Safety and Efficacy of Retifanlimab (INCMGA00012) Alone or in Combination With Other Therapies in Participants With Advanced or Metastatic Endometrial Cancer Who Have Progressed on or After Platinum-based Chemotherapy.

Study Overview
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Brief Summary
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This is a multicenter, open-label, nonrandomized, Phase 2 umbrella study of retifanlimab in participants who have advanced or metastatic endometrial cancer that has progressed on or after platinum-based chemotherapy. retifanlimab will be administered as monotherapy or in combination with other immunotherapy or targeted agents.

Official Title
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An Umbrella Study of INCMGA00012 Alone and in Combination With Other Therapies in Participants With Advanced or Metastatic Endometrial Cancer Who Have Progressed on or After Platinum-Based Chemotherapy (POD1UM-204)

Conditions
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Endometrial Cancer

Intervention / Treatment
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* Drug: retifanlimab
* Drug: epacadostat
* Drug: pemigatinib
* Drug: INCAGN02385
* Drug: INCAGN02390


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to comprehend and willingness to sign a written ICF for the study. Note for Germany: This excludes individuals who are housed in an institution due to official or court order Women 18 years of age or older (or as applicable per local country requirements). Histologically confirmed diagnosis of advanced or metastatic endometrial cancer with disease progression on or after treatment with at least 1 platinum-containing regimen for advanced or metastatic disease. Groups A, B, and E: Have not been previously treated with a PD-(L)1 inhibitor. Group A only: Tumor tissue tested as MSI-High Group B only: Tumor tissue tested as deficient MMR or an ultra-mutated POLE tumor. Group D only: Tumor tissue tested as having an FGFR 1,2,3 mutation or alteration characterized as per protocol. Group E: Tumor tissue tested as MSS and PD-L1 positive. Group F: Radiological evidence of disease progression on or after prior PD (L)1 therapy and Tumor tissue tested as MSI-H Must have at least 1 measurable tumor lesion per RECIST v1.1. Willing to provide tumor tissue sample (fresh or archived). ECOG performance status 0 to 1. Willingness to avoid pregnancy. Exclusion Criteria: Group A, B and E only: Histologically confirmed diagnosis of carcinosarcoma of the uterus. Histologically confirmed diagnosis of sarcoma of the uterus. Has disease eligible for potentially curative treatment. Receipt of anticancer therapy within 28 days of the first administration of study treatment, with the exception of localized radiotherapy. Toxicity of prior therapy that has not recovered to ≤ Grade 1 or baseline unless approved by the medical monitor. Groups C, D and F (combinations): limiting immune-related toxicity during prior checkpoint inhibitor therapy. Group F only: Previous treatment with LAG-# or TIM-3 therapy or lenvatinib; multiple metastases that achieved mixed tumor response to prior anti-PD-(L)1 therapy Has an active autoimmune disease requiring systemic immunosuppression with corticosteroids (> 10 mg/day of prednisone or equivalent) or immunosuppressive drugs within 14 days before the first dose of study treatment. Receiving chronic systemic steroids (> 10 mg/day of prednisone or equivalent): Known active CNS metastases and/or carcinomatous meningitis. Has known active hepatitis B or C. Has received a live vaccine within 28 days of the planned start of study treatment. Evidence of interstitial lung disease or active, noninfectious pneumonitis. Participants who are known to be HIV-positive with some protocol exceptions.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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: Group A - retifanlimab<br>Select participants naïve to checkpoint inhibitors will be administered retifanlimab intravenously | Drug: retifanlimab<br>* INCMGA00012 administered intravenously on Day 1 of each 28-day cycle for up to 26 cycles.<br>* Other names: INCMGA00012;|
| Experimental: Group B - retifanlimab<br>Select participants naïve to checkpoint inhibitors will be administered retifanlimab intravenously | Drug: retifanlimab<br>* INCMGA00012 administered intravenously on Day 1 of each 28-day cycle for up to 26 cycles.<br>* Other names: INCMGA00012;|
| Experimental: Group C - retifanlimab + epacadostat<br>Select participants who are allowed on prior checkpoint inhibitors will be administered retifanlimab intravenously in combination with oral epacadostat (IDO1 inhibitor) | Drug: retifanlimab<br>* INCMGA00012 administered intravenously on Day 1 of each 28-day cycle for up to 26 cycles.<br>* Other names: INCMGA00012;Drug: epacadostat<br>* epacadostat will be administered orally BID.<br>|
| Experimental: Group D - retifanlimab + pemigatinib<br>Select participants who are allowed on prior checkpoint inhibitors will be administered retifanlimab intravenously in combination with oral pemigatininb (FGFR 1,2,3 inhibitor) | Drug: retifanlimab<br>* INCMGA00012 administered intravenously on Day 1 of each 28-day cycle for up to 26 cycles.<br>* Other names: INCMGA00012;Drug: pemigatinib<br>* pemigatinib will be administered orally QD.<br>|
| Experimental: Group E - retifanlimab + epacadostat<br>Select participants naïve to checkpoint inhibitors will be administered retifanlimab intravenously in combination with oral epacadostat | Drug: retifanlimab<br>* INCMGA00012 administered intravenously on Day 1 of each 28-day cycle for up to 26 cycles.<br>* Other names: INCMGA00012;Drug: epacadostat<br>* epacadostat will be administered orally BID.<br>|
| Experimental: Group F - retifanlimab + INCAGN02385 and INCAGN02390<br>Select participants who are allowed on prior checkpoint inhibitors will be administered retifanlimab in combination with INCAGN02385 and INCAGN02390 intravenously | Drug: INCAGN02385<br>* INCAGN2385 will be administered every 2 weeks<br>Drug: INCAGN02390<br>* INCAGN2390 will be administered every 2 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Group A - Objective Response Rate | Defined as the proportion of participants having a CR or PR according to RECIST v1.1, as assessed by Independent Central Review committee | up to 2.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Group A -Duration of Response | Defined as the time from the first documented objective response (CR or PR) according to RECIST v1.1 (as determined by ICR) until disease progression or death due to any cause. | up to 2.5 years | 
| Group A - Disease Control Rate | Defined as the proportion of participants with CR, PR, or SD (as determined by ICR) as best response. | up to 2.5 years | 
| Group A - Overall Survival | Defined as the time from the first dose of study treatment until death due to any cause. | up to 3.5 years | 
| Group A - Progression Free Survival | Defined as the time from the first dose of study treatment until disease progression (as determined by ICR) or death due to any cause. | up to 3.5 years | 
| Group B -Duration of Response | Defined as the time from the first documented objective response (CR or PR) according to RECIST v1.1 (as determined by ICR) until disease progression or death due to any cause. | up to 2.5 years | 
| Group B - Disease Control Rate | Defined as the proportion of participants with CR, PR, or SD (as determined by ICR) as best response. | up to 2.5 years | 
| Group B - Overall Survival | Defined as the time from the first dose of study treatment until death due to any cause. | up to 3.5 years | 
| Groups B - Objective Response Rate | Defined as the proportion of participants having a CR or PR according to RECIST v1.1, as assessed by Independent Central Review committee | up to 2 years | 
| Group B - Progression Free Survival | Defined as the time from the first dose of study treatment until disease progression (as determined by ICR) or death due to any cause. | up to 3.5 years | 
| Groups C, D, E and F - Objective Response Rate | Defined as the proportion of participants having a CR or PR according to RECIST v1.1, as assessed by Independent Central Review committee | up to 2 years | 
| Number of Treatment-Related Adverse Events | Adverse events reported for the first time or worsening of a pre-existing event after first dose of study drug/treatment. | up to 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic, PD-1, PD-L1, retifanlimab, INCMGA0012, INCAGN02385, Endometrial Carcinoma, Endometrium Cancer, Neoplasms Endometrial, Advanced, INCAGN02390, PODIUM, LAG-3, TIM-3