An Early Access Study of Ivosidenib in Patients With a Pretreated Locally Advanced or Metastatic Cholangiocarcinoma

Study Overview
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Brief Summary
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A Phase 3b research study to consolidate the data that ivosidenib is safe and effective in adult patients with previously treated, locally advanced, or metastatic cholangiocarcinoma (CCA). All patients who meet inclusion criteria will be enrolled to receive ivosidenib tablets orally once daily for 28 day cycles, continuing as long as clinical benefit and consent for participation is maintained. There will be a minimum of 6 study visits from screening until the final follow-up, if one cycle of treatment is completed and consent is maintained through 18 months of follow-up. Each additional cycle completed will add one study visit, on the first day of each cycle.

Detailed Description
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Ivosidenib is approved in the United States and in EU for the treatment of advanced or metastatic CCA; this study is being conducted to conslidate the data related to the safety, efficacy, and impact on quality of life for patients. This is an open-label, single-arm study of ivosidenib, which means that all patients meeting eligibility criteria will receive two 250 mg ivosidenib tablets, totaling 500mg of drug, to be taken orally, once daily, for 28 consecutive days, also referred to as one cycle. Additional cycles can continue as long as clinical benefit is confirmed by an investigator, and consent is maintained. There will be a screening visit, study visit on day 1 of each cycle, withdrawal visit within 42 days of stopping treatment, and a follow-up visit every 6 months for up to 18 months after stopping treatment. This results in a minimum of 6 study visits for the completion of one 28-day cycle of ivosidenib. One additional study visit will be added on day one of each additional cycle of treatment. Study visits will include an electrocardiogram (ECG), physical exam, tumor assessment, according to local practive at a given site and blood and urine analyses. If at any point ivosidenib is made available as a medical prescription at the patient's site, patients will be withdrawn from the study treatment and patients will be followed to collect data on overall survival.

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

Conditions
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Cholangiocarcinoma

Intervention / Treatment
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* Drug: Ivosidenib Oral Tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of nonresectable or metastatic Cholangiocarcinoma (CCA), not eligible for curative-intent resection, transplantation, or ablative therapies Have a documented IDH1 R132C, R132L, R132G, R132H, or R132S gene-mutated disease Have tried at least 1 prior type of systemic therapy for CCA, and have recovered from any side effects Female patients of childbearing potential must have a negative blood pregnancy test prior to starting treatment and must agree to use 2 forms of contraception from the time they enroll to 1 month after their last dose of study drug Male patients with a female partner with childbearing potential must also agree to use 2 forms of contraception from the time they enroll to 1 month after their last dose of study drug Exclusion Criteria: Received a prior IDH1 inhibitor Have received a transplant Have received systemic cancer treatment or radiotherapy within 2 weeks prior to Day 1 of Cycle 1 Have received hepatic radiation, chemoembolization, and radiofrequency ablation within 4 weeks prior to Day 1 of Cycle 1 Have ongoing brain metastases requiring steroids Have underwent major surgery within 4 weeks of Day 1 of Cycle 1 prior to C1D1 Have an active hepatitis B (HBV) or hepatitis C (HCV) infections, known positive human immunodeficiency virus (HIV) antibody results, or acquired immunodeficiency syndrome (AIDS) related illness Are pregnant or breastfeeding

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: Ivosidenib<br>Ivosidenib 500 mg, taken orally as two 250 mg tablets once daily for an unlimited amount of continuous 28-day cycles | Drug: Ivosidenib Oral Tablet<br>* Ivosidenib 500 mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Adverse Events (AEs) from Day 1 of Cycle 1 through 28 days after last study treatment | AEs will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. All reported AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), using the latest version. | Day 1 of cycle 1, Day 1 of each consecutive cycle, 28 days after last study treatment | 
| Number of Serious Adverse Events (SAEs) during the study treatment period (from Day 1 of Cycle 1 through the last study treatment intake or withdrawal of consent, whichever comes first). | SAEs related to study drug will be collected irrespective of the time of onset. AEs will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. | Day 1 of cycle 1, Day 1 of each consecutive cycle, 28 + 14 days (maximum) after last study treatment, 6 months after last study treatment, 12 months after last study treatment, 18 months after last study treatment | 
| Number of QT prolongation events during electrocardiogram (ECG) assessed as Grade 2 or worse occurring from Day 1 of Cycle 1 through 28 days after last study treatment | QT interval, using Fridericia's formula [QTcF], to average QTc interval > 480 to 500msec (Grade 2) or worse, as seen during an ECG. This is classified as an Adverse Event of Special Interest (AESI) for this study. | Day 1 of cycle 1, week 2 of cycle 1, week 3 of cycle 1, Day 1 of each consecutive cycle, 28 days after last study treatment | 
| Change in Eastern Cooperative Oncology Group (ECOG) performance status (PS) score from baseline to worst value out of the post-baseline assessments. | ECOG PS scoring consists of Grade 0 - 5, with 0 being the patient is fully active and 5 being the patient is dead. Descriptive statistics of ECOG PS over time will be summarized by frequency. Shift tables may be provided for ECOG PS from baseline to worst value of post-baseline assessments. | Screening visit, Day 1 of cycle 1, Day 1 of each consecutive cycle, 28 + 14 days (maximum) after last study treatment | 
| Number of Adverse Events (AEs) leading to discontinuation or death from day 1 through 28 days after the last study treatment | Total number of AEs that result in discontinuation from treatment or death. AEs will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. | Day 1 of cycle 1, Day 1 of each consecutive cycle, 28 days after last study treatment | 
| Total laboratory abnormalities using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 grading scale or the low/normal/high classifications based on laboratory normal ranges. | Listing of all laboratory hematology, coagulation, and chemistry data with values flagged as abnormal to show the corresponding NCI-CTCAE grades and the classifications relative to the laboratory normal ranges. | Screening visit, Day 1 of cycle 1, Day 1 of each consecutive cycle, 28 + 14 days (maximum) after last study treatment | 
| Change from baseline to the worst on-treatment value of laboratory abnormalities. | Abnormalities will be classified by using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 grading scale or the low/normal/high classifications based on laboratory normal ranges. Shift tables using NCI-CTCAE grades to compare baseline to the worst on-treatment value will be used. For laboratory tests, including hematology, coagulation, and chemistry, where NCI-CTCAE grades are not defined, shift tables using the low/normal/high [low and high] classification to compare baseline to the worst on treatment may be generated. On-treatment is considered from Day 1 of Cycle 1 through 28 days after the last dose. | Screening visit, Day 1 of cycle 1, Day 1 of each consecutive cycle, 28 + 14 days (maximum) after last study treatment | 
| Number of patients with vital sign values outside limits of the normal range at each time point. | Vital signs include systolic and diastolic blood pressure, heart rate, respiratory rate, and temperature. | Screening visit, Day 1 of cycle 1, Day 1 of each consecutive cycle, 28 + 14 days (maximum) after last study treatment | 
| Mean change from baseline values to the worst on-treatment value of patients with vital signs outside limits of the normal range | On-treatment is considered from Day 1 of Cycle 1 through 28 days after the last dose. Vital signs include systolic and diastolic blood pressure, heart rate, respiratory rate, and temperature. | Screening visit, Day 1 of cycle 1, Day 1 of each consecutive cycle, 28 + 14 days (maximum) after last study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) time beginning at enrollement | PFS is defined as the time from the date of enrollment to the date at which the disease escalates or progresses. It will be assessed using the Kaplan-Meier (KM) method curves and estimates. This will be based on tumor assessments conducted by the investigator according to local clinical practice. | through 28 days after last treatment | 
| Overall survival (OS) | OS is defined as the time from date of enrollment to the date of death due to any cause. It will be assessed using the Kaplan-Meier (KM) method curves and estimates. | through 28 days after last treatment | 
| Duration of response (DOR) | DOR is defined as the time from the date of response to either progression or death. It will be assessed using the Kaplan-Meier (KM) method curves and estimates. This will be based on tumor assessments conducted by the investigator according to local clinical practice. | through 28 days after last treatment | 
| Time to response (TTR) | TTR is defined as the time from the date of enrollment to the date of response. It will be assessed using the Kaplan-Meier (KM) method curves and estimates. This will be based on tumor assessments conducted by the investigator according to local clinical practice. | through 28 days after last treatment | 
| Change from baseline of Quality of life scores | Measured by the validated European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Cholangiocarcinoma and Gallbladder Cancer Module (QLQ-BIL21). EORTC QLQ-BIL21, will be evaluated for patients with a baseline assessment and at least 1 post-baseline QLQ-BIL21 assessment that generates a score. Change from baseline for each time point, will be summarized using descriptive statistics. | through 28 days after last study treatment | 
| Proportion of days at home or hospital for all patients |  | through 28 days after last treatment | 
| Change from baseline of health economic measures, as assessed by the 5-level EuroQol 5-dimensional questionnaire (EQ-5D-5). | Health economic measures, as assessed by the EQ-5D-5L, will be evaluated for patients with a baseline assessment and at least 1 post-baseline EQ-5D-5L assessment that generate a score. Change from baseline scores for each time point will be quantified with descriptive statistics. | through 28 days after last treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CCA, Pretreated locally advanced or metastatic cholangiocarcinoma