Intralesional Nivolumab for Oral Precancerous Conditions

Overseen By Moran Amit, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Antineoplastics, Monoclonal antibodies

Disqualifiers: Active TB, Active infection, Others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 6-8 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety of a drug called nivolumab, injected directly into oral precancerous lesions (spots that could turn into cancer). It targets individuals with untreated, biopsy-confirmed lesions inside their mouths. Participants must be willing to provide an oral tissue sample. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative treatment.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are on any anti-cancer treatments or have recently received certain therapies, you may need to wait before starting the trial. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that nivolumab, a drug under study for oral precancerous conditions, is generally safe. In earlier studies, some participants experienced side effects like skin reactions and diarrhea, and a few had mouth problems. Despite these side effects, nivolumab demonstrated potential benefits, such as reducing pre-cancerous spots in many patients. While some risks exist, the treatment could be promising for those with high-risk oral conditions. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Most treatments for oral precancerous conditions involve surgical removal or laser therapy to eliminate lesions. However, Nivolumab offers a unique approach by being directly injected into the oral lesion. This method allows the drug to potentially activate the body's immune system right at the site, targeting the abnormal cells more precisely. Researchers are excited because Nivolumab harnesses the power of immunotherapy, which may lead to more effective and possibly less invasive treatment options compared to traditional methods.

What evidence suggests that nivolumab might be an effective treatment for oral precancerous conditions?

Research has shown that injecting nivolumab directly into lesions may help treat oral conditions that could become cancerous. In this trial, participants will receive nivolumab as an injection directly into an oral lesion. Studies have found that people generally tolerate it well, and it appears effective in these conditions. Nivolumab has already been used successfully in other cancers, such as advanced lung cancer and melanoma, where it helped people live longer and shrink tumors. This success suggests it might also be effective for high-risk oral lesions. Overall, early evidence indicates that nivolumab could be a helpful option for these oral conditions. ^{2 6 7 8 9}

Who Is on the Research Team?

Moran Amit, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with high-risk oral premalignant lesions that haven't been treated yet. Participants must be able to consent, have an ECOG performance status of 0-2, and show proper organ function. Women who can bear children need a negative pregnancy test and agree to use birth control; men also need to commit to contraception.

Inclusion Criteria

Willing and able to provide written informed consent for the trial

I can take care of myself and perform daily activities.

My organs are functioning well.

Exclusion Criteria

I have or had lung inflammation not caused by an infection.

Pregnant or breastfeeding or expecting to conceive or father children within the projected duration of treatment with pembrolizumab, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment

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

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Nivolumab is injected directly into high-risk oral premalignant lesions to assess safety and tolerability

6-8 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Nivolumab

Trial Overview The study tests the safety of Nivolumab when injected directly into the lesion in the mouth. It's open-label, meaning everyone knows they're getting Nivolumab, and it's not randomized so there are no comparison groups.

How Is the Trial Designed?

Group I: Nivolumab Experimental Treatment 1 Intervention

Nivolumab will be given as an injection directly into an oral lesion.

Nivolumab is already approved in United States, European Union, Canada, Switzerland for the following indications:

Approved in United States as Opdivo for:

• Advanced or metastatic gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma
• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Esophageal squamous cell carcinoma

Approved in European Union as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Canada as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Switzerland as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Published Research Related to This Trial

Nivolumab, a monoclonal antibody targeting the programmed death receptor-1, has shown promising efficacy in treating advanced malignant melanoma, with nearly 25% of patients achieving a partial tumor response in a phase II trial involving previously treated stage III/IV patients.

The treatment demonstrated a durable clinical benefit, with a median progression-free survival of 172 days and an acceptable safety profile, as less than 18% of patients experienced severe adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab: a review of its use in patients with malignant melanoma. Deeks, ED.[2021]

Nivolumab, an antibody used to treat advanced non-small cell lung cancer, can lead to serious immune-related adverse effects, including persistent oral ulcerative and lichenoid lesions, which may not respond to standard treatments like topical corticosteroids.

In this case, the oral lesions were associated with nivolumab-induced adrenal insufficiency, and discontinuing the treatment resulted in healing of the oral lesions and remission of adrenal insufficiency, highlighting the importance of monitoring for these rare but significant side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Severe oral ulcerative and lichenoid lesions associated with adrenal insufficiency in a patient treated with nivolumab: Report of a case and review of literature. Gobbi, MF., Eduardo, FP., Bezinelli, LM., et al.[2022]

Nivolumab, an immune checkpoint inhibitor, significantly improves overall survival and progression-free survival in patients with advanced stage squamous cell non-small cell lung cancer (NSCLC) compared to docetaxel, as shown in the CHECKMATE 017 study.

The safety and tolerability of nivolumab are favorable, and interestingly, the expression of the PD-L1 ligand does not predict treatment outcomes, suggesting that other factors may influence the effectiveness of this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab in the treatment of metastatic squamous non-small cell lung cancer: a review of the evidence. Lim, JS., Soo, RA.[2018]

Nivolumab (Opdivo) monotherapy led to complete regression of local recurrence and multiple lung metastases in a patient with recurrent skin melanoma and a positive BRAF mutation, demonstrating its efficacy as a treatment option.

After 5 courses of nivolumab, the patient experienced significant improvement in her condition, achieving an ECOG performance status of 0, indicating a return to an active lifestyle without pain, and normal serum LDH levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[EVALUATION OF THE EFFICASY OF THE DRUG OPDIVO (NIVOLUMAB) IN A PATIENT DIAGNOSED WITH UNRESECTABLE SKIN MELANOMA, POSITIVE BRAF MUTATION AND DISEASE DISSEMINATION (CASE REPORT)]. Samsonia, M., Kandelaki, M., Gibradze, O., et al.[2021]

Anti-PD-1 antibodies, like nivolumab, are effective treatments for advanced melanoma and non-small-cell lung cancer, but they can cause immune-related adverse events (irAE), including oral lichenoid reactions that result in painful ulcers in the mouth.

In two reported cases, nivolumab treatment led to significant oral ulcers, but with early recognition and management using corticosteroids, treatment could be resumed without recurrence, highlighting the importance of monitoring and addressing side effects to maintain patient quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral lichenoid reaction showing multiple ulcers associated with anti-programmed death cell receptor-1 treatment: A report of two cases and published work review. Obara, K., Masuzawa, M., Amoh, Y.[2019]

Nivolumab demonstrated efficacy in treating recurrent/metastatic oral squamous cell carcinoma, with an overall response rate of 27.3% and a disease control rate of 46.2% among 143 patients studied.

The treatment was generally well tolerated, with only 8 patients experiencing grade ≥3 immune-related adverse events, indicating a favorable safety profile for this immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter retrospective study of nivolumab for recurrent/metastatic oral squamous cell carcinoma. Yamakawa, N., Umeda, M., Yoshii, Y., et al.[2023]

Immune checkpoint inhibitors (ICI), particularly nivolumab, are being investigated as a promising treatment option for patients with locally-advanced oral squamous cell carcinoma, aiming to improve outcomes without sacrificing long-term quality of life.

The NICO trial is specifically focusing on the use of neoadjuvant and adjuvant ICI in the management of resectable locally-advanced oral cavity cancers, highlighting the potential for these therapies to enhance treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NICO Phase II clinical trial - focus on an emerging immunotherapy strategy for the adjuvant treatment of locally-advanced oral cancers. Brooker, RC., Schache, AG., Sacco, JJ.[2021]

Immune checkpoint inhibitors, like nivolumab, are effective in cancer treatment by blocking immune suppression signals, but they can cause various side effects, including dermatologic issues.

This case highlights a rare instance of oral lichen planus developing in a patient treated with nivolumab, emphasizing the need for awareness of unusual oral reactions to these therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab-related lichen planus of the lip in a patient with head and neck cancer. Economopoulou, P., Nicolatou-Galitis, O., Kotsantis, I., et al.[2021]

Nivolumab (OPDIVO) received accelerated FDA approval for treating unresectable or metastatic melanoma based on a 31.7% objective response rate in a study of 120 patients, showing promising efficacy after prior treatments.

The treatment demonstrated durable responses, with 87% of responding patients maintaining their response for at least 6 months, although it carries risks of immune-mediated adverse reactions that were monitored in a safety assessment of 268 patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

U.S. FDA Approval Summary: Nivolumab for Treatment of Unresectable or Metastatic Melanoma Following Progression on Ipilimumab. Hazarika, M., Chuk, MK., Theoret, MR., et al.[2023]

Nivolumab, an anti-PD-1 antibody, was administered to a 63-year-old female patient with metastatic melanoma after renal transplantation, highlighting the potential for anti-tumor activity in high-risk patients, despite the challenges of concurrent immunosuppression.

The patient experienced acute renal allograft rejection and renal failure shortly after starting nivolumab, indicating significant risks associated with this treatment in transplant recipients, but she later showed a positive clinical response after re-challenging with nivolumab while on hemodialysis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor activity of nivolumab on hemodialysis after renal allograft rejection. Ong, M., Ibrahim, AM., Bourassa-Blanchette, S., et al.[2023]

In a mouse model of oral carcinogenesis, treatment with anti-PD-1 antibodies significantly reduced the development of oral premalignant lesions and prevented their progression to cancer, suggesting a potential preventive strategy against oral squamous cell carcinoma (OSCC).

The anti-PD-1 treatment enhanced T-cell activity in the tumor microenvironment, indicated by increased recruitment of CD8+ and CD4+ T cells, and promoted apoptosis in the epithelial cells of lesions, highlighting the mechanism by which PD-1 blockade exerts its immunopreventive effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PD-1 Blockade Prevents the Development and Progression of Carcinogen-Induced Oral Premalignant Lesions. Wang, J., Xie, T., Wang, B., et al.[2020]

Nivolumab, an immune checkpoint inhibitor, significantly improved overall survival and progression-free survival compared to docetaxel in patients with advanced squamous non-small cell lung cancer (NSCLC) in the CheckMate 017 trial.

Nivolumab was better tolerated than docetaxel, with manageable adverse effects, making it a promising treatment option for patients who have already undergone chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab: a review in advanced squamous non-small cell lung cancer. Keating, GM.[2022]

In a mouse model of oral cancer, resistance to anti-PD-1 therapy was linked to reduced T cell infiltration and function in the tumor microenvironment, highlighting the importance of T cell activity in treatment efficacy.

The study identified an increase in regulatory T cells (Tregs) and the immunosuppressive molecule TIM-3 as key factors contributing to resistance against anti-PD-1 therapy, suggesting potential new targets for enhancing immunotherapy effectiveness in early tumor development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Contributions of T cell dysfunction to the resistance against anti-PD-1 therapy in oral carcinogenesis. Wen, L., Lu, H., Li, Q., et al.[2022]

Increased levels of PD-1 and PD-L1 were found in oral leukoplakia (OLP) that underwent malignant transformation, suggesting these markers could indicate a higher risk of cancer progression.

The study indicates that elevated PD-L1 levels may create an immunosuppressive environment that allows tumors to evade the immune system, highlighting the potential for checkpoint inhibitors as a therapeutic strategy in high-risk precancerous lesions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Importance of the PD-1/PD-L1 Axis for Malignant Transformation and Risk Assessment of Oral Leukoplakia. Ries, J., Agaimy, A., Wehrhan, F., et al.[2021]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.6016

Intralesional nivolumab in oral potentially malignant ... Conclusions: Intralesional nivolumab is well tolerated in OPMD with suggested potential biological and clinical activity. A randomized phase II ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06561087

Controlled Study of Intralesional Nivolumab for High-risk ... Study Overview. Brief Summary. To evaluate the antitumor efficacy of intralesional injections of nivolumab in patients with high-risk oral premalignant lesions.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12244976/

Phase I Trial to Evaluate the Safety of Intralesional ... Intralesional nivolumab is safe and well-tolerated in men living with or without HIV who have limited cutaneous KS.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT05327270

NCT05327270 | Non-randomized, Open-label Study of ... To characterize the safety and tolerability of nivolumab injected intralesionally in patients with high-risk oral premalignant lesions. Detailed Description.

5. withpower.com withpower.com/trial/intralesional-nivolumab-for-precancerous-conditions-c6bb7

Intralesional Nivolumab for Precancerous Conditions Nivolumab has shown effectiveness in treating advanced lung cancer and melanoma by improving survival rates and tumor response. This suggests it may have ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10654930/

Nivolumab for Patients With High-Risk Oral Leukoplakia Nivolumab showed potential clinical activity in this immune checkpoint therapy trial for high-risk oral precancerous disease; future trials ...

7. annalsofoncology.org annalsofoncology.org/article/S0923-7534(22)02625-4/fulltext

650O A phase II study of nivolumab for high-risk oral ... Nivolumab yielded a best response of PL regression among 37% of pts with a favorable overall CFS. This is the first study to demonstrate evidence of efficacy ...

8. withpower.com withpower.com/trial/early-phase-1-head-and-neck-cancer-8-2022-70d4d

Intralesional Nivolumab for Oral Precancerous Conditions Nivolumab, also known as Opdivo, is generally safe for humans but can cause side effects. Some people have experienced skin reactions, diarrhea, and rare oral ...

9. hsdm.harvard.edu hsdm.harvard.edu/news/researchers-explore-immune-checkpoint-therapy-treat-aggressive-form-oral-cancer

Researchers explore immune checkpoint therapy to treat ... Their study, Nivolumab for Patients With High-Risk Oral Leukoplakia published in JAMA Oncology, followed the treatment of 33 patients with high- ...