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

Advanced Solid Tumor Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02553499
• Other study ID #: 1248-001
• Secondary ID: MK-1248-001
• Status: Terminated
• Phase: Phase 1
• Start date: November 12, 2015
• Est. completion date: October 17, 2018

Study information

• Verified date: October 2019
• Source: Merck Sharp & Dohme Corp.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 37
• Est. completion date: October 17, 2018
• Est. primary completion date: October 17, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Advanced Solid Tumor
• Neoplasms

Intervention

Biological:
• MK-1248
IV infusion
• pembrolizumab
IV infusion

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme Corp.

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)