Study of Favezelimab Coformulated With Pembrolizumab (MK-4280A) in Participants With Selected Solid Tumors (MK-4280A-010)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate pathological complete response (pCR) rate of coformulated favezelimab/pembrolizumab (MK-4280A) or pembrolizumab as assessed by blinded central pathology review (BICR) in participants with cutaneous squamous cell carcinoma (cSCC) [Cohort A] and to evaluate lenvatinib in combination with coformulated favezelimab/pembrolizumab or pembrolizumab with respect to objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as assessed by investigator in participants proficient in mismatch repair (pMMR) endometrial cancer (EC) [Cohort B].

Official Title
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A Multicenter, Randomized, Double-Blind, Phase 2, Basket Study of MK-4280A, a Coformulation of Favezelimab (MK-4280) With Pembrolizumab (MK-3475) in Selected Solid Tumors (KeyForm-010)

Conditions
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Solid Tumor, Cutaneous Squamous Cell Carcinoma, Endometrial Cancer

Intervention / Treatment
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* Biological: favezelimab/pembrolizumab
* Biological: pembrolizumab
* Drug: lenvatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Cohort A only Histologically confirmed diagnosis of resectable cutaneous squamous cell carcinoma (cSCC) as the primary site of malignancy (metastatic skin involvement from another primary cancer or from an unknown primary cancer is not permitted) Stage II to Stage IV disease without distant metastasis (M1). cSCC tumors arising in the head and neck will be staged according to American Joint Committee on Cancer (AJCC) Edition (Ed.) 8 and cSCC tumors arising in non-head and neck locations will be staged according to Union for International Cancer Control (UICC) Ed. 8 Is systemic treatment naïve Archival tumor tissue sample, or newly obtained surgical resection, or biopsy sample of a tumor lesion not previously irradiated has been provided Is an individual of any sex/gender, at least 18 years of age at the time of providing the informed consent Cohort B only Histologically confirmed diagnosis of endometrial cancer (EC) that is not deficient in mismatch repair (dMMR) proficient in mismatch repair (pMMR) as documented by a local test report Documented evidence of stage IVB (per 2009 International Federation of Gynecology and Obstetrics (FIGO) staging), recurrent, or metastatic EC, and are not candidates for curative surgery or radiation Has radiographic evidence of disease progression after 1 prior systemic, platinum-based chemotherapy regimen for EC in any setting Measurable disease per Response Evaluation Criteria In Solid Tumors (RECIST 1.1) by investigator (before first dose of study intervention) Is assigned female sex at birth, at least 18 years of age at the time of providing the informed consent Has adequately controlled blood pressure without antihypertensive medication All Cohorts Agrees to follow contraception guidelines if a participant of childbearing potential Has a life expectancy >3 years per investigator assessment Has adequate organ function Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 If positive for hepatitis B, has received antiviral therapy for ≥4 weeks and undetectable viral load prior to randomization If positive for hepatitis C, has undetectable viral load at screening If positive for human immunodeficiency virus (HIV), has well-controlled HIV on a stable highly active antiretroviral therapy Exclusion Criteria: All Cohorts Has known hypersensitivity to active substances or their excipients including previous clinically significant hypersensitivity reaction to treatment with other monoclonal antibody (mAb) History of allogeneic tissue/solid organ transplant Cohort A only Received prior radiotherapy to the index lesion (in-field lesion) Participants for whom the primary site of cSCC was anogenital area (penis, scrotum, vulva, perianal region) are not eligible Cohort B Has had major surgery within 3 weeks prior to first dose of study interventions Has preexisting ≥Grade 3 gastrointestinal or non-gastrointestinal fistula Has urine protein ≥1 g/24 hours Has a left ventricle ejection fraction (LVEF) below the institutional (or local laboratory) normal range, as determined by multi-gated acquisition (MUGA) or echocardiogram (ECHO) Has radiographic evidence of encasement or invasion of a major blood vessel, or of intratumoral cavitation Has clinically significant cardiovascular disease within 12 months from first dose of study intervention

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: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Favezelimab/Pembrolizumab<br>Participants will receive coformulated favezelimab/pembrolizumab (800 mg/200 mg) via an intravenous (IV) infusion every 3 weeks (Q3W) for 3 cycles in the neoadjuvant period and 14 cycles of adjuvant therapy. Each cycle is 21 days. Participants who do not complete all 3 neoadjuvant cycles should have additional cycles in the adjuvant period so that the total number of study intervention administrations is 17 treatment cycles. | Biological: favezelimab/pembrolizumab<br>* IV infusion<br>* Other names: MK-4280A;|
| Experimental: Pembrolizumab<br>Participants will receive 200 mg pembrolizumab via an IV infusion Q3W for 3 cycles in the neoadjuvant period and 14 cycles of adjuvant therapy. Each cycle is 21 days. Participants who do not complete all 3 neoadjuvant cycles should have additional cycles in the adjuvant period so that the total number of study intervention administrations is 17 treatment cycles. | Biological: pembrolizumab<br>* IV infusion<br>* Other names: Keytruda®;|
| Experimental: Favezelimab/Pembrolizumab + Lenvatinib (Cohort B)<br>Participants will receive coformulated favezelimab/pembrolizumab (800 mg/200 mg) via IV infusion Q3W for up to 35 cycles (each cycle is 21 days) PLUS lenvatinib every day (QD) 20 mg orally until disease progression, unacceptable toxicity, or discontinuation criteria are met. | Biological: favezelimab/pembrolizumab<br>* IV infusion<br>* Other names: MK-4280A;Drug: lenvatinib<br>* Oral administration of capsule<br>|
| Experimental: Pembrolizumab + Lenvatinib (Cohort B)<br>Participants will receive 200 mg pembrolizumab via IV infusion Q3W for up to 35 cycles (each cycle is 21 days) PLUS lenvatinib QD 20 mg orally until disease progression, unacceptable toxicity, or discontinuation criteria are met. | Biological: pembrolizumab<br>* IV infusion<br>* Other names: Keytruda®;Drug: lenvatinib<br>* Oral administration of capsule<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological Complete Response (pCR) - Cohort A | pCR is defined as complete absence of viable tumor in the surgical resection sample as assessed by central review of the pathology results. Number of Cohort A participants with pCR will be reported. | Up to approximately 22 months | 
| Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by Investigator - Cohort B | The ORR is defined as the percentage of participants who have an OR per investigator assessment. The OR is defined as a Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions) per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1). The percentage of participants who experience CR or PR as assessed by Blinded Independent Central Review (BICR) will be presented. | Up to approximately 21 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) - All Cohorts | OS is defined as the time from randomization to death from any cause. | Up to approximately 41 months | 
| Clinical Benefit Rate - Cohort A | Clinical benefit rate is defined as the percentage of participants who have clinical benefit. Clinical benefit is defined as pCR in participants who undergo surgery or clinical complete response (cCR) [defined as residual tumor not visible on clinical exam or on imaging and a negative biopsy, if biopsy is available, in participants who decline surgery. | Up to approximately 22 months | 
| Event-Free Survival (EFS) - Cohort A | EFS is defined as the time from randomization to first progression prior to surgical resection as assessed by investigator, inability to resect tumor, recurrence (postsurgical resection), or death from any cause, whichever occurs first. | Up to approximately 41 months | 
| Major Pathological Response (mPR) - Cohort A | mPR is defined as ≤10% of viable tumor cells in the surgical resection sample as assessed by central review of the pathology results. The number of Cohort A participants with mPR will be reported. | Up to approximately 22 months | 
| ORR per RECIST 1.1 as assessed by Investigator - Cohort A | The ORR is defined as the percentage of participants who have an OR per investigator assessment. The OR is defined as a Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions) per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1). The percentage of participants who experience CR or PR as assessed by Blinded Independent Central Review (BICR) will be presented. | Up to approximately 22 months | 
| Number of participants with an adverse event (AE) - Cohorts A and B | An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. The number of participants who experience an AE will be reported. | Up to approximately 41 months | 
| Number of participants discontinuing from study therapy due to AE - Cohorts A and B | An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. The number of participants who discontinue study treatment due to an AE will be reported. | Up to approximately 41 months | 
| Number of participants experiencing perioperative complications - Cohort A | The number of participants who experience perioperative complications will be assessed. | Up to approximately 18 weeks | 
| Number of participants with an AE that precludes surgery/initiation of adjuvant therapy - Cohort A | An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. The number of Cohort A participants with an AE that precludes surgery or initiation of adjuvant therapy will be reported. | Up to approximately 2 months | 
| Progression Free Survival (PFS) - Cohort B | PFS is defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurs first as assessed by the investigator. Per RECIST 1.1, or by histopathologic confirmation of disease progression (PD), PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions is also considered PD. Unequivocal progression of non-target lesions is also considered PD. | Up to approximately 41 months | 
| Duration of Response (DOR) - Cohort B | DOR is defined as the time from first documented evidence of CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions) until progressive disease (PD) or death. Per RECIST 1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD. DOR as assessed by Blinded Independent Central Review (BICR) will be presented. | Up to approximately 41 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Programmed Cell Death-1 (PD1, PD-1), Programmed Cell Death-2 (PD2, PD-2), Programmed Cell Death Receptor Ligand 1 (PDL1, PD-L1), Programmed Cell Death Receptor Ligand 2 (PDL2, PD-L2), Lymphocyte-Activation Gene 3 (LAG-3)