Phase Ib of L-NMMA and Pembrolizumab

NCT03236935 | Completed Phase 1 Results FDA Drug

• 1 other identifier: Pro00017492
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief 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, 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.

Conditions

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

Outcome Measures

Primary Outcomes (1)

• Maximum Tolerated Dose (MTD)

  Assess the MTD of L-NMMA in combination with pembrolizumab

  18 weeks

Secondary Outcomes (4)

• Dose-limiting Toxicities (DLTs) and Other Adverse Events

  18 weeks

• Recommended Phase 2 Dose (RP2D) of L-NMMA in Combination With Pembrolizumab

  18 weeks

• Antitumor Activity

  18 weeks

• Plasma Concentrations of L-NMMA When Combined With Pembrolizumab

  18 weeks

Study Arms (3)

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.

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.

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.

Drug: L-NMMA; Drug: Pembrolizumab

Interventions

L-NMMA DRUG

pan-nitric oxide synthase inhibitor

Also known as: NG-monomethyl-L-arginine

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

Pembrolizumab DRUG

PD-1 inhibitor

Also known as: Keytruda

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

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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;

You may not qualify if:

• 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;

Sponsors & Collaborators

• The Methodist Hospital Research Institute: lead

Study Sites (1)

Houston Methodist Cancer Center

Houston, Texas, 77030, United States

Location

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Melanoma; Squamous Cell Carcinoma of Head and Neck; DNA Repair-Deficiency Disorders

Interventions

omega-N-Methylarginine; pembrolizumab

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Skin Diseases; Skin and Connective Tissue Diseases; Carcinoma, Squamous Cell; Carcinoma; Neoplasms, Glandular and Epithelial; Head and Neck Neoplasms; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Arginine; Amino Acids, Basic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Diamino; Amino Acids, Essential

Results Point of Contact

• Title: Ethan Burns, M.D.
• Organization: Houston Methodist Neal Cancer Center

eaburns@houstonmethodist.org

832-544-4231

Study Officials

• Jun Zhang, M.D.

  Houston Methodist Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: Dose escalation/Dose de-escalation trial with 3 dose levels

Study Record Dates

• First Submitted: July 28, 2017
• First Posted: August 2, 2017
• Study Start: August 27, 2018
• Primary Completion: October 31, 2021
• Study Completion: April 22, 2022
• Last Updated: April 9, 2026
• Results First Posted: April 9, 2026

Record last verified: 2026-03

Locations

US (1)