Intralesional Nivolumab for Precancerous Conditions

Overseen By Moran Amit, MD, PHD

Age: 18+

Sex: Any

Trial Phase: Phase 2

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)

Prior Safety Data This treatment has passed at least one previous human trial

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: 12 weeks

45 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a treatment called nivolumab, delivered through injections directly into the lesion, to determine if it can prevent oral precancerous conditions from becoming cancerous. Researchers aim to discover if this method can halt or slow the progression of these risky oral spots. Individuals with a biopsy-confirmed precancerous lesion inside their mouth who have not yet received treatment might be suitable for this trial. Participants will be randomly assigned to receive either nivolumab or a placebo to compare results. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to significant advancements in oral cancer prevention.

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 currently receiving any study therapy with potential anti-cancer activity or have had recent chemotherapy, targeted therapy, or radiation therapy, you may not be eligible to participate.

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

Research has shown that nivolumab has been tested for safety in large groups of patients. In previous studies, common side effects included rash, tiredness, and diarrhea, affecting more than 20% of patients. While some side effects are common, they are usually manageable.

Nivolumab is already approved for other conditions, providing some confidence in its overall safety. However, this trial involves injecting it directly into a lesion, which might have different effects. One study specifically examined this method for high-risk oral premalignant lesions. The main goal was to assess its safety and tolerability, focusing on how well patients handle the treatment.

Overall, while side effects can occur, existing data suggest that nivolumab is generally well-tolerated. Always consult a healthcare provider to determine if joining a trial is the right choice. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for precancerous conditions, which often involve surgical removal or topical therapies, Nivolumab offers a novel approach by harnessing the body's immune system. Nivolumab is an immune checkpoint inhibitor that works by blocking the PD-1 pathway, which can sometimes prevent the immune system from attacking cancerous or precancerous cells effectively. This targeted mechanism allows the immune system to recognize and destroy abnormal cells more efficiently, offering the potential for a less invasive and more precise treatment option. Researchers are excited about Nivolumab because it could provide a new, effective strategy for managing precancerous conditions without the need for more aggressive interventions.

What evidence suggests that intralesional nivolumab could be an effective treatment for high-risk oral premalignant lesions?

Research has shown that nivolumab, which participants in this trial may receive, may help treat high-risk oral precancerous lesions. One study found that 36% of patients experienced significant improvement, with some improving by more than 80%. Additionally, 78% of patients remained cancer-free for two years, a crucial outcome given the high risk of these lesions becoming cancerous. Nivolumab helps the immune system identify and attack abnormal cells, potentially preventing cancer development. These findings suggest that nivolumab could effectively lower the risk of these oral lesions turning into cancer. ^{6 7 8 9 10}

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 individuals with high-risk oral premalignant lesions, which are early signs that may lead to cancer. Specific eligibility criteria details are not provided.

Inclusion Criteria

1. Presence of a treatment naïve, biopsy proven, intraoral premalignant lesion visible from oral cavity.

2. Be willing and able to provide written informed consent for the trial. In the event that non-English speaking participants are eligible for this study, a short form (if applicable) or an ICD in their language, will be utilized and completed in accordance with the MDACC "Policy For Consenting Non-English Speaking Participants."

4. Be willing to provide tissue, either archive or from a newly obtained oral biopsy.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive intralesional injections of nivolumab or placebo for high-risk oral premalignant lesions

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

What Are the Treatments Tested in This Trial?

Interventions

• Nivolumab

Trial Overview The study tests the effectiveness of nivolumab, an immunotherapy drug, administered directly into the lesion in the mouth to see if it can prevent these early signs from developing into cancer.

How Is the Trial Designed?

Group I: Nivolumab/Placebo Experimental Treatment 1 Intervention

Participants will be screened for LOH and randomly assigned to trial

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 (Opdivo) significantly improves overall survival and response rates in previously-treated patients with advanced nonsquamous non-small cell lung cancer (NSCLC) compared to docetaxel, as shown in the CheckMate 057 trial.

Nivolumab has a manageable adverse event profile and is better tolerated than docetaxel, making it a valuable treatment option for patients who have progressed after chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab: A Review in Advanced Nonsquamous Non-Small Cell Lung Cancer. Keating, GM.[2018]

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]

Certain benign breast lesions, such as atypical ductal hyperplasia and lobular carcinoma in situ, have significant premalignant potential and can evolve into invasive breast cancer over time.

Advancements in molecular genetics are helping researchers understand the diverse genetic mechanisms behind breast cancer development, which may lead to targeted prevention strategies for premalignant lesions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Premalignant and in situ breast disease: biology and clinical implications. Arpino, G., Laucirica, R., Elledge, RM.[2019]

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]

The study demonstrated that intralesional injections of the PD-1 inhibitor pembrolizumab are safe and well-tolerated in patients with high-risk ductal carcinoma in situ (DCIS), with significant increases in total and CD8+ T cell populations observed after treatment.

Despite the robust immune response, there was no significant change in tumor volume or evidence of cell death, indicating that while pembrolizumab can enhance T cell activity, additional strategies may be necessary to improve anti-tumor effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modulation of the immune microenvironment of high-risk ductal carcinoma in situ by intralesional pembrolizumab injection. Glencer, AC., Wong, JM., Hylton, NM., et al.[2023]

In a study of 14,419 women treated for ductal carcinoma in situ (DCIS) in the Netherlands, those who underwent breast-conserving surgery (BCS) alone had a higher risk of developing ipsilateral invasive breast cancer (iIBC) compared to those who received BCS plus radiotherapy (RT), with a cumulative incidence of 7.1% versus 3.1% after 10 years.

The risk of iIBC remained significantly elevated in the BCS alone group for at least 10 years post-treatment, indicating that adding radiotherapy after BCS may provide a protective effect against the development of invasive cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effects of contemporary treatment of DCIS on the risk of developing an ipsilateral invasive Breast cancer (iIBC) in the Dutch population. Alaeikhanehshir, S., Schmitz, RSJM., van den Belt-Dusebout, AW., 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, 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, a PD-1 inhibitor, has demonstrated significant safety and efficacy in treating various advanced solid tumors, including melanoma and lung cancer, based on multiple high-level studies.

Future research should aim to identify predictive biomarkers for treatment response and explore the potential of combining nivolumab with other therapies, as well as determining the best treatment strategies and duration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An update on the pharmacodynamics, pharmacokinetics, safety and clinical efficacy of nivolumab in the treatment of solid cancers. Wong, AC., Ma, B.[2018]

In situ breast cancer is being diagnosed more frequently due to better screening methods, but treatment options remain controversial, especially regarding the balance between effective therapy and preserving breast appearance.

Ongoing studies like the NSABP B-17 trial aim to clarify the best treatment approaches for ductal and lobular carcinoma in situ, helping oncologists make informed decisions that consider patient preferences and risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vexed surgeons, perplexed patients, and breast cancers which may not be cancer. Ketcham, AS., Moffat, FL.[2019]

In a study of 73 BRCA1/2-associated breast cancers compared to 146 sporadic cases, 59% of BRCA1/2 tumors had preinvasive lesions, indicating that these cancers can develop through similar pathways as sporadic cancers.

The most common preinvasive lesion found was ductal carcinoma in situ (DCIS), which was present in 56% of BRCA1/2-associated cancers, suggesting that DCIS should be recognized as part of the tumor spectrum for BRCA1/2 mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High prevalence of preinvasive lesions adjacent to BRCA1/2-associated breast cancers. Arun, B., Vogel, KJ., Lopez, A., et al.[2021]

Citations

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Nivolumab for Patients With High-Risk Oral Leukoplakia Twelve patients (36%) (95% CI, 20.4%-54.8%) demonstrated a best overall response of MR or PR, with 3 (9%) demonstrating a greater than 80% ...

2. targetedonc.com targetedonc.com/view/nivolumab-reduces-transformation-of-precancerous-leukoplakia-to-oral-cancer

Nivolumab Reduces Transformation of Precancerous ... There was a 78% rate of cancer-free survival at 2 years, which is encouraging given the high risk of PL transforming into cancer. Hanna says ...

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Shifting the paradigm for resectable NSCLC - Opdivo View efficacy information for OPDIVO® (nivolumab) in previously treated metastatic non-small cell lung cancer. Please see Indications and Important Safety ...

4. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK603612/

Clinical Review - Nivolumab (Opdivo) - NCBI Bookshelf - NIH Survival is typically less than 1 year; among responding patients, few live beyond 15 months to 18 months. There is an unmet need for more effective therapies ...

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Clinical Trial Results Select your cancer type above to see how OPDIVO, alone or in combination with other therapies, performed in clinical trials.

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Safety Information | OPDIVO® (nivolumab) In Checkmate 274, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=351) were rash (36%), fatigue (36%), diarrhea (30%), ...

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2022/125554s112lbl.pdf

OPDIVO (nivolumab) injection Label - accessdata.fda.gov The data in WARNINGS AND PRECAUTIONS reflect exposure to OPDIVO as a single agent in. 1994 patients enrolled in CHECKMATE-037, CHECKMATE-017, CHECKMATE-057 ...

8. accc-cancer.org accc-cancer.org/docs/mediaroom/mediaroom/pdf/opdivo-bms-fact-sheet-3-5-15

Product Fact Sheet for OPDIVO® (nivolumab) Metastatic Squamous Non-Small Cell Lung Cancer. The safety of OPDIVO was evaluated in Trial 3, a single-arm multinational, multicenter trial in 117 patients ...

9. ec.europa.eu ec.europa.eu/health/documents/community-register/2015/20150619132099/anx_132099_en.pdf

OPDIVO, INN-nivolumab Description of selected adverse reactions. Data for the following immune-related adverse reactions are based on patients who received nivolumab 3 mg/kg in two ...

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