Clinical trial NCT05921760: Ivosidenib, Nivolumab, and Ipilimumab Combination in Previously Treated Subjects With Nonresectable or Metastatic IDH1 Mutant Cholangiocarcinoma
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: IDH1-mutant Cholangiocarcinoma
Lead sponsor: Servier
Sponsor class: INDUSTRY
Collaborators: name: Institut de Recherches Internationales Servier
First posted: 2023-06-27
Enrollment: 7
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Safety Phase: Number of dose limiting toxicities (DLTs) associated with study drug regimen, during the first 2 cycles of treatment
timeFrame: Through the end of Cycle 2, day 42 (Cycle 1 and 2 are each 21 days)
measure: Safety Phase: To determine the recommended combination dose (RDC) of ivosidenib in combination of immunotherapy
timeFrame: Through the end of Cycle 2, day 42 (Cycle 1 and 2 are each 21 days)
measure: Expansion Phase: To assess the Objective Response (confirmed complete response [CR] or confirmed partial response [PR]) of antitumor activity using RECIST v1.1)
timeFrame: up to 3 years
measure: Safety Phase: Number of Adverse Events (AEs)
timeFrame: Up to 3 years
measure: Safety Phase: Number of Adverse Events of Special Interests (AESIs)
timeFrame: Up to 3 years
measure: Safety Phase: Number of Serious Adverse Events (SAEs)
timeFrame: Up to 3 years
Secondary outcomes:
measure: Safety Phase: area under the concentration-vs-time curve (AUC) from 0 to time of last measurable concentration (AUC0-t)
timeFrame: Up to 3 years
measure: Safety Phase: Plasma 2-hydroxyglutarate (2-HG) concentration
timeFrame: up to 3 years
measure: Expansion Phase: Number of Adverse Events (AEs)
timeFrame: Up to 3 years
measure: Expansion Phase: Duration of response (DOR)
timeFrame: up to 3 years
measure: Expansion Phase: progression-free survival (PFS)
timeFrame: up to 3 years
measure: Expansion Phase: disease control (DC) (complete response-CR, partial response-PR, or stable disease-SD)
timeFrame: up to 3 years
measure: Expansion Phase: time to response (TTR) according to RECIST v1.1
timeFrame: up to 3 years
measure: Expansion Phase: Overall survival (OS)
timeFrame: up to 3 years
measure: Expansion Phase : area under the concentration-vs-time curve (AUC) from 0 to time of last measurable concentration (AUC0-t)
timeFrame: Up to 3 years
measure: Expansion Phase: Plasma 2-hydroxygluturate (2-HG) concentration
timeFrame: up to 3 years
measure: Safety Phase: AUC over 1 dosing interval at steady state (AUCtau,ss)
timeFrame: Up to 3 years
measure: Safety Phase: time to maximum concentration (Tmax)
timeFrame: Up to 3 years
measure: Safety Phase: maximum concentration (Cmax)
timeFrame: Up to 3 years
measure: Safety Phase: trough concentration (Ctrough)
timeFrame: Up to 3 years
measure: Safety Phase: apparent volume of distribution (Vd/F)
timeFrame: Up to 3 years
measure: Safety Phase: apparent clearance (CL/F)
timeFrame: Up to 3 years
measure: Expansion Phase: Number of Adverse Events of Special Interests (AESIs)
timeFrame: Up to 3 years
measure: Expansion Phase: Number of Serious Adverse Events (SAEs)
timeFrame: Up to 3 years
measure: Expansion Phase: AUC over 1 dosing interval at steady state (AUCtau,ss)
timeFrame: Up to 3 years
measure: Expansion Phase: time to maximum concentration (Tmax)
timeFrame: Up to 3 years
measure: Expansion Phase: maximum concentration (Cmax)
timeFrame: Up to 3 years
measure: Expansion Phase: trough concentration (Ctrough)
timeFrame: Up to 3 years
measure: Expansion Phase: apparent volume of distribution (Vd/F)
timeFrame: Up to 3 years
measure: Expansion Phase: apparent clearance (CL/F)
timeFrame: Up to 3 years
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: UCSF - Medical Center at Mission Bay
state: California
city: San Francisco
country: United States
facility: Ucsf Helen Diller Family Comprehensive Cancer Center
state: California
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center At Johns Hopkins
state: Maryland
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: London
country: United Kingdom
facility: UCLH
Study officials:
References:
citation: Kelley RK, Cleary JM, Sahai V, Baretti M, Bridgewater JA, Hua Z, Gliser C, Bian Y, Abou-Alfa GK. 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 IDH1-mutated nonresectable or metastatic cholangiocarcinoma. J Clin Oncol. 2024 May 29;42(16_Supplement):TPS4197. doi: https://doi.org/10.1200/JCO.2024.42.16_suppl.TPS4197