Ivosidenib, Nivolumab, and Ipilimumab Combination in Previously Treated Subjects With Nonresectable or Metastatic IDH1 Mutant Cholangiocarcinoma

A Phase 1/2, Safety Lead-in and Dose Expansion, Open-label, Multicenter Trial Investigating the Safety, Tolerability, and Preliminary Activity of Ivosidenib in Combination With Nivolumab and Ipilimumab in Previously Treated Subjects With Nonresectable or Metastatic Cholangiocarcinoma With an IDH1 Mutation

This is a Phase 1/2 study evaluating the safety, tolerability, and activity of ivosidenib in combination with immunotherapy in participants with nonresectable or metastatic cholangiocarcinoma. The study includes two phases: the safety lead-in phase to determine the recommended combination dose (RCD) of ivosidenib in combination with immunotherapy and the dose expansion phase to assess the efficacy of ivosidenib in combination with immunotherapy. Study treatment will be administered until participant experiences unacceptable toxicity, disease progression, or other discontinuation criteria are met.

Study Overview

• Status: Recruiting
• Conditions: IDH1-mutant Cholangiocarcinoma
• Intervention / Treatment: Drug: Ivosidenib; Drug: Nivolumab; Drug: Ipilimumab; Drug: Recommended Combination Dose (RCD) of ivosidenib

• Study Type: Interventional
• Enrollment (Estimated): 92
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Institut de Recherches Internationales Servier; Phone Number: +33 1 55 72 60-00; Email: scientificinformation@servier.com

Study Locations

• United Kingdom
  • Bebington, United Kingdom, L63 4JY
    • Withdrawn
    • Clatterbridge Hospital
  • London, United Kingdom, NW1 2PG
    • Recruiting
    • UCLH
  • Manchester, United Kingdom, M20 4BX
    • Not yet recruiting
    • Christie Hospital
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • Not yet recruiting
      • Mayo Clinic
    • Tucson, Arizona, United States, 85719-1478
      • Withdrawn
      • The University of Arizona Cancer Center (Uacc)
  • California
    • San Francisco, California, United States, 94158
      • Recruiting
      • UCSF Helen Diller Family Comprehensive Cancer Center
    • San Francisco, California, United States, 94158
      • Recruiting
      • UCSF - Medical Center at Mission Bay
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Not yet recruiting
      • Mayo Clinic - Jacksonville, Fl
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • Recruiting
      • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Recruiting
      • Dana Farber Cancer Institute
    • Boston, Massachusetts, United States, 02114
      • Not yet recruiting
      • Massachusetts General Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-2800
      • Recruiting
      • The University of Michigan Rogel Cancer Center
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Not yet recruiting
      • Mayo Clinic - Rochester, Mn
  • New York
    • New York, New York, United States, 10065
      • Not yet recruiting
      • Memorial Sloan Kettering Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Not yet recruiting
      • Sarah Cannon Research Institute
  • Texas
    • Houston, Texas, United States, 77030
      • Not yet recruiting
      • The University of Texas MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male of female participant age ≥ 18 years old
• Have documented IDH1 gene-mutated disease based on local testing procedure (R132C/L/G/H/S mutations variants tested)
• Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1
• Has a histopathological diagnosis consistent with nonresectable or metastatic cholangiocarcinoma and are not eligible for curative resection, transplantation, or ablative therapies
• Participants must have at least one measurable lesion as defined by RECIST Version 1.1. Subjects who have received prior local therapy (including but not limited to embolization, chemoembolization, radiofrequency ablation, or radiation therapy) are eligible provided measurable disease falls outside of the treatment field or if within the field but has shown ≥ 20% growth in size post-treatment assessment.

Exclusion Criteria:

• Received prior treatment with an IDH inhibitor or prior treatment with an immune checkpoint inhibitor other than anti-PD1/L1
• Have active autoimmune disease or any condition requiring systemic treatment with either corticosteroids (> 10 mg daily of prednisone equivalents) or other immunosuppressive medications within 14 days of study treatment
• Participants who have not recovered from toxicity of previous anticancer therapy, including Grade ≥ 1 non-hematologic toxicity, according to the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0, prior to the first IMP administration. Residual Grade ≤ 2 toxicity from chemotherapy (e.g., alopecia, neuropathy) may be allowed.
• Have known symptomatic brain metastases requiring steroids. Subjects with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to study entry, have discontinued corticosteroid treatment for these metastases for at least 4 weeks, and have radiographically stable disease for at least 3 months prior to study entry. Note: Up to 10 mg per day of prednisone equivalent will be allowed.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Safety Lead-In Phase - ivosidenib; First phase of the study.	Drug: Ivosidenib; ivosidenib taken once daily; Drug: Nivolumab; Nivolumab taken by intravenous infusion; Drug: Ipilimumab; Ipilimumab taken by intravenous infusion
Experimental: Experimental Phase - Cohort 1; Second phase of the study. Cohort 1 will include the anti-PD1/L1-naïve subpopulation.	Drug: Nivolumab; Nivolumab taken by intravenous infusion; Drug: Ipilimumab; Ipilimumab taken by intravenous infusion; Drug: Recommended Combination Dose (RCD) of ivosidenib; The RCD of ivosidenib taken once daily
Experimental: Experimental Phase - Cohort 2; Second phase of the study. Cohort 2 will include the anti-PD1/L1 previously treated subpopulation.	Drug: Nivolumab; Nivolumab taken by intravenous infusion; Drug: Ipilimumab; Ipilimumab taken by intravenous infusion; Drug: Recommended Combination Dose (RCD) of ivosidenib; The RCD of ivosidenib taken once daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety Phase: Number of dose limiting toxicities (DLTs) associated with study drug regimen, during the first 2 cycles of treatment	Occurring during the safety lead-in phase	Through the end of Cycle 2, day 42 (Cycle 1 and 2 are each 21 days)
Safety Phase: To determine the recommended combination dose (RDC) of ivosidenib in combination of immunotherapy	Occurring during the safety lead-in phase	Through the end of Cycle 2, day 42 (Cycle 1 and 2 are each 21 days)
Expansion Phase: To assess the Objective Response (confirmed complete response [CR] or confirmed partial response [PR]) of antitumor activity using RECIST v1.1)	To assess the Objective Response (confirmed complete response [CR] or confirmed partial response [PR]) of antitumor activity using RECIST v1.1)	up to 3 years
Safety Phase: Number of Adverse Events (AEs)	Occurring during the safety lead-in phase	Up to 3 years
Safety Phase: Number of Adverse Events of Special Interests (AESIs)	Occurring during the safety lead-in phase	Up to 3 years
Safety Phase: Number of Serious Adverse Events (SAEs)	Occurring during the safety lead-in phase	Up to 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety Phase: area under the concentration-vs-time curve (AUC) from 0 to time of last measurable concentration (AUC0-t)	Occurring during the safety lead-in phase	Up to 3 years
Safety Phase: Plasma 2-hydroxyglutarate (2-HG) concentration	Occurring during the safety lead-in phase	up to 3 years
Expansion Phase: Number of Adverse Events (AEs)	Occurring during the expansion phase	Up to 3 years
Expansion Phase: Duration of response (DOR)	Occurring during the expansion phase	up to 3 years
Expansion Phase: progression-free survival (PFS)	Occurring during the expansion phase	up to 3 years
Expansion Phase: disease control (DC) (complete response-CR, partial response-PR, or stable disease-SD)	Occurring during the expansion phase	up to 3 years
Expansion Phase: time to response (TTR) according to RECIST v1.1	Occurring during the expansion phase	up to 3 years
Expansion Phase: Overall survival (OS)	Occurring during the expansion phase	up to 3 years
Expansion Phase : area under the concentration-vs-time curve (AUC) from 0 to time of last measurable concentration (AUC0-t)	Occurring during the expansion phase	Up to 3 years
Expansion Phase: Plasma 2-hydroxygluturate (2-HG) concentration	Occurring during the expansion phase	up to 3 years
Safety Phase: AUC over 1 dosing interval at steady state (AUCtau,ss)	Occurring during the safety lead-in phase	Up to 3 years
Safety Phase: time to maximum concentration (Tmax)	Occurring during the safety lead-in phase	Up to 3 years
Safety Phase: maximum concentration (Cmax)	Occurring during the safety lead-in phase	Up to 3 years
Safety Phase: trough concentration (Ctrough)	Occurring during the safety lead-in phase	Up to 3 years
Safety Phase: apparent volume of distribution (Vd/F)	Occurring during the safety lead-in phase	Up to 3 years
Safety Phase: apparent clearance (CL/F)	Occurring during the safety lead-in phase	Up to 3 years
Expansion Phase: Number of Adverse Events of Special Interests (AESIs)	Occurring during the expansion phase	Up to 3 years
Expansion Phase: Number of Serious Adverse Events (SAEs)	Occurring during the expansion phase	Up to 3 years
Expansion Phase: AUC over 1 dosing interval at steady state (AUCtau,ss)	Occurring during the expansion phase	Up to 3 years
Expansion Phase: time to maximum concentration (Tmax)	Occurring during the expansion phase	Up to 3 years
Expansion Phase: maximum concentration (Cmax)	Occurring during the expansion phase	Up to 3 years
Expansion Phase: trough concentration (Ctrough)	Occurring during the expansion phase	Up to 3 years
Expansion Phase: apparent volume of distribution (Vd/F)	Occurring during the expansion phase	Up to 3 years
Expansion Phase: apparent clearance (CL/F)	Occurring during the expansion phase	Up to 3 years

Collaborators and Investigators

• Sponsor: Servier Bio-Innovation LLC
• Collaborators: Institut de Recherches Internationales Servier

Study record dates

Study Major Dates

• Study Start (Actual): October 23, 2023
• Primary Completion (Estimated): March 1, 2026
• Study Completion (Estimated): March 1, 2026

Study Registration Dates

• First Submitted: April 21, 2023
• First Submitted That Met QC Criteria: June 19, 2023
• First Posted (Actual): June 27, 2023

Study Record Updates

• Last Update Posted (Actual): April 9, 2024
• Last Update Submitted That Met QC Criteria: April 8, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Cholangiocarcinoma; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Glycine Agents; Nivolumab; Ipilimumab; Ivosidenib; Glycine
• Other Study ID Numbers: CL1-95031-006; 2023-503236-41 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD 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.

• IPD Sharing Time Frame: After Marketing Authorization in EEA or US if the study is used for the approval.
• IPD Sharing 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No