Advanced Solid Tumor
Conditions
Keywords
Solid tumor, PD1, PD-L1, PDL1
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.
Interventions
BIOLOGICALMK-1248
IV infusion
BIOLOGICALpembrolizumab
IV infusion
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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) |
| 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) |
| 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) |
| 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. |
| 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. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| MK-1248 0.12 mg Participants received MK-1248 0.12 mg via IV infusion on Day 1 of each 21-day cycle for up to 4 cycles (up to approximately 3 months). | 2 |
| MK-1248 0.6 mg Participants received MK-1248 0.6 mg via IV infusion on Day 1 of each 21-day cycle for up to 4 cycles (up to approximately 3 months). | 2 |
| MK-1248 3 mg Participants received MK-1248 3 mg via IV infusion on Day 1 of each 21-day cycle for up to 4 cycles (up to approximately 3 months). | 2 |
| MK-1248 10 mg Participants received MK-1248 10 mg via IV infusion on Day 1 of each 21-day cycle for up to 4 cycles (up to approximately 3 months). | 2 |
| MK-1248 30 mg Participants received MK-1248 30 mg via IV infusion on Day 1 of each 21-day cycle for up to 4 cycles (up to approximately 3 months). | 3 |
| MK-1248 60 mg Participants received MK-1248 60 mg via IV infusion on Day 1 of each 21-day cycle for up to 4 cycles (up to approximately 3 months). | 3 |
| MK-1248 120 mg Participants received MK-1248 120 mg via IV infusion on Day 1 of each 21-day cycle for up to 4 cycles (up to approximately 3 months). | 3 |
| MK-1248 170 mg Participants received MK-1248 170 mg via IV infusion on Day 1 of each 21-day cycle for up to 4 cycles (up to approximately 3 months). | 3 |
| MK-1248 0.12 mg + Pembrolizumab Participants received MK-1248 0.12 mg via IV infusion on Day 1 of each 21-day cycle for up to 4 cycles (up to approximately 3 months) PLUS pembrolizumab 200 mg via IV infusion on Day 1 of each 21-day cycle for up to 35 cycles (up to approximately 24 months). | 3 |
| MK-1248 0.6 mg + Pembrolizumab Participants received MK-1248 0.6 mg via IV infusion on Day 1 of each 21-day cycle for up to 4 cycles (up to approximately 3 months) PLUS pembrolizumab 200 mg via IV infusion on Day 1 of each 21-day cycle for up to 35 cycles (up to approximately 24 months). | 3 |
| MK-1248 3 mg + Pembrolizumab Participants received MK-1248 3 mg via IV infusion on Day 1 of each 21-day cycle for up to 4 cycles (up to approximately 3 months) PLUS pembrolizumab 200 mg via IV infusion on Day 1 of each 21-day cycle for up to 35 cycles (up to approximately 24 months). | 3 |
| MK-1248 10 mg + Pembrolizumab Participants received MK-1248 10 mg via IV infusion on Day 1 of each 21-day cycle for up to 4 cycles (up to approximately 3 months) PLUS pembrolizumab 200 mg via IV infusion on Day 1 of each 21-day cycle for up to 35 cycles (up to approximately 24 months). | 3 |
| MK-1248 30 mg + Pembrolizumab Participants received MK-1248 30 mg via IV infusion on Day 1 of each 21-day cycle for up to 4 cycles (up to approximately 3 months) PLUS pembrolizumab 200 mg via IV infusion on Day 1 of each 21-day cycle for up to 35 cycles (up to approximately 24 months). | 3 |
| MK-1248 60 mg + Pembrolizumab Participants received MK-1248 60 mg via IV infusion on Day 1 of each 21-day cycle for up to 4 cycles (up to approximately 3 months) PLUS pembrolizumab 200 mg via IV infusion on Day 1 of each 21-day cycle for up to 35 cycles (up to approximately 24 months). | 2 |
| Total | 37 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 | FG013 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Death | 0 | 1 | 1 | 0 | 1 | 2 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Physician Decision | 0 | 1 | 1 | 0 | 1 | 0 | 0 | 1 | 1 | 2 | 1 | 3 | 1 | 0 |
| Overall Study | Progressive Disease | 0 | 0 | 0 | 2 | 1 | 1 | 1 | 0 | 0 | 1 | 0 | 0 | 2 | 1 |
| Overall Study | Study Terminated by Sponsor | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | MK-1248 0.12 mg | MK-1248 0.6 mg | MK-1248 3 mg | MK-1248 10 mg | MK-1248 30 mg | MK-1248 60 mg | MK-1248 120 mg | MK-1248 170 mg | MK-1248 0.12 mg + Pembrolizumab | MK-1248 0.6 mg + Pembrolizumab | MK-1248 3 mg + Pembrolizumab | MK-1248 10 mg + Pembrolizumab | MK-1248 30 mg + Pembrolizumab | MK-1248 60 mg + Pembrolizumab | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 68.0 Years STANDARD_DEVIATION 1.4 | 43.5 Years STANDARD_DEVIATION 3.5 | 58.5 Years STANDARD_DEVIATION 12.9 | 49.5 Years STANDARD_DEVIATION 17.7 | 63.7 Years STANDARD_DEVIATION 3.8 | 50.3 Years STANDARD_DEVIATION 14 | 58.3 Years STANDARD_DEVIATION 3.1 | 69.3 Years STANDARD_DEVIATION 6 | 54.0 Years STANDARD_DEVIATION 19.1 | 77.3 Years STANDARD_DEVIATION 8.7 | 57.7 Years STANDARD_DEVIATION 5 | 71.3 Years STANDARD_DEVIATION 8.6 | 51.7 Years STANDARD_DEVIATION 7.5 | 72.5 Years STANDARD_DEVIATION 7.8 | 60.7 Years STANDARD_DEVIATION 12.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 2 Participants | 37 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 2 Participants | 37 Participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants | 2 Participants | 3 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 15 Participants |
| Sex: Female, Male Male | 2 Participants | 1 Participants | 2 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants | 3 Participants | 3 Participants | 1 Participants | 2 Participants | 2 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 2 / 2 | 2 / 2 | 0 / 2 | 3 / 3 | 2 / 3 | 1 / 3 | 3 / 3 | 2 / 3 | 0 / 3 | 1 / 3 | 2 / 3 | 1 / 3 | 2 / 2 |
| other Total, other adverse events | 2 / 2 | 2 / 2 | 2 / 2 | 2 / 2 | 3 / 3 | 3 / 3 | 2 / 3 | 3 / 3 | 3 / 3 | 3 / 3 | 2 / 3 | 3 / 3 | 3 / 3 | 2 / 2 |
| serious Total, serious adverse events | 0 / 2 | 2 / 2 | 0 / 2 | 0 / 2 | 0 / 3 | 1 / 3 | 2 / 3 | 1 / 3 | 1 / 3 | 2 / 3 | 0 / 3 | 2 / 3 | 0 / 3 | 0 / 2 |
Outcome results
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.
Time frame: Cycle 1 (Up to 21 days)
Population: The DLT analysis population consisted of all participants who received MK-1248 and were observed for safety for 21 days after the first dose of MK-1248 or experienced a DLT prior to 21 days after the first dose of MK-1248.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MK-1248 0.12 mg | Number of Participants Experiencing a Dose-Limiting Toxicity (DLT) | 0 Participants |
| MK-1248 0.6 mg | Number of Participants Experiencing a Dose-Limiting Toxicity (DLT) | 0 Participants |
| MK-1248 3 mg | Number of Participants Experiencing a Dose-Limiting Toxicity (DLT) | 0 Participants |
| MK-1248 10 mg | Number of Participants Experiencing a Dose-Limiting Toxicity (DLT) | 0 Participants |
| MK-1248 30 mg | Number of Participants Experiencing a Dose-Limiting Toxicity (DLT) | 0 Participants |
| MK-1248 60 mg | Number of Participants Experiencing a Dose-Limiting Toxicity (DLT) | 0 Participants |
| MK-1248 120 mg | Number of Participants Experiencing a Dose-Limiting Toxicity (DLT) | 0 Participants |
| MK-1248 170 mg | Number of Participants Experiencing a Dose-Limiting Toxicity (DLT) | 0 Participants |
| MK-1248 0.12 mg + Pembrolizumab | Number of Participants Experiencing a Dose-Limiting Toxicity (DLT) | 0 Participants |
| MK-1248 0.6 mg + Pembrolizumab | Number of Participants Experiencing a Dose-Limiting Toxicity (DLT) | 0 Participants |
| MK-1248 3 mg + Pembrolizumab | Number of Participants Experiencing a Dose-Limiting Toxicity (DLT) | 0 Participants |
| MK-1248 10 mg + Pembrolizumab | Number of Participants Experiencing a Dose-Limiting Toxicity (DLT) | 0 Participants |
| MK-1248 30 mg + Pembrolizumab | Number of Participants Experiencing a Dose-Limiting Toxicity (DLT) | 0 Participants |
| MK-1248 60 mg + Pembrolizumab | Number of Participants Experiencing a Dose-Limiting Toxicity (DLT) | 0 Participants |
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)
Time frame: At designated timepoints (Up to ~3 months)
Population: The analysis population consisted of all participants who received MK-1248 and had blood samples assessed for MK-1248 AUC0-inf.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| MK-1248 0.12 mg | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 3 | 91700 Days*pg/mL | — |
| MK-1248 0.12 mg | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 1 | 99200 Days*pg/mL | Geometric Coefficient of Variation 123.5 |
| MK-1248 0.12 mg | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 2 | 120000 Days*pg/mL | Geometric Coefficient of Variation 40.8 |
| MK-1248 0.6 mg | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 2 | 77200 Days*pg/mL | Geometric Coefficient of Variation 5679.1 |
| MK-1248 0.6 mg | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 1 | 1010000 Days*pg/mL | Geometric Coefficient of Variation 70.8 |
| MK-1248 3 mg | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 2 | 5600000 Days*pg/mL | Geometric Coefficient of Variation 24.1 |
| MK-1248 3 mg | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 1 | 4390000 Days*pg/mL | Geometric Coefficient of Variation 24.9 |
| MK-1248 3 mg | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 3 | 1770000 Days*pg/mL | Geometric Coefficient of Variation 212.1 |
| MK-1248 3 mg | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 4 | 864000 Days*pg/mL | Geometric Coefficient of Variation 439.4 |
| MK-1248 10 mg | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 1 | 25100000 Days*pg/mL | Geometric Coefficient of Variation 3.6 |
| MK-1248 30 mg | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 4 | 460000000 Days*pg/mL | — |
| MK-1248 30 mg | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 1 | 117000000 Days*pg/mL | Geometric Coefficient of Variation 57.5 |
| MK-1248 30 mg | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 2 | 84200000 Days*pg/mL | Geometric Coefficient of Variation 618.4 |
| MK-1248 30 mg | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 3 | 124000000 Days*pg/mL | Geometric Coefficient of Variation 783.4 |
| MK-1248 60 mg | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 3 | 50500000 Days*pg/mL | — |
| MK-1248 60 mg | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 4 | 21200000 Days*pg/mL | — |
| MK-1248 60 mg | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 1 | 175000000 Days*pg/mL | Geometric Coefficient of Variation 26 |
| MK-1248 60 mg | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 2 | 105000000 Days*pg/mL | Geometric Coefficient of Variation 304.5 |
| MK-1248 120 mg | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 2 | 604000000 Days*pg/mL | Geometric Coefficient of Variation 111.5 |
| MK-1248 120 mg | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 1 | 354000000 Days*pg/mL | Geometric Coefficient of Variation 73.5 |
| MK-1248 120 mg | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 3 | 737000000 Days*pg/mL | Geometric Coefficient of Variation 172.7 |
| MK-1248 120 mg | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 4 | 1440000000 Days*pg/mL | — |
| MK-1248 170 mg | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 3 | 218000000 Days*pg/mL | — |
| MK-1248 170 mg | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 2 | 341000000 Days*pg/mL | — |
| MK-1248 170 mg | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 4 | 250000000 Days*pg/mL | — |
| MK-1248 170 mg | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 1 | 596000000 Days*pg/mL | Geometric Coefficient of Variation 34.2 |
| MK-1248 0.12 mg + Pembrolizumab | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 1 | 78000 Days*pg/mL | Geometric Coefficient of Variation 9.4 |
| MK-1248 0.12 mg + Pembrolizumab | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 2 | 80400 Days*pg/mL | Geometric Coefficient of Variation 70.4 |
| MK-1248 0.12 mg + Pembrolizumab | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 3 | 393000 Days*pg/mL | Geometric Coefficient of Variation 1325.8 |
| MK-1248 0.12 mg + Pembrolizumab | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 4 | 84300 Days*pg/mL | Geometric Coefficient of Variation 378 |
| MK-1248 0.6 mg + Pembrolizumab | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 2 | 273000 Days*pg/mL | Geometric Coefficient of Variation 33.3 |
| MK-1248 0.6 mg + Pembrolizumab | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 3 | 94300 Days*pg/mL | Geometric Coefficient of Variation 76.7 |
| MK-1248 0.6 mg + Pembrolizumab | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 1 | 608000 Days*pg/mL | Geometric Coefficient of Variation 14.3 |
| MK-1248 3 mg + Pembrolizumab | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 3 | 1010000 Days*pg/mL | Geometric Coefficient of Variation 79.4 |
| MK-1248 3 mg + Pembrolizumab | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 4 | 295000 Days*pg/mL | Geometric Coefficient of Variation 347.2 |
| MK-1248 3 mg + Pembrolizumab | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 1 | 3260000 Days*pg/mL | Geometric Coefficient of Variation 78.8 |
| MK-1248 3 mg + Pembrolizumab | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 2 | 3860000 Days*pg/mL | Geometric Coefficient of Variation 44.1 |
| MK-1248 10 mg + Pembrolizumab | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 4 | 3040000 Days*pg/mL | — |
| MK-1248 10 mg + Pembrolizumab | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 1 | 28100000 Days*pg/mL | Geometric Coefficient of Variation 27.5 |
| MK-1248 10 mg + Pembrolizumab | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 3 | 802000 Days*pg/mL | Geometric Coefficient of Variation 289.8 |
| MK-1248 30 mg + Pembrolizumab | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 1 | 77900000 Days*pg/mL | Geometric Coefficient of Variation 89.3 |
| MK-1248 30 mg + Pembrolizumab | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 3 | 139000000 Days*pg/mL | Geometric Coefficient of Variation 125.9 |
| MK-1248 30 mg + Pembrolizumab | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 2 | 64900000 Days*pg/mL | Geometric Coefficient of Variation 285.6 |
| MK-1248 30 mg + Pembrolizumab | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 4 | 112000000 Days*pg/mL | Geometric Coefficient of Variation 259.6 |
| MK-1248 60 mg + Pembrolizumab | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 1 | 128000000 Days*pg/mL | Geometric Coefficient of Variation 28.2 |
| MK-1248 60 mg + Pembrolizumab | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 4 | 22100000 Days*pg/mL | — |
| MK-1248 60 mg + Pembrolizumab | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 3 | 31500000 Days*pg/mL | — |
| MK-1248 60 mg + Pembrolizumab | Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum | Cycle 2 | 77300000 Days*pg/mL | — |
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.
Time frame: At designated timepoints (Up to ~4.5 months)
Population: The analysis population consisted of all participants who received MK-1248 and had blood samples assessed for GITR receptor target engagement.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MK-1248 0.12 mg | Maximum Concentration (Cmax) of Glucocorticoid-induced Tumor Necrosis Factor Receptor-related Protein (GITR) Receptor Target Engagement | 32.1 Percent Target Engagement | Geometric Coefficient of Variation 141.4 |
| MK-1248 0.6 mg | Maximum Concentration (Cmax) of Glucocorticoid-induced Tumor Necrosis Factor Receptor-related Protein (GITR) Receptor Target Engagement | 83.8 Percent Target Engagement | — |
| MK-1248 3 mg | Maximum Concentration (Cmax) of Glucocorticoid-induced Tumor Necrosis Factor Receptor-related Protein (GITR) Receptor Target Engagement | 94.5 Percent Target Engagement | Geometric Coefficient of Variation 7.8 |
| MK-1248 30 mg | Maximum Concentration (Cmax) of Glucocorticoid-induced Tumor Necrosis Factor Receptor-related Protein (GITR) Receptor Target Engagement | 84.5 Percent Target Engagement | Geometric Coefficient of Variation 13.5 |
| MK-1248 60 mg | Maximum Concentration (Cmax) of Glucocorticoid-induced Tumor Necrosis Factor Receptor-related Protein (GITR) Receptor Target Engagement | 69.7 Percent Target Engagement | Geometric Coefficient of Variation 29.6 |
| MK-1248 120 mg | Maximum Concentration (Cmax) of Glucocorticoid-induced Tumor Necrosis Factor Receptor-related Protein (GITR) Receptor Target Engagement | 96.8 Percent Target Engagement | Geometric Coefficient of Variation 1.9 |
| MK-1248 170 mg | Maximum Concentration (Cmax) of Glucocorticoid-induced Tumor Necrosis Factor Receptor-related Protein (GITR) Receptor Target Engagement | 47.3 Percent Target Engagement | Geometric Coefficient of Variation 58 |
| MK-1248 0.12 mg + Pembrolizumab | Maximum Concentration (Cmax) of Glucocorticoid-induced Tumor Necrosis Factor Receptor-related Protein (GITR) Receptor Target Engagement | 71.6 Percent Target Engagement | Geometric Coefficient of Variation 20.4 |
| MK-1248 0.6 mg + Pembrolizumab | Maximum Concentration (Cmax) of Glucocorticoid-induced Tumor Necrosis Factor Receptor-related Protein (GITR) Receptor Target Engagement | 89.3 Percent Target Engagement | Geometric Coefficient of Variation 6.2 |
| MK-1248 3 mg + Pembrolizumab | Maximum Concentration (Cmax) of Glucocorticoid-induced Tumor Necrosis Factor Receptor-related Protein (GITR) Receptor Target Engagement | 89.9 Percent Target Engagement | Geometric Coefficient of Variation 7.8 |
| MK-1248 10 mg + Pembrolizumab | Maximum Concentration (Cmax) of Glucocorticoid-induced Tumor Necrosis Factor Receptor-related Protein (GITR) Receptor Target Engagement | 68.9 Percent Target Engagement | Geometric Coefficient of Variation 41.5 |
| MK-1248 30 mg + Pembrolizumab | Maximum Concentration (Cmax) of Glucocorticoid-induced Tumor Necrosis Factor Receptor-related Protein (GITR) Receptor Target Engagement | 80.8 Percent Target Engagement | Geometric Coefficient of Variation 24.7 |
| MK-1248 60 mg + Pembrolizumab | Maximum Concentration (Cmax) of Glucocorticoid-induced Tumor Necrosis Factor Receptor-related Protein (GITR) Receptor Target Engagement | 68.0 Percent Target Engagement | Geometric Coefficient of Variation 46.3 |
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)
Time frame: At designated timepoints (Up to ~3 months)
Population: The analysis population consisted of all participants who received MK-1248 and had blood samples assessed for MK-1248 Cmax.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| MK-1248 0.12 mg | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 4 | 1000000 pg/mL | — |
| MK-1248 0.12 mg | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 1 | 45800 pg/mL | Geometric Coefficient of Variation 82.5 |
| MK-1248 0.12 mg | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 3 | 17600 pg/mL | Geometric Coefficient of Variation 312.1 |
| MK-1248 0.12 mg | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 2 | 112000 pg/mL | Geometric Coefficient of Variation 27 |
| MK-1248 0.6 mg | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 3 | 52400 pg/mL | — |
| MK-1248 0.6 mg | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 1 | 378000 pg/mL | Geometric Coefficient of Variation 63.9 |
| MK-1248 0.6 mg | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 2 | 154000 pg/mL | Geometric Coefficient of Variation 247.8 |
| MK-1248 0.6 mg | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 4 | 5090 pg/mL | — |
| MK-1248 3 mg | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 3 | 842000 pg/mL | Geometric Coefficient of Variation 16.5 |
| MK-1248 3 mg | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 4 | 566000 pg/mL | Geometric Coefficient of Variation 45.8 |
| MK-1248 3 mg | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 2 | 1260000 pg/mL | Geometric Coefficient of Variation 69.1 |
| MK-1248 3 mg | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 1 | 853000 pg/mL | Geometric Coefficient of Variation 19.9 |
| MK-1248 10 mg | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 1 | 3550000 pg/mL | Geometric Coefficient of Variation 23.1 |
| MK-1248 10 mg | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 2 | 186000 pg/mL | Geometric Coefficient of Variation 1615.9 |
| MK-1248 10 mg | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 3 | 843000 pg/mL | — |
| MK-1248 30 mg | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 1 | 10200000 pg/mL | Geometric Coefficient of Variation 39 |
| MK-1248 30 mg | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 4 | 17100000 pg/mL | — |
| MK-1248 30 mg | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 3 | 10200000 pg/mL | Geometric Coefficient of Variation 65.9 |
| MK-1248 30 mg | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 2 | 8590000 pg/mL | Geometric Coefficient of Variation 64.1 |
| MK-1248 60 mg | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 4 | 12600000 pg/mL | — |
| MK-1248 60 mg | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 2 | 6240000 pg/mL | Geometric Coefficient of Variation 481.2 |
| MK-1248 60 mg | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 1 | 13300000 pg/mL | Geometric Coefficient of Variation 110.7 |
| MK-1248 60 mg | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 3 | 21500000 pg/mL | — |
| MK-1248 120 mg | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 2 | 41500000 pg/mL | Geometric Coefficient of Variation 40 |
| MK-1248 120 mg | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 1 | 38600000 pg/mL | Geometric Coefficient of Variation 32.8 |
| MK-1248 120 mg | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 3 | 52600000 pg/mL | Geometric Coefficient of Variation 46.9 |
| MK-1248 120 mg | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 4 | 70700000 pg/mL | — |
| MK-1248 170 mg | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 2 | 6980000 pg/mL | Geometric Coefficient of Variation 24178.9 |
| MK-1248 170 mg | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 3 | 67400000 pg/mL | — |
| MK-1248 170 mg | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 4 | 66300000 pg/mL | — |
| MK-1248 170 mg | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 1 | 59400000 pg/mL | Geometric Coefficient of Variation 12.2 |
| MK-1248 0.12 mg + Pembrolizumab | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 3 | 170000 pg/mL | Geometric Coefficient of Variation 284.4 |
| MK-1248 0.12 mg + Pembrolizumab | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 4 | 76300 pg/mL | Geometric Coefficient of Variation 320.4 |
| MK-1248 0.12 mg + Pembrolizumab | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 2 | 41900 pg/mL | Geometric Coefficient of Variation 28.5 |
| MK-1248 0.12 mg + Pembrolizumab | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 1 | 69500 pg/mL | Geometric Coefficient of Variation 32.7 |
| MK-1248 0.6 mg + Pembrolizumab | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 2 | 141000 pg/mL | Geometric Coefficient of Variation 13.5 |
| MK-1248 0.6 mg + Pembrolizumab | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 3 | 136000 pg/mL | Geometric Coefficient of Variation 59.4 |
| MK-1248 0.6 mg + Pembrolizumab | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 4 | 3460 pg/mL | Geometric Coefficient of Variation 229.1 |
| MK-1248 0.6 mg + Pembrolizumab | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 1 | 567000 pg/mL | Geometric Coefficient of Variation 650.2 |
| MK-1248 3 mg + Pembrolizumab | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 3 | 891000 pg/mL | Geometric Coefficient of Variation 37.1 |
| MK-1248 3 mg + Pembrolizumab | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 1 | 820000 pg/mL | Geometric Coefficient of Variation 51.4 |
| MK-1248 3 mg + Pembrolizumab | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 2 | 981000 pg/mL | Geometric Coefficient of Variation 17.7 |
| MK-1248 3 mg + Pembrolizumab | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 4 | 568000 pg/mL | Geometric Coefficient of Variation 224.7 |
| MK-1248 10 mg + Pembrolizumab | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 1 | 4360000 pg/mL | Geometric Coefficient of Variation 21 |
| MK-1248 10 mg + Pembrolizumab | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 3 | 2270000 pg/mL | Geometric Coefficient of Variation 39.8 |
| MK-1248 10 mg + Pembrolizumab | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 2 | 1950000 pg/mL | Geometric Coefficient of Variation 14.3 |
| MK-1248 10 mg + Pembrolizumab | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 4 | 911000 pg/mL | Geometric Coefficient of Variation 481.5 |
| MK-1248 30 mg + Pembrolizumab | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 3 | 12300000 pg/mL | Geometric Coefficient of Variation 30.3 |
| MK-1248 30 mg + Pembrolizumab | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 1 | 8710000 pg/mL | Geometric Coefficient of Variation 42.8 |
| MK-1248 30 mg + Pembrolizumab | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 4 | 12200000 pg/mL | Geometric Coefficient of Variation 45.2 |
| MK-1248 30 mg + Pembrolizumab | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 2 | 10400000 pg/mL | Geometric Coefficient of Variation 43.4 |
| MK-1248 60 mg + Pembrolizumab | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 4 | 12800000 pg/mL | — |
| MK-1248 60 mg + Pembrolizumab | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 3 | 16100000 pg/mL | — |
| MK-1248 60 mg + Pembrolizumab | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 1 | 12900000 pg/mL | Geometric Coefficient of Variation 44.8 |
| MK-1248 60 mg + Pembrolizumab | Maximum Concentration (Cmax) of MK-1248 in Serum | Cycle 2 | 16900000 pg/mL | — |
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)
Time frame: At designated timepoints (Up to ~3 months)
Population: The analysis population consisted of all participants who received MK-1248 and had blood samples assessed for MK-1248 Ctrough. Ctrough data were not collected for the MK-1248 10 mg group
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| MK-1248 0.12 mg | Trough Concentration (Ctrough) of MK-1248 in Serum | Cycle 2 | 106 pg/mL | — |
| MK-1248 0.12 mg | Trough Concentration (Ctrough) of MK-1248 in Serum | Cycle 3 | 102 pg/mL | — |
| MK-1248 0.12 mg | Trough Concentration (Ctrough) of MK-1248 in Serum | Cycle 1 | 74.1 pg/mL | Geometric Coefficient of Variation 186.2 |
| MK-1248 0.6 mg | Trough Concentration (Ctrough) of MK-1248 in Serum | Cycle 1 | 427 pg/mL | — |
| MK-1248 3 mg | Trough Concentration (Ctrough) of MK-1248 in Serum | Cycle 3 | 14200 pg/mL | — |
| MK-1248 3 mg | Trough Concentration (Ctrough) of MK-1248 in Serum | Cycle 1 | 14100 pg/mL | — |
| MK-1248 3 mg | Trough Concentration (Ctrough) of MK-1248 in Serum | Cycle 2 | 23900 pg/mL | — |
| MK-1248 30 mg | Trough Concentration (Ctrough) of MK-1248 in Serum | Cycle 1 | 767000 pg/mL | Geometric Coefficient of Variation 798.2 |
| MK-1248 30 mg | Trough Concentration (Ctrough) of MK-1248 in Serum | Cycle 2 | 485000 pg/mL | Geometric Coefficient of Variation 24904.1 |
| MK-1248 30 mg | Trough Concentration (Ctrough) of MK-1248 in Serum | Cycle 3 | 6840000 pg/mL | — |
| MK-1248 60 mg | Trough Concentration (Ctrough) of MK-1248 in Serum | Cycle 1 | 282000 pg/mL | Geometric Coefficient of Variation 1824 |
| MK-1248 60 mg | Trough Concentration (Ctrough) of MK-1248 in Serum | Cycle 3 | 123000 pg/mL | — |
| MK-1248 60 mg | Trough Concentration (Ctrough) of MK-1248 in Serum | Cycle 2 | 112000 pg/mL | — |
| MK-1248 120 mg | Trough Concentration (Ctrough) of MK-1248 in Serum | Cycle 2 | 9530000 pg/mL | Geometric Coefficient of Variation 130.5 |
| MK-1248 120 mg | Trough Concentration (Ctrough) of MK-1248 in Serum | Cycle 1 | 1290000 pg/mL | Geometric Coefficient of Variation 21562.3 |
| MK-1248 120 mg | Trough Concentration (Ctrough) of MK-1248 in Serum | Cycle 3 | 25600000 pg/mL | — |
| MK-1248 170 mg | Trough Concentration (Ctrough) of MK-1248 in Serum | Cycle 1 | 4660000 pg/mL | — |
| MK-1248 170 mg | Trough Concentration (Ctrough) of MK-1248 in Serum | Cycle 3 | 119000 pg/mL | — |
| MK-1248 170 mg | Trough Concentration (Ctrough) of MK-1248 in Serum | Cycle 2 | 828000 pg/mL | — |
| MK-1248 0.12 mg + Pembrolizumab | Trough Concentration (Ctrough) of MK-1248 in Serum | Cycle 2 | 41.0 pg/mL | Geometric Coefficient of Variation 95.6 |
| MK-1248 0.12 mg + Pembrolizumab | Trough Concentration (Ctrough) of MK-1248 in Serum | Cycle 4 | 25.1 pg/mL | — |
| MK-1248 0.12 mg + Pembrolizumab | Trough Concentration (Ctrough) of MK-1248 in Serum | Cycle 1 | 56.2 pg/mL | Geometric Coefficient of Variation 142.3 |
| MK-1248 0.12 mg + Pembrolizumab | Trough Concentration (Ctrough) of MK-1248 in Serum | Cycle 3 | 48.8 pg/mL | — |
| MK-1248 0.6 mg + Pembrolizumab | Trough Concentration (Ctrough) of MK-1248 in Serum | Cycle 1 | 98.1 pg/mL | Geometric Coefficient of Variation 28.4 |
| MK-1248 3 mg + Pembrolizumab | Trough Concentration (Ctrough) of MK-1248 in Serum | Cycle 1 | 18400 pg/mL | — |
| MK-1248 30 mg + Pembrolizumab | Trough Concentration (Ctrough) of MK-1248 in Serum | Cycle 3 | 1670000 pg/mL | Geometric Coefficient of Variation 290.5 |
| MK-1248 30 mg + Pembrolizumab | Trough Concentration (Ctrough) of MK-1248 in Serum | Cycle 1 | 345000 pg/mL | Geometric Coefficient of Variation 2621.6 |
| MK-1248 30 mg + Pembrolizumab | Trough Concentration (Ctrough) of MK-1248 in Serum | Cycle 2 | 2180000 pg/mL | Geometric Coefficient of Variation 130 |
| MK-1248 30 mg + Pembrolizumab | Trough Concentration (Ctrough) of MK-1248 in Serum | Cycle 4 | 4830000 pg/mL | — |
| MK-1248 60 mg + Pembrolizumab | Trough Concentration (Ctrough) of MK-1248 in Serum | Cycle 3 | 15700 pg/mL | — |
| MK-1248 60 mg + Pembrolizumab | Trough Concentration (Ctrough) of MK-1248 in Serum | Cycle 2 | 295000 pg/mL | — |
| MK-1248 60 mg + Pembrolizumab | Trough Concentration (Ctrough) of MK-1248 in Serum | Cycle 1 | 1830000 pg/mL | — |
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.
Time frame: At designated timepoints (Up to ~4.5 months)
Population: The analysis population consisted of all participants who received MK-1248 and had blood samples assessed for GITR receptor target engagement.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MK-1248 0.12 mg | Trough (Minimum) Concentration (Ctrough) of Glucocorticoid-induced Tumor Necrosis Factor Receptor-related Protein (GITR) Receptor Target Engagement | 3.2 Percent Target Engagement | Geometric Coefficient of Variation 141.4 |
| MK-1248 0.6 mg | Trough (Minimum) Concentration (Ctrough) of Glucocorticoid-induced Tumor Necrosis Factor Receptor-related Protein (GITR) Receptor Target Engagement | 36.6 Percent Target Engagement | — |
| MK-1248 3 mg | Trough (Minimum) Concentration (Ctrough) of Glucocorticoid-induced Tumor Necrosis Factor Receptor-related Protein (GITR) Receptor Target Engagement | 48.9 Percent Target Engagement | — |
| MK-1248 30 mg | Trough (Minimum) Concentration (Ctrough) of Glucocorticoid-induced Tumor Necrosis Factor Receptor-related Protein (GITR) Receptor Target Engagement | 94.0 Percent Target Engagement | Geometric Coefficient of Variation 2.1 |
| MK-1248 60 mg | Trough (Minimum) Concentration (Ctrough) of Glucocorticoid-induced Tumor Necrosis Factor Receptor-related Protein (GITR) Receptor Target Engagement | 83.7 Percent Target Engagement | Geometric Coefficient of Variation 23 |
| MK-1248 120 mg | Trough (Minimum) Concentration (Ctrough) of Glucocorticoid-induced Tumor Necrosis Factor Receptor-related Protein (GITR) Receptor Target Engagement | 89.1 Percent Target Engagement | Geometric Coefficient of Variation 5.4 |
| MK-1248 170 mg | Trough (Minimum) Concentration (Ctrough) of Glucocorticoid-induced Tumor Necrosis Factor Receptor-related Protein (GITR) Receptor Target Engagement | 57.3 Percent Target Engagement | Geometric Coefficient of Variation 50.8 |
| MK-1248 0.12 mg + Pembrolizumab | Trough (Minimum) Concentration (Ctrough) of Glucocorticoid-induced Tumor Necrosis Factor Receptor-related Protein (GITR) Receptor Target Engagement | 33.7 Percent Target Engagement | Geometric Coefficient of Variation 4 |
| MK-1248 0.6 mg + Pembrolizumab | Trough (Minimum) Concentration (Ctrough) of Glucocorticoid-induced Tumor Necrosis Factor Receptor-related Protein (GITR) Receptor Target Engagement | 6.2 Percent Target Engagement | Geometric Coefficient of Variation 95.2 |
| MK-1248 3 mg + Pembrolizumab | Trough (Minimum) Concentration (Ctrough) of Glucocorticoid-induced Tumor Necrosis Factor Receptor-related Protein (GITR) Receptor Target Engagement | 88.7 Percent Target Engagement | Geometric Coefficient of Variation 3.6 |
| MK-1248 10 mg + Pembrolizumab | Trough (Minimum) Concentration (Ctrough) of Glucocorticoid-induced Tumor Necrosis Factor Receptor-related Protein (GITR) Receptor Target Engagement | 5.9 Percent Target Engagement | Geometric Coefficient of Variation 173.2 |
| MK-1248 30 mg + Pembrolizumab | Trough (Minimum) Concentration (Ctrough) of Glucocorticoid-induced Tumor Necrosis Factor Receptor-related Protein (GITR) Receptor Target Engagement | 96.7 Percent Target Engagement | — |
| MK-1248 60 mg + Pembrolizumab | Trough (Minimum) Concentration (Ctrough) of Glucocorticoid-induced Tumor Necrosis Factor Receptor-related Protein (GITR) Receptor Target Engagement | 70.2 Percent Target Engagement | Geometric Coefficient of Variation 2.6 |