A Phase 2 Study of Ivosidenib in Previously Treated Japanese Subjects With Nonresectable or Metastatic Cholangiocarcinoma With an IDH1 Mutation

Study Overview
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Brief Summary
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This study will enroll participants with nonresectable or metastatic cholangiocarcinoma with an Isocitrate dehydrogenase protein, 1 (IDH1) mutation, who have previously received at least 1, but no more than 2, prior regimens for advanced disease. All participants will receive ivosidenib daily throughout multiple 28 day cycles. Study treatment will be administered until participant experiences unacceptable toxicity, disease progression, or other discontinuation criteria are met. Study visits will be conducted every week during Cycle 1 (Days 1, 8, 15, and 22), every other week during Cycles 2 and 3, and Day 1 of each cycle thereafter. After the last dose of treatment, participants will attend an end of treatment and a post-treatment follow-up visit, and participants will be followed to assess overall survival. Study visits may include a tumor assessment, physical exam, electrocardiogram (ECG), blood and urine analysis, and questionnaires.

Official Title
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A Phase 2, Open-label, Multicenter Study of Orally Administered Ivosidenib in Previously Treated Japanese Subjects With Nonresectable or Metastatic Cholangiocarcinoma With an IDH1 Mutation

Conditions
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Cholangiocarcinoma Non-resectable, Cholangiocarcinoma Metastatic

Intervention / Treatment
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* Drug: Ivosidenib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have nonresectable or metastatic cholangiocarcinoma and are not eligible for curative resection, transplantation or ablative therapies Have documented IDH1 gene-mutated disease from a tumor biopsy Have an ECOG PS score of 0 or 1 Have an expected survival of 3 months or more Have at least one evaluable and measurable lesion Have disease progression following the most recent of 1 or 2 prior systemic regimens for advanced disease with progression on the treatment that was most recently given at a minimum, and must have received at least 1 gemcitabine- or 5-FU -containing regimen Have recovered from side effects associated with the prior treatment therapy Have adequate bone marrow function Have adequate hepatic (liver) and renal (kidney) function Women of child bearing potential must have a negative serum pregnancy test before starting study treatment, and use birth control during the study and for 90 days after the last dose of ivosidenib Fertile men with female partners of child bearing potential must use birth control during the study and for 90 days after the last dose of ivosidenib Exclusion Criteria: Received a prior IDH inhibitor. Have known symptomatic brain metastases requiring steroids. Pregnancy, possibility of becoming pregnant during the study and breast-feeding women or woman who plans to restart breast-feeding after the study drug administration/intake. Are taking known strong cytochrome P450 (CYP) 3A4 inducers or sensitive CYP3A4 substrate medications with a narrow therapeutic window Have significant heart disease, including congestive heart failure, myocardial infarction (heart attack) unstable angina (chest pain) and/or stroke, within 6 months before starting the study Have a heart-rate corrected QT interval ≥450 msec or other factors that increase the risk of QT prolongation or arrhythmic events . Have active inflammatory gastrointestinal disease, chronic diarrhea, previous gastric resection or lap band dysphagia, short-gut syndrome, gastroparesis (paralysis of the stomach), or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally. Have known medical history of progressive multifocal leukoencephalopathy (PML)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Open-Label Ivosidenib<br>250 mg Tablets | Drug: Ivosidenib<br>* Subjects will take 2 tablets (500 mg total) orally once daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6-month Progression Free Survival (PFS) rate | Proportion of subjects who are alive and progression-free (using RECIST v1.1) at 6 months after Day 1 (C1D1) per Independent Radiology Center (IRC) | Through 6 months after the first dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | The time from Day 1 to the date of first documentation of disease progression as assessed by the Investigator and by the IRC per RECIST v1.1. or death due to any cause | Through 2 years after the last subject was enrolled | 
| Overall Survival (OS) |  | Through 2 years after the last subject was enrolled | 
| Objective Response (OR) rate | Complete response or partial response | Through 2 years after the last subject was enrolled | 
| Duration of Response (DOR) | The time from date of first documented confirmed complete response (CR) or confirmed partial response (PR) to date of first documented disease progression or death due to any cause | Through 2 years after the last subject was enrolled | 
| Time to Response (TTR) | The time from Day 1 to date of first documented confirmed complete response (CR) or confirmed partial response (PR) | Through 2 years after the last subject was enrolled | 
| Change from baseline in Health-Related Quality of Life using EORTC-QLQ-C30 questionnaire scores. | The European Organisation for Research and Treatment of Cancer - Quality Of Life Questionnaire - Core Questionnaire (EORTC-QLQ-C30) scores range from 0 - 100 and asses both functional scores and symptom scores; for the functional score the higher score represents better functioning and for the symptom scores the higher score represents an increase in symptoms. | Through 2 years after the last subject was enrolled | 
| Change from baseline in Health-Related Quality of Life using EORTC-QLQ-BIL21 questionnaire scores. | The European Organisation for Research and Treatment of Cancer - Quality Of Life Questionnaire - Cholangiocarcinoma and Gallbladder Cancer Module (EORTC-QLQ-BIL21) scores range from 0 - 100 with higher scores representing more severe symptoms. | Through 2 years after the last subject was enrolled | 
| Average EQ-5D-5L scores | The 5-level EuroQol five dimensions questionnaire (EQ-5D-5L) scores range from 5 to 25 with a higher number representing a worse health status. | Through the End of Treatment Visit (within 5 to 33 days after last dose of treatment) | 
| Total Number of Adverse Events (AEs) |  | Through the Safety Follow-up Visit (28-33 days after discontinuation of treatment) | 
| Total Number of Adverse Events (AEs) leading to dose modifications |  | Through the Safety Follow-up Visit (28-33 days after discontinuation of treatment) | 
| Total Number of Adverse Events (AEs) leading to discontinuation |  | Through the Safety Follow-up Visit (28-33 days after discontinuation of treatment) | 
| Total Number of Serious Adverse Events (SAEs) |  | Through the Safety Follow-up Visit (28-33 days after discontinuation of treatment) | 
| Total Number of Adverse Events (AEs) leading to death |  | Through the Safety Follow-up Visit (28-33 days after discontinuation of treatment) | 
| Average area under the concentration-vs time curve from 0 to time of last measurable concentration (AUC0-t) |  | Each cycle is 28 days: Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 3 Day 1, End of Treatment (within 33 days of last dose) | 
| Average AUC over 1 dosing interval at steady state (AUCtau,ss) |  | Each cycle is 28 days: Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 3 Day 1 | 
| Average time to maximum concentration (Tmax) |  | Each cycle is 28 days: Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 3 Day 1, End of Treatment (within 33 days of last dose) | 
| Average maximum concentration (Cmax) |  | Each cycle is 28 days: Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 3 Day 1, End of Treatment (within 33 days of last dose) | 
| Average trough concentration (Ctrough) |  | Each cycle is 28 days: Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 3 Day 1, End of Treatment (within 33 days of last dose) | 
| Average plasma 2-hydroxyglutarate (2-HG) concentrations |  | Each cycle is 28 days: Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 3 Day 1, End of Treatment (within 33 days of last dose) | 
| Change from baseline in Eastern Cooperative Oncology Group (ECOG) performance status (ECOG PS) | From baseline to worst value of post-baseline assessments. ECOG PS scores range from 0 to 5 with 0 representing a person being fully active and 5 being the patient is dead. | Through the End of Treatment Visit (occurring 28 - 33 days after the last dose) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cholangiocarcinoma Non-resectable with an IDH-1 Mutation, IDH-1 Mutation, Cholangiocarcinoma Metastatic with an IDH-1 Mutation