan drug under the designation number EU/3/18/1994. The trial aims to evaluate the safety of Ivosidenib in patients with pretreated locally advanced or metastatic cholangiocarcinoma.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus remains solely on the administration of Ivosidenib. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen. The trial is conducted as an open-label study, allowing for direct observation of the effects of Ivosidenib on the target patient population.

Efficacy

Efficacy in the clinical trial of **ivosidenib** for patients with pretreated locally advanced or metastatic cholangiocarcinoma will be assessed through several 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 assessed 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 evaluated 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 Yet Recruiting	30 Jan 2023	13
Germany	Not Yet Recruiting	30 Jan 2023	30
The Netherlands	Not Yet Recruiting	30 Jan 2023	—
Sweden	Not Yet Recruiting	30 Jan 2023	10
Netherlands	—	—	12