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)

Merck Sharp & Dohme (MSD)

Status and phase

Completed

Phase 1

Conditions

Neoplasms

Treatments

Biological: Favezelimab/Pembrolizumab

Drug: Irinotecan

Biological: Favezelimab

Drug: Lenvatinib

Drug: Leucovorin (Calcium Folinate)

Drug: Oxaliplatin

Drug: Fluorouracil [5-FU]

Biological: Pembrolizumab

Study type

Interventional

Funder types

Industry

Identifiers

NCT02720068

2017-001464-38 (EudraCT Number)

4280-001

MK-4280-001 (Other Identifier)

183971 (Other Identifier)

Details and patient eligibility

About

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.

Full description

All participants who completed the first course were eligible for second course treatment after Sponsor consultation if there was investigator-determined progressive disease after initial treatment had been been completed.

Enrollment

481 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

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.

Trial design

Primary purpose

Treatment

Allocation

Non-Randomized

Interventional model

Parallel Assignment

Masking

None (Open label)

481 participants in 18 patient groups

Part A: Favezelimab 7 mg Monotherapy

Experimental group

Description:

Participants received favezelimab 7 mg intravenous (IV) infusion on Day 1 of each 21-day cycle.

Treatment:

Biological: Favezelimab

Part A: Favezelimab 21 mg Monotherapy

Experimental group

Description:

Participants received favezelimab 21 mg IV infusion on Day 1 of each 21-day cycle.

Treatment:

Biological: Favezelimab

Part A: Favezelimab 70 mg Monotherapy

Experimental group

Description:

Participants received favezelimab 70 mg IV infusion on Day 1 of each 21-day cycle.

Treatment:

Biological: Favezelimab

Part A: Favezelimab 210 mg Monotherapy

Experimental group

Description:

Participants received favezelimab 210 mg IV infusion on Day 1 of each 21-day cycle.

Treatment:

Biological: Favezelimab

Part A: Favezelimab 700 mg Monotherapy

Experimental group

Description:

Participants received favezelimab 700 mg IV infusion on Day 1 of each 21-day cycle.

Treatment:

Biological: Favezelimab

Part A: Favezelimab 7 mg + Pembrolizumab 200 mg

Experimental group

Description:

Participants received favezelimab 7 mg IV infusion on Day 1 of each 21-day cycle PLUS pembrolizumab 200 mg IV infusion administered sequentially on Day 1 of each 21-day cycle.

Treatment:

Biological: Pembrolizumab

Biological: Favezelimab

Part A: Favezelimab 21 mg + Pembrolizumab 200 mg

Experimental group

Description:

Participants received favezelimab 21 mg IV infusion on Day 1 of each 21-day cycle PLUS pembrolizumab 200 mg IV infusion administered sequentially on Day 1 of each 21-day cycle.

Treatment:

Biological: Pembrolizumab

Biological: Favezelimab

Part A: Favezelimab 70 mg + Pembrolizumab 200 mg

Experimental group

Description:

Participants received favezelimab 70 mg IV infusion on Day 1 of each 21-day cycle PLUS pembrolizumab 200 mg IV infusion administered sequentially on Day 1 of each 21-day cycle.

Treatment:

Biological: Pembrolizumab

Biological: Favezelimab

Part A: Favezelimab 210 mg + Pembrolizumab 200 mg

Experimental group

Description:

Participants received favezelimab 210 mg IV infusion on Day 1 of each 21-day cycle PLUS pembrolizumab 200 mg IV infusion administered sequentially on Day 1 of each 21-day cycle.

Treatment:

Biological: Pembrolizumab

Biological: Favezelimab

Part A: Favezelimab 700 mg + Pembrolizumab 200 mg

Experimental group

Description:

Participants received favezelimab 700 mg IV infusion on Day 1 of each 21-day cycle PLUS pembrolizumab 200 mg IV infusion administered sequentially on Day 1 of each 21-day cycle.

Treatment:

Biological: Pembrolizumab

Biological: Favezelimab

Part B: Favezelimab 800 mg Monotherapy (Arm 1)

Experimental group

Description:

Participants received favezelimab 800 mg monotherapy IV infusion on Day 1 of each 21-day cycle.

Treatment:

Biological: Favezelimab

Part B: Favezelimab 200 mg + Pembrolizumab 200 mg (Arm 2A)

Experimental group

Description:

Participants received favezelimab 200 mg IV infusion on Day 1 of each 21-day cycle PLUS pembrolizumab 200 mg IV infusion administered sequentially on Day 1 of each 21-day cycle.

Treatment:

Biological: Pembrolizumab

Biological: Favezelimab

Part B: Favezelimab 700 mg + Pembrolizumab 200 mg (Arm 2B)

Experimental group

Description:

Participants received favezelimab 700 mg IV infusion on Day 1 of each 21-day cycle PLUS pembrolizumab 200 mg IV infusion administered sequentially on Day 1 of each 21-day cycle.

Treatment:

Biological: Pembrolizumab

Biological: Favezelimab

Part B: Favezelimab 800 mg + Pembrolizumab 200 mg (Arm 2C)

Experimental group

Description:

Participants received favezelimab 800 mg IV infusion on Day 1 of each 21-day cycle PLUS pembrolizumab 200 mg IV infusion administered sequentially on Day 1 of each 21-day cycle.

Treatment:

Biological: Pembrolizumab

Biological: Favezelimab

Part B: Favezelimab 800 mg + Pembrolizumab 200 mg + mFOLFOX7 (Arm 3)

Experimental group

Description:

Participants received favezelimab 800 mg IV infusion on Day 1 of each 21-day cycle PLUS pembrolizumab 200 mg 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 \[Q2W\]).

Treatment:

Biological: Pembrolizumab

Drug: Fluorouracil [5-FU]

Drug: Leucovorin (Calcium Folinate)

Drug: Oxaliplatin

Biological: Favezelimab

Part B: Favezelimab 800 mg + Pembrolizumab 200 mg + FOLFIRI (Arm 4)

Experimental group

Description:

Participants received favezelimab 800 mg IV infusion on Day 1 of each 21-day cycle PLUS pembrolizumab 200 mg IV infusion 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).

Treatment:

Biological: Pembrolizumab

Drug: Fluorouracil [5-FU]

Drug: Leucovorin (Calcium Folinate)

Biological: Favezelimab

Drug: Irinotecan

Part B: MK-4280A (Arm 5)

Experimental group

Description:

Participants received MK-4280A, a coformulation of favezelimab 800 mg + pembrolizumab 200 mg IV infusion on Day 1 of each 21-day cycle.

Treatment:

Biological: Favezelimab/Pembrolizumab