Clinical Trials /

Safety, Pharmacokinetics (PK), and Efficacy of MK-1308 in Combination With Pembrolizumab (MK-3475) 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
  • Melanoma
  • Non-Small Cell Lung Carcinoma
  • Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

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
  • SECONDARY ID: 173820
  • NCT ID: NCT03179436

Conditions

  • Advanced Solid Tumors

Interventions

DrugSynonymsArms
MK-1308Confirmation: DL 1 MK-1308 Schedule 1 + Pembro (NSCLC): Arm A
PembrolizumabKeytruda®Confirmation: DL 1 MK-1308 Schedule 1 + Pembro (NSCLC): Arm A

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 Phase or Dose
      Confirmation Phase. The Dose Escalation Phase consists of 3 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 5 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 modified 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.

      Protocol Amendment 4 will enroll participants with melanoma in a limited Efficacy Expansion
      Cohort. During the Efficacy Expansion Phase, participants will be randomized to receive
      either MK-1308 in combination with pembrolizumab or MK-1308 monotherapy.
    

Trial Arms

NameTypeDescriptionInterventions
Escalation: Dose Level (DL) 1 MK-1308 + Pembro: Cohort 1ExperimentalOn Cycle 1, Day 1 of the Dose Escalation Phase, advanced solid tumor participants receive a single monotherapy dose lead-in with MK-1308 at dose level 1 (DL1). On Cycle 2, Day 1, and for 3 subsequent cycles on Day 1 (Cycles 3 to 5), these participants receive MK-1308 at DL1 in combination with pembrolizumab (pembro) at pembrolizumab dose level 1 (PDL1) 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.
  • MK-1308
  • Pembrolizumab
Escalation: DL 2 MK-1308 + Pembro: Cohort 2ExperimentalOn Cycle 1, Day 1 of the Dose Escalation Phase, participants with advanced solid tumors except NSCLC receive a single monotherapy dose lead-in with MK-1308 at DL2. On Cycle 2, Day 1, and for 3 subsequent cycles on Day 1 (Cycles 3 to 5), these participants receive MK-1308 at DL2 in combination with pembrolizumab at PDL1 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.
  • MK-1308
  • Pembrolizumab
Escalation: DL 3 MK-1308 + Pembro: Cohort 3ExperimentalOn Cycle 1, Day 1 of the Dose Escalation Phase, participants with advanced solid tumors except NSCLC receive a single monotherapy dose lead-in with MK-1308 at DL3. On Cycle 2, Day 1, and for 3 subsequent cycles on Day 1 (Cycles 3 to 5), these participants receive MK-1308 at DL3 in combination with pembrolizumab at PDL1 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.
  • MK-1308
  • Pembrolizumab
Confirmation: DL 1 MK-1308 Schedule 1 + Pembro (NSCLC): Arm AExperimentalOn Cycle 1, Day 1 of the Dose Confirmation Phase and during all subsequent cycles, participants with NSCLC receive MK-1308 at DL1 in combination with pembrolizumab at PDL1, both according to Schedule 1. Participants will be treated for up to 35 cycles total on study.
  • MK-1308
  • Pembrolizumab
Confirmation: DL 1 MK-1308 Schedule 2 + Pembro (NSCLC): Arm BExperimentalOn Cycle 1, Day 1 of the Dose Confirmation Phase, participants with NSCLC receive MK-1308 at DL1 in combination with pembrolizumab at PDL1. On all subsequent cycles, participants receive pembrolizumab at PDL1 according to Schedule 1 and MK-1308 at DL1 according to Schedule 2. Participants will be treated for up to 35 cycles total on study.
  • MK-1308
  • Pembrolizumab
Confirmation: DL 2 MK-1308 Schedule 2 + Pembro (NSCLC): Arm CExperimentalOn Cycle 1, Day 1 of the Dose Confirmation Phase, participants with NSCLC receive MK-1308 at DL2 in combination with pembrolizumab at PDL1. On all subsequent cycles, participants receive pembrolizumab at PDL1 according to Schedule 1 and MK-1308 at DL2 according to Schedule 2. Participants will be treated for up to 35 cycles total on study.
  • MK-1308
  • Pembrolizumab
Confirmation: DL 2 MK-1308 Schedule 2 + Pembro (SCLC): Arm DExperimentalOn Cycle 1, Day 1 of the Dose Confirmation Phase, participants with SCLC receive MK-1308 at DL2 in combination with pembrolizumab at PDL1. On all subsequent cycles, participants receive pembrolizumab at PDL1 according to Schedule 1 and MK-1308 at DL2 according to Schedule 2. Participants will be treated for up to 35 cycles total on study.
  • MK-1308
  • Pembrolizumab
Confirmation: DL 2 MK-1308 Schedule 1 + Pembro (NSCLC): Arm EExperimentalOn Cycle 1, Day 1 of the Dose Confirmation Phase and during all subsequent cycles, participants with NSCLC receive MK-1308 at DL2 in combination with pembrolizumab at PDL1 according to Schedule 1. Participants will be treated for up to 35 cycles total on study.
  • MK-1308
  • Pembrolizumab
Expansion: DL1 MK-1308 Schedule 2+PDL2 Pembro Schedule 2:Arm FExperimentalOn Cycle 1, Day 1 of the Efficacy Expansion Phase and during all subsequent cycles, participants with melanoma receive MK-1308 at DL1 in combination with pembrolizumab at pembrolizumab dose level 2 (PDL2). Both MK-1308 and pembrolizumab will be administered according to Schedule 2 for up to 24 months on study.
  • MK-1308
  • Pembrolizumab
Expansion: DL1 MK-1308 Schedule 2 Monotherapy: Arm GExperimentalOn Cycle 1, Day 1 of the Efficacy Expansion Phase and during all subsequent cycles, participants with melanoma receive MK-1308 at DL1 according to Schedule 2 for up to 24 months on study. Participants who demonstrate radiographically confirmed progressive disease in Arm G will be eligible to receive combination therapy with pembrolizumab (crossover).
  • MK-1308

Eligibility Criteria

        Inclusion Criteria:

        For Dose Escalation Phase:

          -  Have any histologically- or cytologically-confirmed advanced/metastatic solid tumor
             (except NSCLC for Cohorts 2 and 3) 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 (A, B, C, and E):

          -  Have newly diagnosed histologically or cytologically-confirmed stage IIIB/stage IV
             NSCLC. Epidermal growth factor receptor (EGFR)-and anaplastic lymphoma kinase (ALK)
             translocation-directed therapy is not indicated as primary therapy. 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 (Arm D):

          -  Have histologically- or cytologically-confirmed metastatic (Stage III/IV) SCLC with
             progressive disease after ≥1 platinum-based chemotherapy regimen. Participants with
             platinum-sensitive disease are eligible

          -  Have measurable 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)

        For Efficacy Expansion Phase Arms F and G:

          -  Have histologically/cytologically-confirmed unresectable Stage III or Stage IV
             melanoma per American Joint Committee on Cancer (AJCC) staging system version 8, not
             amenable to local therapy

          -  Have at least 1 measurable lesion by CT or MRI per RECIST 1.1. 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

          -  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

        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.

          -  Has a history of a second malignancy, unless potentially curative treatment has been
             completed with no evidence of malignancy for 3 years

        For Dose Escalation Cohorts (1-3) and Dose Confirmation Arms (A-E) ONLY:

          -  Has known untreated central nervous system (CNS) metastases. Has known carcinomatous
             meningitis

          -  Has received any prior immunotherapy and was discontinued from that treatment due to a
             Grade 3 or higher immune-related adverse events (irAE)

          -  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 clinically significant cardiac disease

          -  Has received a live-virus vaccine within 28 days of planned treatment start

          -  Has known history of human immunodeficiency virus (HIV) and/or known active Hepatitis
             B or C infections, and/or known to be positive for hepatitis B surface antigen
             (HBsAg)/ hepatitis B virus (HBV) DNA

          -  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, starting with screening and for up to 120 days
             following cessation of study medication(s)

          -  Has not fully recovered from any effects of major surgery without significant
             detectable infection

        For Efficacy Expansion Phase Arms (F and G) ONLY:

          -  Has known active CNS metastases and/or carcinomatous meningitis

          -  Has not had resolution of anti-PD-1 antibody-related AEs, including immune-mediated
             AEs back to Grade ≤1 or baseline

          -  Has not discontinued steroid treatment for an irAE for at least 2 weeks prior to the
             first dose of study drug

          -  Has ocular melanoma
      
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 (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.

Secondary Outcome Measures

Measure:Dose Escalation: Area under the plasma concentration time curve (AUC) of MK-1308 at steady state
Time Frame: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 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 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 2 years. 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) 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: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 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 during the Dose Escalation phase to assess the Cmax of MK-1308.
Measure:Dose Confirmation: AUC of MK-1308 at steady state
Time Frame: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 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 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 2 years. 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) during the Dose Confirmation phase to assess the Cmin of MK-1308.
Measure:Dose Confirmation: Cmax of MK-1308 at steady state
Time Frame: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 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 during the Dose Confirmation phase to assess the Cmax of MK-1308.
Measure:Dose Escalation and Dose Confirmation: ORR as assessed by investigator based on modified RECIST 1.1
Time Frame:Up to approximately 4 years
Safety Issue:
Description: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:Efficacy Expansion: Duration of Response (DOR) as assessed by BICR based on modified RECIST 1.1
Time Frame:Up to approximately 4 years
Safety Issue:
Description: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).

Details

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

Trial Keywords

  • Programmed Death-1 (PD-1, PD1),
  • Programmed Death-Ligand 1 (PD-L1, PDL1)

Last Updated

December 5, 2019