Clinical Trials /

Safety, Pharmacokinetics (PK), and Efficacy of MK-1308 in Combination With Pembrolizumab in Advanced Solid Tumors (MK-1308-001)

NCT03179436

Description:

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.

Related Conditions:
  • Malignant Solid Tumor
  • Non-Small Cell Lung Carcinoma
  • Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Safety, Pharmacokinetics (PK), and Efficacy of MK-1308 in Combination With Pembrolizumab in Advanced Solid Tumors (MK-1308-001)
  • Official Title: A Phase 1 Open Label, Multi-Arm, Multicenter Study of MK-1308 in Combination With Pembrolizumab for Subjects With Advanced Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: 1308-001
  • SECONDARY ID: MK-1308-001
  • NCT ID: NCT03179436

Conditions

  • Advanced Solid Tumors

Interventions

DrugSynonymsArms
MK-1308Escalation: Dose Level 1 MK-1308 + Pembro
PembrolizumabKeytruda®Escalation: Dose Level 1 MK-1308 + Pembro

Purpose

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.

Detailed Description

      After screening, participants are assigned to either the dose escalation or dose confirmation
      phase. The dose escalation phase consists of 2 cohorts and will evaluate available PK and
      safety data from the first 6 participants of each cohort, including dose limiting toxicities
      (DLTs). The purpose of the dose confirmation phase is to gather additional safety,
      tolerability, PK, and preliminary efficacy data of MK-1308 in combination with pembrolizumab.
      The 4 arms of the dose confirmation phase will include advanced/metastatic non-small cell
      lung cancer (NSCLC) and second line advanced/metastatic small cell lung cancer (SCLC). In
      participants who have initial evidence of radiological progressive disease (PD) by Response
      Evaluation Criteria in Solid Tumors (RECIST) version 1.1, it will be at the discretion of the
      investigator whether to continue a participant on study treatment until repeat imaging is
      obtained.
    

Trial Arms

NameTypeDescriptionInterventions
Escalation: Dose Level 1 MK-1308 + PembroExperimentalOn Cycle 1, Day 1 of the Escalation Phase, advanced solid tumor participants receive a single monotherapy dose lead-in with MK-1308 at dose level 1. On Cycle 2, Day 1, and for 3 subsequent cycles on Day 1 (Cycles 3 to 5), these participants receive MK-1308 at dose level 1 in combination with 200 mg pembrolizumab (pembro) according to Schedule 1. For all subsequent cycles (starting with Cycle 6), all participants receive pembrolizumab monotherapy according to Schedule 1. Participants will be treated for up to 35 cycles total on study.
    Escalation: Dose Level 2 MK-1308 + PembroExperimentalOn Cycle 1, Day 1 of the Escalation Phase, participants with advanced solid tumors except NSCLC receive a single monotherapy dose lead-in with MK-1308 at dose level 2. On Cycle 2, Day 1, and for 3 subsequent cycles on Day 1 (Cycles 3 to 5), these participants receive MK-1308 at dose level 2 in combination with 200 mg pembrolizumab according to Schedule 1. For all subsequent cycles (starting with Cycle 6), all participants receive pembrolizumab monotherapy according to Schedule 1. Participants will be treated for up to 35 cycles total on study.
      Confirmation: Dose Level 1 MK-1308 Schedule 1 + Pembro (NSCLC)ExperimentalOn Cycle 1, Day 1 of the Confirmation Phase and during all subsequent cycles, participants with NSCLC receive MK-1308 at dose level 1 in combination with 200 mg pembrolizumab, both according to Schedule 1. Participants will be treated for up to 35 cycles total on study.
        Confirmation: Dose Level 1 MK-1308 Schedule 2 + Pembro (NSCLC)ExperimentalOn Cycle 1, Day 1 of the Confirmation Phase, participants with NSCLC receive MK-1308 at dose level 1 in combination with 200 mg pembrolizumab. On all subsequent cycles, participants receive 200 mg pembrolizumab according to Schedule 1 and MK-1308 at dose level 1 according to Schedule 2. Participants will be treated for up to 35 cycles total on study.
          Confirmation: Dose Level 2 MK-1308 Schedule 2 + Pembro (NSCLC)ExperimentalOn Cycle 1, Day 1 of the Confirmation Phase, participants with NSCLC receive MK-1308 at dose level 2 in combination with 200 mg pembrolizumab. On all subsequent cycles, participants receive 200 mg pembrolizumab according to Schedule 1 and MK-1308 at dose level 2 according to Schedule 2. Participants will be treated for up to 35 cycles total on study.
            Confirmation: Dose Level 2 MK-1308 Schedule 2 + Pembro (SCLC)ExperimentalOn Cycle 1, Day 1 of the Confirmation Phase, participants with SCLC receive MK-1308 at dose level 2 in combination with 200 mg pembrolizumab. On all subsequent cycles, participants receive 200 mg pembrolizumab according to Schedule 1 and MK-1308 at dose level 2 according to Schedule 2. Participants will be treated for up to 35 cycles total on study.

              Eligibility Criteria

                      Inclusion Criteria:
              
                        -  For Dose Escalation Phase: Have any histologically- or cytologically-confirmed
                           advanced/metastatic solid tumor (except NSCLC for Cohort 2) by pathology report and
                           have received, been intolerant to, been ineligible for, or refused all treatment known
                           to confer clinical benefit
              
                        -  For Dose Confirmation Phase NSCLC Arms: Have newly diagnosed histologically or
                           cytologically-confirmed stage IIIB/stage IV NSCLC and must be negative for epidermal
                           growth factor receptor (EGFR) mutation and negative for anaplastic lymphoma kinase
                           (ALK) translocation. Participant must not have received prior systemic treatment for
                           advanced NSCLC or must have received previous neoadjuvant and adjuvant chemotherapies
                           ≥6 months before dosing of study drug if prior systemic treatment was given for early
                           stage disease
              
                        -  For Dose Confirmation Phase SCLC Arm: Have histologically- or cytologically-confirmed
                           advanced/metastatic SCLC. Participants must have received one prior treatment regimen
                           with a platinum-containing agent. Participants with platinum refractory, resistant, or
                           sensitive disease are eligible. Participants with an initial diagnosis of limited or
                           extensive disease are eligible but must now have advanced (Stage III/IV) disease
              
                        -  Have measureable disease by RECIST 1.1 as assessed by the local site
                           investigator/radiology
              
                        -  Have Eastern Cooperative Oncology Group (ECOG) Performance Scale status of 0 or 1
              
                        -  Female participants of childbearing potential must have negative urine or serum
                           pregnancy test within 72 hours prior to receiving the first dose of study treatment
                           and be willing to use an adequate method of contraception for the course of the study
                           through 120 days after the last dose of study medication
              
                        -  Male participants with a female partner(s) of child-bearing potential must be willing
                           to use an adequate method of contraception for the course of the study through 120
                           days after the last dose of study medication and refrain from donating sperm during
                           this period
              
                        -  Must submit an evaluable baseline tumor sample for analysis (either a recent or
                           archival tumor sample)
              
                      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) or programmed cell death ligand 1
                           (PD-L1)
              
                        -  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
              
                        -  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.
              
                        -  Has a history of a second malignancy, unless potentially curative treatment has been
                           completed with no evidence of malignancy for 3 years
              
                        -  Has known active central nervous system (CNS) metastases and/or carcinomatous
                           meningitis
              
                        -  For dose escalation phase, has received previous anti-PD-1/PD-L1 and was discontinued
                           from that treatment due to a Grade 3 or higher immune-related AE
              
                        -  Has had a severe hypersensitivity reaction to treatment with any monoclonal antibody
                           or components of the study drug
              
                        -  Has any active infection requiring therapy
              
                        -  Has a history of interstitial lung disease, history of non-infectious pneumonitis that
                           required steroids (or has current pneumonitis), or history of inflammatory bowel
                           disease
              
                        -  Has an active autoimmune disease that has required systemic treatment in the past 2
                           years
              
                        -  Has severe cardiovascular disease
              
                        -  Has received a live-virus vaccine within 28 days of planned treatment start
              
                        -  Has known human immunodeficiency virus (HIV) and/or Hepatitis B or C infections, or
                           known to be positive for hepatitis B surface antigen (HBsAg)/ hepatitis B virus (HBV)
                           DNA or Hepatitis C antibody or RNA.
              
                        -  Has known psychiatric or substance abuse disorders that would interfere with the
                           participant's ability to cooperate with the requirements of the trial
              
                        -  Is pregnant or breastfeeding, or expecting to conceive or father children within the
                           projected duration of the study
              
                        -  Has not fully recovered from any effects of major surgery without significant
                           detectable infection
                    
              Maximum Eligible Age:N/A
              Minimum Eligible Age:18 Years
              Eligible Gender:All
              Healthy Volunteers:No

              Primary Outcome Measures

              Measure:Number of participants with a Dose Limiting Toxicity (DLT)
              Time Frame:Up to 6 weeks
              Safety Issue:
              Description:DLTs will be assessed during the first 6 weeks of treatment for all phases of the study and are defined as toxicities that meet pre-defined severity criteria, that are possibly, probably, or definitely related to study therapy, and may result in a change in the given dose. These toxicities include Grade 4 non-hematologic toxicity (not laboratory); Grade 4 hematologic toxicity lasting ≥7 days (except thrombocytopenia); most non-hematologic AEs ≥Grade 3 in severity; any Grade 3 or Grade 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; Grade 3 or Grade 4 febrile neutropenia; a prolonged delay in initiating Cycle 2 or 3 due to treatment-related toxicity; any treatment-related toxicity that causes the participant to discontinue treatment during Cycle 1 or 2, and Grade 5 toxicity.

              Secondary Outcome Measures

              Measure:Dose Escalation: Area under the plasma concentration time curve (AUC) of MK-1308 at steady state
              Time Frame:pre-dose Cycles 1, 2, 3, 5, 6, 7, 9 and every 4 cycles up to 3 years, postdose (30 min): cycles 1, 2, 3, 5, and 9, Days 8 and 15 of cycles 1, 2, & 3. Cycle = 21 days
              Safety Issue:
              Description: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 (pre-dose and post-dose) during the Dose Escalation phase to assess the AUC of MK-1308.
              Measure:Dose Escalation: Minimum concentration (Cmin) of MK-1308 at steady state
              Time Frame:pre-dose Cycles 1, 2, 3, 5, 6, 7, 9 and every 4 cycles up to 3 years, postdose (30 min): cycles 1, 2, 3, 5, and 9, Days 8 and 15 of cycles 1, 2, & 3. Cycle = 21 days
              Safety Issue:
              Description: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 and post-dose) during the Dose Escalation phase to assess the Cmin of MK-1308.
              Measure:Dose Escalation: Maximum concentration (Cmax) of MK-1308 at steady state
              Time Frame:pre-dose Cycles 1, 2, 3, 5, 6, 7, 9 and every 4 cycles up to 3 years, postdose (30 min): cycles 1, 2, 3, 5, and 9, Days 8 and 15 of cycles 1, 2, & 3. Cycle = 21 days
              Safety Issue:
              Description:Cmax is the maximum or "peak" concentration of a drug observed after its administration. Blood samples will be collected at multiple time points (pre-dose and post-dose) during the Dose Escalation phase to assess the Cmax of MK-1308.
              Measure:Dose Confirmation: AUC of MK-1308 at steady state
              Time Frame:pre-dose cycles 1, 2, 3, 4, 5, 6, 8, and every 4 cycles up to 3 years, post-dose (30 min): cycles 1, 2, 3, 4, and 8, Days 8 & 15 in cycles 1, 2, & 3. Cycle = 21 days
              Safety Issue:
              Description: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 (pre-dose and post-dose) during the Dose Confirmation phase to assess the AUC of MK-1308.
              Measure:Dose Confirmation: Cmin of MK-1308 at steady state
              Time Frame:pre-dose cycles 1, 2, 3, 4, 5, 6, 8, and every 4 cycles up to 3 years, post-dose (30 min): cycles 1, 2, 3, 4, and 8, Days 8 & 15 in cycles 1, 2, & 3. Cycle = 21 days
              Safety Issue:
              Description: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 and post-dose) during the Dose Confirmation phase to assess the Cmin of MK-1308.
              Measure:Dose Confirmation: Cmax of MK-1308 at steady state
              Time Frame:pre-dose cycles 1, 2, 3, 4, 5, 6, 8, and every 4 cycles up to 3 years, post-dose (30 min): cycles 1, 2, 3, 4, and 8, Days 8 & 15 in cycles 1, 2, & 3. Cycle = 21 days
              Safety Issue:
              Description:Cmax is the maximum or "peak" concentration of a drug observed after its administration. Blood samples will be collected at multiple time points (pre-dose and post-dose) during the Dose Confirmation phase to assess the Cmax of MK-1308.
              Measure:Objective Response Rate (ORR) as assessed by investigator based on RECIST 1.1
              Time Frame:Up to 3 years
              Safety Issue:
              Description: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) based on imaging per RECIST 1.1. According to 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 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:ORR as assessed by investigator based on immune-related RECIST (irRECIST) in conjunction with RECIST 1.1
              Time Frame:Up to 3 years
              Safety Issue:
              Description:ORR is defined as the percentage of participants whose best response based on imaging is CR or PR per irRECIST. irRECIST is a modification to RECIST that takes into account unique patterns of atypical response in immunotherapy and enables treatment beyond initial radiographic progression. The irRECIST modification to RECIST is used in conjunction with RECIST 1.1 to determine the BOR. At initial PD by RECIST 1.1, if participant is clinically stable the investigator may continue to treat and scan again ≥4 weeks later to see if PD confirmed. CR is disappearance of all lesions (target, non-target, and new lesions if any had appeared). PR is a decrease of ≥30% in the SOD of target lesions from baseline, with no indication of further progression by non-target or new lesions. BOR during irRECIST portion is the most favorable visit response observed, with no confirmation requirement. BOR for the participant overall is the more favorable of the RECIST 1.1 (pre-PD) and irRECIST (post-PD) BORs.

              Details

              Phase:Phase 1
              Primary Purpose:Interventional
              Overall Status:Recruiting
              Lead Sponsor:Merck Sharp & Dohme Corp.

              Trial Keywords

              • PD1
              • PD-1
              • PDL1
              • PD-L1

              Last Updated

              July 28, 2017