Clinical Trials /

Phase Ib of L-NMMA and Pembrolizumab

NCT03236935

Description:

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, or microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) cancer. 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.

Related Conditions:
  • Head and Neck Squamous Cell Carcinoma
  • Hodgkin Lymphoma
  • Malignant Solid Tumor
  • Melanoma
  • Non-Small Cell Lung Carcinoma
  • Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Phase Ib of L-NMMA and Pembrolizumab
  • 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, or Microsatellite Instability-High/Mismatch Repair Deficient Cancer

Clinical Trial IDs

  • ORG STUDY ID: Pro00017492
  • NCT ID: NCT03236935

Conditions

  • Non-Small Cell Lung Cancer
  • Malignant Melanoma
  • Head and Neck Squamous Cell Carcinoma
  • Classical Hodgkin Lymphoma
  • Urothelial Carcinoma Bladder
  • DNA Repair-Deficiency Disorders

Interventions

DrugSynonymsArms
L-NMMANG-monomethyl-L-arginineL-NMMA Plus Pembrolizumab
PembrolizumabKeytrudaL-NMMA Plus Pembrolizumab

Purpose

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, or microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) cancer. 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.

Detailed Description

      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, or microsatellite instability-high (MSI-H)/mismatch repair
      deficient (dMMR) cancer. 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.
    

Trial Arms

NameTypeDescriptionInterventions
L-NMMA Plus PembrolizumabExperimentalL-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.
  • L-NMMA
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Female or male aged ≥ 18 years on the day of informed consent signing;

          -  Has histologically confirmed metastatic melanoma that is treatment naïve or has
             relapsed after or is refractory to ipilimumab or BRAF inhibitor (if BRAF mutation
             positive), OR histologically confirmed metastatic NSCLC that has high programmed
             death-ligand 1 (PD-L1) expression (tumor proportion score [TPS] ≥50%) with no
             epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic
             tumor aberrations or histologically confirmed metastatic NSCLC that is PD-L1 positive
             (TPS ≥1%) and has progressed on or after platinum containing therapy (subjects with
             NSCLC harboring EGFR/ALK genomic aberrations must have received an FDA-approved
             targeted therapy for these aberrations) OR histologically confirmed HNSCC that has
             relapsed after or is refractory to platinum-containing chemotherapy, OR histologically
             confirmed cHL that has relapsed after three or more lines of therapy or is refractory
             to treatment OR histologically confirmed locally advanced or metastatic urothelial
             carcinoma that is not eligible for platinum-containing chemotherapy or that has
             relapsed after or is refractory to platinum-containing chemotherapy OR MSI-H or dMMR
             unresectable or metastatic cancer that has relapsed after prior treatment and has no
             satisfactory alternative treatment options;

          -  Measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1;

          -  Eastern Cooperative Oncology Group performance status of 0−2;

          -  Life expectancy ≥ 6 months;

          -  Adequate organ function:

        Absolute neutrophil count ≥1,500/mm3, platelets ≥100,000/mm3, hemoglobin ≥9 g/dL
        (transfusion permitted), serum creatinine OR measured or calculated creatinine clearance
        ≤1.5 X upper limit of normal (ULN) OR ≥60 mL/min for subject with creatinine levels > 1.5 X
        institutional ULN, serum total bilirubin ≤ 1.5 X ULN OR direct bilirubin ≤ ULN for subjects
        with total bilirubin levels > 1.5 ULN, alanine transaminase and aspartate transaminase ≤
        2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases, albumin >2.5 mg/dL,
        International normalized ratio or prothrombin time ≤1.5 X ULN, and activated partial
        thromboplastin time ≤1.5 X ULN;

          -  Cardiac ejection fraction of ≥ 45%;

          -  Female subjects of childbearing potential should have a negative serum pregnancy
             (beta-human chorionic gonadotropin) within 7 days prior to receiving the first dose of
             trial treatment and should not be lactating;

          -  Female subjects of childbearing potential must be willing to use an adequate method of
             contraception for the course of the trial through 120 days after the last dose of
             trial treatment;

          -  Male subjects of childbearing potential must be willing to use an adequate method of
             contraception for the course of the trial through 120 days after the last dose of
             trial treatment;

          -  Willing and able to provide written informed consent/assent for the trial.

        Exclusion Criteria:

          -  History of poorly controlled hypertension (defined as systolic blood pressure >150
             mmHg);

          -  History of New York Heart Association class III or greater cardiac disease;

          -  History of myocardial infarction, stroke, ventricular arrhythmia, or symptomatic
             conduction abnormality within the past 12 months;

          -  History of congenital QT prolongation;

          -  Absolute corrected QT interval of >480 milliseconds in the presence of potassium >4.0
             milliequivalent/L and magnesium >1.8 mg/dL;

          -  Currently participating and receiving study therapy or has participated in a study of
             an investigational agent and received study therapy or used an investigational device
             within 4 weeks of the first dose of the trial treatment;

          -  Concurrent use of medications that interact with nitrate/nitrites;

          -  Concurrent use of any complementary or alternative medicines;

          -  Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
             other form of immunosuppressive therapy within 7 days prior to the first dose of trial
             treatment;

          -  Known history of active tuberculosis (Bacillus Tuberculosis);

          -  Hypersensitivity to L-NMMA, pembrolizumab, or any of their excipients;

          -  Has had a prior anticancer monoclonal antibody within 4 weeks prior to study Day 1 or
             who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to
             agents administered more than 4 weeks earlier;

          -  Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
             within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at
             baseline) from adverse events due to a previously administered agent;

          -  Has a known additional malignancy that is progressing or requires active treatment.
             Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
             skin that has undergone potentially curative therapy or in situ cervical cancer.

          -  Has known active central nervous system metastases and/or carcinomatous meningitis.
             Subjects with previously treated brain metastases may participate provided they are
             stable (without evidence of progression by imaging for at least 4 weeks prior to the
             first dose of trial treatment and any neurologic symptoms have returned to baseline),
             have no evidence of new or enlarging brain metastases, and are not using steroids for
             at least 7 days prior to trial treatment. This exception does not include
             carcinomatous meningitis which is excluded regardless of clinical stability;

          -  Has active autoimmune disease that has required systemic treatment in the past 2 years
             (i.e., with use of disease-modifying agents, corticosteroids or immunosuppressive
             drugs);

          -  History of non-infectious pneumonitis that required steroids or current pneumonitis;

          -  Has an active infection requiring systemic therapy;

          -  History or current evidence of any condition, therapy, or laboratory abnormality that
             might confound the results of the trial, interfere with the subject's participation
             for the full duration of the trial, or is not in the best interest of the subject to
             participate, in the opinion of the treating investigator;

          -  Known psychiatric or substance abuse disorders that would interfere with cooperation
             with the requirements of the trial;

          -  Is pregnant or breastfeeding, or expecting to conceive a child within the projected
             duration of the trial, starting with the prescreening or screening visit through 120
             days after the last dose of trial treatment;

          -  Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent;

          -  Known history of human immunodeficiency virus;

          -  Has known active hepatitis B or hepatitis C;

          -  Received a live vaccine within 30 days of planned start of the trial treatment;

          -  Unwilling or unable to comply with the trial protocol.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD)
Time Frame:18 weeks
Safety Issue:
Description:Assess the MTD of L-NMMA in combination with pembrolizumab

Secondary Outcome Measures

Measure:Dose-limiting toxicities (DLTs) and other adverse events
Time Frame:18 weeks
Safety Issue:
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
Safety Issue:
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
Safety Issue:
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
Safety Issue:
Description:Measure plasma concentrations of L-NMMA over time

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Jorge G. Darcourt

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