<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03010176</url>
  </required_header>
  <id_info>
    <org_study_id>1454-001</org_study_id>
    <secondary_id>MK-1454-001</secondary_id>
    <secondary_id>2016-003160-40</secondary_id>
    <nct_id>NCT03010176</nct_id>
  </id_info>
  <brief_title>Study of Ulevostinag (MK-1454) Alone or in Combination With Pembrolizumab (MK-3475) in Participants With Advanced/Metastatic Solid Tumors or Lymphomas (MK-1454-001)</brief_title>
  <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</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Merck Sharp &amp; Dohme LLC</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Merck Sharp &amp; Dohme LLC</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to identify a maximum tolerated dose (MTD) or maximum&#xD;
      administered dose (MAD) of ulevostinag alone and of ulevostinag in combination with&#xD;
      pembrolizumab in participants with advanced/metastatic solid tumors or lymphomas in Part 1,&#xD;
      and to evaluate the safety and efficacy of ulevostinag via intratumoral (IT) injection in&#xD;
      combination with pembrolizumab in selected solid tumors in Part 2.&#xD;
&#xD;
      Ulevostinag will be administered IT; pembrolizumab (pembro) will be administered via&#xD;
      intravenous (IV) infusion. In Part 1, participants will be allocated to one of three&#xD;
      treatment arms: ulevostinag monotherapy (cutaneous/subcutaneous [cut/subcut] lesions),&#xD;
      ulevostinag +pembro (cut/subcut lesions), or ulevostinag +pembro (visceral lesions).&#xD;
&#xD;
      In Part 2, participants with head and neck squamous cell carcinoma (HNSCC) who are&#xD;
      anti-programmed cell death-protein 1 or anti-programmed cell death-ligand 1 (anti-PD-1/PD-L1)&#xD;
      refractory or with anti-PD-1/PD-L1 treatment (TrT)-naïve triple-negative breast cancer (TNBC)&#xD;
      or with anti-PD-1/PD-L1 TrT-naïve solid tumors with liver metastases/lesions will receive&#xD;
      ulevostinag via IT injection at the RP2D determined in Part 1 PLUS pembrolizumab via IV&#xD;
      infusion for up 35 cycles (up approximately 2 years).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Participants will receive either ulevostinag monotherapy or ulevostinag in combination with&#xD;
      pembrolizumab for up to 35 cycles (approximately 2 years). Participants will undergo at least&#xD;
      a 24-hour inpatient observation period following the first dose administration of ulevostinag&#xD;
      on Cycle 1 Day 1 in Part 1. For Part 2, the length of the observation period following&#xD;
      administration of the first dose of ulevostinag on Cycle 1 Day 1 is at least 8 hours.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">February 3, 2017</start_date>
  <completion_date type="Actual">April 21, 2022</completion_date>
  <primary_completion_date type="Actual">April 21, 2022</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <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)</measure>
    <time_frame>Up to 3 weeks at each dose level</time_frame>
    <description>DLTs will be assessed during the first cycle (21 days) &amp; 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 &gt;1 week); Gr 3 or 4 febrile neutropenia; drug-related toxicity that causes treatment discontinuation or dose delay &gt;7 days between consecutive doses during Cycle 1; drug-related toxicity that causes a &gt;2 week delay in Cycle 2 initiation; elevated aspartate aminotransferase or alanine aminotransferase lab value that is ≥3× upper limit of normal (ULN) &amp; an elevated total bilirubin value ≥2× ULN &amp; an alkaline phosphatase value &lt;2× ULN, in which no alternative reasons can be found; ≥Gr 2 immune-mediated uveitis; or Gr 5 toxicity.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Parts 1 and 2: Percentage of Participants Who Discontinue Study Drug Due to an Adverse Event (AE)</measure>
    <time_frame>Up to approximately 2 years</time_frame>
    <description>AEs are defined as any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of study treatment or protocol-specified procedure, whether or not considered related to the study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of the study treatment, is also an AE. The percentage of participants who discontinue study treatment due to an AE will be presented.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Parts 1 and 2: Ulevostinag Area Under the Plasma Drug Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24)</measure>
    <time_frame>Cycle 1 Day 1: Predose, at end of IT injection (up to 15 minutes) and 0.5, 1, 1.5, 4, 6, 12, and 24 hours postdose. Each cycle is 21 days.</time_frame>
    <description>The AUC0-24 of ulevostinag when administered as monotherapy and as combination therapy with pembrolizumab will be determined.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Parts 1 and 2: Ulevostinag Minimum Plasma Concentration (Cmin)</measure>
    <time_frame>Cycle 1 Day 1: Predose, at end of IT injection (up to 15 minutes) and 0.5, 1, 1.5, 4, 6, 12, and 24 hours postdose; Cycle 2 Day 1: Predose, at end of IT injection (up to 15 minutes) and 0.5, 1, 1.5, 4 and 6 hours postdose. Each cycle is 21 days.</time_frame>
    <description>The observed Cmin of ulevostinag when administered as monotherapy and as combination therapy with pembrolizumab will be determined.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Parts 1 and 2: Ulevostinag Maximum Plasma Concentration (Cmax)</measure>
    <time_frame>Cycle 1 Day 1: Predose, at end of IT injection (up to 15 minutes) and 0.5, 1, 1.5, 4, 6, 12, and 24 hours postdose; Cycle 2 Day 1: Predose, at end of IT injection (up to 15 minutes) and 0.5, 1, 1.5, 4 and 6 hours postdose. Each cycle is 21 days.</time_frame>
    <description>The observed Cmax of ulevostinag when administered as monotherapy and as combination therapy with pembrolizumab will be determined.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Parts 1 and 2: Pembrolizumab Minimum Plasma Concentration (Cmin)</measure>
    <time_frame>Predose on Day 1 of Cycles 1, 2, and 4, and every 4 cycles thereafter up to Cycle 35 (up to 2 years). Each cycle is 21 days.</time_frame>
    <description>The Cmin of pembrolizumab when administered as combination therapy with ulevostinag will be determined.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 2: Objective Response Rate (ORR) As Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)</measure>
    <time_frame>Up to approximately 2 years</time_frame>
    <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 ulevostinag 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 reported.</description>
  </secondary_outcome>
  <number_of_arms>6</number_of_arms>
  <enrollment type="Actual">157</enrollment>
  <condition>Solid Tumors</condition>
  <condition>Lymphoma</condition>
  <arm_group>
    <arm_group_label>Part 1 Arm 1: Ulevostinag (Cut/Subcut Lesions)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants with cutaneous (cut) or subcutaneous (subcut) lesions receive escalating doses of ulevostinag 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).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 1 Arm 2: Ulevostinag +Pembro (Cut/Subcut Lesions)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants with cut or subcut lesions receive escalating doses of ulevostinag 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).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 1 Arm 3: Ulevostinag+Pembro (Visceral Lesions)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants with visceral lesions receive escalating dose frequencies of ulevostinag 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).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 2 Cohort A: HNSCC Anti-PD-1/PD-L1 Refractory</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants with HNSCC who are anti-programmed cell death-1 or anti-programmed cell death-ligand 1 refractory receive ulevostinag 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).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 2 Cohort B: Anti-PD-1/PD-L1 TrT-Naïve or Refractory TNBC</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants with TNBC who are anti-PD-1/PD-L1 treatment-naïve or who have refractory unresectable locally advanced or metastatic TNBC receive ulevostinag 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).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 2 Cohort C: Anti-PD-1/PD-L1 TrT-Naïve Solid Tumors-Liver</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants with solid tumors with liver metastases/lesions who are anti-PD-1/PD-L1 treatment-naïve receive ulevostinag at the preliminary RP2D based on Part 1: ulevostinag +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).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ulevostinag</intervention_name>
    <description>IT injection</description>
    <arm_group_label>Part 1 Arm 1: Ulevostinag (Cut/Subcut Lesions)</arm_group_label>
    <arm_group_label>Part 1 Arm 2: Ulevostinag +Pembro (Cut/Subcut Lesions)</arm_group_label>
    <arm_group_label>Part 1 Arm 3: Ulevostinag+Pembro (Visceral Lesions)</arm_group_label>
    <arm_group_label>Part 2 Cohort A: HNSCC Anti-PD-1/PD-L1 Refractory</arm_group_label>
    <arm_group_label>Part 2 Cohort B: Anti-PD-1/PD-L1 TrT-Naïve or Refractory TNBC</arm_group_label>
    <arm_group_label>Part 2 Cohort C: Anti-PD-1/PD-L1 TrT-Naïve Solid Tumors-Liver</arm_group_label>
    <other_name>MK-1454</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Pembrolizumab</intervention_name>
    <description>IV infusion</description>
    <arm_group_label>Part 1 Arm 2: Ulevostinag +Pembro (Cut/Subcut Lesions)</arm_group_label>
    <arm_group_label>Part 1 Arm 3: Ulevostinag+Pembro (Visceral Lesions)</arm_group_label>
    <arm_group_label>Part 2 Cohort A: HNSCC Anti-PD-1/PD-L1 Refractory</arm_group_label>
    <arm_group_label>Part 2 Cohort B: Anti-PD-1/PD-L1 TrT-Naïve or Refractory TNBC</arm_group_label>
    <arm_group_label>Part 2 Cohort C: Anti-PD-1/PD-L1 TrT-Naïve Solid Tumors-Liver</arm_group_label>
    <other_name>MK-3475</other_name>
    <other_name>Keytruda®</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        All Arms and Cohorts (Parts 1 and 2):&#xD;
&#xD;
          -  Has ≥1 injectable lesion which is measurable and amenable to injection and biopsy.&#xD;
&#xD;
          -  Has an Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1.&#xD;
&#xD;
          -  Demonstrates adequate organ function within 7 days prior to treatment initiation.&#xD;
&#xD;
          -  Female participants of childbearing potential must be using a contraceptive method&#xD;
             that is highly effective or be abstinent from heterosexual intercourse (on a long-term&#xD;
             and persistent basis) during the intervention period and for at least 130 days after&#xD;
             the last dose of study intervention and agrees not to donate eggs to others or&#xD;
             freeze/store for personal use for the purpose of reproduction during this period. Male&#xD;
             participants must agree to refrain from donating sperm PLUS either be abstinent from&#xD;
             heterosexual intercourse (on a long-term and persistent basis) OR agree to use a male&#xD;
             condom plus partner use of an additional contraceptive method when having&#xD;
             penile-vaginal intercourse contraception, unless confirmed to be azoospermic&#xD;
             (vasectomized) during the intervention period and for at least 130 days after the last&#xD;
             dose of study intervention.&#xD;
&#xD;
          -  Human Immunodeficiency (HIV)-infected participants must meet these additional&#xD;
             criteria: a) Has laboratory-test-documented HIV-1 infection; b) Has well-controlled&#xD;
             HIV on anti-retroviral therapy (ART), defined as: 1) must have a cluster of&#xD;
             differentiation (CD4+) T-cell count &gt;350 cells/mm^3 at time of screening; 2) must have&#xD;
             achieved and maintained virologic suppression defined as confirmed HIV ribonucleic&#xD;
             acid (RNA) level below 50 or the lower limit of quantification (LLOQ) using the&#xD;
             locally available assay at the time of screening and for ≥12 weeks prior to screening;&#xD;
             and, 3) must have been on a stable regimen, without changes in drugs or dose&#xD;
             modification, for ≥4 weeks prior to study entry (Day 1).&#xD;
&#xD;
        All Part 1 Arms:&#xD;
&#xD;
        -Has ≥1 distant, discrete non-injected lesion which is amenable to biopsy. This lesion must&#xD;
        be measurable as defined by the response criteria used to assess the participant (RECIST&#xD;
        1.1 for solid tumors or revised International Working Group [IWG] criteria for lymphomas).&#xD;
&#xD;
        Part 1 Arm 1: Ulevostinag (Cut/Subcut Lesions) and Part 1 Arm 2: Ulevostinag+Pembro&#xD;
        (Cut/Subcut Lesions):&#xD;
&#xD;
          -  Has a histologically- or cytologically-confirmed advanced/metastatic solid tumor or&#xD;
             lymphoma by pathology report and who has received, or been intolerant to, all&#xD;
             treatment known to confer clinical benefit. Solid tumors and lymphomas of any type are&#xD;
             eligible for enrollment.&#xD;
&#xD;
          -  Has stage III or stage IV disease that is not surgically resectable. Stage IIB&#xD;
             (T3N0M0B0-1) cutaneous T cell lymphoma (CTCL) participants are eligible.&#xD;
&#xD;
        Part 1 Arm 3: Ulevostinag+Pembro (Visceral Lesions):&#xD;
&#xD;
          -  Has stage III or stage IV disease that is not surgically resectable.&#xD;
&#xD;
          -  Has metastatic liver involvement that does not exceed one third of the total liver&#xD;
             volume in participants to be treated by liver IT injection. Hepatocellular carcinoma&#xD;
             participants are excluded from eligibility of IT liver injection.&#xD;
&#xD;
        All Part 2 Expansion Cohorts:&#xD;
&#xD;
        Part 2 Cohort A: HNSCC Anti-PD-1/PD-L1 Refractory:&#xD;
&#xD;
          -  Has HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx; anti-PD-1/PD-L1&#xD;
             refractory metastatic or recurrent. Participants may not have a primary tumor site of&#xD;
             the nasopharynx (any histology).&#xD;
&#xD;
          -  Has histologically confirmed Stage III, IVa, or IVb disease per TNM (Tumor, Nodes,&#xD;
             Metastasis) staging, American Joint Committee on Cancer (AJCC, 8th edition), with&#xD;
             recurrent or persistent disease after definitive chemoradiation, deemed unresectable&#xD;
             and considered refractory to both platinum-based combination chemotherapy and&#xD;
             anti-programmed cell death-ligand 1 (anti-PD-1/PD-L1) antibody therapy.&#xD;
&#xD;
        OR&#xD;
&#xD;
          -  Has histologically confirmed Stage IVc disease per TNM staging, AJCC 8th edition,&#xD;
             considered refractory to platinum-based combination chemotherapy and anti-PD-1/PD-L1&#xD;
             antibody therapy.&#xD;
&#xD;
        Part 2 Cohort B: Anti-PD-1/PD-L1 TrT-Naïve or Refractory TNBC:&#xD;
&#xD;
          -  Has confirmed unresectable locally advanced or metastatic TNBC as locally determined&#xD;
             according to the American Society of Clinical Oncology-College of American&#xD;
             Pathologists (ASCO-CAP) guidelines on a newly obtained core or excisional biopsy from&#xD;
             a metastatic, not previously irradiated, tumor lesion.&#xD;
&#xD;
          -  Has received at least one prior systemic treatment for metastatic breast cancer and&#xD;
             has intolerance to, or documented disease progression on or after their most recent&#xD;
             therapy.&#xD;
&#xD;
          -  Has been previously treated with an anthracycline and/or taxane in the (neo)adjuvant&#xD;
             or metastatic setting unless there was a medical contraindication to this treatment&#xD;
             regimen.&#xD;
&#xD;
          -  Have lactate dehydrogenase (LDH) &lt;2.5 × upper limit of normal (ULN)&#xD;
&#xD;
        Part 2 Cohort C: Anti-PD-1/PD-L1 TrT-Naïve Solid Tumors-Liver:&#xD;
&#xD;
          -  Has histologically or cytologically confirmed Stage IV solid tumor that is not&#xD;
             surgically resectable.&#xD;
&#xD;
          -  Complete resolution of toxic effect(s) of the most recent prior chemotherapy to Grade&#xD;
             1 or baseline (except alopecia). If participant received major surgery or radiation&#xD;
             therapy of &gt;30 Gray (Gy), they must have recovered from the toxicity and/or&#xD;
             complications from the intervention.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        All Arms and Cohorts (Parts 1 and 2):&#xD;
&#xD;
          -  Has had chemotherapy, definitive radiation, or biological cancer therapy within 4&#xD;
             weeks prior to the first dose of study drug, or has not recovered to Baseline or&#xD;
             Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 from the adverse events&#xD;
             due to cancer therapeutics administered &gt;4 weeks earlier.&#xD;
&#xD;
          -  Is currently participating and receiving study therapy or has participated in a study&#xD;
             of an investigational agent and has received study therapy or has used an&#xD;
             investigational device within 28 days of administration of ulevostinag. Note: Prior&#xD;
             exposure to immunotherapeutics is allowed, including PD-1 and PD-L1 inhibitors&#xD;
&#xD;
          -  Is expected to require any other form of antineoplastic therapy while on study.&#xD;
&#xD;
          -  Is on chronic systemic steroid therapy in excess of replacement doses (prednisone ≤ 10&#xD;
             mg/day is acceptable), or on any other form of immunosuppressive medication.&#xD;
&#xD;
          -  Has a history of a second malignancy, unless potentially curative treatment has been&#xD;
             completed, with no evidence of malignancy for 2 years.&#xD;
&#xD;
          -  Has clinically active central nervous system metastases and/or carcinomatous&#xD;
             meningitis.&#xD;
&#xD;
          -  Has had a severe hypersensitivity reaction to treatment with a monoclonal antibody.&#xD;
&#xD;
          -  Has an active autoimmune disease that has required systemic treatment in the past 2&#xD;
             years.&#xD;
&#xD;
          -  Has a history of vasculitis.&#xD;
&#xD;
          -  Has an active infection requiring therapy.&#xD;
&#xD;
          -  Has a history of (non-infectious) pneumonitis that required steroids or current&#xD;
             pneumonitis.&#xD;
&#xD;
          -  Has undergone prior allogeneic hematopoietic stem cell transplantation within the last&#xD;
             5 years.&#xD;
&#xD;
          -  Has Hepatitis B or C infection(s).&#xD;
&#xD;
          -  Is pregnant or breastfeeding, or expecting to conceive or father children within the&#xD;
             projected duration of the study.&#xD;
&#xD;
          -  Has not fully recovered from any effects of major surgery, and is free of significant&#xD;
             detectable infection.&#xD;
&#xD;
          -  Has received a live vaccine within 30 days prior to first dose of study drug.&#xD;
&#xD;
          -  Has a history of re-irradiation for squamous cell carcinoma of the head &amp; neck (HNSCC)&#xD;
             at the projected injection site.&#xD;
&#xD;
          -  Has a tumor(s) in direct contact or encases a major blood vessel, and has ulceration&#xD;
             and/or fungation onto the skin surface at the projected injection site.&#xD;
&#xD;
          -  HIV-infected participants with history of Kaposi's sarcoma and/or multicentric&#xD;
             Castleman's disease&#xD;
&#xD;
          -  HIV-infected participants who have had an HIV-related opportunistic infection within 6&#xD;
             months&#xD;
&#xD;
          -  Has been treated with a Stimulator of Interferon Genes (STING) agonist (e.g.&#xD;
             ulevostinag, ADU-S100).&#xD;
&#xD;
        All Part 2 Expansion Cohorts:&#xD;
&#xD;
          -  Has experienced weight loss &gt;10% over 2 months prior to first dose of study treatment.&#xD;
&#xD;
          -  Has clinically relevant ascites at baseline (defined as requiring paracentesis) or&#xD;
             with moderate radiographic ascites. A minimal amount of radiographic ascites is&#xD;
             allowed.&#xD;
&#xD;
          -  Has a history of interstitial lung disease.&#xD;
&#xD;
          -  For Part 2 Cohort C: Anti-PD-1/PD-L1 TrT-Naïve Solid Tumors-Liver, participants with&#xD;
             MSI-H CRC are excluded.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Medical Director</last_name>
    <role>Study Director</role>
    <affiliation>Merck Sharp &amp; Dohme LLC</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Alabama ( Site 0009)</name>
      <address>
        <city>Birmingham</city>
        <state>Alabama</state>
        <zip>35294</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of California San Francisco ( Site 0007)</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94143</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UCSF ( Site 0015)</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94158</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UCLA Medical Center ( Site 0005)</name>
      <address>
        <city>Santa Monica</city>
        <state>California</state>
        <zip>90404</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Henry Ford Health System ( Site 0014)</name>
      <address>
        <city>Detroit</city>
        <state>Michigan</state>
        <zip>48202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mount Sinai Hospital ( Site 0002)</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10029</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Columbia University ( Site 0003)</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10032</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UPMC Hillman Cancer Center ( Site 0013)</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15232</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mary Crowley Cancer Research Center ( Site 0001)</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75230</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Huntsman Cancer Institute ( Site 0004)</name>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <zip>84112</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut Claudius Regaud ( Site 0051)</name>
      <address>
        <city>Toulouse Cedex 9</city>
        <state>Haute-Garonne</state>
        <zip>31059</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut Gustave Roussy ( Site 0049)</name>
      <address>
        <city>Villejuif</city>
        <state>Val-de-Marne</state>
        <zip>94805</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut Curie ( Site 0050)</name>
      <address>
        <city>Paris</city>
        <zip>75005</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rambam Medical Center ( Site 0041)</name>
      <address>
        <city>Haifa</city>
        <zip>3109601</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sheba Medical Center ( Site 0040)</name>
      <address>
        <city>Ramat Gan</city>
        <zip>5265601</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Severance Hospital ( Site 0103)</name>
      <address>
        <city>Seoul</city>
        <zip>03722</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Asan Medical Center ( Site 0104)</name>
      <address>
        <city>Seoul</city>
        <zip>05505</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Royal Marsden Foundation Trust ( Site 0031)</name>
      <address>
        <city>London</city>
        <state>London, City Of</state>
        <zip>SW3 6JJ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Royal Marsden NHS Foundation Trust. ( Site 0032)</name>
      <address>
        <city>Sutton</city>
        <state>Surrey</state>
        <zip>SM2 5PT</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
    <country>Israel</country>
    <country>Korea, Republic of</country>
    <country>United Kingdom</country>
    <country>United States</country>
  </location_countries>
  <verification_date>June 2022</verification_date>
  <study_first_submitted>January 3, 2017</study_first_submitted>
  <study_first_submitted_qc>January 3, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 4, 2017</study_first_posted>
  <last_update_submitted>June 10, 2022</last_update_submitted>
  <last_update_submitted_qc>June 10, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">June 13, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Programmed Cell Death-1 (PD1, PD-1)</keyword>
  <keyword>Programmed Death-Ligand 1 (PDL1, PD-L1)</keyword>
  <keyword>Intratumoral (IT)</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lymphoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pembrolizumab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf</ipd_description>
    <ipd_url>http://engagezone.msd.com/ds_documentation.php</ipd_url>
  </patient_data>
  <pending_results>
    <submitted>April 18, 2023</submitted>
  </pending_results>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03010176
org study id: 1454-001
secondary id: MK-1454-001
secondary id: 2016-003160-40
nct id: NCT03010176
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
The purpose of this study is to identify a maximum tolerated dose (MTD) or maximum
      administered dose (MAD) of ulevostinag alone and of ulevostinag in combination with
      pembrolizumab in participants with advanced/metastatic solid tumors or lymphomas in Part 1,
      and to evaluate the safety and efficacy of ulevostinag via intratumoral (IT) injection in
      combination with pembrolizumab in selected solid tumors in Part 2.

      Ulevostinag 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: ulevostinag monotherapy (cutaneous/subcutaneous [cut/subcut] lesions),
      ulevostinag +pembro (cut/subcut lesions), or ulevostinag +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
      ulevostinag via IT injection at the RP2D determined in Part 1 PLUS pembrolizumab via IV
      infusion for up 35 cycles (up approximately 2 years).
Participants will receive either ulevostinag monotherapy or ulevostinag 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 ulevostinag
      on Cycle 1 Day 1 in Part 1. For Part 2, the length of the observation period following
      administration of the first dose of ulevostinag on Cycle 1 Day 1 is at least 8 hours.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
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
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.
measure: Parts 1 and 2: Percentage of Participants Who Discontinue Study Drug Due to an Adverse Event (AE)
time frame: Up to approximately 2 years
description: AEs are defined as any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of study treatment or protocol-specified procedure, whether or not considered related to the study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of the study treatment, is also an AE. The percentage of participants who discontinue study treatment due to an AE will be presented.
measure: Parts 1 and 2: Ulevostinag Area Under the Plasma Drug Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24)
time frame: Cycle 1 Day 1: Predose, at end of IT injection (up to 15 minutes) and 0.5, 1, 1.5, 4, 6, 12, and 24 hours postdose. Each cycle is 21 days.
description: The AUC0-24 of ulevostinag when administered as monotherapy and as combination therapy with pembrolizumab will be determined.
measure: Parts 1 and 2: Ulevostinag Minimum Plasma Concentration (Cmin)
time frame: Cycle 1 Day 1: Predose, at end of IT injection (up to 15 minutes) and 0.5, 1, 1.5, 4, 6, 12, and 24 hours postdose; Cycle 2 Day 1: Predose, at end of IT injection (up to 15 minutes) and 0.5, 1, 1.5, 4 and 6 hours postdose. Each cycle is 21 days.
description: The observed Cmin of ulevostinag when administered as monotherapy and as combination therapy with pembrolizumab will be determined.
measure: Parts 1 and 2: Ulevostinag Maximum Plasma Concentration (Cmax)
time frame: Cycle 1 Day 1: Predose, at end of IT injection (up to 15 minutes) and 0.5, 1, 1.5, 4, 6, 12, and 24 hours postdose; Cycle 2 Day 1: Predose, at end of IT injection (up to 15 minutes) and 0.5, 1, 1.5, 4 and 6 hours postdose. Each cycle is 21 days.
description: The observed Cmax of ulevostinag when administered as monotherapy and as combination therapy with pembrolizumab will be determined.
measure: Parts 1 and 2: Pembrolizumab Minimum Plasma Concentration (Cmin)
time frame: Predose on Day 1 of Cycles 1, 2, and 4, and every 4 cycles thereafter up to Cycle 35 (up to 2 years). Each cycle is 21 days.
description: The Cmin of pembrolizumab when administered as combination therapy with ulevostinag will be determined.
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
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 ulevostinag 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 reported.
arm group label: Part 1 Arm 1: Ulevostinag (Cut/Subcut Lesions)
arm group type: Experimental
description: Participants with cutaneous (cut) or subcutaneous (subcut) lesions receive escalating doses of ulevostinag 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).
arm group label: Part 1 Arm 2: Ulevostinag +Pembro (Cut/Subcut Lesions)
arm group type: Experimental
description: Participants with cut or subcut lesions receive escalating doses of ulevostinag 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).
arm group label: Part 1 Arm 3: Ulevostinag+Pembro (Visceral Lesions)
arm group type: Experimental
description: Participants with visceral lesions receive escalating dose frequencies of ulevostinag 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).
arm group label: Part 2 Cohort A: HNSCC Anti-PD-1/PD-L1 Refractory
arm group type: Experimental
description: Participants with HNSCC who are anti-programmed cell death-1 or anti-programmed cell death-ligand 1 refractory receive ulevostinag 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).
arm group label: Part 2 Cohort B: Anti-PD-1/PD-L1 TrT-Naïve or Refractory TNBC
arm group type: Experimental
description: Participants with TNBC who are anti-PD-1/PD-L1 treatment-naïve or who have refractory unresectable locally advanced or metastatic TNBC receive ulevostinag 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).
arm group label: Part 2 Cohort C: Anti-PD-1/PD-L1 TrT-Naïve Solid Tumors-Liver
arm group type: Experimental
description: Participants with solid tumors with liver metastases/lesions who are anti-PD-1/PD-L1 treatment-naïve receive ulevostinag at the preliminary RP2D based on Part 1: ulevostinag +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).
intervention type: Drug
intervention name: Ulevostinag
description: IT injection
arm group label: Part 1 Arm 1: Ulevostinag (Cut/Subcut Lesions)
arm group label: Part 1 Arm 2: Ulevostinag +Pembro (Cut/Subcut Lesions)
arm group label: Part 1 Arm 3: Ulevostinag+Pembro (Visceral Lesions)
arm group label: Part 2 Cohort A: HNSCC Anti-PD-1/PD-L1 Refractory
arm group label: Part 2 Cohort B: Anti-PD-1/PD-L1 TrT-Naïve or Refractory TNBC
arm group label: Part 2 Cohort C: Anti-PD-1/PD-L1 TrT-Naïve Solid Tumors-Liver
other name: MK-1454
intervention type: Biological
intervention name: Pembrolizumab
description: IV infusion
arm group label: Part 1 Arm 2: Ulevostinag +Pembro (Cut/Subcut Lesions)
arm group label: Part 1 Arm 3: Ulevostinag+Pembro (Visceral Lesions)
arm group label: Part 2 Cohort A: HNSCC Anti-PD-1/PD-L1 Refractory
arm group label: Part 2 Cohort B: Anti-PD-1/PD-L1 TrT-Naïve or Refractory TNBC
arm group label: Part 2 Cohort C: Anti-PD-1/PD-L1 TrT-Naïve Solid Tumors-Liver
other name: MK-3475
other name: Keytruda®
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Medical Director
role: Study Director
affiliation: Merck Sharp & Dohme LLC
facility: 
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country: France
country: Israel
country: Korea, Republic of
country: United Kingdom
country: United States
responsible party type: Sponsor
mesh term: Lymphoma
mesh term: Pembrolizumab
sharing ipd: Yes
ipd description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
ipd url: http://engagezone.msd.com/ds_documentation.php
submitted: April 18, 2023