5-Azacytidine + Nivolumab for Squamous Cell Carcinoma

Overseen by Barbara Burtness, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Barbara Burtness

Must not be taking: Anticoagulants, Corticosteroids

Disqualifiers: Invasive malignancy, Autoimmune disease, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

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, and we wish to evaluate whether taking 5-azacytidine will make HPV-associated head and neck cancer more sensitive to treatment with nivolumab. 5-Azacytidine (5-AZA) is a chemotherapy, and nivolumab is an immunotherapy. Both drugs are approved for use in the US by the Food and Drug Administration (FDA) for use in the treatment of different types of cancer, and nivolumab is approved for use in head and neck cancer that has previously been treated with chemotherapy. Because they are not approved to be used together in HPV-associated head and neck cancer, these drugs are considered experimental in this study. For this study, the drugs will be used either together or separately.

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.

What data supports the effectiveness of the drug combination 5-azacytidine and nivolumab for squamous cell carcinoma?

Nivolumab has been shown to improve survival and quality of life in patients with recurrent squamous-cell carcinoma of the head and neck, and it has also been effective in treating advanced squamous non-small cell lung cancer. This suggests that nivolumab may be beneficial in treating squamous cell carcinoma when combined with other drugs like 5-azacytidine. ^{1 2 3 4 5}

Is the combination of 5-Azacytidine and Nivolumab safe for humans?

Nivolumab, used in various cancer treatments, has a manageable safety profile, though it can cause immune-related side effects. While specific safety data for the combination with 5-Azacytidine is not provided, Nivolumab alone has been generally well-tolerated in studies for other cancers. ^{3 4 6 7 8}

How is the drug combination of 5-azacytidine and nivolumab unique for treating squamous cell carcinoma?

The combination of 5-azacytidine and nivolumab is unique because it combines a drug that modifies DNA (5-azacytidine) with an immune system booster (nivolumab), potentially offering a new approach for squamous cell carcinoma, especially when other treatments have limited options or high side effects. ^{1 3 7 9 10}

Research Team

Barbara Burtness, MD

Principal Investigator

Yale University

Eligibility Criteria

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.

Trial Timeline

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)

Treatment Details

Interventions

• 5-azacytidine (Chemotherapy)
• Combination 5-azacytidine and nivolumab (Chemotherapy; Checkpoint Inhibitor)
• Nivolumab (Checkpoint Inhibitor)

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.

Participant Groups

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 Canada, Japan for the following indications:

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+

Janice S. Lee

National Institute of Dental and Craniofacial Research (NIDCR)

Clinical Director

DDS, MD, MS

Jennifer Webster-Cyriaque

National Institute of Dental and Craniofacial Research (NIDCR)

Acting Director

DDS, PhD

Findings from Research

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]

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]

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 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]

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]

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]

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]

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]

References

1. England 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. [2023]

2. England pubmed.ncbi.nlm.nih.gov

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

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

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

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

Mocetinostat in Combination With Durvalumab for Patients With Advanced NSCLC: Results From a Phase I/II Study. [2023]

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

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

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

First-line nivolumab + ipilimumab in advanced NSCLC: CheckMate 227 subpopulation analyses in Asian patients. [2022]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Clinical Remission of Cutaneous Squamous Cell Carcinoma of the Auricle with Cetuximab and Nivolumab. [2020]

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

Squamous cell carcinoma or squamous proliferation associated with nivolumab treatment for metastatic melanoma. [2022]

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

Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. [2022]

10. France pubmed.ncbi.nlm.nih.gov

[Regression of cutaneous basal cell and squamous cell carcinoma under pembrolizumab]. [2020]