<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/NCT03236935</url>
  </required_header>
  <id_info>
    <org_study_id>Pro00017492</org_study_id>
    <nct_id>NCT03236935</nct_id>
  </id_info>
  <brief_title>Phase Ib of L-NMMA and Pembrolizumab</brief_title>
  <official_title>Phase Ib Trial of L-NMMA in Combination With Pembrolizumab in Patients With Melanoma, Non-Small Cell Lung Cancer, Head and Neck Squamous Cell Carcinoma, Classical Hodgkin Lymphoma, Urothelial Carcinoma, Cervical Cancer, Esophageal Cancer, Gastric Cancer, Hepatocellular Carcinoma, Merkel Cell Carcinoma, Primary Mediastinal Large B-cell Lymphoma, Renal Cell Carcinoma, Small Cell Lung Cancer, Microsatellite Instability-High/Mismatch Repair Deficient Cancer, or for the Treatment of Adult Patients With Unresectable or Metastatic Tumor Mutational Burden-High Solid Tumors</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>The Methodist Hospital Research Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>The Methodist Hospital Research Institute</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 Phase Ib study is to test the safety of NG-monomethyl-L-arginine (L-NMMA)&#xD;
      and pembrolizumab when used together in participants with melanoma, non-small cell lung&#xD;
      cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), classical Hodgkin lymphoma&#xD;
      (cHL), urothelial carcinoma, Cervical Cancer, Esophageal Cancer, Gastric Cancer,&#xD;
      Hepatocellular Carcinoma, Merkel Cell Carcinoma, Primary Mediastinal Large B-cell Lymphoma,&#xD;
      Renal Cell Carcinoma, Small Cell Lung Cancer, microsatellite instability-high&#xD;
      (MSI-H)/mismatch repair deficient (dMMR) cancer or for the Treatment of Adult Patients with&#xD;
      Unresectable or Metastatic Tumor Mutational Burden-High Solid Tumors. Pembrolizumab is a type&#xD;
      of treatment that stimulates the immune system to attack cancer cells. The immune system is&#xD;
      normally the body's first defense against threats like cancer. However, sometimes cancer&#xD;
      cells produce signals like programmed death-1 (PD-1) that prevent the immune system from&#xD;
      detecting and killing them. Pembrolizumab blocks PD-1 so your immune system can detect and&#xD;
      attack cancer cells. To help further boost the cancer-fighting ability of your immune system,&#xD;
      L-NMMA will be used along with pembrolizumab. L-NMMA is a nitric oxide synthase inhibitor.&#xD;
      The presence of nitric oxide synthase in the area around the cancer cells blocks the&#xD;
      cancer-fighting ability of the immune system. Thus, the use of L-NMMA and pembrolizumab&#xD;
      together may make the immune system work harder to attack and destroy the cancer cells.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The purpose of this Phase Ib study is to test the safety of NG-monomethyl-L-arginine (L-NMMA)&#xD;
      and pembrolizumab when used together in participants with melanoma, non-small cell lung&#xD;
      cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), classical Hodgkin lymphoma&#xD;
      (cHL), urothelial carcinoma, Cervical Cancer, Esophageal Cancer, Gastric Cancer,&#xD;
      Hepatocellular Carcinoma, Merkel Cell Carcinoma, Primary Mediastinal Large B-cell Lymphoma,&#xD;
      Renal Cell Carcinoma, Small Cell Lung Cancer, microsatellite instability-high&#xD;
      (MSI-H)/mismatch repair deficient (dMMR) cancer or for the Treatment of Adult Patients with&#xD;
      Unresectable or Metastatic Tumor Mutational Burden-High Solid Tumors. Pembrolizumab is a type&#xD;
      of treatment that stimulates the immune system to attack cancer cells. The immune system is&#xD;
      normally the body's first defense against threats like cancer. However, sometimes cancer&#xD;
      cells produce signals like PD-L1 that prevent the immune system from detecting and killing&#xD;
      them. Pembrolizumab blocks programmed death-1 (PD-1) so your immune system can detect and&#xD;
      attack cancer cells. To help further boost the cancer-fighting ability of your immune system,&#xD;
      L-NMMA will be used along with pembrolizumab. L-NMMA is a nitric oxide synthase inhibitor.&#xD;
      The presence of nitric oxide synthase in the area around the cancer cells blocks the&#xD;
      cancer-fighting ability of the immune system. Thus, the use of L-NMMA and pembrolizumab&#xD;
      together may make the immune system work harder to attack and destroy the cancer cells.&#xD;
&#xD;
      In this study, up to 3 different doses of L-NMMA will be studied (12.5, 15, and 20 mg/kg).&#xD;
      Participants will only receive one of the three L-NMMA doses. The first several study&#xD;
      participants will receive the 15 mg/kg dose. If the 15 mg/kg dose of L-NMMA causes serious&#xD;
      side effects, L-NMMA will be given to other study participants at the lower dose of 12.5&#xD;
      mg/kg. If the 15 mg/kg dose of L-NMMA does not cause serious side effects, L-NMMA will be&#xD;
      given to other study participants at the higher dose of 20 mg/kg. All study participants will&#xD;
      be given the same dose of pembrolizumab (200 mg). This study will allow us to see the highest&#xD;
      dose of L-NMMA that can be used safely with pembrolizumab in participants with melanoma,&#xD;
      NSCLC, HNSCC, cHL, urothelial carcinoma, or MSI-H/dMMR cancer.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">August 3, 2018</start_date>
  <completion_date type="Anticipated">December 28, 2023</completion_date>
  <primary_completion_date type="Actual">October 31, 2021</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Maximum tolerated dose (MTD)</measure>
    <time_frame>18 weeks</time_frame>
    <description>Assess the MTD of L-NMMA in combination with pembrolizumab</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Dose-limiting toxicities (DLTs) and other adverse events</measure>
    <time_frame>18 weeks</time_frame>
    <description>Describe the DLTs and other adverse events associated with the combination of L-NMMA and pembrolizumab, as assessed by the Common Terminology Criteria for Adverse Events V4.03</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Recommended Phase 2 dose (RP2D) of L-NMMA in combination with pembrolizumab</measure>
    <time_frame>18 weeks</time_frame>
    <description>Determine the RP2D of L-NMMA in combination with pembrolizumab based on the occurrence of DLTs and MTD determination</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Antitumor activity</measure>
    <time_frame>18 weeks</time_frame>
    <description>Assess the antitumor activity of L-NMMA in combination with pembrolizumab, as assessed by the RECIST 1.1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma concentrations of L-NMMA when combined with pembrolizumab</measure>
    <time_frame>18 weeks</time_frame>
    <description>Measure plasma concentrations of L-NMMA over time</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">12</enrollment>
  <condition>Non-Small Cell Lung Cancer</condition>
  <condition>Malignant Melanoma</condition>
  <condition>Head and Neck Squamous Cell Carcinoma</condition>
  <condition>Classical Hodgkin Lymphoma</condition>
  <condition>Urothelial Carcinoma Bladder</condition>
  <condition>DNA Repair-Deficiency Disorders</condition>
  <arm_group>
    <arm_group_label>L-NMMA Plus Pembrolizumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>L-NMMA and pembrolizumab will be administered for 6 cycles. Cycle length will be 21 days. L-NMMA will be administered as a 2-hour intravenous (IV) infusion on Days 1-5 at each cycle. The dose levels of L-NMMA are as follows: Dose Level -1, 12.5 mg/kg; Dose Level 0 (starting dose), 15.0 mg/kg; and Dose Level 1, 20 mg/kg. L-NMMA dose will escalate/de-escalate based on the occurrence of dose-limiting toxicities. Pembrolizumab at a fixed dose of 200 mg will be IV infused over 30 minutes on Day 5 at each cycle. Pembrolizumab will be administered 1 hour after L-NMMA infusion on Day 5 at each cycle. Subjects without disease progression after 6 cycles of L-NMMA and pembrolizumab will continue pembrolizumab until disease progression or unacceptable AEs.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>L-NMMA</intervention_name>
    <description>pan-nitric oxide synthase inhibitor</description>
    <arm_group_label>L-NMMA Plus Pembrolizumab</arm_group_label>
    <other_name>NG-monomethyl-L-arginine</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pembrolizumab</intervention_name>
    <description>PD-1 inhibitor</description>
    <arm_group_label>L-NMMA Plus Pembrolizumab</arm_group_label>
    <other_name>Keytruda</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Female or male aged ≥ 18 years on the day of informed consent signing;&#xD;
&#xD;
          -  Has histologically confirmed metastatic melanoma that is treatment naïve or has&#xD;
             relapsed after or is refractory to ipilimumab or BRAF inhibitor (if BRAF&#xD;
             mutation-positive), OR histologically confirmed metastatic NSCLC that has high&#xD;
             programmed death-ligand 1 (PD-L1) expression (tumor proportion score [TPS] ≥50%) with&#xD;
             no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic&#xD;
             tumor aberrations or histologically confirmed metastatic NSCLC that is PD-L1 positive&#xD;
             (TPS ≥1%) and has progressed on or after platinum-containing therapy (subjects with&#xD;
             NSCLC harboring EGFR/ALK genomic aberrations must have received an FDA-approved&#xD;
             targeted therapy for these aberrations) OR histologically confirmed HNSCC that has&#xD;
             relapsed after or is refractory to platinum-containing chemotherapy, OR histologically&#xD;
             confirmed cHL that has relapsed after three or more lines of therapy or is refractory&#xD;
             to treatment OR histologically confirmed locally advanced or metastatic urothelial&#xD;
             carcinoma that is not eligible for platinum-containing chemotherapy or that has&#xD;
             relapsed after or is refractory to platinum-containing chemotherapy OR histologically&#xD;
             confirmed advanced, PD-L1-positive cervical cancer with disease progression on or&#xD;
             after chemotherapy that is not eligible for platinum-containing chemotherapy or that&#xD;
             has relapsed after or is refractory to platinum-containing chemotherapy OR&#xD;
             histologically confirmed recurrent, locally advanced, or metastatic, squamous cell&#xD;
             carcinoma of the esophagus (ESCC) whose tumors express PD-L1 (Combined Positive Score&#xD;
             [CPS] ≥10), as determined by an FDA-approved test, with disease progression after one&#xD;
             or more prior lines of systemic therapy.&#xD;
&#xD;
        OR histologically confirmed recurrent, locally advanced, or metastatic Gastric Cancer, with&#xD;
        disease progression on or after two or more systemic therapies, including fluoropyrimidine-&#xD;
        and platinum-containing chemotherapy and, if appropriate, HER2/neu-targeted therapy, and&#xD;
        whose tumors express programmed death-ligand 1 (PD-L1), as determined by an FDA-approved&#xD;
        test.&#xD;
&#xD;
        OR histologically confirmed hepatocellular carcinoma (HCC) who have been previously treated&#xD;
        with sorafenib. recurrent locally advanced or metastatic MCC who had not received prior&#xD;
        systemic therapy for their advanced disease OR histologically confirmed recurrent, locally&#xD;
        advanced or metastatic Merkel Cell Carcinoma (MCC) who had not received prior systemic&#xD;
        therapy for their advanced disease OR histologically confirmed advanced renal cell&#xD;
        carcinoma (RCC) first-line treatment.&#xD;
&#xD;
        OR histologically confirmed metastatic small cell lung cancer (SCLC) with disease&#xD;
        progression on or after platinum-based chemotherapy and at least one other prior line of&#xD;
        therapy.&#xD;
&#xD;
        OR histologically confirmed refractory primary mediastinal large B-cell lymphoma (PMBCL),&#xD;
        who have relapsed after two or more prior lines of therapy.&#xD;
&#xD;
        OR MSI-H or dMMR unresectable or metastatic cancer that has relapsed after prior treatment&#xD;
        and has no satisfactory alternative treatment options.&#xD;
&#xD;
        OR adult patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10&#xD;
        mutations/megabase (mut/Mb)] solid tumors;&#xD;
&#xD;
          -  Measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1;&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group performance status of 0-2;&#xD;
&#xD;
          -  Life expectancy ≥ 6 months;&#xD;
&#xD;
          -  Adequate organ function:&#xD;
&#xD;
        Absolute neutrophil count ≥1,500/mm3, platelets ≥100,000/mm3, hemoglobin ≥9 g/dL&#xD;
        (transfusion permitted), serum creatinine OR measured or calculated creatinine clearance&#xD;
        ≤1.5 X upper limit of normal (ULN) OR ≥60 mL/min for subject with creatinine levels &gt; 1.5 X&#xD;
        institutional ULN, serum total bilirubin ≤ 1.5 X ULN OR direct bilirubin ≤ ULN for subjects&#xD;
        with total bilirubin levels &gt; 1.5 ULN, alanine transaminase and aspartate transaminase ≤&#xD;
        2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases, albumin &gt;2.5 mg/dL,&#xD;
        International normalized ratio or prothrombin time ≤1.5 X ULN, and activated partial&#xD;
        thromboplastin time ≤1.5 X ULN;&#xD;
&#xD;
          -  Cardiac ejection fraction of ≥ 45%;&#xD;
&#xD;
          -  Female subjects of childbearing potential should have a negative serum pregnancy&#xD;
             (beta-human chorionic gonadotropin) within 7 days prior to receiving the first dose of&#xD;
             trial treatment and should not be lactating;&#xD;
&#xD;
          -  Female subjects of childbearing potential must be willing to use an adequate method of&#xD;
             contraception for the course of the trial through 120 days after the last dose of&#xD;
             trial treatment;&#xD;
&#xD;
          -  Male subjects of childbearing potential must be willing to use an adequate method of&#xD;
             contraception for the course of the trial through 120 days after the last dose of&#xD;
             trial treatment;&#xD;
&#xD;
          -  Willing and able to provide written informed consent/assent for the trial.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History of poorly controlled hypertension (defined as systolic blood pressure &gt;150&#xD;
             mmHg);&#xD;
&#xD;
          -  History of New York Heart Association class III or greater cardiac disease;&#xD;
&#xD;
          -  History of myocardial infarction, stroke, ventricular arrhythmia, or symptomatic&#xD;
             conduction abnormality within the past 12 months;&#xD;
&#xD;
          -  History of congenital QT prolongation;&#xD;
&#xD;
          -  Absolute corrected QT interval of &gt;480 milliseconds in the presence of potassium &gt;4.0&#xD;
             milliequivalent/L and magnesium &gt;1.8 mg/dL;&#xD;
&#xD;
          -  Currently participating and receiving study therapy or has participated in a study of&#xD;
             an investigational agent and received study therapy or used an investigational device&#xD;
             within 4 weeks of the first dose of the trial treatment;&#xD;
&#xD;
          -  Concurrent use of medications that interact with nitrate/nitrites;&#xD;
&#xD;
          -  Concurrent use of any complementary or alternative medicines;&#xD;
&#xD;
          -  Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any&#xD;
             other form of immunosuppressive therapy within 7 days prior to the first dose of trial&#xD;
             treatment;&#xD;
&#xD;
          -  Known history of active tuberculosis (Bacillus Tuberculosis);&#xD;
&#xD;
          -  Hypersensitivity to L-NMMA, pembrolizumab, or any of their excipients;&#xD;
&#xD;
          -  Has had a prior anticancer monoclonal antibody within 4 weeks prior to study Day 1 or&#xD;
             who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to&#xD;
             agents administered more than 4 weeks earlier;&#xD;
&#xD;
          -  Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy&#xD;
             within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at&#xD;
             baseline) from adverse events due to a previously administered agent;&#xD;
&#xD;
          -  Has a known additional malignancy that is progressing or requires active treatment.&#xD;
             Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the&#xD;
             skin that has undergone potentially curative therapy or in situ cervical cancer.&#xD;
&#xD;
          -  Has known active central nervous system metastases and/or carcinomatous meningitis.&#xD;
             Subjects with previously treated brain metastases may participate provided they are&#xD;
             stable (without evidence of progression by imaging for at least 4 weeks prior to the&#xD;
             first dose of trial treatment and any neurologic symptoms have returned to baseline),&#xD;
             have no evidence of new or enlarging brain metastases, and are not using steroids for&#xD;
             at least 7 days prior to trial treatment. This exception does not include&#xD;
             carcinomatous meningitis which is excluded regardless of clinical stability;&#xD;
&#xD;
          -  Has active autoimmune disease that has required systemic treatment in the past 2 years&#xD;
             (i.e., with use of disease-modifying agents, corticosteroids or immunosuppressive&#xD;
             drugs);&#xD;
&#xD;
          -  History of non-infectious pneumonitis that required steroids or current pneumonitis;&#xD;
&#xD;
          -  Has an active infection requiring systemic therapy;&#xD;
&#xD;
          -  History or current evidence of any condition, therapy, or laboratory abnormality that&#xD;
             might confound the results of the trial, interfere with the subject's participation&#xD;
             for the full duration of the trial, or is not in the best interest of the subject to&#xD;
             participate, in the opinion of the treating investigator;&#xD;
&#xD;
          -  Known psychiatric or substance abuse disorders that would interfere with cooperation&#xD;
             with the requirements of the trial;&#xD;
&#xD;
          -  Is pregnant or breastfeeding, or expecting to conceive a child within the projected&#xD;
             duration of the trial, starting with the prescreening or screening visit through 120&#xD;
             days after the last dose of trial treatment;&#xD;
&#xD;
          -  Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent;&#xD;
&#xD;
          -  Known history of human immunodeficiency virus;&#xD;
&#xD;
          -  Has known active hepatitis B or hepatitis C;&#xD;
&#xD;
          -  Received a live vaccine within 30 days of planned start of the trial treatment;&#xD;
&#xD;
          -  Unwilling or unable to comply with the trial protocol.&#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>Jun Zhang, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Houston Methodist Cancer Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Houston Methodist Cancer Center</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>July 28, 2017</study_first_submitted>
  <study_first_submitted_qc>July 28, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 2, 2017</study_first_posted>
  <last_update_submitted>May 3, 2023</last_update_submitted>
  <last_update_submitted_qc>May 3, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 6, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>The Methodist Hospital Research Institute</investigator_affiliation>
    <investigator_full_name>Jun Zhang</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lymphoma</mesh_term>
    <mesh_term>Carcinoma</mesh_term>
    <mesh_term>Lung Neoplasms</mesh_term>
    <mesh_term>Carcinoma, Non-Small-Cell Lung</mesh_term>
    <mesh_term>Melanoma</mesh_term>
    <mesh_term>Carcinoma, Squamous Cell</mesh_term>
    <mesh_term>Hodgkin Disease</mesh_term>
    <mesh_term>Carcinoma, Transitional Cell</mesh_term>
    <mesh_term>Squamous Cell Carcinoma of Head and Neck</mesh_term>
    <mesh_term>Urinary Bladder Neoplasms</mesh_term>
    <mesh_term>DNA Repair-Deficiency Disorders</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pembrolizumab</mesh_term>
    <mesh_term>omega-N-Methylarginine</mesh_term>
  </intervention_browse>
  <!-- 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/NCT03236935
org study id: Pro00017492
nct id: NCT03236935
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
The purpose of this Phase Ib study is to test the safety of NG-monomethyl-L-arginine (L-NMMA)
      and pembrolizumab when used together in participants with melanoma, non-small cell lung
      cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), classical Hodgkin lymphoma
      (cHL), urothelial carcinoma, Cervical Cancer, Esophageal Cancer, Gastric Cancer,
      Hepatocellular Carcinoma, Merkel Cell Carcinoma, Primary Mediastinal Large B-cell Lymphoma,
      Renal Cell Carcinoma, Small Cell Lung Cancer, microsatellite instability-high
      (MSI-H)/mismatch repair deficient (dMMR) cancer or for the Treatment of Adult Patients with
      Unresectable or Metastatic Tumor Mutational Burden-High Solid Tumors. Pembrolizumab is a type
      of treatment that stimulates the immune system to attack cancer cells. The immune system is
      normally the body's first defense against threats like cancer. However, sometimes cancer
      cells produce signals like programmed death-1 (PD-1) that prevent the immune system from
      detecting and killing them. Pembrolizumab blocks PD-1 so your immune system can detect and
      attack cancer cells. To help further boost the cancer-fighting ability of your immune system,
      L-NMMA will be used along with pembrolizumab. L-NMMA is a nitric oxide synthase inhibitor.
      The presence of nitric oxide synthase in the area around the cancer cells blocks the
      cancer-fighting ability of the immune system. Thus, the use of L-NMMA and pembrolizumab
      together may make the immune system work harder to attack and destroy the cancer cells.
The purpose of this Phase Ib study is to test the safety of NG-monomethyl-L-arginine (L-NMMA)
      and pembrolizumab when used together in participants with melanoma, non-small cell lung
      cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), classical Hodgkin lymphoma
      (cHL), urothelial carcinoma, Cervical Cancer, Esophageal Cancer, Gastric Cancer,
      Hepatocellular Carcinoma, Merkel Cell Carcinoma, Primary Mediastinal Large B-cell Lymphoma,
      Renal Cell Carcinoma, Small Cell Lung Cancer, microsatellite instability-high
      (MSI-H)/mismatch repair deficient (dMMR) cancer or for the Treatment of Adult Patients with
      Unresectable or Metastatic Tumor Mutational Burden-High Solid Tumors. Pembrolizumab is a type
      of treatment that stimulates the immune system to attack cancer cells. The immune system is
      normally the body's first defense against threats like cancer. However, sometimes cancer
      cells produce signals like PD-L1 that prevent the immune system from detecting and killing
      them. Pembrolizumab blocks programmed death-1 (PD-1) so your immune system can detect and
      attack cancer cells. To help further boost the cancer-fighting ability of your immune system,
      L-NMMA will be used along with pembrolizumab. L-NMMA is a nitric oxide synthase inhibitor.
      The presence of nitric oxide synthase in the area around the cancer cells blocks the
      cancer-fighting ability of the immune system. Thus, the use of L-NMMA and pembrolizumab
      together may make the immune system work harder to attack and destroy the cancer cells.

      In this study, up to 3 different doses of L-NMMA will be studied (12.5, 15, and 20 mg/kg).
      Participants will only receive one of the three L-NMMA doses. The first several study
      participants will receive the 15 mg/kg dose. If the 15 mg/kg dose of L-NMMA causes serious
      side effects, L-NMMA will be given to other study participants at the lower dose of 12.5
      mg/kg. If the 15 mg/kg dose of L-NMMA does not cause serious side effects, L-NMMA will be
      given to other study participants at the higher dose of 20 mg/kg. All study participants will
      be given the same dose of pembrolizumab (200 mg). This study will allow us to see the highest
      dose of L-NMMA that can be used safely with pembrolizumab in participants with melanoma,
      NSCLC, HNSCC, cHL, urothelial carcinoma, or MSI-H/dMMR cancer.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Maximum tolerated dose (MTD)
time frame: 18 weeks
description: Assess the MTD of L-NMMA in combination with pembrolizumab
measure: Dose-limiting toxicities (DLTs) and other adverse events
time frame: 18 weeks
description: Describe the DLTs and other adverse events associated with the combination of L-NMMA and pembrolizumab, as assessed by the Common Terminology Criteria for Adverse Events V4.03
measure: Recommended Phase 2 dose (RP2D) of L-NMMA in combination with pembrolizumab
time frame: 18 weeks
description: Determine the RP2D of L-NMMA in combination with pembrolizumab based on the occurrence of DLTs and MTD determination
measure: Antitumor activity
time frame: 18 weeks
description: Assess the antitumor activity of L-NMMA in combination with pembrolizumab, as assessed by the RECIST 1.1
measure: Plasma concentrations of L-NMMA when combined with pembrolizumab
time frame: 18 weeks
description: Measure plasma concentrations of L-NMMA over time
arm group label: L-NMMA Plus Pembrolizumab
arm group type: Experimental
description: L-NMMA and pembrolizumab will be administered for 6 cycles. Cycle length will be 21 days. L-NMMA will be administered as a 2-hour intravenous (IV) infusion on Days 1-5 at each cycle. The dose levels of L-NMMA are as follows: Dose Level -1, 12.5 mg/kg; Dose Level 0 (starting dose), 15.0 mg/kg; and Dose Level 1, 20 mg/kg. L-NMMA dose will escalate/de-escalate based on the occurrence of dose-limiting toxicities. Pembrolizumab at a fixed dose of 200 mg will be IV infused over 30 minutes on Day 5 at each cycle. Pembrolizumab will be administered 1 hour after L-NMMA infusion on Day 5 at each cycle. Subjects without disease progression after 6 cycles of L-NMMA and pembrolizumab will continue pembrolizumab until disease progression or unacceptable AEs.
intervention type: Drug
intervention name: L-NMMA
description: pan-nitric oxide synthase inhibitor
arm group label: L-NMMA Plus Pembrolizumab
other name: NG-monomethyl-L-arginine
intervention type: Drug
intervention name: Pembrolizumab
description: PD-1 inhibitor
arm group label: L-NMMA Plus Pembrolizumab
other name: Keytruda
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Jun Zhang, M.D.
role: Principal Investigator
affiliation: Houston Methodist Cancer Center
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: The Methodist Hospital Research Institute
investigator full name: Jun Zhang
investigator title: Principal Investigator
mesh term: Lymphoma
mesh term: Carcinoma
mesh term: Lung Neoplasms
mesh term: Carcinoma, Non-Small-Cell Lung
mesh term: Melanoma
mesh term: Carcinoma, Squamous Cell
mesh term: Hodgkin Disease
mesh term: Carcinoma, Transitional Cell
mesh term: Squamous Cell Carcinoma of Head and Neck
mesh term: Urinary Bladder Neoplasms
mesh term: DNA Repair-Deficiency Disorders
mesh term: Pembrolizumab
mesh term: omega-N-Methylarginine