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

• ClinicalTrials.gov Identifier: NCT05876754
• Recruitment Status: Recruiting
• First Posted: May 25, 2023
• Last Update Posted: March 5, 2024
• Sponsor: Servier Affaires Médicales
• Information provided by (Responsible Party): Servier ( Servier Affaires Médicales )

Tracking Information

• First Submitted Date: May 17, 2023
• First Posted Date: May 25, 2023
• Last Update Posted Date: March 5, 2024
• Actual Study Start Date: May 3, 2023
• Estimated Primary Completion Date: June 1, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 8, 2023)

• Number of Adverse Events (AEs) from Day 1 of Cycle 1 through 28 days after last study treatment [ Time Frame: Day 1 of cycle 1, Day 1 of each consecutive cycle, 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.
• 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). [ Time Frame: 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 ]
  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.
• 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 [ Time Frame: 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 ]
  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.
• Change in Eastern Cooperative Oncology Group (ECOG) performance status (PS) score from baseline to worst value out of the post-baseline assessments. [ Time Frame: Screening visit, Day 1 of cycle 1, Day 1 of each consecutive cycle, 28 + 14 days (maximum) after last study treatment ]
  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.
• Number of Adverse Events (AEs) leading to discontinuation or death from day 1 through 28 days after the last study treatment [ Time Frame: Day 1 of cycle 1, Day 1 of each consecutive cycle, 28 days after 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.
• 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. [ Time Frame: Screening visit, Day 1 of cycle 1, Day 1 of each consecutive cycle, 28 + 14 days (maximum) after last study treatment ]
  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.
• Change from baseline to the worst on-treatment value of laboratory abnormalities. [ Time Frame: Screening visit, Day 1 of cycle 1, Day 1 of each consecutive cycle, 28 + 14 days (maximum) after last study treatment ]
  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.
• Number of patients with vital sign values outside limits of the normal range at each time point. [ Time Frame: Screening visit, Day 1 of cycle 1, Day 1 of each consecutive cycle, 28 + 14 days (maximum) after last study treatment ]
  Vital signs include systolic and diastolic blood pressure, heart rate, respiratory rate, and temperature.
• Mean change from baseline values to the worst on-treatment value of patients with vital signs outside limits of the normal range [ Time Frame: Screening visit, Day 1 of cycle 1, Day 1 of each consecutive cycle, 28 + 14 days (maximum) after last study treatment ]
  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.

Original Primary Outcome Measures (submitted: May 17, 2023)

• Number of Adverse Events (AEs) from Day 1 of Cycle 1 through 28 days after last treatment [ Time Frame: Day 1 of cycle 1, Day 1 of each consecutive cycle, 28 days after last 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. All reported AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), using the latest version.
• Number of Serious Adverse Events (SAEs) from Day 1 of Cycle 1 through study termination or withdrawal of consent, whichever comes first [ Time Frame: Day 1 of cycle 1, Day 1 of each consecutive cycle, 28 + 14 days (maximum) after last treatment, 6 months after last treatment, 12 months after last treatment, 18 months after last treatment ]
  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.
• 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 treatment [ Time Frame: 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 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.
• Change in Eastern Cooperative Oncology Group (ECOG) performance status (PS) score from baseline to worst value out of the post-baseline assessments. [ Time Frame: Screening visit, Day 1 of cycle 1, Day 1 of each consecutive cycle, 28 + 14 days (maximum) after last treatment ]
  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.
• Number of Adverse Events (AEs) leading to discontinuation or death from day 1 through 28 days after the last treatment [ Time Frame: Day 1 of cycle 1, Day 1 of each consecutive cycle, 28 days after last 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.
• 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. [ Time Frame: Screening visit, Day 1 of cycle 1, Day 1 of each consecutive cycle, 28 + 14 days (maximum) after last treatment ]
  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.
• Change from baseline to the worst on-treatment value of laboratory abnormalities. [ Time Frame: Screening visit, Day 1 of cycle 1, Day 1 of each consecutive cycle, 28 + 14 days (maximum) after last treatment ]
  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.
• Number of patients with vital sign values outside limits of the normal range at each time point. [ Time Frame: Screening visit, Day 1 of cycle 1, Day 1 of each consecutive cycle, 28 + 14 days (maximum) after last treatment ]
  Vital signs include systolic and diastolic blood pressure, heart rate, respiratory rate, and temperature.
• Mean change from baseline values to the worst on-treatment value of patients with vital signs outside limits of the normal range [ Time Frame: Screening visit, Day 1 of cycle 1, Day 1 of each consecutive cycle, 28 + 14 days (maximum) after last treatment ]
  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.

Current Secondary Outcome Measures (submitted: June 8, 2023)

• Progression-free survival (PFS) time beginning at enrollement [ Time Frame: through 28 days after last treatment ]
  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.
• Overall survival (OS) [ Time Frame: through 28 days after last treatment ]
  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.
• Duration of response (DOR) [ Time Frame: through 28 days after last treatment ]
  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.
• Time to response (TTR) [ Time Frame: through 28 days after last treatment ]
  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.
• Change from baseline of Quality of life scores [ Time Frame: through 28 days after last study treatment ]
  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.
• Proportion of days at home or hospital for all patients [ Time Frame: 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). [ Time Frame: through 28 days after last treatment ]
  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.

Original Secondary Outcome Measures (submitted: May 17, 2023)

• Progression-free survival (PFS) time beginning at screening [ Time Frame: through 28 days after last treatment ]
  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.
• Overall survival (OS) [ Time Frame: through 28 days after last treatment ]
  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.
• Duration of response (DOR) [ Time Frame: through 28 days after last treatment ]
  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.
• Time to response (TTR) [ Time Frame: through 28 days after last treatment ]
  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.
• Change from baseline of Quality of life scores [ Time Frame: through 28 days after last treatment ]
  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.
• Proportion of days at home or hospital for all patients [ Time Frame: 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). [ Time Frame: through 28 days after last treatment ]
  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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: An Early Access Study of Ivosidenib in Patients With a Pretreated Locally Advanced or Metastatic Cholangiocarcinoma
• Official Title: An Open-Label Early Access Phase 3b Study of Ivosidenib in Patients With a Pretreated Locally Advanced or Metastatic Cholangiocarcinoma
• Brief Summary: 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: 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.
• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Masking Description:

All patients, care providers, investigators, and outcomes assessors will know that each patient is taking the active study drug, ivosidenib.

Primary Purpose: Treatment

• Condition: Cholangiocarcinoma

Intervention

Drug: Ivosidenib Oral Tablet

Ivosidenib 500 mg

Study Arms

Experimental: Ivosidenib

Ivosidenib 500 mg, taken orally as two 250 mg tablets once daily for an unlimited amount of continuous 28-day cycles

Intervention: Drug: Ivosidenib Oral Tablet

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: May 17, 2023): 220
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: June 1, 2025
• Estimated Primary Completion Date: June 1, 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Institut de Recherches Internationales Servier, Clinical Studies Department; +33 1 55 72 60 00; scientificinformation@servier.com

• Listed Location Countries: Australia, Austria, Belgium, France, Germany, Italy, Netherlands, Spain, Sweden, United Kingdom

Administrative Information

• NCT Number: NCT05876754
• Other Study ID Numbers: DIM-95031-002; 2022-501463-40 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

IPD Sharing Statement

• Plan to Share IPD: Yes

Plan Description

Qualified scientific and medical researchers can request access to anonymized patient-level and study-level clinical trial data.

Access can be requested for all interventional clinical studies:

• used for Marketing Authorization (MA) of medicines and new indications approved after 1 January 2014 in the European Economic Area (EEA) or the United States (US).
• where Servier is the Marketing Authorization Holder (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 for this scope.

In addition, access can be requested for 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 Marketing authorization (MA) approval.

• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: After Marketing Authorization in EEA or US if the study is used for the approval.
• Access Criteria: Researchers should register on Servier Data Portal and fill in the research proposal form. This form in four parts should be fully documented. The Research Proposal Form will not be reviewed until all mandatory fields are completed.
• URL: http://clinicaltrials.servier.com/

• Current Responsible Party: Servier ( Servier Affaires Médicales )
• Original Responsible Party: Servier
• Current Study Sponsor: Servier Affaires Médicales
• Original Study Sponsor: Servier
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Servier
• Verification Date: March 2024