A Study Exploring the Safety and Efficacy of INCAGN01949 in Combination With Immune Therapies in Advanced or Metastatic Malignancies

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety, tolerability, and efficacy of INCAGN01949 when given in combination with immune therapies in participants with advanced or metastatic malignancies.

Official Title
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A Phase 1/2 Study Exploring the Safety, Tolerability, and Efficacy of INCAGN01949 in Combination With Immune Therapies in Subjects With Advanced or Metastatic Malignancies

Conditions
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Advanced Malignancies

Intervention / Treatment
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* Drug: INCAGN01949
* Drug: Nivolumab
* Drug: Ipilimumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Locally advanced or metastatic disease; locally advanced disease must not be amenable to resection with curative intent. Phase 1: Subjects with advanced or metastatic solid tumors. Phase 1: Subjects who have disease progression after treatment with available therapies. Phase 2: Subjects with advanced or metastatic gastric cancer, SCCHN, NSCLC, or RCC and are considered refractory to prior PD-1/L1 therapy. Presence of measurable disease based on RECIST v1.1. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1. Exclusion Criteria: Laboratory and medical history parameters not within the Protocol-defined range Receipt of anticancer medications or investigational drugs within protocol-defined intervals before the first administration of study drug. Has not recovered to ≤ Grade 1 from toxic effects of prior therapy. Active autoimmune disease. Known active central nervous system metastases and/or carcinomatous meningitis. Evidence of active, noninfectious pneumonitis or history of interstitial lung disease. Evidence of hepatitis B virus or hepatitis C virus infection or risk of reactivation. Known history of human immunodeficiency virus (HIV); HIV 1/2 antibodies.

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: Phase 1, Dose Escalation: INCAGN01949 + Nivolumab<br>INCAGN01949 (70, 200, 350, or 700 milligrams [mg]) combined with nivolumab 240 mg in participants with advanced or metastatic select solid tumors | Drug: INCAGN01949<br>* In Phase 1, participants will receive INCAGN01949 administered intravenously (IV) at the protocol-defined dose according to cohort enrollment. In Phase 2, participants will receive INCAGN01949 administered IV at the recommended dose from Phase 1.<br>Drug: Nivolumab<br>* Nivolumab will be administered IV at the protocol-defined dose according to assigned treatment group.<br>|
| Experimental: Phase 1, Dose Escalation: INCAGN01949 + Ipilimumab<br>INCAGN01949 (70, 200, 350, or 700 mg) combined with ipilimumab 1 mg/kilogram (kg) in participants with advanced or metastatic select solid tumors | Drug: INCAGN01949<br>* In Phase 1, participants will receive INCAGN01949 administered intravenously (IV) at the protocol-defined dose according to cohort enrollment. In Phase 2, participants will receive INCAGN01949 administered IV at the recommended dose from Phase 1.<br>Drug: Ipilimumab<br>* Ipilimumab will be administered IV at the protocol-defined dose according to assigned treatment group.<br>|
| Experimental: Phase 1, Dose Escalation: INCAGN01949 + Nivolumab + Ipilimumab<br>INCAGN01949 combined with nivolumab 3 mg/kg and ipilimumab 1 mg/kg in participants with advanced or metastatic select solid tumors | Drug: INCAGN01949<br>* In Phase 1, participants will receive INCAGN01949 administered intravenously (IV) at the protocol-defined dose according to cohort enrollment. In Phase 2, participants will receive INCAGN01949 administered IV at the recommended dose from Phase 1.<br>Drug: Nivolumab<br>* Nivolumab will be administered IV at the protocol-defined dose according to assigned treatment group.<br>Drug: Ipilimumab<br>* Ipilimumab will be administered IV at the protocol-defined dose according to assigned treatment group.<br>|
| Experimental: Phase 1, Safety Expansion: INCAGN01949 + Nivolumab<br>Run-in with INCAGN01949 (70, 200, or 350 mg) x 2 doses, followed by INCAGN01949 (70, 200, or 350 mg) combined with nivolumab 240 mg in participants with advanced or metastatic select solid tumors | Drug: INCAGN01949<br>* In Phase 1, participants will receive INCAGN01949 administered intravenously (IV) at the protocol-defined dose according to cohort enrollment. In Phase 2, participants will receive INCAGN01949 administered IV at the recommended dose from Phase 1.<br>Drug: Nivolumab<br>* Nivolumab will be administered IV at the protocol-defined dose according to assigned treatment group.<br>|
| Experimental: Phase 1, Safety Expansion: INCAGN01949 + Nivolumab + Ipilimumab<br>Run-in with INCAGN01949 x 2 doses, followed by INCAGN01949 combined with nivolumab 3 mg/kg and ipilimumab 1 mg/kg in participants with advanced or metastatic select solid tumors | Drug: INCAGN01949<br>* In Phase 1, participants will receive INCAGN01949 administered intravenously (IV) at the protocol-defined dose according to cohort enrollment. In Phase 2, participants will receive INCAGN01949 administered IV at the recommended dose from Phase 1.<br>Drug: Nivolumab<br>* Nivolumab will be administered IV at the protocol-defined dose according to assigned treatment group.<br>Drug: Ipilimumab<br>* Ipilimumab will be administered IV at the protocol-defined dose according to assigned treatment group.<br>|
| Experimental: Phase 2, Part A: INCAGN01949 + nivolumab<br>INCAGN01949 combined with nivolumab in programmed cell death protein 1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) refractory participants with gastric cancer, squamous cell carcinoma of the head and neck (SCCHN), non-small cell lung cancer (NSCLC), or renal cell carcinoma (RCC) | Drug: INCAGN01949<br>* In Phase 1, participants will receive INCAGN01949 administered intravenously (IV) at the protocol-defined dose according to cohort enrollment. In Phase 2, participants will receive INCAGN01949 administered IV at the recommended dose from Phase 1.<br>Drug: Nivolumab<br>* Nivolumab will be administered IV at the protocol-defined dose according to assigned treatment group.<br>|
| Experimental: Phase 2, Part B: INCAGN01949; INCAGN01949 + nivolumab; INCAGN01949 + nivolumab + ipilimumab<br>INCAGN01949 alone, combined with nivolumab, and combined with nivolumab and ipilimumab in PD-1/L1 refractory participants with advanced or metastatic gastric cancer, SCCHN, NSCLC, or RCC | Drug: INCAGN01949<br>* In Phase 1, participants will receive INCAGN01949 administered intravenously (IV) at the protocol-defined dose according to cohort enrollment. In Phase 2, participants will receive INCAGN01949 administered IV at the recommended dose from Phase 1.<br>Drug: Nivolumab<br>* Nivolumab will be administered IV at the protocol-defined dose according to assigned treatment group.<br>Drug: Ipilimumab<br>* Ipilimumab will be administered IV at the protocol-defined dose according to assigned treatment group.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | An adverse event (AE) was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related, that occurred after a participant provided informed consent. Abnormal laboratory values or test results that occurred after informed consent constituted AEs only if they induced clinical signs or symptoms, were considered clinically meaningful, required therapy (e.g., hematologic abnormality that required transfusion), or required changes in the study drug(s). A TEAE was defined as any adverse event either reported for the first time or the worsening of a pre-existing event after the first dose of study drug. | up to 17.4 months | 
| Phase 1: Number of Participants With a Grade 3 or Higher TEAE | An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related, that occurred after a participant provided informed consent. A TEAE was defined as any adverse event either reported for the first time or the worsening of a pre-existing event after the first dose of study drug. The severity of AEs was assessed using Common Terminology Criteria for Adverse Events (CTCAE) v4.03. Grade 1: mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2: moderate; minimal, local, or noninvasive intervention indicated; limiting age-appropriate activities of daily living. Grade 3: severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living. Grade 4: life-threatening consequences; urgent intervention indicated. Grade 5: death due to AE. | up to 17.4 months | 
| Phase 2: Objective Response Rate (ORR) | ORR was defined as the percentage of participants with a confirmed best overall response of complete response (CR) or partial response (PR), per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (v1.1), as determined by investigator assessment of radiographic disease assessments, recorded before and including the first event of progressive disease (PD). CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to <10 millimeters (mm). PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions. | up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: ORR | ORR was defined as the percentage of participants with a confirmed best overall response of CR or PR, per RECIST v1.1, as determined by investigator assessment of radiographic disease assessments, recorded before and including the first event of PD. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to <10 mm. PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions. | up to 15.6 months | 
| Phase 1: Duration of Response (DOR) | DOR was defined as the time from the first overall response contributing to a confirmed objective response (CR or PR) to the earlier of the participant's death from any cause or first assessment of PD, determined by investigator assessment of radiographic disease assessments per RECIST v1.1. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to <10 mm. PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions. PD: progression of a target or non-target lesion or presence of a new lesion. | up to 11.0 months | 
| Phase 2: DOR | DOR was defined as the time from the first overall response contributing to a confirmed objective response (CR or PR) to the earlier of the participant's death from any cause or first assessment of PD, determined by investigator assessment of radiographic disease assessments per RECIST v1.1. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to <10 mm. PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions. PD: progression of a target or non-target lesion or presence of a new lesion. | up to 24 months | 
| Phase 1: Disease Control Rate (DCR) | DCR was defined as the percentage of participants with a CR, PR, or stable disease (SD), determined by investigator assessment of radiographic disease assessments per RECIST v1.1. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to <10 mm. PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions. SD: no change in target lesions to qualify for CR, PR, or PD. | up to 15.6 months | 
| Phase 2: DCR | DCR was defined as the percentage of participants with a CR, PR, or SD, determined by investigator assessment of radiographic disease assessments per RECIST v1.1. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to <10 mm. PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions. SD: no change in target lesions to qualify for CR, PR, or PD. | up to 24 months | 
| Phase 1: Duration of Disease Control | Duration of disease control (CR, PR, and SD) was measured from the first report of SD or better until PD or death from any cause, if occurring sooner than progression, determined by investigator assessment of radiographic disease assessments per RECIST v1.1. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to <10 mm. PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions. SD: no change in target lesions to qualify for CR, PR, or PD. PD: progression of a target or non-target lesion or presence of a new lesion. | up to 15.4 months | 
| Phase 2: Duration of Disease Control | Duration of disease control (CR, PR, and SD) was measured from the first report of SD or better until PD or death from any cause, if occurring sooner than progression, determined by investigator assessment of radiographic disease assessments per RECIST v1.1. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to <10 mm. PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions. SD: no change in target lesions to qualify for CR, PR, or PD. PD: progression of a target or non-target lesion or presence of a new lesion. | up to 24 months | 
| Phase 1: Progression-free Survival (PFS) | PFS was defined as the length of time between the Baseline visit (Day 1) and the earlier of death or the first assessment of PD, as determined by investigator assessment of objective radiographic disease assessments per RECIST v1.1. | up to 15.6 months | 
| Phase 2: PFS | PFS was defined as the length of time between the Baseline visit (Day 1) and the earlier of death or the first assessment of PD, as determined by investigator assessment of objective radiographic disease assessments per RECIST v1.1. | up to 24 months | 
| Phase 2: Number of Participants With TEAEs | An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related, that occurred after a participant provided informed consent. Abnormal laboratory values or test results that occurred after informed consent constituted AEs only if they induced clinical signs or symptoms, were considered clinically meaningful, required therapy (e.g., hematologic abnormality that required transfusion), or required changes in the study drug(s). A TEAE was defined as any adverse event either reported for the first time or the worsening of a pre-existing event after the first dose of study drug. | up to 24 months | 
| Phase 2: Number of Participants With a Grade 3 or Higher TEAE | An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related, that occurred after a participant provided informed consent. A TEAE was defined as any adverse event either reported for the first time or the worsening of a pre-existing event after the first dose of study drug. The severity of AEs was assessed using CTCAE v4.03. Grade 1: mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2: moderate; minimal, local, or noninvasive intervention indicated; limiting age-appropriate activities of daily living. Grade 3: severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living. Grade 4: life-threatening consequences; urgent intervention indicated. Grade 5: death due to AE. | up to 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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advanced or metastatic cervical cancer, endometrial cancer, esophageal cancer, hepatocellular carcinoma (HCC), melanoma, Merkel cell carcinoma, mesothelioma, microsatellite instability-high colorectal cancer, non-small cell lung cancer (NSCLC), ovarian cancer, squamous cell carcinoma of the head and neck, small cell lung cancer (SLCL), renal cell carcinoma (RCC), triple-negative breast cancer, TNBC, urothelial carcinoma, OX40 ligand (OX40), SCCHN, MSI-H CRC, gastric cancer (including stomach and gastroesophageal junction [GEJ])