5-Azacytidine + Nivolumab for Squamous Cell Carcinoma

Overseen By Carole Ramm

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Barbara Burtness

Must not be taking: Anticoagulants, Corticosteroids

Disqualifiers: Invasive malignancy, Autoimmune disease, 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

Compensation: Varies

Number of Visits: 2

Duration: 2-3 weeks

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of two cancer treatments, 5-azacytidine (a chemotherapy) and nivolumab (an immunotherapy), used alone or together on HPV-associated head and neck cancer. Researchers aim to determine if 5-azacytidine increases the cancer's responsiveness to nivolumab. Individuals with doctor-confirmed squamous cell carcinoma in the throat area who have not received prior treatments for this cancer may qualify for the trial. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group of participants.

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 full-dose anticoagulation or have certain medical conditions, you may not be eligible to participate.

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

Research shows that both 5-azacytidine and nivolumab are generally safe when used separately to treat cancer. The FDA has approved 5-azacytidine for certain types of cancer, and its safety profile is well-documented. Common side effects include nausea and low blood cell counts, which can usually be managed with medication.

Nivolumab is also FDA-approved for various cancers, including head and neck cancer previously treated with chemotherapy. Its safety is well understood. Some individuals may experience fatigue or skin rashes, but these side effects are typically mild and treatable.

Less information exists about using 5-azacytidine and nivolumab together. However, a small study in patients with a type of blood cancer showed that this combination was generally safe. Most side effects resembled those seen when each drug is used alone.

As this trial is in an earlier phase, researchers continue to collect more safety data. However, the approval of both drugs for other conditions provides some reassurance about their safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they bring innovative approaches to tackling squamous cell carcinoma. Unlike the standard treatments, which typically involve surgery, radiation, or chemotherapy, 5-azacytidine works by altering the DNA in cancer cells to stop them from growing. Meanwhile, nivolumab is an immunotherapy drug that enhances the body's immune response against cancer cells. The combination of 5-azacytidine and nivolumab is particularly promising because it may simultaneously disrupt cancer cell growth at a genetic level and boost the immune system's ability to attack these cells. This dual action could offer a more effective treatment option with potentially faster results compared to existing therapies.

What evidence suggests that this trial's treatments could be effective for HPV-associated head and neck cancer?

Research has shown that using 5-azacytidine with nivolumab may help treat HPV-related head and neck cancer. In this trial, participants in Arm C will receive this combination, which previous studies found to be generally well-tolerated and achieved a 78% success rate in reducing cancer, with some patients experiencing significant tumor shrinkage. 5-azacytidine slows cancer cell growth, while nivolumab helps the immune system find and attack cancer cells. Participants in Arm B will receive nivolumab alone, which has also proven effective in treating some head and neck cancers, especially after chemotherapy. Both treatments in this trial aim to boost the body's ability to target and destroy cancer cells. ^{3 4 6 7 8}

Who Is on the Research Team?

Barbara Burtness, MD

Principal Investigator

Yale University

Are You a Good Fit for This Trial?

This trial is for adults with resectable HPV-associated squamous cell carcinoma of the oropharynx, without prior systemic therapy or radiation. Participants must have certain blood counts and organ function levels within normal ranges, not be on full dose anticoagulation, and women must not be pregnant or breastfeeding.

Inclusion Criteria

Willing and able to provide written informed consent

My biopsy samples are large enough for research, matching or exceeding the size of three 3mm biopsies.

I have a type of throat cancer that can be surgically removed.

Exclusion Criteria

I cannot have surgery through the mouth due to health reasons.

I am on a full dose of blood thinner medication.

I am unable to understand and agree to the study's details.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive pre-operative treatment with 5-azacytidine alone, nivolumab alone, or the combination of both drugs

2-3 weeks

Multiple visits for drug administration

Surgery

Surgery is performed to resect the tumor

1 week

In-person surgical visit

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

2 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• 5-azacytidine
• Combination 5-azacytidine and nivolumab
• Nivolumab

Trial Overview The study tests if 5-Azacytidine (a chemotherapy drug) can make head and neck cancer more responsive to Nivolumab (an immunotherapy). Patients will receive either one of these drugs alone or in combination to assess their effectiveness against this type of cancer.

How Is the Trial Designed?

Group I: Arm C: Combination 5-azacytidine and Nivolumab Experimental Treatment 1 Intervention

Patients will receive 5-azacytidine 75mg/m2 IV daily x 5. Treatment must begin on a Monday. 5-azacytidine will be given prior to nivolumab on day 2. Patients will receive anti-emetic premedication with prochlorperazine 10 mg IV, a 5HT3 antagonist per institutional guidelines, aprepitant or fos-aprepitant, and prn lorazepam on day 1. Day 2-5 patients will receive prochlorperazine 10 mg IV. Subsequent day 5HT3 antagonist therapy will be determined per institutional guidelines, as recommendations vary based on the half-life of the agent chosen. PRN lorazepam can be used days 2-5. Nivolumab will be administered at a dose of 240 mg IV day 2 and day 16. No additional premedication will be given on day 16. Dexamethasone will be reserved for patients whose nausea and/or emesis is not controlled by the initial regimen. Surgery will be scheduled in the period of day 17 through day 18.

Group II: Arm A: 5-azacytidine Active Control 1 Intervention

Patients will receive 5-azacytidine 75mg/m2 IV daily x 5. Treatment must begin on a Monday. Patients will receive anti-emetic premedication with prochlorperazine 10 mg IV, a 5HT3 antagonist per institutional guidelines, aprepitant or fos-aprepitant, and prn lorazepam on day 1. Day 2-5 patients will receive prochlorperazine 10 mg IV. Subsequent day 5HT3 antagonist therapy will be determined per institutional guidelines, as recommendations vary based on the half-life of the agent chosen. PRN lorazepam can be used days 2-5. Dexamethasone will be reserved for patients who are not controlled by the initial regimen. A single cycle of 5-azacytidine will be administered and the patient scheduled for surgery in the period of day 16 through day 18.

Group III: Arm B: Nivolumab Active Control 1 Intervention

Nivolumab will be administered at a dose of 240 mg IV day 1 and day 15. Treatment must be given on a Monday or Tuesday. No premedication will be given. Patients will be observed following the initial dose of nivolumab per institutional Surgery will be scheduled in the period of day 16 through day 18.

5-azacytidine is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in European Union as Azacitidine for:

• Myelodysplastic syndromes
• Acute myeloid leukemia
• Chronic myelomonocytic leukemia

Approved in Canada as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Japan as Azacitidine for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Who Is Running the Clinical Trial?

Barbara Burtness

Lead Sponsor

Trials

1

Recruited

50+

National Institute of Dental and Craniofacial Research (NIDCR)

Collaborator

Trials

312

Recruited

853,000+

Published Research Related to This Trial

Combining nivolumab with ipilimumab results in higher response rates in cancer treatment compared to using nivolumab alone, indicating a potentially more effective therapeutic strategy.

This combination therapy may enhance the immune response against cancer, but specific details on the number of subjects or study duration are not provided in the abstract.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus Ipilimumab Achieves Responses in dMMR/MSI-H Tumors. [2019]

In a phase 3 trial involving 361 patients with recurrent squamous-cell carcinoma of the head and neck, nivolumab significantly improved overall survival compared to standard therapy, with a median survival of 7.5 months versus 5.1 months.

Nivolumab also had a better safety profile, with fewer severe treatment-related adverse events (13.1% vs. 35.1% in standard therapy), and patients reported stable quality of life compared to those receiving standard treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. Ferris, RL., Blumenschein, G., Fayette, J., et al.[2022]

In a pooled analysis of 1332 patients with advanced non-small-cell lung cancer (NSCLC), the combination of nivolumab and ipilimumab showed a median overall survival (OS) of 18.6 months and a 3-year OS rate of 35%, indicating significant long-term survival benefits compared to traditional chemotherapy.

The study found that patients who responded to treatment at 6 months had markedly better survival rates, with a 3-year OS of 66% for responders, highlighting the importance of early response in predicting long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term survival with first-line nivolumab plus ipilimumab in patients with advanced non-small-cell lung cancer: a pooled analysis. Borghaei, H., Ciuleanu, TE., Lee, JS., et al.[2023]

Nivolumab treatment resulted in an increased overall survival rate of 7.5 months compared to 5.1 months for the control group, indicating its efficacy in extending life for patients.

Patients receiving nivolumab also reported a better quality of life, suggesting that the treatment not only prolongs survival but also improves the well-being of those undergoing therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab for recurrent squamous-cell carcinoma of the head and neck. [2018]

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]

A 69-year-old man with advanced squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) showed significant tumor regression after treatment with pembrolizumab, an anti-PD1 antibody, indicating its potential efficacy as a second-line therapy.

After 11 courses of pembrolizumab, the patient achieved a complete response for SCC, along with notable regression of BCC and Bowen disease, suggesting that pembrolizumab may be a promising treatment option for advanced skin cancers, although further clinical trials are needed to establish its role in therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Regression of cutaneous basal cell and squamous cell carcinoma under pembrolizumab]. Delaitre, L., Martins-Héricher, J., Truchot, E., et al.[2020]

Cetuximab and nivolumab, two immunotherapy agents, showed significant effectiveness in achieving clinical remission of invasive, poorly differentiated cutaneous squamous cell carcinoma in a patient with challenging tumors in the head and neck region.

This case highlights the potential of combining EGFR and PD-1 inhibitors as a promising treatment strategy for squamous cell carcinomas that are difficult to surgically remove and resistant to traditional therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Remission of Cutaneous Squamous Cell Carcinoma of the Auricle with Cetuximab and Nivolumab. Chen, A., Ali, N., Boasberg, P., et al.[2020]

The combination of mocetinostat (70 mg TIW) and durvalumab was generally well tolerated in patients with advanced non-small cell lung cancer (NSCLC), with an objective response rate (ORR) of 11.5% across all phase II cohorts, indicating some effectiveness in this challenging population.

Notably, the treatment showed a higher ORR of 23.1% in patients whose disease was refractory to prior checkpoint inhibitor therapies, suggesting that mocetinostat may help overcome resistance to existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mocetinostat in Combination With Durvalumab for Patients With Advanced NSCLC: Results From a Phase I/II Study. Johnson, ML., Strauss, J., Patel, MR., et al.[2023]

In the Asian subpopulation with advanced non-small cell lung cancer (NSCLC) and PD-L1 expression ≥1%, patients treated with nivolumab plus ipilimumab showed significantly improved overall survival (OS) and progression-free survival (PFS) compared to those receiving chemotherapy, with a 3-year OS rate of 53% versus 37%.

The safety profile of nivolumab plus ipilimumab was manageable, with grade 3-4 treatment-related adverse events occurring in 40% of patients, similar to the 36% in the chemotherapy group, indicating no new safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line nivolumab + ipilimumab in advanced NSCLC: CheckMate 227 subpopulation analyses in Asian patients. O'Byrne, KJ., Lee, KH., Kim, SW., et al.[2022]

Nivolumab is an effective PD1 immune checkpoint inhibitor used to treat various cancers, including non-small cell lung carcinoma and melanoma.

Despite its efficacy as an immunotherapy, nivolumab is associated with a range of immune-related adverse events, which continue to emerge even years after its introduction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Squamous cell carcinoma or squamous proliferation associated with nivolumab treatment for metastatic melanoma. Vu, M., Chapman, S., Lenz, B., et al.[2022]

Citations

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Evaluating the Addition of Azacitidine to Nivolumab for ... Azacitidine is a chemotherapy drug that works by slowing down the growth of cancer cells. It has been shown to improve the cell's ability to make some proteins ...

4. opdivo.com opdivo.com/head-and-neck-cancer/clinical-trial-results

Clinical trial results for previously treated head and neck ... See how OPDIVO® (nivolumab) performed in clinical trials for certain adults with previously treated squamous cell head and neck cancer (SCCHN).

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A combination of 5-azacytidine and nivolumab is ... Results: This regimen was well-tolerated, especially in elderly patients. The overall response rate was 78%, including four partial responses ( ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05317000

5-Azacytidine and/or Nivolumab in Resectable HPV ... This study is being done because both 5-azacytidine and nivolumab can influence the immune system's response to HPV-associated head and neck cancer, ...

7. yalemedicine.org yalemedicine.org/clinical-trials/a-window-trial-of-5-azacytidine-or-nivolumab-or-combination-nivolumab-plus-5-azacytidine-in-resectab

A Window Trial of 5-Azacytidine or Nivolumab ... This study is being done because both 5-azacytidine and nivolumab can influence the immune system's response to HPV-associated head and neck ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4346216/

Nivolumab in NSCLC: latest evidence and clinical potential This review will discuss results from early phase studies of nivolumab in solid tumors including non-small cell lung cancer (NSCLC)