This study will assess the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of escalating doses of MK-1308 when used in combination with pembrolizumab in participants with advanced solid tumors.
Name: MK-1308
Name: Pembrolizumab
Name: MK-1308A
Description: DLTs will be assessed during the first 6 weeks (2 cycles) of treatment for the Dose Escalation and the first 3 weeks (1 cycle) of treatment for the Dose Confirmation. DLT is defined as toxicity that is possibly, probably, or definitely related to study therapy and may result in a change in the given dose. DLTs include Grade (Gr)4 non-hematologic toxicity (not laboratory); Gr 4 hematologic toxicity lasting ≥7 days (except thrombocytopenia); most non-hematologic AEs ≥ Gr 3 in severity; any Gr 3 or Gr 4 non-hematologic laboratory value that requires clinically significant medical intervention, leads to hospitalization, persists for >1 week, or results in a drug-induced liver injury; Gr 3 or Gr 4 febrile neutropenia; a prolonged delay in initiating Cycle 2 or 3 of Dose Escalation or Cycle 2 of Dose Confirmation due to treatment-related toxicity; any treatment-related toxicity that causes the participant to discontinue treatment during the DLT observation period, and Gr 5 toxicity.
Measure: Number of participants with a Dose Limiting Toxicity (DLT) Time: Up to 6 weeksDescription: An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product temporally associated with the use of study treatment, whether or not considered related to the study treatment.
Measure: Number of participants with ≥1 adverse event (AE) Time: Up to approximately 2.5 yearsDescription: An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product temporally associated with the use of study treatment, whether or not considered related to the study treatment.
Measure: Number of participants discontinuing study treatment due to an AE Time: Up to approximately 2 yearsDescription: An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product temporally associated with the use of study treatment, whether or not considered related to the study treatment.
Measure: Coformulation Phase: Number of participants with ≥1 AE Time: Up to approximately 2.5 yearsDescription: An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product temporally associated with the use of study treatment, whether or not considered related to the study treatment.
Measure: Coformulation Phase: Number of participants discontinuing study treatment due to an AE Time: Up to approximately 2 yearsDescription: An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product temporally associated with the use of study treatment, whether or not considered related to the study treatment.
Measure: Efficacy Expansion: Number of participants with ≥1 AE Time: Up to approximately 2.5 yearsDescription: An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product temporally associated with the use of study treatment, whether or not considered related to the study treatment
Measure: Efficacy Expansion: Number of participants discontinuing study treatment due to an AE Time: Up to approximately 2 yearsDescription: ORR is defined as the percentage of participants in the analysis population whose best overall response (BOR) is confirmed complete response (CR) or partial response (PR) as assessed by BICR and based on imaging per modified RECIST 1.1. Tumor responses evaluated using modified RECIST 1.1 follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ and require confirmation per RECIST 1.1. According to modified RECIST 1.1, CR is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR according to modified RECIST 1.1 is at least a 30% decrease in the sum of diameters (SOD) of target lesions as assessed by the investigator, taking as reference the baseline SOD.
Measure: Efficacy Expansion: Objective Response Rate (ORR) as assessed by blinded independent central review (BICR) based on modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 Time: Up to approximately 4 yearsDescription: AUC is the area under the plot of plasma concentration of drug against time after drug administration and is of particular use in estimating bioavailability of drugs, and in estimating total clearance of drugs. Blood samples will be collected at multiple time points during the Dose Escalation phase to assess the AUC of MK-1308.
Measure: Dose Escalation: Area under the plasma concentration time curve (AUC) of MK-1308 at steady state Time: Cycles 1, 2 and 3: end of infusion (up to approximately 30 minutes), Day 8, and Day 15. Cycles 5 and 9: end of infusion (up to 30 minutes). Cycle = 21 daysDescription: Cmin is the minimum or "trough" concentration of a drug observed after its administration and just prior to the administration of a subsequent dose. Blood samples will be collected at multiple time points (pre-dose) during the Dose Escalation phase to assess the Cmin of MK-1308.
Measure: Dose Escalation: Minimum concentration (Cmin) of MK-1308 at steady state Time: Pre-dose Cycles 1, 2, 3, 5, 6, 7, 9 and every 4 cycles up to 2 years. Cycle = 21 daysDescription: Cmax is the maximum or "peak" concentration of a drug observed after its administration. Blood samples will be collected at multiple time points during the Dose Escalation phase to assess the Cmax of MK-1308.
Measure: Dose Escalation: Maximum concentration (Cmax) of MK-1308 at steady state Time: Cycles 1, 2 and 3: end of infusion (up to approximately 30 minutes), Day 8, and Day 15. Cycles 5 and 9: end of infusion (up to 30 minutes). Cycle = 21 daysDescription: AUC is the area under the plot of plasma concentration of drug against time after drug administration and is of particular use in estimating bioavailability of drugs, and in estimating total clearance of drugs. Blood samples will be collected at multiple time points during the Dose Confirmation phase to assess the AUC of MK-1308.
Measure: Dose Confirmation: AUC of MK-1308 at steady state Time: Cycles 1, 2, 3: end of infusion (up to approximately 30 minutes), Day 8, and Day 15. Cycle 4 and 8: end of infusion (up to 30 minutes). Cycle = 21 daysDescription: Cmin is the minimum or "trough" concentration of a drug observed after its administration and just prior to the administration of a subsequent dose. Blood samples will be collected at multiple time points (pre-dose) during the Dose Confirmation phase to assess the Cmin of MK-1308.
Measure: Dose Confirmation: Cmin of MK-1308 at steady state Time: Pre-dose cycles 1, 2, 3, 4, 5, 6, 8, and every 4 cycles up to 2 years. Cycle = 21 daysDescription: Cmax is the maximum or "peak" concentration of a drug observed after its administration. Blood samples will be collected at multiple time points during the Dose Confirmation phase to assess the Cmax of MK-1308.
Measure: Dose Confirmation: Cmax of MK-1308 at steady state Time: Cycles 1, 2, 3: end of infusion (up to approximately 30 minutes), Day 8, and Day 15. Cycle 4 and 8: end of infusion (up to 30 minutes). Cycle = 21 daysDescription: ORR is defined as the percentage of participants in the analysis population whose BOR is confirmed CR or PR as assessed by investigator and based on imaging per modified RECIST 1.1. Tumor responses evaluated using modified RECIST 1.1 follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ and require confirmation per RECIST 1.1. According to modified RECIST 1.1, CR is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR according to modified RECIST 1.1 is at least a 30% decrease in the SOD of target lesions as assessed by the investigator, taking as reference the baseline SOD.
Measure: Dose Escalation, Dose Confirmation, and Coformulation: ORR as assessed by investigator based on modified RECIST 1.1 Time: Up to approximately 4 yearsDescription: DOR was defined as the time from first documented evidence of CR or PR until disease progression or death due to any cause, whichever occurs first (for responders only).
Measure: Efficacy Expansion: Duration of Response (DOR) as assessed by BICR based on modified RECIST 1.1 Time: Up to approximately 4 yearsAllocation: Non-Randomized
Parallel Assignment
There is one SNP
Cutaneous lesions and other superficial lesions are not considered measurable lesions for the purposes of this protocol, but may be considered as non-target lesions - Participants with unresectable Stage III or Stage IV disease must have progressed on treatment with an anti-PD-1/L1 monoclonal antibody (mAb) administered either as monotherapy, or in combination with other checkpoint inhibitors or other therapies (combinations with anti-cytotoxic T-lymphocyte associated protein 4 [CTLA-4] agents will not be allowed) - Participants who receive anti-PD-1 therapy as adjuvant treatment following complete resection of Stage III or IV melanoma and have disease recurrence (unresectable loco-regional disease or distant metastases) while on active treatment or within 6 months of stopping anti-PD-1 are eligible - Have submitted pre-trial imaging and provided a baseline tumor sample - Proto-oncogene B-raf (BRAF) V600 mutation-positive melanoma participants may have received targeted therapy for advanced or metastatic disease (eg, BRAF/MEK inhibitor, alone or in combination) prior to enrolling on this study; however, they are not required to progress on this treatment - BRAF V600E mutation-positive melanoma participants who have NOT received a BRAF inhibitor (either as adjuvant therapy or in the metastatic disease setting) with lactate dehydrogenase (LDH) < local upper limit of normal (ULN), no clinically significant tumor-related symptoms, and absence of rapidly progressing metastatic melanoma For Dose Coformulation Phase Arm I - Have any histologically- or cytologically-confirmed advanced/metastatic solid tumor by pathology report and have received, been intolerant to, been ineligible for or refused all treatment known to confer clinical benefit - Meet all requirements for Dose Escalation Phase and Dose Confirmation Phase Exclusion Criteria: - For all phases of the study: Has received previous treatment with another agent targeting cytotoxic T lymphocyte leukocyte antigen (CTLA)-4 For Dose Confirmation Phase only: - Has received previous treatment with another agent targeting programmed cell death protein 1 (PD-1), programmed cell death ligand 1 (PD-L1), or anti PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor - Has had chemotherapy, definitive radiation, or biological cancer therapy within 4 weeks (2 weeks for palliative radiation) prior to the first dose of study therapy, or has not recovered to Common Toxicity Criteria for Adverse Events (CTCAE) Grade 1 or better from any AEs that were due to cancer therapeutics administered more than 4 weeks earlier - Has received lung radiation therapy of >30 Gray (Gy) within 6 months before the first dose of study treatment - Is currently participating and receiving study therapy in a study of an investigational agent or has participated and received study therapy in a study of an investigational agent or has used an investigational device within 28 days of administration of MK-1308. --- V600E ---