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

18 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

To characterize the safety and tolerability of nivolumab injected intralesionally in patients with high-risk oral premalignant lesions.

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 nivolumab safe for humans?

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 issues like ulcers and lichen planus (a condition causing white patches in the mouth). It's important to monitor for these effects and manage them with medical guidance. ^{1 2 3 4 5}

How is the drug Nivolumab unique for treating oral precancerous conditions?

Nivolumab is unique because it is an immune checkpoint inhibitor that blocks the PD-1 pathway, helping the immune system to better recognize and attack precancerous cells in the mouth, potentially preventing their progression to cancer. Unlike traditional treatments, it is administered directly into the lesions (intralesional), which may enhance its effectiveness in targeting specific areas. ^{3 6 7 8 9}

What data supports the effectiveness of the drug Nivolumab (Opdivo) for treating oral precancerous conditions?

Nivolumab (Opdivo) has shown effectiveness in treating advanced cancers like non-small cell lung cancer and melanoma by improving survival rates and reducing tumor size. This suggests it may help in other conditions by boosting the immune system to fight abnormal cells. ^{10 11 12 13 14}

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

I haven't had chemotherapy, targeted therapy, or radiation in the last 2 weeks and have recovered from any side effects.

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, 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]

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]

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, 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 (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]

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]

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]

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 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]

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]

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]

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]

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]

Citations

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

Antitumor activity of nivolumab on hemodialysis after renal allograft rejection. [2023]

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

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

3. England pubmed.ncbi.nlm.nih.gov

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

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

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

5. Georgia (Republic) 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)]. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Nivolumab-related lichen planus of the lip in a patient with head and neck cancer. [2021]

7. England 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. [2019]

8. Denmark pubmed.ncbi.nlm.nih.gov

Multicenter retrospective study of nivolumab for recurrent/metastatic oral squamous cell carcinoma. [2023]

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

U.S. FDA Approval Summary: Nivolumab for Treatment of Unresectable or Metastatic Melanoma Following Progression on Ipilimumab. [2023]

10. United States 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. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Contributions of T cell dysfunction to the resistance against anti-PD-1 therapy in oral carcinogenesis. [2022]

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

PD-1 Blockade Prevents the Development and Progression of Carcinogen-Induced Oral Premalignant Lesions. [2020]

13. Switzerland pubmed.ncbi.nlm.nih.gov

Importance of the PD-1/PD-L1 Axis for Malignant Transformation and Risk Assessment of Oral Leukoplakia. [2021]

14. Scotland 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. [2021]