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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety of two treatments, L-NMMA (an experimental treatment) and pembrolizumab, used together to boost the immune system against various cancers, including melanoma, lung, and cervical cancer. Pembrolizumab aids the immune system in recognizing and attacking cancer cells, while L-NMMA enhances this effect by blocking a chemical that weakens the immune response. Suitable candidates for this trial include those with advanced cancers like melanoma, non-small cell lung cancer, or cervical cancer, particularly if previous treatments have failed. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive this new treatment combination.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that pembrolizumab, a treatment that aids the immune system in fighting cancer, is generally safe. Studies have demonstrated long-term benefits for patients with advanced melanoma, with over one-third living for 10 years after treatment, indicating it is well-tolerated over time.

L-NMMA is currently being tested with other treatments. Research suggests that L-NMMA can enhance the effectiveness of other cancer treatments, potentially boosting the immune system's ability to combat cancer.

This trial is in its early stages and primarily focuses on assessing the safety of using L-NMMA with pembrolizumab. While pembrolizumab has been safely used in other contexts, the safety of L-NMMA remains under study. Participants in early-stage trials like this are closely monitored to identify any side effects and ensure safety. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about L-NMMA combined with pembrolizumab because it introduces a fresh approach to cancer treatment by targeting nitric oxide synthase. This is different from most current treatments that typically focus on directly attacking cancer cells. L-NMMA works by inhibiting nitric oxide production, potentially reducing tumor growth and improving the immune system's ability to fight cancer. When paired with pembrolizumab, a well-known immunotherapy drug, this combination might enhance the body's immune response against cancer more effectively than current standard treatments alone.

What evidence suggests that L-NMMA plus pembrolizumab could be an effective treatment for cancer?

Research shows that pembrolizumab, one of the treatments in this trial, helps the immune system find and attack cancer cells by blocking a signal called PD-1. This signal normally prevents the immune system from attacking cancer. Studies have found that pembrolizumab effectively treats several cancers, such as melanoma and non-small cell lung cancer. L-NMMA, the other treatment in this trial, boosts the immune response by reducing the effects of a substance that can weaken the immune system's attack on cancer cells. Early research suggests that combining L-NMMA with other treatments might strengthen the body's ability to fight cancer. This combination aims to enhance the immune system's ability to destroy cancer cells. ^{2 3 6 7 8}

Who Is on the Research Team?

Jun Zhang, M.D.

Principal Investigator

Houston Methodist Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11685991/

NOS inhibition sensitizes metaplastic breast cancer to PI3K ... These results suggest that L-NMMA augments the effect of PI3K inhibitor in inducing DNA damage in MpBC cells with PIK3CA or PIK3R1 mutations ...

2. science.org science.org/doi/10.1126/scitranslmed.abj5070

A phase 1/2 clinical trial of the nitric oxide synthase ... We report a first-in-class phase 1/2 trial of L-NMMA combined with taxane for treating patients with chemorefractory, locally advanced breast cancer (LABC) or ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03236935?term=AREA%5BConditionSearch%5D(%22Renal%20Cell%20Carcinoma,%20Nonpapillary%22)%20AND%20AREA%5BInterventionSearch%5D(%22Nitric%20Oxide%22)&rank=1

Study Details | Phase Ib of L-NMMA and Pembrolizumab There are three types of violations: Failure to submit required clinical trial information; Submission of false or misleading clinical trial information ...

4. mdpi.com mdpi.com/2072-6694/13/2/288

Role of Bladder Cancer Metabolic Reprogramming in the ... Here, we review UC MR and its impact on immune cells in UC in order to explore research opportunities that may improve immunotherapy.

5. sigma.larvol.com sigma.larvol.com/product.php?e1=3614&tab=newstrac&page=708

Keytruda (pembrolizumab) News Our results suggested that c-MET inhibition promotes perforin expression in CD8 T cells. Therefore, c-MET inhibitors can activate the immune system and may play ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03236935

NCT03236935 | Phase Ib of L-NMMA and Pembrolizumab 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 ...

7. merck.com merck.com/news/ten-year-data-for-mercks-keytruda-pembrolizumab-demonstrates-sustained-overall-survival-benefit-versus-ipilimumab-in-advanced-melanoma/

Ten-Year Data for Merck's KEYTRUDA® (pembrolizumab ... At 10 years, more than one-third (34.0%) of patients with advanced melanoma were alive after treatment with KEYTRUDA, compared to 23.6% of patients treated ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT01295827

NCT01295827 | Study of Pembrolizumab (MK-3475) in ... The study will investigate the safety, tolerability, and efficacy of pembrolizumab (2 mg/kg and 10 mg/kg) in participants with advanced or metastatic MEL.