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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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IDH1-mutant Cholangiocarcinoma

Intervention / Treatment
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* Drug: Ivosidenib
* Drug: Recommended Combination Dose (RCD) of ivosidenib
* Drug: Nivolumab
* Drug: Ipilimumab


Participation Criteria
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Eligibility Criteria
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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.

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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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 |