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

Phase 1

Terminated

• Conditions: Advanced Solid Tumor
• Interventions: Biological: MK-1248; Biological: pembrolizumab

• Registration Number: NCT02553499
• Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2015-09-16
• Study First Submitted QC: 2015-09-16
• Study First Posted: 2015-09-17
• Study Start: 2015-11-12
• Primary Completion: 2018-10-17
• Study Completion: 2018-10-17
• Results First Submitted: 2019-08-30
• Status Verified: 2019-10
• Results First Submitted QC: 2019-10-15
• Last Update Submitted: 2019-10-15
• Results First Posted: 2019-11-04
• Last Update Posted: 2019-11-04

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 37

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
MK-1248	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).
MK-1248 + Pembrolizumab	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).
MK-1248 + Pembrolizumab	MK-1248	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).

Primary Outcome Measures

Name	Time	Method
Number of Participants Experiencing a Dose-Limiting Toxicity (DLT)	Cycle 1 (Up to 21 days)	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.

Secondary Outcome Measures

Name	Time	Method
Maximum Concentration (Cmax) of MK-1248 in Serum	At designated timepoints (Up to ~3 months)	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)
Maximum Concentration (Cmax) of Glucocorticoid-induced Tumor Necrosis Factor Receptor-related Protein (GITR) Receptor Target Engagement	At designated timepoints (Up to ~4.5 months)	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.
Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum	At designated timepoints (Up to ~3 months)	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)
Trough Concentration (Ctrough) of MK-1248 in Serum	At designated timepoints (Up to ~3 months)	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)
Trough (Minimum) Concentration (Ctrough) of Glucocorticoid-induced Tumor Necrosis Factor Receptor-related Protein (GITR) Receptor Target Engagement	At designated timepoints (Up to ~4.5 months)	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.