L-NMMA + Pembrolizumab for Cancer

Overseen By Jorge Darcourt, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Jorge G. Darcourt

Must not be taking: Steroids, Immunosuppressants, Nitrates, others

Disqualifiers: Hypertension, Cardiac disease, Autoimmune, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 5

Duration: 18 weeks

12 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but you cannot use medications that interact with nitrate/nitrites or any complementary or alternative medicines. It's best to discuss your current medications with the trial team.

What makes the drug L-NMMA + Pembrolizumab unique for cancer treatment?

The combination of L-NMMA and Pembrolizumab is unique because it pairs a nitric oxide synthase inhibitor (L-NMMA) with an immune checkpoint inhibitor (Pembrolizumab), potentially enhancing the immune system's ability to fight cancer by blocking pathways that tumors use to evade immune detection. ^{1 2 3 4 5}

Research Team

Jun Zhang, M.D.

Principal Investigator

Houston Methodist Cancer Center

Eligibility Criteria

Adults with certain advanced cancers (like melanoma, lung cancer, and others) who have specific health criteria like a good heart function and life expectancy of at least 6 months. They should not be pregnant or breastfeeding and must agree to use contraception. People with HIV, recent vaccines, active infections like TB or hepatitis B/C, autoimmune diseases needing treatment in the last 2 years, or those on immunosuppressants can't join.

Inclusion Criteria

Your heart pumps blood effectively, with a measurement of at least 45%.

You are expected to live for at least 6 more months.

Adequate organ function

Exclusion Criteria

You have a known history of HIV.

You have a condition where your heart takes longer than normal to recharge between beats.

You are taking medications that can interact with nitrates or nitrites.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive L-NMMA and pembrolizumab for 6 cycles, with each cycle lasting 21 days. L-NMMA is administered as a 2-hour IV infusion on Days 1-5, and pembrolizumab is administered on Day 5.

18 weeks

5 visits per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of plasma concentrations and adverse events.

4 weeks

Extension

Participants without disease progression after 6 cycles may continue pembrolizumab until disease progression or unacceptable adverse events.

Until disease progression

Treatment Details

Interventions

• L-NMMA
• Pembrolizumab

Trial Overview The trial is testing L-NMMA combined with Pembrolizumab for various advanced cancers. L-NMMA inhibits nitric oxide synthase which may enhance immune response against cancer cells. Pembrolizumab blocks PD-1 signals that let cancer hide from the immune system.

Participant Groups

Group I: L-NMMA Plus Pembrolizumab Experimental Treatment 2 Interventions

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.

Who Is Running the Clinical Trial?

Jorge G. Darcourt

Lead Sponsor

Trials

1

Recruited

10+

The Methodist Hospital Research Institute

Lead Sponsor

Trials

299

Recruited

82,500+

Findings from Research

Pembrolizumab (Keytruda) was approved by the FDA for treating metastatic non-small cell lung cancer (mNSCLC) in patients with tumors expressing PD-L1, showing significant improvements in overall survival (OS) and progression-free survival (PFS) in two major clinical trials with thousands of participants.

In the KEYNOTE-024 trial, pembrolizumab demonstrated a 40% reduction in the risk of death compared to chemotherapy, while in the KEYNOTE-010 trial, it also showed a significant survival advantage over chemotherapy in patients who had previously progressed on treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for Treatment of Metastatic Non-Small Cell Lung Cancer: First-Line Therapy and Beyond. Pai-Scherf, L., Blumenthal, GM., Li, H., et al.[2022]

In a phase II trial involving 15 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant treatment with pembrolizumab showed a major pathologic response in 27% of patients, indicating promising antitumor activity before surgery.

The treatment was found to be feasible and safe, with only 33% of patients experiencing moderate adverse events, and no postoperative mortality, suggesting that pembrolizumab does not compromise surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Eichhorn, F., Klotz, LV., Kriegsmann, M., et al.[2022]

Pembrolizumab (Keytruda) effectively blocks the PD-1 pathway, enhancing T-cell activity against tumors, which supports its role in promoting tumor regression and immune rejection.

Preclinical studies in cynomolgus monkeys showed that pembrolizumab has a favorable safety profile with no significant toxicological findings, aligning with its demonstrated safety and efficacy in human clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biophysical and Immunological Characterization and In Vivo Pharmacokinetics and Toxicology in Nonhuman Primates of the Anti-PD-1 Antibody Pembrolizumab. Hutchins, B., Starling, GC., McCoy, MA., et al.[2021]

Pembrolizumab (Keytruda) is the first anti-PD-1 therapy approved in the US for treating advanced malignant melanoma, specifically for patients who have progressed after prior treatments.

It is designed to target the PD-1 protein, enhancing the immune system's ability to fight cancer, and is currently under review for approval in the EU.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab: first global approval. Poole, RM.[2021]

Pembrolizumab (Keytruda) is approved for treating advanced endometrial carcinoma that is microsatellite instability-high or mismatch repair deficient, specifically for patients whose disease has progressed after previous treatments.

This approval is significant for patients who are not candidates for curative surgery or radiation, providing a new therapeutic option for a challenging stage of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Approved Use for Keytruda. Aschenbrenner, DS.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for Treatment of Metastatic Non-Small Cell Lung Cancer: First-Line Therapy and Beyond. [2022]

2. Ireland pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Biophysical and Immunological Characterization and In Vivo Pharmacokinetics and Toxicology in Nonhuman Primates of the Anti-PD-1 Antibody Pembrolizumab. [2021]

4. New Zealand pubmed.ncbi.nlm.nih.gov

Pembrolizumab: first global approval. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

New Approved Use for Keytruda. [2022]