Study of REGN5678 (Anti-PSMAxCD28) With or Without Cemiplimab (Anti-PD-1) in Patients With Metastatic Castration-resistant Prostate Cancer and Other Tumors

Study Overview
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Brief Summary
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The main purpose of this study is to determine the safety, tolerability (how your body reacts to the drug) and effectiveness of REGN5678 with or without cemiplimab. There are additional purposes of this study including measurement of the levels of REGN5678 in your blood when given alone and when given in combination with cemiplimab, and collection of any evidence of tumor shrinkage. The study has 2 parts. The goal of Part 1 is to determine a safe dose(s) of REGN5678 when it is given alone and then followed by combination with cemiplimab. The goal of Part 2 of the study is to use the REGN5678 drug dose(s) found in Part 1 to see how well REGN5678 alone or in combination with cemiplimab works to shrink tumors. Note: All the above primary, secondary objectives will apply to each cohort (unless specified) in the study including those who receive sarilumab and those who do not receive sarilumab.

Official Title
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A Phase 1/2 Study of REGN5678 (Anti-PSMAxCD28) With or Without Cemiplimab (Anti-PD-1) in Patients With Metastatic Castration-Resistant Prostate Cancer and Other Tumors Associated With PSMA Expression

Conditions
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Metastatic Castration-resistant Prostate Cancer (mCRPC), Clear Cell Renal Cell Carcinoma (ccRCC)

Intervention / Treatment
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* Drug: REGN5678
* Drug: Cemiplimab
* Drug: Sarilumab


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Histologically or cytologically confirmed adenocarcinoma of the prostate without pure small cell carcinoma (mCRPC cohorts). Metastatic, castration-resistant prostate cancer (mCRPC) with PSA value at screening ≥4 ng/mL that has progressed within 6 months prior to screening as defined in the protocol (mCRPC cohorts). (mCRPC cohorts) Has received ≥2 lines prior systemic therapy approved in the metastatic and/or castration-resistant setting (in addition to androgen deprivation therapy [ADT]) including at least: one second-generation anti-androgen therapy (eg, abiraterone, enzalutamide, apalutamide, or darolutamide) (post-177Lu-PSMA-617 radiotherapy expansion cohort only) Has received at least 2 doses of 177Lu-PSMA-617. Prior therapy 177Lu-PSMA-617 is not permitted in other cohorts Histologically or cytologically confirmed RCC with a clear-cell component. Diagnosis of metastatic ccRCC with at least one measurable lesion via RECIST 1.1 criteria Tumor PSMA expression via PSMA-positron emission tomography (PET), as defined by at least one PSMA-PET positive lesion with signal above liver background via visual assessment per central review Has progressed on or after ≥1 line prior systemic therapy approved in the metastatic setting. Prior treatment must include an anti-programmed death-1 (receptor) [PD-1]/programmed death-ligand 1 (PD-L1) therapy and either ipilimumab and/or a tyrosine kinase inhibitor Key Exclusion Criteria: Has received treatment with an approved systemic therapy within 3 weeks of dosing or has not yet recovered (ie, grade ≤1 or baseline) from any acute toxicities Has received any previous systemic biologic therapy within 5 half-lives of first dose of study therapy Has received prior PSMA-targeting therapy Dose Expansion (mCRPC only): Has had prior anti-cancer immunotherapy Any condition that requires ongoing/continuous corticosteroid therapy (>10 mg prednisone/day or anti-inflammatory equivalent) within 1 week prior to the first dose of study therapy Ongoing or recent (within 5 years) evidence of significant autoimmune disease that required treatment with systemic immunosuppressive treatments Encephalitis, meningitis, neurodegenerative disease (with the exception of mild dementia that does not interfere with activities of daily living [ADLs]) or uncontrolled seizures in the year prior to first dose of study therapy Uncontrolled infection with human immunodeficiency virus (HIV), hepatitis B or hepatitis C infection; or diagnosis of immunodeficiency NOTE: Other protocol defined Inclusion/Exclusion Criteria apply - At this time, we are only enrolling the REGN5678 monotherapy expansion cohort

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

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: mCRPC - dose escalation cohort<br>Participants will receive monotherapy lead-in of REGN5678 followed by a combination of REGN5678 and cemiplimab, with or without sarilumab prophylaxis. | Drug: REGN5678<br>* Administered at the assigned dose level (DL) by intravenous (IV) infusion or subcutaneous (SC) administration<br>Drug: Cemiplimab<br>* Administered at the assigned DL by intravenous (IV) infusion<br>* Other names: LIBTAYO;Drug: Sarilumab<br>* Administered by IV infusion<br>* Other names: KEVZARA;|
| Experimental: mCRPC - dose expansion cohort<br>Participants will receive either REGN5678 monotherapy or combination therapy of REGN5678 (with or without a monotherapy lead-in) at the recommended phase 2 dose (RP2D) and cemiplimab for mCRPC. Expansion cohorts may be performed in cohorts with or without sarilumab and participants with mCRPC that have received prior received prostate-specific membrane antigen (PSMA)-targeted lutetium Lu 177 vipivotide tetraxetan radiotherapy (177Lu-PSMA-617). | Drug: REGN5678<br>* Administered at the assigned dose level (DL) by intravenous (IV) infusion or subcutaneous (SC) administration<br>Drug: Cemiplimab<br>* Administered at the assigned DL by intravenous (IV) infusion<br>* Other names: LIBTAYO;Drug: Sarilumab<br>* Administered by IV infusion<br>* Other names: KEVZARA;|
| Experimental: ccRCC - dose expansion cohort<br>Participants will receive REGN5678 in combination therapy of REGN5678 at the MTD/presumptive RP2D(s) and cemiplimab. Expansion cohorts may be performed in cohorts with or without sarilumab. | Drug: REGN5678<br>* Administered at the assigned dose level (DL) by intravenous (IV) infusion or subcutaneous (SC) administration<br>Drug: Cemiplimab<br>* Administered at the assigned DL by intravenous (IV) infusion<br>* Other names: LIBTAYO;Drug: Sarilumab<br>* Administered by IV infusion<br>* Other names: KEVZARA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of treatment-emergent adverse events (TEAEs) | Dose Escalation Phase | Through study completion, Up to 5 years | 
| Incidence and severity of adverse event of special interests (AESIs) | Dose Escalation Phase | Through study completion, Up to 5 years | 
| Incidence and severity of serious adverse events (SAEs) | Dose Escalation Phase | Through study completion, Up to 5 years | 
| Number of participants with Grade ≥3 laboratory abnormalities | Dose Escalation Phase | Through study completion, Up to 5 years | 
| Incidence of dose-limiting toxicities (DLTs) | Dose Escalation Phase | First dose through day 42 of last participant in each dose level | 
| Concentration of REGN5678 in serum over time | Dose Escalation Phase | Through study completion, Up to 5 years | 
| Concentration of REGN5678 in combination with cemiplimab in serum over time | Dose Escalation Phase | Through study completion, Up to 5 years | 
| Objective response rate (ORR) per modified Prostate Cancer Working Group 3 (PCWG3) criteria | Dose Expansion Phase - mCRPC cohort | Through study completion, Up to 5 years | 
| ORR per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria | Dose Expansion Phase - ccRCC cohort | Through study completion, Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR per modified PCWG3 criteria | Dose Escalation Phase | Through study completion, Up to 5 years | 
| Incidence and severity of TEAEs | Dose Expansion Phase | Through study completion, Up to 5 years | 
| Incidence and severity of AESIs | Dose Expansion Phase | Through study completion, Up to 5 years | 
| Incidence and severity of SAEs | Dose Expansion Phase | Through study completion, Up to 5 years | 
| Number of participants with grade ≥3 laboratory abnormalities | Dose Expansion Phase | Through study completion, Up to 5 years | 
| Concentration of REGN5678 in combination with cemiplimab in serum over time | Dose Expansion Phase | Through study completion, Up to 5 years | 
| ORR based upon prostate specific antigen (PSA) response | Dose Escalation and Dose Expansion Phases - mCRPC cohorts | Through study completion, Up to 5 years | 
| Percentage of participants with ≥90% decline of PSA | Dose Escalation and Dose Expansion Phases- mCRPC cohorts | Through study completion, Up to 5 years | 
| Percentage of participants who have achieved conversion of circulating tumor cell (CTC) count from baseline of ≥5 cells/7.5mL to <5 cells/7.5mL | Dose Escalation and Dose Expansion Phases- mCRPC cohorts | Through study completion, Up to 5 years | 
| Presence or absence of antibodies against REGN5678 | Dose Escalation and Dose Expansion Phases | Through study completion, Up to 5 years | 
| Presence or absence of antibodies against cemiplimab | Dose Escalation and Dose Expansion Phases | Through study completion, Up to 5 years |