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Study of MK-2118 Administered as Intratumoral Injection as Monotherapy and in Combination With Pembrolizumab (MK-3475) or by Subcutaneous Injection in Combination With Pembrolizumab in the Treatment of Adults With Advanced/Metastatic Solid Tumors or Lymphomas (MK-2118-001)

NCT03249792

Description:

The purposes of this study are to: 1) assess the safety and tolerability and 2) establish a preliminary recommended Phase 2 dose (RP2D) and/or a maximum tolerated dose (MTD) or a maximum administered dose (MAD) of MK-2118 when administered via intratumoral (IT) injection as monotherapy and in combination with pembrolizumab (MK-3475) intravenous (IV) infusion, or via subcutaneous (SC) injection in combination with pembrolizumab IV infusion in the treatment of adult participants with advanced/metastatic solid tumors or lymphomas.

Related Conditions:
  • Lymphoma
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study of MK-2118 Administered as Intratumoral Injection as Monotherapy and in Combination With Pembrolizumab (MK-3475) or by Subcutaneous Injection in Combination With Pembrolizumab in the Treatment of Adults With Advanced/Metastatic Solid Tumors or Lymphomas (MK-2118-001)
  • Official Title: A Phase 1 Open-label, Multicenter Study of MK-2118 Administered by Intratumoral Injection as Monotherapy and in Combination With Pembrolizumab or by Subcutaneous Injection in Combination With Pembrolizumab for Patients With Advanced/Metastatic Solid Tumors or Lymphomas

Clinical Trial IDs

  • ORG STUDY ID: 2118-001
  • SECONDARY ID: MK-2118-001
  • NCT ID: NCT03249792

Conditions

  • Solid Tumor
  • Lymphoma

Interventions

DrugSynonymsArms
MK-2118 (IT)Arm 1: MK-2118 IT Monotherapy
MK-2118 (SC)Arm 4: MK-2118 SC+Pembro Combo Therapy
PembrolizumabMK-3475Arm 2: MK-2118 IT+Pembro Combo Therapy

Purpose

The purposes of this study are to: 1) assess the safety and tolerability and 2) establish a preliminary recommended Phase 2 dose (RP2D) and/or a maximum tolerated dose (MTD) or a maximum administered dose (MAD) of MK-2118 when administered via intratumoral (IT) injection as monotherapy and in combination with pembrolizumab (MK-3475) intravenous (IV) infusion, or via subcutaneous (SC) injection in combination with pembrolizumab IV infusion in the treatment of adult participants with advanced/metastatic solid tumors or lymphomas.

Detailed Description

      Participants will receive either MK-2118 monotherapy or MK-2118 in combination with
      pembrolizumab for up to 35 cycles for Arms 1-3 or up to 36 cycles for Arm 4 (approximately 2
      years).

      All participants will undergo at least a 24-hour observation period following the first three
      administrations of MK-2118 (Arms 1-3: Cycle 1 Days 1, 8, and 15. Arm 4: Cycle 1 Days 1 and 8;
      and Cycle 2 Day 1).
    

Trial Arms

NameTypeDescriptionInterventions
Arm 1: MK-2118 IT MonotherapyExperimentalParticipants receive MK-2118 via IT injection once weekly (Q1W) on Days 1, 8 and 15 of Cycles 1-3 followed by MK-2118 via IT injection once every 3 weeks (Q3W) on Day 1 of Cycle 4 and beyond, for a total of up to 35 cycles (approximately 2 years). Each cycle is 3 weeks long.
  • MK-2118 (IT)
Arm 2: MK-2118 IT+Pembro Combo TherapyExperimentalParticipants receive pembrolizumab (pembro) 200 mg via IV infusion on Day 1 of each cycle for up to 35 cycles (approximately 2 years) and receive MK-2118 via IT injection Q1W on Days 1, 8 and 15 of Cycles 1-3 followed by MK-2118 IT injection Q3W on Day 1 of Cycle 4 and beyond, for a total of up to 35 cycles (approximately 2 years). Each cycle is 3 weeks long.
  • MK-2118 (IT)
  • Pembrolizumab
Arm 3: MK-2118 Visceral IT+Pembro Combo TherapyExperimentalParticipants receive pembrolizumab 200 mg via IV infusion on Day 1 of each cycle for up to 35 cycles (approximately 2 years) and receive MK-2118 via IT injection Q1W on Days 1, 8 and 15 of Cycles 1-2 followed by MK-2118 IT injection Q3W on Day 1 of Cycle 3 and beyond, for a total of up to 35 cycles (approximately 2 years). Each cycle is 3 weeks long.
  • MK-2118 (IT)
  • Pembrolizumab
Arm 4: MK-2118 SC+Pembro Combo TherapyExperimentalParticipants receive MK-2118 monotherapy via subcutaneous (SC) injection Q1W on Cycle 1 Days 1 and 8 followed by MK-2118 SC injection Q1W on Cycles 2-4 Days 1, 8 and 15, for a total of up to 36 cycles (approximately 2 years) plus pembrolizumab 200 mg via IV infusion on Day 1 of Cycle 2 and beyond for up to 36 cycles (approximately 2 years). Cycle 1 is 2 weeks long and Cycles 2 and beyond are 3 weeks long.
  • MK-2118 (SC)
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

        Arms 1 and 2 Participants:

          -  Has any histologically or cytologically confirmed advanced/metastatic solid tumor by
             pathology report and has received, or have been intolerant to all treatment known to
             confer clinical benefit. Solid tumors and lymphomas of any type are eligible for
             enrollment. For cutaneous T-cell lymphoma (CTCL), histopathological diagnosis should
             be confirmed in a skin biopsy representative of disease.

          -  Has Stage III or Stage IV disease that is not surgically resectable. Stage IIB
             (T3N0M0B0-1) CTCL participants are eligible.

        Arm 3 Participants:

        - Has metastatic liver and/or liver lesion involvement that does not exceed one third of
        the total liver volume in participants to be treated by liver IT injection. Hepatocellular
        carcinoma participants are excluded from eligibility of IT liver injection.

        All Participants:

          -  Has Stage III or Stage IV disease that is not surgically resectable.

          -  Has ≥1 injectable lesion that is amenable to injection and biopsy via visual
             inspection for a cutaneous lesion, or via ultrasound guidance for a subcutaneous
             lesion.

          -  Has ≥1 discrete, distant noninjected lesion that is amenable to biopsy via visual
             inspection or amenable to biopsy via image guidance.

          -  Has Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.

          -  Demonstrates adequate organ function.

          -  A male participant is eligible to participate if he agrees to the following during the
             intervention period and for at least 120 days after the last dose of study
             intervetnion:

               1. Refrain from donating sperm.

               2. Be abstinent from heterosexual intercourse as their preferred and usual lifestyle
                  and agree to remain abstinent OR must agree to use contraception unless confirmed
                  to be azoospermic.

          -  A female participant is eligible to participate if she is not pregnant or
             breastfeeding, and at least one of the following conditions applies:

               1. Is not a woman of childbearing potential (WOCBP).

               2. Is a WOCBP and using a contraceptive method that is highly effective with low
                  user dependency, or be abstinent from heterosexual intercourse as their preferred
                  and usual lifestyle (abstinent on a long term and persistent basis), during the
                  intervention period and for at least 120 days after the last dose of study
                  intervention, AND agrees not to donate eggs (ova, oocytes) to others or
                  freeze/store for her own use for the purpose of reproduction during this period.

          -  Human Immunodeficiency Virus (HIV)-infected participants must meet these additional
             criteria:

               1. Has HIV-1 infection documented by laboratory test.

               2. Has well-controlled HIV on anti-retroviral therapy (ART), defined as: 1) must
                  have a CD4+ T-cell count >350 cells/mm^3 at time of screening; 2) must have
                  achieved and maintained virologic suppression defined as confirmed HIV
                  ribonucleic acid (RNA) level <50 or below the lower limit of quantification
                  (LLOQ) using the locally available assay at the time of screening and for ≥12
                  weeks prior to screening; and 3) must have been on a stable regimen, without
                  changes in drugs or dose modification, for ≥4 weeks prior to study entry (Day 1).

        Exclusion Criteria:

          -  Has history of a second malignancy, unless potentially curative treatment has been
             completed, with no evidence of malignancy for 2 years (except for successful
             definitive resection of basal cell carcinoma of the skin, superficial bladder cancer,
             or in situ cervical cancer).

          -  Has clinically active central nervous system metastases and/or carcinomatous
             meningitis.

          -  Has severe hypersensitivity reaction to treatment with a monoclonal antibody (mAb).

          -  Has active autoimmune disease that has required systemic treatment in the past 2
             years.

          -  Has history of vasculitis.

          -  Has active infection requiring therapy.

          -  Has history of (noninfectious) pneumonitis that required steroids or current
             pneumonitis.

          -  Has undergone prior allogeneic hematopoietic stem cell transplantation within the last
             5 years.

          -  Has known Hepatitis B or C infection.

          -  Has known psychiatric or substance abuse disorders that would interfere in cooperation
             with the requirements of the trial.

          -  Is pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the study.

          -  Is not fully recovered from any effects of major surgery, and is free of significant
             detectable infection.

          -  HIV-infected participants with history of Kaposi's sarcoma and/or multicentric
             Castleman's disease.

          -  HIV-infected participants who have had an HIV-related opportunistic infection within 6
             months.

          -  Has had chemotherapy, definitive radiation, or biological cancer therapy within 4
             weeks (2 weeks for palliative radiation) prior to the first dose of study treatment,
             or has not recovered to baseline or Common Terminology Criteria for Adverse Events
             (CTCAE) Grade 1 from the AEs due to cancer therapeutics administered >4 weeks earlier.

          -  Has been treated within 2 weeks of Cycle 1 Day1 with any of the following:
             strong/moderate Cytochrome P450 2C9 (CYP2C9) inhibitors, such as: amiodarone,
             felbamate, fluconazole, miconazole, piperine, oxandrolone, fluorouracil and its
             derivatives (combination drug tegafur/gimeracil/oteracil [TS-1], Uftoral [UFT],
             tegafur, carmofur, doxifluridine, capecitabine), sulfaphenazole, cyclosporine,
             bucurol, tienilic acid; UGT1A3 inhibitors (including ritonavir, quinidine, probenecid,
             and valproic acid); or strong carbonyl reductase (CBR) inhibitors (including
             quercetin, menadione, glycyrrhetinic acid, and flufenamic acid).

          -  Is currently participating and receiving study therapy or has participated in a study
             of an investigational agent and has received study therapy or has used an
             investigational device within 28 days of administration of MK-2118.

          -  Is expected to require any other form of antineoplastic therapy while on study.

          -  Is on chronic systemic steroid therapy in excess of replacement doses (prednisone ≤10
             mg/day is acceptable), or on any other form of immunosuppressive medication. For CTCL,
             continued use of either prednisone ≤10 mg/day or continued use of topical steroids is
             acceptable.

          -  Has received a live vaccine within 28 days prior to first dose.

          -  Has been treated with a stimulator of interferon genes (STING) agonist (eg, MK-1454,
             ADU-S100 [synthetic cyclic dinucleotide (CDN)]).

          -  Has a history of re-irradiation for head and neck squamous cell carcinoma (HNSCC) at
             the projected injection site.

          -  Has a tumor(s) in direct contact or encases a major blood vessel and has ulceration
             and/or fungation onto the skin surface at the projected injection site.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose-limiting Toxicities (DLTs)
Time Frame:Arms 1, 2 & 3: Cycle 1 (Up to 21 days); Arm 4: Cycles 1 & 2 (Up to 35 days)
Safety Issue:
Description:A DLT is defined as the following toxicities, if related to study treatment: Grade 4 nonhematologic toxicity; Grade 4 hematologic toxicity lasting ≥7 days, except thrombocytopenia (Grade 4 thrombocytopenia of any duration, Grade 3 thrombocytopenia with clinically significant bleeding); Non-hematologic adverse event (AE) ≥Grade 3 (with exceptions); Grade 3 or Grade 4 nonhematologic abnormality; Febrile neutropenia Grade 3 or 4; Any toxicity causing treatment discontinuation or causing participant to miss ≥1 dose during the DLT period; Any toxicity that causes a >2 week delay initiating Cycle 2 of pembrolizumab; Any elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) value that is ≥3× upper limit of normal (ULN) & an elevated total bilirubin value that is ≥2× ULN & an alkaline phosphatase value that is <2× ULN with no alternative explanation; Any ≥Grade 2 immune-mediated uveitis; Grade 5 toxicity. The number of participants who experience a DLT will be presented.

Secondary Outcome Measures

Measure:MK-2118 Minimum Plasma Concentration (Cmin)
Time Frame:At designated time points (Up to approximately 2 months)
Safety Issue:
Description:The observed Cmin of MK-2118 when administered as monotherapy and as combination therapy with pembrolizumab will be determined. Samples will be collected at the following designated time points: Cycle 1 Day 1: Predose and 0.5, 1, 2, 4, 6, 8, 12 and 24 hours postdose; Cycle 2 Day 1: Predose and 0.5, 1, 2, 4, 6 and 8 hours postdose. Arm 4 includes additional timepoints for Cycle 3 Day 1: Predose and 0.5, 1, 2, 4, 6 and 8 hours postdose. For Arms 1-3, each cycle is 3 weeks. For Arm 4, Cycle 1 is 2 weeks and Cycles 2 and beyond are 3 weeks.
Measure:MK-2118 Maximum Plasma Concentration (Cmax)
Time Frame:At designated time points (Up to approximately 2 months)
Safety Issue:
Description:The observed Cmax of MK-2118 when administered as monotherapy and as combination therapy with pembrolizumab will be determined. Samples will be collected at the following designated time points: Cycle 1 Day 1: Predose and 0.5, 1, 2, 4, 6, 8, 12 and 24 hours postdose; Cycle 2 Day 1: Predose and 0.5, 1, 2, 4, 6 and 8 hours postdose. Arm 4 includes additional timepoints for Cycle 3 Day 1: Predose and 0.5, 1, 2, 4, 6 and 8 hours postdose. For Arms 1-3, each cycle is 3 weeks. For Arm 4, Cycle 1 is 2 weeks and Cycles 2 and beyond are 3 weeks.
Measure:MK-2118 Area Under the Concentration-time Curve from 0 to 24 hours (AUC 0-24hr)
Time Frame:At designated time points (Up to approximately 24 hours)
Safety Issue:
Description:The AUC 0-24hr of MK-2118 when administered as monotherapy and as combination therapy with pembrolizumab will be determined. Samples will be collected at the following designated time points: Cycle 1 Day 1: Predose and 0.5, 1, 2, 4, 6, 8, 12 and 24 hours postdose. For Arms 1-3, each cycle is 3 weeks. For Arm 4, Cycle 1 is 2 weeks and Cycles 2 and beyond are 3 weeks.
Measure:Pembrolizumab Cmin
Time Frame:At designated time points (Up to approximately 27 months)
Safety Issue:
Description:The observed Cmin of pembrolizumab when administered as combination therapy with MK-2118 will be determined. This assessment will be performed only on participants in the MK-2118+Pembro combination therapy arms. Samples will be collected at the following designated time points: For Arms 1-3: Predose on Day 1 of Cycles 1, 2, 4, and every 4 cycles up to Cycle 35. For Arm 4: Predose on Day 1 of Cycles 2, 3, 5, and every 4 cycles up to Cycle 36. For Arms 1-3, each cycle is 3 weeks. For Arm 4, Cycle 1 is 2 weeks and Cycles 2 and beyond are 3 weeks.

Details

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

Last Updated

November 23, 2020