Antineoplastic Agents

All Drugs and Chemicals

Pembrolizumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

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).

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

Medical Director

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 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.

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.

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)

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)

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)

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.

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.

Merck Sharp & Dohme LLC

Safety Population: All participants who received ≥1 dose of study treatment. Per protocol, disease progression of cancer under study was not considered an adverse event (AE) unless considered related to study treatment. Therefore, Medical Dictionary for Regulatory Activities (MedDRA) preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" not related to study treatment are excluded as AEs.

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).

MK-1248 0.12 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).

MK-1248 0.6 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).

MK-1248 3 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).

MK-1248 10 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).

MK-1248 30 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).

MK-1248 60 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).

MK-1248 120 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).

MK-1248 170 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) 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).

MK-1248 0.12 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).

MK-1248 0.6 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).

MK-1248 3 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).

MK-1248 10 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).

MK-1248 30 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).

MK-1248 60 mg + Pembrolizumab

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Enrollment into this study was prematurely discontinued due to program prioritization and not related to any safety concerns.

Senior Vice President, Global Clinical Development

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.

Number of Participants Experiencing a Dose-Limiting Toxicity (DLT)

Cycle 1

Cycle 2

Cycle 3

Cycle 4

The analysis population consisted of all participants who received MK-1248 and had blood samples assessed for MK-1248 Cmax.

Maximum Concentration (Cmax) of MK-1248 in Serum

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

Trough Concentration (Ctrough) of MK-1248 in Serum

The analysis population consisted of all participants who received MK-1248 and had blood samples assessed for MK-1248 AUC0-inf.

Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of MK-1248 in Serum

The analysis population consisted of all participants who received MK-1248 and had blood samples assessed for GITR receptor target engagement.

Maximum Concentration (Cmax) of Glucocorticoid-induced Tumor Necrosis Factor Receptor-related Protein (GITR) Receptor Target Engagement

Participants received MK-1248 at selected monotherapy dose (170 mg) via IV infusion on Day 1 of each 21-day cycle for a maximum of 4 cycles (up to \~3 months).

Trough (Minimum) Concentration (Ctrough) of Glucocorticoid-induced Tumor Necrosis Factor Receptor-related Protein (GITR) Receptor Target Engagement

Participants received MK-1248 0.12 mg via intravenous (IV) infusion on Day 1 of each 21-day cycle for up to 4 cycles (up to approximately 3 months).

Spots Global Cancer Trial Database for Study of MK-1248 With and Without Pembrolizumab (MK-3475) for Participants With Advanced Solid Tumors (MK-1248-001)

Trial Identification

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Interventions

Study Description

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Eligibility

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