Study of MK-1248 With and Without Pembrolizumab (MK-3475) for Participants With Advanced Solid Tumors (MK-1248-001)

A Phase 1 Trial of MK-1248 as Monotherapy and in Combination With Pembrolizumab in Subjects With Advanced Solid Tumors.

In this study, participants with advanced solid tumors were assigned to receive escalating doses of either MK-1248 alone or MK-1248 in combination with pembrolizumab (MK-3475). This study used the number of dose-limiting toxicities (DLTs) at each dose level to find and confirm the maximum tolerated dose (or maximum administered dose) for MK-1248 alone and in combination with pembrolizumab.

Study Overview

• Status: Terminated
• Conditions: Advanced Solid Tumor
• Intervention / Treatment: Biological: pembrolizumab; Biological: MK-1248

• Study Type: Interventional
• Enrollment (Actual): 37
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically- or cytologically-confirmed metastatic solid tumor for which there is no available therapy that may convey clinical benefit
• Measurable disease by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria
• Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale
• Adequate organ function
• Female participants of childbearing potential should be willing to use adequate contraception for the course of the study through 120 days after the last dose of study medication
• Male participants should agree to use adequate contraception starting with the first dose of study therapy through 180 days after the last dose of study medication
• Can submit a baseline tumor sample

Exclusion Criteria:

• Has had chemotherapy, radiation, or biological cancer therapy within 4 weeks prior to the first dose of study medication, or not recovered from adverse events due to cancer therapeutics administered more than 4 weeks earlier
• 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 medication
• Previous treatment with another agent targeting the glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) receptor
• Previous treatment with an immunomodulatory therapy and was discontinued from that therapy due to an immune-related adverse event
• Expected to require any other form of antineoplastic therapy while on study
• On chronic systemic steroid therapy in excess of replacement doses, or on any other form of immunosuppressive medication
• History of a previous, additional malignancy, unless potentially curative treatment has been completed, with no evidence of malignancy for 5 years with the exception of successful definitive resection of basal cell carcinoma of the skin, superficial bladder cancer or in situ cervical cancer
• Known active central nervous system (CNS) metastases and/or carcinomatous meningitis
• Severe hypersensitivity reaction to treatment with another monoclonal antibody
• Active autoimmune disease or a documented history of autoimmune disease with the exception of vitiligo or resolved childhood asthma/atopy, or endocrine deficiency following treatment with an immunomodulatory agent
• Active infection requiring therapy
• Active or a history of non-infectious pneumonitis
• Prior stem cell or bone marrow transplant
• Known history of human immunodeficiency virus (HIV), active chronic or acute hepatitis B or C
• Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study
• Regular user (including "recreational use") of any illicit drugs or had a recent history (within the last year) of substance abuse (including alcohol), at the time of signing informed consent
• Symptomatic ascites or pleural effusion
• Pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the study through 180 days after the last dose of study medication
• Major surgery within 16 weeks prior to screening
• Live vaccine within 30 days prior to first dose of study medication

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MK-1248; Participants received escalating doses of MK-1248 at assigned dose (dose range: 0.12 mg to 170 mg MK-1248) via intravenous (IV) infusion on Day 1 of each 21-day cycle for up to 4 cycles (up to ~3 months).	Biological: MK-1248; IV infusion
Experimental: MK-1248 + Pembrolizumab; Participants received escalating doses of MK-1248 at assigned dose (dose range: 0.12 mg to 60 mg MK-1248) via IV infusion on Day 1 of each 21-day cycle for a maximum of 4 cycles (up to ~3 months) PLUS pembrolizumab 200 mg via IV infusion on Day 1 of each 21-day cycle for up to 35 cycles (up to ~24 months).	Biological: pembrolizumab; IV infusion; Other Names: MK-3475; KEYTRUDA®; Biological: MK-1248; IV infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Experiencing a Dose-Limiting Toxicity (DLT)	The occurrence of any of the following toxicities during Cycle 1 (21 days), if possibly, probably or definitely related to study treatment, was considered a DLT: 1. Grade 4 non-hematological toxicity 2. Grade 4 hematological toxicity lasting >7 days, except thrombocytopenia a. Grade 4 thrombocytopenia of any duration b. Grade 3 thrombocytopenia is a DLT if associated with bleeding 3. Any Grade 3 non-hematological toxicity, with the exceptions 4. Any Grade 3 or Grade 4 non-hematological laboratory abnormality, if medical intervention was required, or abnormality led to hospitalization, or abnormality persisted for >1 week 5. Febrile neutropenia Grade 3 or Grade 4 6. Any drug-related AE which caused participant to discontinue study treatment during Cycle 1 7. Grade 5 toxicity 8. Any treatment-related toxicity which caused a >2-week delay in initiation of Cycle 2.	Cycle 1 (Up to 21 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Concentration (Cmax) of MK-1248 in Serum	Cmax is the maximum (peak) concentration of MK-1248 observed in blood serum. Blood samples were obtained at designated timepoints for the analysis of MK-1248 Cmax. Timepoints: Cycles 1-4 Day 1: Predose, post MK-1248 infusion end (~0.5 hours), 2 hours post MK-1248 infusion start (~2 hours); Cycles 1-4 Days 2, 3, 5, 8 & 15. Each cycle was 21 days. (Up to ~3 months)	At designated timepoints (Up to ~3 months)
Trough Concentration (Ctrough) of MK-1248 in Serum	Ctrough is the lowest concentration of MK-1248 in blood serum just before the next dose. Blood samples were obtained at designated timepoints for the analysis of MK-1248 Ctrough, except for during Cycle 1. No blood samples were collected for the analysis of Ctrough in Cycle 1. No samples were collected for the MK-1248 0.6 mg group in Cycles 3 or 4, for the MK-1248 10 mg group in Cycles 1-4, or for the MK-1248 60 mg + Pembrolizumab group in Cycle 4. Timepoints: Cycles 1-4 Day 1: Predose, post MK-1248 infusion end (~0.5 hours), 2 hours post MK-1248 infusion start (~2 hours); Cycles 1-4 Days 2, 3, 5, 8 & 15. Each cycle was 21 days. (Up to ~3 months)	At designated timepoints (Up to ~3 months)
Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum	AUC0-infinity is the area under the serum concentration-time curve from time zero to infinity. It is a measure of the amount of MK-1248 in blood serum from pre-dose to infinite time. Blood samples were obtained at designated timepoints for the analysis of MK-1248 AUC0-inf. No blood samples were collected for the MK-1248 0.6 mg group in Cycle 4, for the MK-1248 10 mg group in Cycle or for the MK-1248 60 mg + Pembrolizumab group in Cycle 4. Timepoints: Cycles 1-4 Day 1: Predose, post MK-1248 infusion end (~0.5 hours), 2 hours post MK-1248 infusion start (~2 hours); Cycles 1-4 Days 2, 3, 5, 8 & 15. Each cycle was 21 days. (Up to ~3 months)	At designated timepoints (Up to ~3 months)
Maximum Concentration (Cmax) of Glucocorticoid-induced Tumor Necrosis Factor Receptor-related Protein (GITR) Receptor Target Engagement	GITR protein is internalized upon binding by MK-1248. To evaluate GITR target engagement, a GITR receptor availability assay was developed to assess the availability of surface GITR following administration of MK-1248. GITR is detected on CD4+CD25+ and CD4+CD95+ T-cell sub-populations using flow cytometry and compared to pre-dose baseline. GITR target engagement is calculated as 100% - (%) GITR receptor availability. The Cmax of percent GITR target engagement on CD4+CD25+ T-cells is presented. Timepoints: Arm 1: Screening; Cycles 1-4 Day 1: Predose MK-1248, At end of MK-1248 infusion (0.5 hours), 2 hours after start of MK-1248 infusion (2 hours); Cycles 1-4 Days 2, 8 & 15. Arm 2: Screening; Cycles 1-4 Day 1: Predose pembrolizumab, At end of MK-1248 infusion (0.5 hours), 2 hours after start of MK-1248 infusion (2 hours): Cycles 1-4 Days 2, 3, 8 & Day 15: Cycles 5-6: Predose. Each cycle was 21 days.	At designated timepoints (Up to ~4.5 months)
Trough (Minimum) Concentration (Ctrough) of Glucocorticoid-induced Tumor Necrosis Factor Receptor-related Protein (GITR) Receptor Target Engagement	GITR protein is internalized upon binding by MK-1248. To evaluate GITR target engagement, a GITR receptor availability assay was developed to assess the availability of surface GITR following administration of MK-1248. GITR is detected on CD4+CD25+ and CD4+CD95+ T-cell sub-populations using flow cytometry and compared to pre-dose baseline. GITR target engagement is calculated as 100% - (%) GITR receptor availability. The Ctrough of percent GITR target engagement on CD4+CD25+ T-cells is presented. Timepoints: Arm 1: Screening; Cycles 1-4 Day 1: Predose MK-1248, At end of MK-1248 infusion (0.5 hours), 2 hours after start of MK-1248 infusion (2 hours); Cycles 1-4 Days 2, 8 & 15. Arm 2: Screening; Cycles 1-4 Day 1: Predose pembrolizumab, At end of MK-1248 infusion (0.5 hours), 2 hours after start of MK-1248 infusion (2 hours): Cycles 1-4 Days 2, 3, 8 & Day 15: Cycles 5-6: Predose. Each cycle was 21 days.	At designated timepoints (Up to ~4.5 months)

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Geva R, Voskoboynik M, Dobrenkov K, Mayawala K, Gwo J, Wnek R, Chartash E, Long GV. First-in-human phase 1 study of MK-1248, an anti-glucocorticoid-induced tumor necrosis factor receptor agonist monoclonal antibody, as monotherapy or with pembrolizumab in patients with advanced solid tumors. Cancer. 2020 Nov 15;126(22):4926-4935. doi: 10.1002/cncr.33133. Epub 2020 Aug 18.

Study record dates

Study Major Dates

• Study Start (Actual): November 12, 2015
• Primary Completion (Actual): October 17, 2018
• Study Completion (Actual): October 17, 2018

Study Registration Dates

• First Submitted: September 16, 2015
• First Submitted That Met QC Criteria: September 16, 2015
• First Posted (Estimate): September 17, 2015

Study Record Updates

• Last Update Posted (Actual): November 4, 2019
• Last Update Submitted That Met QC Criteria: October 15, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Keywords: PD-L1; Solid tumor; PD1; PDL1
• Additional Relevant MeSH Terms: Neoplasms; Antineoplastic Agents; Antineoplastic Agents, Immunological; Pembrolizumab
• Other Study ID Numbers: 1248-001; MK-1248-001 (Other Identifier: Merck)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No