Clinical trial NCT02720068: 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)
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Neoplasms
Keywords: Programmed Cell Death-1 (PD1, PD-1)
Programmed Cell Death 1 Ligand 1 (PDL1, PD-L1)
Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2)
Lymphocyte-activation gene 3 (LAG3, LAG-3, CD223)
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2016-03-25
Enrollment: 481
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Participants were allocated to arms in a non-random fashion, except in the case of those with gastric cancer enrolled in Part B, who were randomized 1:1 between Arm 2A and Arm 2B (favezelimab 200 mg and 800 mg, respectively). Part B initiated after determination of a favezelimab recommended phase 2 dose (RP2D) from Part A.
Primary purpose: TREATMENT

Brief summary: 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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number of Participants Who Experienced a Dose-Limiting Toxicity (DLT)
timeFrame: Up to 21 days (Cycle 1)
measure: Number of Participants Who Experienced an Adverse Event (AE)
timeFrame: Up to approximately 31.3 months
measure: Number of Participants Who Discontinued Study Treatment Due to an AE
timeFrame: Up to approximately 28.3 months
Secondary outcomes:
measure: Objective Response Rate (ORR) for Part B Participants
timeFrame: Up to approximately 92 months
measure: Area Under the Curve From Time 0 to Infinity (AUC0-inf) of Favezelimab
timeFrame: Predose, 2 hours post start of infusion, and post infusion on Day 1 of cycles 1-4 and 8; Day 2 postdose in cycle 1; Days 8 and 15 in cycles 2, 4, and 8; and at the discontinuation and safety follow-up visit if performed prior to the end of Cycle 8
measure: Area Under the Curve From Time 0 to 21 Days (AUC0-21 Days) of Favezelimab
timeFrame: Predose, 2 hours post start of infusion, and post infusion on Day 1 of cycles 1-4 and 8; Day 2 postdose in cycle 1; Days 8 and 15 in cycles 2, 4, and 8; and at the discontinuation and safety follow-up visit if performed prior to the end of Cycle 8
measure: Maximum Serum Concentration (Cmax) of Favezelimab
timeFrame: Predose, 2 hours post start of infusion, and post infusion on Day 1 of cycles 1-4 and 8; Day 2 postdose in cycle 1; Days 8 and 15 in cycles 2, 4, and 8; and at the discontinuation and safety follow-up visit if performed prior to the end of Cycle 8
measure: AUC0-inf of Pembrolizumab
timeFrame: Predose, 2 hours post start of infusion, and post infusion on Day 1 of cycles 1-4 and 8; Day 2 postdose in cycle 1; Days 8 and 15 in cycles 2, 4, and 8; and at the discontinuation and safety follow-up visit if performed prior to the end of Cycle 8
measure: AUC0-21 Days of Pembrolizumab
timeFrame: Predose, 2 hours post start of infusion, and post infusion on Day 1 of cycles 1-4 and 8; Day 2 postdose in cycle 1; Days 8 and 15 in cycles 2, 4, and 8; and at the discontinuation and safety follow-up visit if performed prior to the end of Cycle 8
measure: Cmax of Pembrolizumab
timeFrame: Predose, 2 hours post start of infusion, and post infusion on Day 1 of cycles 1-4 and 8; Day 2 postdose in cycle 1; Days 8 and 15 in cycles 2, 4, and 8; and at the discontinuation and safety follow-up visit if performed prior to the end of Cycle 8
measure: Predose Serum Concentration of Favezelimab
timeFrame: Predose on Day 1 of cycles 1-4, 6, and 8. Per protocol, different arms had different sampling schedules and therefore were not analyzed for all cycles.
measure: AUC0-inf of Lenvatinib
timeFrame: Up to 4 hours postdose, and between 6-10 hours postdose on Cycle 1 Day 1; Predose and between 2-12 hours postdose on Cycle 1 Day 15; Predose, between 0.5-4 hours postdose, and between 6-10 hours postdose on Cycle 2 Day 1
measure: AUC0-21 Days of Lenvatinib
timeFrame: Up to 4 hours postdose, and between 6-10 hours postdose on Cycle 1 Day 1; Predose and between 2-12 hours postdose on Cycle 1 Day 15; Predose, between 0.5-4 hours postdose, and between 6-10 hours postdose on Cycle 2 Day 1
measure: Cmax of Lenvatinib
timeFrame: Up to 4 hours postdose, and between 6-10 hours postdose on Cycle 1 Day 1; Predose and between 2-12 hours postdose on Cycle 1 Day 15; Predose, between 0.5-4 hours postdose, and between 6-10 hours postdose on Cycle 2 Day 1
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: 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) - Full Text View - ClinicalTrials.gov
citation: Garralda E, Sukari A, Lakhani NJ, Patnaik A, Lou Y, Im SA, Golan T, Geva R, Wermke M, de Miguel M, Palcza J, Jha S, Chaney M, Abraham AK, Healy J, Falchook GS. A first-in-human study of the anti-LAG-3 antibody favezelimab plus pembrolizumab in previously treated, advanced microsatellite stable colorectal cancer. ESMO Open. 2022 Dec;7(6):100639. doi: 10.1016/j.esmoop.2022.100639. Epub 2022 Dec 6.