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

Plain English Summary

Phase Ib of L-NMMA and Pembrolizumab is a Phase 1 clinical trial sponsored by The Methodist Hospital Research Institute studying Non-Small Cell Lung Cancer, Malignant Melanoma, Head and Neck Squamous Cell Carcinoma, Classical Hodgkin Lymphoma, Urothelial Carcinoma Bladder, DNA Repair-Deficiency Disorders. This trial tests a combination of two drugs, L-NMMA and Pembrolizumab, to see if they are safe and effective in treating various advanced cancers. It is for adult patients with specific types of advanced melanoma, lung cancer, head and neck cancer, lymphoma, bladder cancer, cervical cancer, esophageal cancer, gastric cancer, liver cancer, Merkel cell carcinoma, or kidney cancer. Participation involves receiving the study drugs and regular medical check-ups to monitor for side effects and treatment response. Alternative treatments may include standard chemotherapy, radiation therapy, or other targeted therapies depending on the specific cancer type and stage. The trial aims to enroll 12 participants.

Official 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.

Who Can Participate

Here is what you need to know about eligibility for this trial. Adults aged 18 and older with specific types of advanced or metastatic cancers that have not responded to or have relapsed after previous treatments. Patients must have measurable disease and be able to perform daily activities with some assistance (ECOG performance status 0-2). Individuals with poorly controlled high blood pressure or certain heart conditions may not be eligible. Adequate organ function (kidney, liver, blood counts) is required. This trial is studying Non-Small Cell Lung Cancer, Malignant Melanoma, Head and Neck Squamous Cell Carcinoma, Classical Hodgkin Lymphoma, Urothelial Carcinoma Bladder, DNA Repair-Deficiency Disorders, so participants generally need a confirmed diagnosis.

What They're Measuring

The primary outcome measures the maximum dose of L-NMMA that can be safely given with Pembrolizumab over 18 weeks, helping to determine the safest and potentially most effective dose for future studie The specific primary outcome measures are: Maximum Tolerated Dose (MTD) (18 weeks). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 1, the first major stage of clinical testing. Phase 1 trials typically involve 20-100 participants and focus on safety, dosage levels, and side effects. The primary goal is not to test whether the treatment works but to establish that it is safe enough for further testing. About 70% of Phase 1 drugs advance to Phase 2. If successful, the treatment will proceed to Phase 2 efficacy testing.

Why This Trial Matters

This trial explores a novel combination therapy aimed at enhancing the immune system's ability to fight cancer, potentially filling a gap for patients with advanced cancers who have limited treatment This research targets Non-Small Cell Lung Cancer, Malignant Melanoma, Head and Neck Squamous Cell Carcinoma, Classical Hodgkin Lymphoma, Urothelial Carcinoma Bladder, DNA Repair-Deficiency Disorders, where improved treatment options are needed.

Investor Insight

This Phase Ib trial investigates a combination therapy for multiple solid tumors, indicating a broad potential market if successful, though early-stage trials have a high failure rate. Phase 1 trials have approximately a 10% chance of eventually gaining FDA approval.

Is This Trial Right for Me?

Ask your doctor about the specific risks and benefits of L-NMMA and Pembrolizumab for your type of cancer. Understand how the study drugs will be administered and what side effects you might experience. Be prepared for regular clinic visits for assessments, blood tests, and drug infusions. The trial is being conducted at 1 site. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: NON_RANDOMIZED
• Model: SEQUENTIAL
• Masking: NONE
• Enrollment: 12 participants

Interventions

• DRUG: L-NMMA — pan-nitric oxide synthase inhibitor
• DRUG: Pembrolizumab — PD-1 inhibitor

Primary Outcomes

• Maximum Tolerated Dose (MTD) (18 weeks)

Secondary Outcomes

• 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)

Full 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 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;
* 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 c

Trial Locations

• Houston Methodist Cancer Center, Houston, Texas, United States

Frequently Asked Questions

Related Conditions

• 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

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