Non-Small Cell Lung CancerPhase 1NCT03236935
Phase Ib of L-NMMA and Pembrolizumab
A Phase 1 study testing L-NMMA and Pembrolizumab in people with Non-Small Cell Lung Cancer and Malignant Melanoma, run by The Methodist Hospital Research Institute at 1 site in United States.
Trial summary
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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Non-Small Cell Lung Cancer, Malignant Melanoma, Head and Neck Squamous Cell Carcinoma
- What is being tested?
- L-NMMA and Pembrolizumab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 12 participants
- Where
- 1 siteUnited States
- Study dates
- 27 Aug 2018to 22 Apr 2022
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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 histologically confirmed advanced, PD-L1-positive cervical cancer with disease progression on or after chemotherapy that is not eligible for platinum-containing chemotherapy or that has relapsed after or is refractory to platinum-containing chemotherapy OR histologically confirmed recurrent, locally advanced, or metastatic, squamous cell carcinoma of the esophagus (ESCC) whose tumors express PD-L1 (Combined Positive Score [CPS] ≥10), as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.
- OR histologically confirmed recurrent, locally advanced, or metastatic Gastric Cancer, with disease progression on or after two or more systemic therapies, including fluoropyrimidine- and platinum-containing chemotherapy and, if appropriate, HER2/neu-targeted therapy, and whose tumors express programmed death-ligand 1 (PD-L1), as determined by an FDA-approved test.
- OR histologically confirmed hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. recurrent locally advanced or metastatic MCC who had not received prior systemic therapy for their advanced disease OR histologically confirmed recurrent, locally advanced or metastatic Merkel Cell Carcinoma (MCC) who had not received prior systemic therapy for their advanced disease OR histologically confirmed advanced renal cell carcinoma (RCC) first-line treatment.
- OR histologically confirmed metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy.
- OR histologically confirmed refractory primary mediastinal large B-cell lymphoma (PMBCL), who have relapsed after two or more prior lines of therapy.
Show all 18Show fewer
- OR MSI-H or dMMR unresectable or metastatic cancer that has relapsed after prior treatment and has no satisfactory alternative treatment options.
- OR adult patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase (mut/Mb)] solid tumors;
- 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.
Who cannot join
- 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;
Show all 26Show fewer
- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
Houston Methodist Cancer Center
Houston, Texas, 77030
About this study
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
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.
Read the 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, 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.
- Conditions
- Non-Small Cell Lung Cancer, Malignant Melanoma, Head and Neck Squamous Cell Carcinoma, Classical Hodgkin Lymphoma, Urothelial Carcinoma Bladder, DNA Repair-Deficiency Disorders
- Being tested
- L-NMMA, Pembrolizumab
- Medical subject headings
- Carcinoma, Non-Small-Cell Lung, Melanoma, Squamous Cell Carcinoma of Head and Neck, DNA Repair-Deficiency Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
L-NMMADrug
Also called NG-monomethyl-L-arginine
pan-nitric oxide synthase inhibitor
PembrolizumabDrug
Also called Keytruda
PD-1 inhibitor
| Study group | Role | What they receive |
|---|---|---|
| L-NMMA Dose Level -1, 12.5 mg/kg | Experimental | Cohort -1: 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. L-NMMA Dose will be 12.5 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. Receives: Drug: L-NMMA; Drug: Pembrolizumab |
| L-NMMA Dose Level 0 (starting dose), 15.0 mg/kg | Experimental | Cohort 0: 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. L-NMMA Dose will be 15.0 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. Receives: Drug: L-NMMA; Drug: Pembrolizumab |
| L-NMMA Dose Level 1, 20 mg/kg | Experimental | Cohort 1: 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. L-NMMA Dose will be 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. Receives: Drug: L-NMMA; Drug: Pembrolizumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Maximum Tolerated Dose (MTD)
Assess the MTD of L-NMMA in combination with pembrolizumab
Measured: 18 weeks
Secondary outcomes (4)
Dose-limiting Toxicities (DLTs) and Other Adverse Events
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. Patients with any AE is capturing any patient that has had an adverse event on the trial. Patients with grade 3 AE, is capturing the number of patients that were hospitalized due to an adverse event. Patients with grade 4 AE, is capturing the number of patients that experienced a life threataning Adverse event on the trial. Patients with at least 1 DLT is capturing how many patients experienced at least one Dose Limiting Toxicity on the trial. Lower numbers in each row is the better outcome.
Measured: 18 weeks
Recommended Phase 2 Dose (RP2D) of L-NMMA in Combination With Pembrolizumab
Determine the RP2D of L-NMMA in combination with pembrolizumab based on the occurrence of DLTs and MTD determination
Measured: 18 weeks
Antitumor Activity
Assess the antitumor activity of L-NMMA in combination with pembrolizumab, as assessed by the RECIST 1.1
Measured: 18 weeks
Plasma Concentrations of L-NMMA When Combined With Pembrolizumab
Measure plasma concentrations of L-NMMA when combined with pembrolizumab over time
Measured: 18 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Aug 2017
- Study start27 Aug 2018
- Primary completion31 Oct 2021
- Study completion22 Apr 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Non-Small Cell Lung CancerStudies of the same condition, open and under way.
- More trials run by The Methodist Hospital Research InstituteThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Model description
- Dose escalation/Dose de-escalation trial with 3 dose levels
- Masking
- None (open label)
- Enrolment
- 12 participants (actual)
Sponsor and investigators
- Lead sponsor
- The Methodist Hospital Research Institute
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Jun Zhang, The Methodist Hospital Research Institute
- Investigators
- Jun Zhang, M.D., Principal investigator, Houston Methodist Cancer Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03236935
- Sponsor's protocol ID
- Pro00017492
- Status last verified
- Mar 2026
- First submitted
- 28 Jul 2017
- Last updated
- 9 Apr 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 9 Apr 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT03236935
- Acronym / sponsor ID
- Pro00017492
- Conditions
- Non-Small Cell Lung Cancer, Malignant Melanoma, Head and Neck Squamous Cell Carcinoma, Classical Hodgkin Lymphoma, Urothelial Carcinoma Bladder, DNA Repair-Deficiency Disorders
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 12 participants (actual)
- Lead sponsor
- The Methodist Hospital Research InstituteUniversity, hospital or other
- Study start
- 27 Aug 2018 (actual)
- Primary completion
- 31 Oct 2021 (actual)
- Study completion
- 22 Apr 2022 (actual)
- First posted
- 2 Aug 2017 (actual)
- Results
- Posted 9 Apr 2026
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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, 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 3
- Model description
- Dose escalation/Dose de-escalation trial with 3 dose levels
| Arm | Type | Receives |
|---|---|---|
| L-NMMA Dose Level -1, 12.5 mg/kg | Experimental | Drug: L-NMMA, Drug: PembrolizumabCohort -1: 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. L-NMMA Dose will be 12.5 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 Dose Level 0 (starting dose), 15.0 mg/kg | Experimental | Drug: L-NMMA, Drug: PembrolizumabCohort 0: 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. L-NMMA Dose will be 15.0 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 Dose Level 1, 20 mg/kg | Experimental | Drug: L-NMMA, Drug: PembrolizumabCohort 1: 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. L-NMMA Dose will be 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (18 listed)
- 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 histologically confirmed advanced, PD-L1-positive cervical cancer with disease progression on or after chemotherapy that is not eligible for platinum-containing chemotherapy or that has relapsed after or is refractory to platinum-containing chemotherapy OR histologically confirmed recurrent, locally advanced, or metastatic, squamous cell carcinoma of the esophagus (ESCC) whose tumors express PD-L1 (Combined Positive Score [CPS] ≥10), as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.
- OR histologically confirmed recurrent, locally advanced, or metastatic Gastric Cancer, with disease progression on or after two or more systemic therapies, including fluoropyrimidine- and platinum-containing chemotherapy and, if appropriate, HER2/neu-targeted therapy, and whose tumors express programmed death-ligand 1 (PD-L1), as determined by an FDA-approved test.
- OR histologically confirmed hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. recurrent locally advanced or metastatic MCC who had not received prior systemic therapy for their advanced disease OR histologically confirmed recurrent, locally advanced or metastatic Merkel Cell Carcinoma (MCC) who had not received prior systemic therapy for their advanced disease OR histologically confirmed advanced renal cell carcinoma (RCC) first-line treatment.
- OR histologically confirmed metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy.
Key exclusion criteria (26 listed)
- 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;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| L-NMMAAlso: NG-monomethyl-L-argininepan-nitric oxide synthase inhibitor | Drug | L-NMMA Dose Level -1, 12.5 mg/kg, L-NMMA Dose Level 0 (starting dose), 15.0 mg/kg, L-NMMA Dose Level 1, 20 mg/kg |
| PembrolizumabAlso: KeytrudaPD-1 inhibitor | Drug | L-NMMA Dose Level -1, 12.5 mg/kg, L-NMMA Dose Level 0 (starting dose), 15.0 mg/kg, L-NMMA Dose Level 1, 20 mg/kg |
Primary outcome
Maximum Tolerated Dose (MTD)
Time frame: 18 weeks
Assess the MTD of L-NMMA in combination with pembrolizumab
4 secondary outcomes
Dose-limiting Toxicities (DLTs) and Other Adverse Events
Time frame: 18 weeks
Recommended Phase 2 Dose (RP2D) of L-NMMA in Combination With Pembrolizumab
Time frame: 18 weeks
Antitumor Activity
Time frame: 18 weeks
Plasma Concentrations of L-NMMA When Combined With Pembrolizumab
Time frame: 18 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Apr 2026.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Related trials for Non-Small Cell Lung Cancer
RecruitingPhase 1/2
Study of INBRX-106 and INBRX-106 in Combination With Pembrolizumab (Keytruda®) in Subjects With Locally Advanced or Metastatic Solid Tumors (Hexavalent OX40 Agonist)
Solid Tumor, Non-Small Cell Lung Cancer
RecruitingObservational study
A Prospective ,Multicenter ,Non-interventional ,Real-world Study Observing Changes in Molecular Markers Osimertinib Targeted Therapy in EGFRm NSCLC
Non Small Cell Lung Cancer
RecruitingPhase 3
A Study Evaluating Sotorasib Platinum Doublet Combination Versus Pembrolizumab Platinum Doublet Combination as a Front-Line Therapy in Participants With Stage IV or Advanced Stage IIIB/C Nonsquamous Non-Small Cell Lung Cancers (CodeBreaK 202)
Non-Small Cell Lung Cancer (NSCLC)
Active, not recruitingPhase 2
Datopotamab Deruxtecan (Dato-DXd, DS-1062a) in Advanced and/or Unresectable Non-Small Cell Lung Cancer
Metastatic Lung Cancer, Advanced Non Small Cell Lung Cancer
Not yet recruitingPhase 1/2
STAR0602 With Nivolumab in Non Small Cell Lung Cancer and in Metastatic Castrate-Resistant Prostate Cancer, and STAR0602 Alone in Thymic Carcinoma
NSCLC, Non-Small Cell Lung Cancer
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jun Zhang, M.D. principal investigator
Houston Methodist Cancer Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing L-NMMA and Pembrolizumab in people with Non-Small Cell Lung Cancer and Malignant Melanoma, run by The Methodist Hospital Research Institute at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 18 inclusion and 26 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 9 Apr 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 9 Apr 2026). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Maximum Tolerated Dose (MTD) (time frame: 18 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Apr 2026.