Clinical Trials /

Study of MK-1454 Alone or in Combination With Pembrolizumab (MK-3475) in Participants With Advanced/Metastatic Solid Tumors or Lymphomas (MK-1454-001)

NCT03010176

Description:

The purpose of this study is to identify a maximum tolerated dose (MTD) or maximum administered dose (MAD) of MK-1454 alone and of MK-1454 in combination with pembrolizumab (MK-3475) in participants with advanced/metastatic solid tumors or lymphomas in Part 1, and to evaluate the safety and efficacy of MK-1454 via intratumoral (IT) injection in combination with pembrolizumab in selected solid tumors in Part 2. MK-1454 will be administered IT; pembrolizumab (pembro) will be administered via intravenous (IV) infusion. In Part 1, participants will be allocated to one of three treatment arms: MK-1454 monotherapy (cutaneous/subcutaneous [cut/subcut] lesions), MK-1454+pembro (cut/subcut lesions), or MK-1454+pembro (visceral lesions). In Part 2, participants with head and neck squamous cell carcinoma (HNSCC) who are anti-programmed cell death-protein 1 or anti-programmed cell death-ligand 1 (anti-PD-1/PD-L1) refractory or with anti-PD-1/PD-L1 treatment (TrT)-naïve triple-negative breast cancer (TNBC) or with anti-PD-1/PD-L1 TrT-naïve solid tumors with liver metastases/lesions will receive MK-1454 via IT injection at the RP2D determined in Part 1 PLUS pembrolizumab via IV infusion for up 35 cycles (up approximately 2 years).

Related Conditions:
  • Breast Carcinoma
  • Colorectal Carcinoma
  • Lymphoma
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study of MK-1454 Alone or in Combination With Pembrolizumab (MK-3475) in Participants With Advanced/Metastatic Solid Tumors or Lymphomas (MK-1454-001)
  • Official Title: Phase 1 Open-label, Multicenter Study of MK-1454 Administered by Intratumoral Injection as Monotherapy and in Combination With Pembrolizumab for Patients With Advanced/Metastatic Solid Tumors or Lymphomas

Clinical Trial IDs

  • ORG STUDY ID: 1454-001
  • SECONDARY ID: 2016-003160-40
  • SECONDARY ID: MK-1454-001
  • NCT ID: NCT03010176

Conditions

  • Solid Tumors
  • Lymphoma

Interventions

DrugSynonymsArms
MK-1454Part 1 Arm 1: MK-1454 (cut/subcut lesions)
PembrolizumabMK-3475Part 1 Arm 2: MK-1454+Pembro (cut/subcut lesions)

Purpose

The purpose of this study is to identify a maximum tolerated dose (MTD) or maximum administered dose (MAD) of MK-1454 alone and of MK-1454 in combination with pembrolizumab (MK-3475) in participants with advanced/metastatic solid tumors or lymphomas in Part 1, and to evaluate the safety and efficacy of MK-1454 via intratumoral (IT) injection in combination with pembrolizumab in selected solid tumors in Part 2. MK-1454 will be administered IT; pembrolizumab (pembro) will be administered via intravenous (IV) infuison. In Part 1, participants will be allocated to one of three treatment arms: MK-1454 monotherapy (cutaneous/subcutaneous [cut/subcut] lesions), MK-1454+pembro (cut/subcut lesions), or MK-1454+pembro (visceral lesions). In Part 2, participants with head and neck squamous cell carcinoma (HNSCC) who are anti-programmed cell death-protein 1 or anti-programmed cell death-ligand 1 (anti-PD-1/PD-L1) refractory or with anti-PD-1/PD-L1 treatment-naïve triple-negative breast cancer (TNBC) or with anti-PD-1/PD-L1 treatment-naïve solid tumors with liver metastases/lesions will receive MK-1454 via IT injection at the RP2D determined in Part 1 PLUS pembrolizumab via IV infusion for up 35 cycles (up approximately 2 years).

Detailed Description

      Participants will receive either MK-1454 monotherapy or MK-1454 in combination with
      pembrolizumab for up to 35 cycles (approximately 2 years). Participants will undergo at least
      a 24-hour inpatient observation period following the first dose administration of MK-1454 on
      Cycle 1 Day 1 in Part 1. For Part 2, with Protocol Amendment 06 (dated 23 Aug 2019), the
      length of the observation period following administration of the first dose of MK-1454 on
      Cycle 1 Day 1 is at least 8 hours.
    

Trial Arms

NameTypeDescriptionInterventions
Part 1 Arm 1: MK-1454 (cut/subcut lesions)ExperimentalParticipants with cutaneous (cut) or subcutaneous (subcut) lesions receive escalating doses of MK-1454 monotherapy via IT injection on Days 1, 8 and 15 of each 21-day cycle for Cycles 1, 2 and 3 and then on Day 1 of each 21-day cycle for Cycles 4 and beyond for up to 35 cycles (up to approximately 2 years).
  • MK-1454
Part 1 Arm 2: MK-1454+Pembro (cut/subcut lesions)ExperimentalParticipants with cut or subcut lesions receive escalating doses of MK-1454 via IT injection on Days 1, 8 and 15 of each 21-day cycle for Cycles 1, 2 and 3 and then on Day 1 of each 21-day cycle for Cycles 4 and beyond PLUS pembrolizumab (pembro) 200 mg via IV infusion on Day 1 of each 21-day cycle for up to 35 cycles (up to approximately 2 years).
  • MK-1454
  • Pembrolizumab
Part 1 Arm 3: MK-1454+Pembro (visceral lesions)ExperimentalParticipants with visceral lesions receive escalating dose frequencies of MK-1454 via IT injection at escalating dose frequencies (Day 1 of each 21-day cycle for up to 35 cycles, then Days 1 and 8 of each 21-day cycle for two cycles, then Day 1 of each 21 day cycle up to 35 cycles, then Days 1, 8 and 15 of each 21-day cycle for two cycles followed by Day 1 of each 21-day cycle up to 35 cycles, PLUS pembrolizumab 200 mg via IV infusion on Day 1 of each 21-day cycle for up to 35 cycles (approximately 2 years).
  • MK-1454
  • Pembrolizumab
Part 2 Cohort A: Head & Neck Squamous Cell Carcinoma (HNSCC)ExperimentalParticipants with HNSCC who are anti-programmed cell death-1 or anti-programmed cell death-ligand 1 refractory receive MK-1454 at the preliminary Recommended Phase 2 Dose (RP2D) determined by dose escalation in Part 1 Arm 1 and 2 via IT injection on Days 1, 8, and 15 of Cycles 1 and 2 and on Day 1 of each 21-day cycle from Cycle 3 onward (up to a total of 35 cycles) PLUS pembrolizumab 200 mg via IV infusion on Day 1 of each 21-day cycle for up to 35 cycles (up to approximately 2 years).
  • MK-1454
  • Pembrolizumab
Part 2 Cohort B: Triple-Negative Breast Cancer (TNBC)ExperimentalParticipants with TNBC who are anti-PD-1/PD-L1 treatment-naïve receive MK-1454 at the preliminary RP2D determined by dose escalation in Part 1 via IT injection on Days 1, 8, and 15 of Cycles 1 and 2 and on Day 1 of each 21-day cycle from Cycle 3 onward (up to a total of 35 cycles) PLUS pembrolizumab 200 mg via IV infusion on Day 1 of each 21-day cycle for up to 35 cycles (up to approximately 2 years).
  • MK-1454
  • Pembrolizumab
Part 2 Cohort C: Solid Tumors with Liver Metastases/LesionsExperimentalParticipants with solid tumors with liver metastases/lesions who are anti-PD-1/PD-L1 treatment-naïve receive MK-1454 at the preliminary RP2D based on Part 1: MK-1454+pembro (visceral lesions) treatment arm via IT injection in a to-be-determined dose and frequency, based on data from Arm 3, PLUS pembrolizumab 200 mg via IV infusion on Day 1 of each 21-day cycle for up to 35 cycles (up to approximately 2 years).
  • MK-1454
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          -  All Arms and Cohorts (Parts 1 and 2):

          -  Has ≥1 injectable lesion which is measurable and amenable to injection and biopsy.

          -  Has ≥1 distant, discrete non-injected lesion which is amenable to biopsy. This lesion
             must be measurable as defined by the response criteria used to assess the participant
             (RECIST 1.1 for solid tumors or revised International Working Group [IWG] criteria for
             lymphomas).

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

          -  Demonstrates adequate organ function within 7 days prior to treatment initiation.

          -  Female participants of childbearing potential must be willing to use a highly
             effective method of birth control or be surgically sterile, or abstain from
             heterosexual activity for the course of the study through 130 days after last dose of
             study treatment. Male participants of reproductive potential must agree to use a
             highly effective method of contraception during sexual contact with females of
             childbearing potential starting with the first dose of study treatment through 130
             days after the last dose of study treatment.

          -  Human Immunodeficiency (HIV)-infected participants must meet these additional
             criteria: a) Has laboratory-test-documented HIV-1 infection; b) Has well-controlled
             HIV on anti-retroviral therapy (ART), defined as: 1) must have a cluster of
             differentiation (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 below 50 or 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).

          -  Part 1, MK-1454 (cut/subcut lesions) and Part 1, MK-1454+pembro (cut/subcut lesions)
             Arms:

          -  Has a histologically- or cytologically-confirmed advanced/metastatic solid tumor or
             lymphoma by pathology report and who has received, or been intolerant to, all
             treatment known to confer clinical benefit. Solid tumors and lymphomas of any type are
             eligible for enrollment.

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

          -  Part 1, MK-1454+pembro (visceral lesions) Arm:

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

          -  Has metastatic liver 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.

          -  Part 2: HNSCC Cohort:

          -  Has HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx; anti-PD-1/PD-L1
             refractory metastatic or recurrent. Participants may not have a primary tumor site of
             the nasopharynx (any histology).

          -  Has histologically confirmed Stage III, IVa, or IVb disease per TNM (Tumor, Nodes,
             Metastasis) staging, American Joint Committee on Cancer (AJCC, 8th edition), with
             recurrent or persistent disease after definitive chemoradiation, deemed unresectable
             and considered refractory to both platinum-based combination chemotherapy and
             anti-programmed cell death-ligand 1 (anti-PD-1/PD-L1) antibody therapy.

        OR

          -  Has histologically confirmed Stage IVc disease per TNM staging, AJCC 8th edition,
             considered refractory to platinum-based combination chemotherapy and anti-PD-1/PD-L1
             antibody therapy.

          -  Part 2: TNBC Cohort:

          -  Has confirmed metastatic TNBC as locally determined according to the American Society
             of Clinical Oncology-College of American Pathologists (ASCO-CAP) guidelines on a newly
             obtained core or excisional biopsy from a metastatic, not previously irradiated, tumor
             lesion.

          -  Has received either 1 or 2 prior systemic treatments for metastatic breast cancer and
             has intolerance to, or documented disease progression on or after their most recent
             therapy.

          -  Has been previously treated with an anthracycline and/or taxane in the (neo)adjuvant
             or metastatic setting.

          -  Part 2: Solid tumors with liver metastases including pancreatic cancer,
             non-microsatellite instability-high (MSI-H) colorectal cancer CRC, and other solid
             tumors

          -  Has histologically or cytologically confirmed Stage IV solid tumor that is not
             surgically resectable.

          -  Complete resolution of toxic effect(s) of the most recent prior chemotherapy to Grade
             1 or baseline (except alopecia). If participant received major surgery or radiation
             therapy of >30 Gray (Gy), they must have recovered from the toxicity and/or
             complications from the intervention.

        Exclusion Criteria:

          -  All Arms and Cohorts (Parts 1 and 2):

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

          -  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-1454. Note: Prior
             exposure to immunotherapeutics is allowed, including PD-1 and PD-L1 inhibitors

          -  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.

          -  Has a history of a second malignancy, unless potentially curative treatment has been
             completed, with no evidence of malignancy for 2 years.

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

          -  Has had a severe hypersensitivity reaction to treatment with a monoclonal antibody.

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

          -  Has a history of vasculitis.

          -  Has an active infection requiring therapy.

          -  Has a history of (non-infectious) pneumonitis that required steroids or current
             pneumonitis.

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

          -  Has Hepatitis B or C infection(s).

          -  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, and is free of significant
             detectable infection.

          -  Has received a live vaccine within 30 days prior to first dose of study drug.

          -  Has a history of re-irradiation for squamous cell carcinoma of the head & neck (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.

          -  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 been treated with a Stimulator of Interferon Genes (STING) agonist (e.g. MK-1454,
             ADU-S100).

          -  Part 2:

          -  Has experienced weight loss >10% over 2 months prior to first dose of study treatment.

          -  Has clinically relevant ascites at baseline (defined as requiring paracentesis) or
             with moderate radiographic ascites. A minimal amount of radiographic ascites is
             allowed.

          -  For Cohort C, participants with MSI-H CRC are excluded.

          -  Has a history of interstitial lung disease.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Part 1: Percentage of Participants Who Experience a Dose-limiting Toxicity (DLT) Per Common Terminology Criteria for Adverse Events, Version 4.0 (CTCAE 4.0)
Time Frame:Up to 3 weeks at each dose level
Safety Issue:
Description:DLTs will be assessed during the first cycle (21 days) & are defined as: Grade (Gr) 4 nonhematologic toxicity; Gr 4 hematologic toxicity lasting ≥7 days, except thrombocytopenia, Gr 4 thrombocytopenia, Gr 3 thrombocytopenia (if associated with clinically significant bleeding); nonhematologic adverse event (AE) ≥ Gr 3 (with exceptions); Gr 3 or 4 nonhematologic lab abnormality (if medical intervention is required, leads to hospitalization, or persists for >1 week); Gr 3 or 4 febrile neutropenia; drug-related toxicity that causes treatment discontinuation or dose delay >7 days between consecutive doses during Cycle 1; drug-related toxicity that causes a >2 week delay in Cycle 2 initiation; elevated aspartate aminotransferase or alanine aminotransferase lab value that is ≥3× upper limit of normal (ULN) & an elevated total bilirubin value ≥2× ULN & an alkaline phosphatase value <2× ULN, in which no alternative reasons can be found; ≥Gr 2 immune-mediated uveitis; or Gr 5 toxicity.

Secondary Outcome Measures

Measure:Parts 1 and 2: Area Under the Plasma Drug Concentration-Time Curve (AUC) of MK-1454 When Administered as Monotherapy and as Combination Therapy With Pembrolizumab
Time Frame:Cycle 1 Day 1: Predose, at end of IT injection and 0.5, 1, 1.5, 4 and 6 hours postdose; Cycle 2 Day 1: Predose, at end of IT injection and 0.5, 1, 1.5, 4 and 6 hours postdose. Each cycle is 21 days.
Safety Issue:
Description:AUC is the area under the plasma drug concentration-time curve after study treatment administration. The AUC of MK-1454 when administered as monotherapy and as combination therapy with pembrolizumab will be presented.
Measure:Parts 1 and 2: AUC of Pembrolizumab When Administered as Combination Therapy With MK-1454
Time Frame:Cycle 1 Day 1: Predose, at end of IT injection and 0.5, 1, 1.5, 4 and 6 hours postdose; Cycle 2 Day 1: Predose, at end of IT injection and 0.5, 1, 1.5, 4 and 6 hours postdose. Each cycle is 21 days.
Safety Issue:
Description:AUC is the area under the plasma drug concentration-time curve after study treatment administration. The AUC of pembrolizumab when administered as combination therapy with MK-1454 will be presented.
Measure:Part 2: Objective Response Rate (ORR) As Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
Time Frame:Up to approximately 2 years
Safety Issue:
Description:ORR is defined as the percentage of participants in the analysis population who have a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters) per RECIST 1.1. The ORR of MK-1454 at the preliminary RP2D in combination with pembrolizumab will be assessed by RECIST 1.1 modified to follow a maximum of 10 target lesions with a maximum of 5 target lesions per organ. ORR for the three Part 2 cohorts will be presented.

Details

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

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