Study of Favezelimab (MK-4280) as Monotherapy and in Combination With Pembrolizumab (MK-3475) With or Without Chemotherapy or Lenvatinib (MK-7902) AND Favezelimab/Pembrolizumab (MK-4280A) as Monotherapy in Adults With Advanced Solid Tumors (MK-4280-001)

Study Overview
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Brief Summary
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This is a safety and pharmacokinetics study of favezelimab as monotherapy and in combination with pembrolizumab AND favezelimab/pembrolizumab as monotherapy in adults with metastatic solid tumors for which there is no available therapy which may convey clinical benefit. Part A of this study is a dose escalation design in which participants receive favezelimab as monotherapy or favezelimab in combination with pembrolizumab. Part B is a dose confirmation design to estimate the recommended Phase 2 dose (RP2D), as determined by dose-limiting toxicity, for favezelimab in combination with pembrolizumab or pembrolizumab and lenvatinib in participants with advanced solid tumors. Part B will also assess the efficacy of favezelimab as monotherapy; favezelimab in combination with pembrolizumab with and without chemotherapy; favezelimab in combination with pembrolizumab and lenvatinib; and favezelimab/pembrolizumab as monotherapy in expansion cohorts. Participants who have completed the initial course of treatment and have investigator-determined progressive disease may be eligible for a second course of an additional 17 cycles of study treatment.

Official Title
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A Phase 1 Trial of MK-4280 as Monotherapy and in Combination With Pembrolizumab With or Without Chemotherapy or Lenvatinib (E7080/MK-7902) in Subjects With Advanced Solid Tumors

Conditions
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Neoplasms

Intervention / Treatment
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* Biological: Favezelimab
* Biological: Pembrolizumab
* Drug: Oxaliplatin
* Drug: Irinotecan
* Drug: Leucovorin (Calcium Folinate)
* Drug: Fluorouracil [5-FU]
* Biological: Favezelimab/Pembrolizumab
* Drug: Lenvatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Part A and Part B: Has histologically or cytologically-confirmed metastatic solid tumor. Has measurable disease by immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) 1.1 criteria. Has a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale. Demonstrates adequate organ function. If female, is not pregnant or breastfeeding, and if of child-bearing potential, is willing to use an adequate method of contraception for the course of the study and for at least 180 days after the last dose of chemotherapy, 120 days after the last dose of pembrolizumab or favezelimab, or 30 days after the last dose of lenvatinib, whichever occurs last. If male with a female partner(s) of child-bearing potential, both must agree to use an adequate method of contraception starting with the first dose of study drug through 95 days after the last dose of study drug. Exclusion Criteria: Has had chemotherapy, radiation or biological cancer therapy within 4 weeks prior to the first dose of study drug,or has not recovered to Common Terminology Criteria for Adverse Events (CTCAE) Grade 0 or 1 from the AEs due to cancer therapeutics administered more than 4 weeks earlier (this includes participants with previous immunomodulatory therapy with residual immune-related [ir]AEs). Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of study drug. Has received previous treatment with another agent targeting the lymphocyte-activation gene 3 (LAG-3) receptor. Has received previous treatment with an immunomodulatory therapy (e.g., anti-programmed cell death-1/anti-programmed cell death-ligand 1 [anti-PD-1/anti-PD-L1] or cytotoxic T-lymphocyte-associated protein 4 [CTLA 4] agent) and was discontinued from that therapy due to a Grade 3 or higher irAE. Is expected to require any other form of antineoplastic therapy while on study. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy in excess of replacement doses, or on any other form of immunosuppressive medication. Has a history of a previous, additional malignancy, unless potentially curative treatment has been completed, with no evidence of malignancy for 5 years. Time frame exceptions include successful definitive resection of basal cell carcinoma of the skin, superficial bladder cancer or in situ cervical cancer, or other in situ cancers. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Has had a severe hypersensitivity reaction to treatment with another monoclonal antibody. Has an active autoimmune disease or a documented history of autoimmune disease, except vitiligo or resolved childhood asthma/atopy. Has an active infection requiring therapy. Has history of (non-infectious) pneumonitis that required steroids or has current pneumonitis. Has had a prior stem cell or bone marrow transplant. Has a known history of or screens positive for Human Immunodeficiency Virus (HIV), active chronic or acute Hepatitis B or Hepatitis C. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study. Is a regular user as determined by investigator judgement (including recreational use) of any illicit drugs or has a recent history (within the last year) of substance abuse (including alcohol), at the time of signing informed consent. Has symptomatic ascites or pleural effusion. A participant who is clinically stable following treatment for these conditions (including therapeutic thoraco- or paracentesis) is eligible. Has clinically significant heart disease that affects normal activities. Has received a live-virus vaccine within 30 days of planned start of study drug. Seasonal flu vaccines that do not contain live virus are permitted.

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: Part A: Favezelimab Dose A<br>Participants receive favezelimab Dose A intravenous (IV) infusion on Day 1 of each 21-day cycle. | Biological: Favezelimab<br>* IV infusion<br>* Other names: MK-4280;|
| Experimental: Part A: Favezelimab Dose B<br>Participants receive favezelimab Dose B IV infusion on Day 1 of each 21-day cycle. | Biological: Favezelimab<br>* IV infusion<br>* Other names: MK-4280;|
| Experimental: Part A: Favezelimab Dose C<br>Participants receive favezelimab Dose C IV infusion on Day 1 of each 21-day cycle. | Biological: Favezelimab<br>* IV infusion<br>* Other names: MK-4280;|
| Experimental: Part A: Favezelimab Dose D<br>Participants receive favezelimab Dose D IV infusion on Day 1 of each 21-day cycle. | Biological: Favezelimab<br>* IV infusion<br>* Other names: MK-4280;|
| Experimental: Part A: Favezelimab Dose E<br>Participants receive favezelimab Dose E IV infusion on Day 1 of each 21-day cycle. | Biological: Favezelimab<br>* IV infusion<br>* Other names: MK-4280;|
| Experimental: Part A: Favezelimab Dose A+Pembro<br>Participants receive favezelimab Dose A IV infusion on Day 1 of each 21-day cycle PLUS pembrolizumab IV infusion administered sequentially on Day 1 of each 21-day cycle. | Biological: Favezelimab<br>* IV infusion<br>* Other names: MK-4280;Biological: Pembrolizumab<br>* IV infusion<br>* Other names: KEYTRUDA®;|
| Experimental: Part A: Favezelimab Dose B+Pembro<br>Participants receive favezelimab Dose B IV infusion on Day 1 of each 21-day cycle PLUS pembrolizumab IV infusion administered sequentially on Day 1 of each 21-day cycle. | Biological: Favezelimab<br>* IV infusion<br>* Other names: MK-4280;Biological: Pembrolizumab<br>* IV infusion<br>* Other names: KEYTRUDA®;|
| Experimental: Part A: Favezelimab Dose C+Pembro<br>Participants receive favezelimab Dose C IV infusion on Day 1 of each 21-day cycle PLUS pembrolizumab IV infusion administered sequentially on Day 1 of each 21-day cycle. | Biological: Favezelimab<br>* IV infusion<br>* Other names: MK-4280;Biological: Pembrolizumab<br>* IV infusion<br>* Other names: KEYTRUDA®;|
| Experimental: Part A: Favezelimab Dose D+Pembro<br>Participants receive favezelimab Dose D IV infusion on Day 1 of each 21-day cycle PLUS pembrolizumab IV infusion administered sequentially on Day 1 of each 21-day cycle. | Biological: Favezelimab<br>* IV infusion<br>* Other names: MK-4280;Biological: Pembrolizumab<br>* IV infusion<br>* Other names: KEYTRUDA®;|
| Experimental: Part A: Favezelimab Dose E+Pembro<br>Participants receive favezelimab Dose E IV infusion on Day 1 of each 21-day cycle PLUS pembrolizumab IV infusion administered sequentially on Day 1 of each 21-day cycle. | Biological: Favezelimab<br>* IV infusion<br>* Other names: MK-4280;Biological: Pembrolizumab<br>* IV infusion<br>* Other names: KEYTRUDA®;|
| Experimental: Part B: Favezelimab Monotherapy Dose<br>Participants receive favezelimab monotherapy dose IV infusion on Day 1 of each 21-day cycle. | Biological: Favezelimab<br>* IV infusion<br>* Other names: MK-4280;|
| Experimental: Part B: Favezelimab Dose F+Pembro<br>Participants receive favezelimab Dose F IV infusion on Day 1 of each 21-day cycle PLUS pembrolizumab IV infusion administered sequentially on Day 1 of each 21-day cycle. | Biological: Favezelimab<br>* IV infusion<br>* Other names: MK-4280;Biological: Pembrolizumab<br>* IV infusion<br>* Other names: KEYTRUDA®;|
| Experimental: Part B: Favezelimab Dose G+Pembro<br>Participants receive favezelimab Dose G IV infusion on Day 1 of each 21-day cycle PLUS pembrolizumab IV infusion administered sequentially on Day 1 of each 21-day cycle. | Biological: Favezelimab<br>* IV infusion<br>* Other names: MK-4280;Biological: Pembrolizumab<br>* IV infusion<br>* Other names: KEYTRUDA®;|
| Experimental: Part B: Favezelimab Dose H+Pembro<br>Participants receive favezelimab Dose H IV infusion on Day 1 of each 21-day cycle PLUS pembrolizumab IV infusion administered sequentially on Day 1 of each 21-day cycle. | Biological: Favezelimab<br>* IV infusion<br>* Other names: MK-4280;Biological: Pembrolizumab<br>* IV infusion<br>* Other names: KEYTRUDA®;|
| Experimental: Part B: Favezelimab Dose G+Pembro+mFOLFOX7<br>Participants receive favezelimab Dose G IV infusion on Day 1 of each 21-day cycle PLUS pembrolizumab IV infusion administered sequentially on Day 1 of each 21-day cycle PLUS mFOLFOX7 (oxaliplatin 85 mg/m^2 IV, leucovorin [calcium folinate] 400 mg/m^2 IV and fluorouracil [5-FU] 2400 mg/m^2 IV over 46 to 48 hours every 2 weeks [Q2W]). | Biological: Favezelimab<br>* IV infusion<br>* Other names: MK-4280;Biological: Pembrolizumab<br>* IV infusion<br>* Other names: KEYTRUDA®;Drug: Oxaliplatin<br>* IV infusion<br>* Other names: ELOXATIN®;Drug: Leucovorin (Calcium Folinate)<br>* IV infusion<br>* Other names: WELLCOVORIN®;Drug: Fluorouracil [5-FU]<br>* IV infusion<br>* Other names: ADRUCIL®;|
| Experimental: Part B: Favezelimab Dose G+Pembro+FOLFIRI<br>Participants receive favezelimab Dose G IV infusion on Day 1 of each 21-day cycle PLUS pembrolizumab IV administered sequentially on Day 1 of each 21-day cycle PLUS FOLFIRI (irinotecan 180 mg/m^2 IV, leucovorin [calcium folinate] 400 mg/m^2 IV and 5-FU 2400 mg/m^2 IV over 46 to 48 hours Q2W). | Biological: Favezelimab<br>* IV infusion<br>* Other names: MK-4280;Biological: Pembrolizumab<br>* IV infusion<br>* Other names: KEYTRUDA®;Drug: Irinotecan<br>* IV infusion<br>* Other names: CAMPTOSAR®;Drug: Leucovorin (Calcium Folinate)<br>* IV infusion<br>* Other names: WELLCOVORIN®;Drug: Fluorouracil [5-FU]<br>* IV infusion<br>* Other names: ADRUCIL®;|
| Experimental: Part B: Favezelimab/Pembrolizumab<br>Participants receive favezelimab/pembrolizumab (favezelimab and pembrolizumab administered as a co-formulation) IV infusion on Day 1 of each 21-day cycle. | Biological: Favezelimab/Pembrolizumab<br>* IV infusion<br>* Other names: MK-4280A;|
| Experimental: Part B: Favezelimab Dose G+Pembro+Lenvatinib<br>Participants receive favezelimab Dose G IV infusion on Day 1 of each 21 day cycle PLUS pembrolizumab IV infusion administered sequentially on Day 1 of each 21-day cycle PLUS oral lenvatinib (20 mg) each day of 21-day cycle. | Biological: Favezelimab<br>* IV infusion<br>* Other names: MK-4280;Biological: Pembrolizumab<br>* IV infusion<br>* Other names: KEYTRUDA®;Drug: Lenvatinib<br>* Oral<br>* Other names: LENVIMA®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experience a Dose-Limiting Toxicity (DLT) |  | Up to approximately 52 weeks | 
| Number of Participants Who Experience at Least One Adverse Event (AE) |  | Up to approximately 7 years | 
| Number of Participants Who Discontinue Study Drug Due to an AE |  | Up to approximately 7 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum Concentration of Favezelimab When Administered as Monotherapy |  | At designated time points (Up to approximately 2 years) | 
| Serum Concentration of Favezelimab When Administered in Combination With Pembrolizumab |  | At designated time points (Up to approximately 2 years) | 
| Serum Concentration of Favezelimab When Administered in Combination With Pembrolizumab and mFOLFOX7 |  | At designated time points (Up to approximately 2 years) | 
| Serum Concentration of Favezelimab When Administered in Combination With Pembrolizumab and FOLFIRI |  | At designated time points (Up to approximately 2 years) | 
| Serum Concentration of Favezelimab When Administered in Combination With Pembrolizumab and Lenvatinib |  | At designated time points (Up to approximately 2 years) | 
| Serum Concentration of Pembrolizumab When Administered in Combination With Favezelimab and mFOLFOX7 |  | At designated time points (Up to approximately 2 years) | 
| Serum Concentration of Pembrolizumab When Administered in Combination With Favezelimab and FOLFIRI |  | At designated time points (Up to approximately 2 years) | 
| Serum Concentration of Pembrolizumab When Administered in Combination With Favezelimab and Lenvatinib |  | At designated time points (Up to approximately 2 years) | 
| Serum Concentration of Lenvatinib When Administered in Combination With Pembrolizumab and Favezelimab |  | At designated time points (Up to approximately 2 years) | 
| Objective Response Rate (ORR) as Determined by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) as Assessed by Investigator Review of Favezelimab Alone and in Combination With Pembrolizumab |  | Up to approximately 2 years | 
| ORR as Determined by RECIST 1.1 as Assessed by Investigator Review of Two Doses of Favezelimab in Combination With Pembrolizumab for Participants With Advanced Solid Tumors in Cohort E |  | Up to approximately 2 years | 
| ORR as Determined by RECIST 1.1 as Assessed by Investigator Review of Favezelimab in Combination With Pembrolizumab and mFOLFOX7 for Participants With Advanced Solid Tumors in Cohort B |  | Up to approximately 2 years | 
| ORR as Determined by RECIST 1.1 as Assessed by Investigator Review of Favezelimab in Combination With Pembrolizumab and FOLFIRI for Participants With Advanced Solid Tumors in Cohort B |  | Up to approximately 2 years | 
| ORR as Determined by RECIST 1.1 as Assessed by Investigator Review of Favezelimab in Combination With Pembrolizumab and Lenvatinib for Participants With Advanced Solid Tumors in Cohort G |  | Up to approximately 2 years | 
| Serum Concentration of Favezelimab When Administered as a Co-Formulation With Pembrolizumab (MK-4280A) |  | At designated time points (Up to approximately 2 years) | 
| Serum Concentration of Favezelimab When Administered Sequentially With Pembrolizumab |  | At designated time points (Up to approximately 2 years) | 
| Serum Concentration of Pembrolizumab When Administered as a Co-Formulation With Favezelimab (MK-4280A) |  | At designated time points (Up to approximately 2 years) | 
| Serum Concentration of Pembrolizumab When Administered Sequentially With Favezelimab |  | At designated time points (Up to approximately 2 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PD1, PD-1, PDL1, PD-L1