5-Azacytidine and/or Nivolumab in Resectable HPV-Associated HNSCC

NCT05317000 | Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: 20000256321P50DE030707-01
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Squamous Cell Carcinoma of Head and Neck

Keywords

HPV- Associated Head and Neck Squamous Cell Cancer

Outcome Measures

Primary Outcomes (1)

• Increased response for combination therapy compared with either monotherapy

  As assessed by the ir-PRC of Cottrell.

  Day 16-18

Secondary Outcomes (4)

• Increased activated T cell infiltration in 5-Aza containing arms compared to Nivolumab monotherapy arm

  Day 16-18

• Secondary correlative evidence of anti-tumor response

  Screening pre-treatment specimen Day - 8 through day -1; post treatment specimen Day 16-18

• Secondary correlative evidence of disease control

  baseline; 14-30 days prior to surgery, 30 and 90 days post resection surgery

• Occurrence of toxicity

  Time of 1st treatment to 30 days post

Study Arms (3)

Arm A: 5-azacytidine

ACTIVE COMPARATOR

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.

Drug: 5-azacytidine

Arm B: Nivolumab

ACTIVE COMPARATOR

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.

Drug: Nivolumab

Arm C: Combination 5-azacytidine and Nivolumab

EXPERIMENTAL

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.

Drug: Combination 5-azacytidine and nivolumab

Interventions

5-azacytidine DRUG

Chemotherapy is the use of drugs to destroy cancer cells. It usually works by keeping the cancer cells from growing, dividing, and making more cells. Because cancer cells usually grow and divide faster than normal cells, chemotherapy has more of an effect on cancer cells. 5-azacytidine works by slowing down the growth of cancer cells. 5-azacytidine has been demonstrated to improve the cell's ability to make some proteins which signal to the immune system.

Also known as: Vidaza

Arm A: 5-azacytidine

Nivolumab DRUG

Immunotherapy is a type of treatment that uses your body's own immune system to help fight cancer. Specifically, Nivolumab belongs to a class of anti-cancer drugs known as immune checkpoint inhibitors. Cancer cells are able to "turn off" the immune system by increasing the production of a protein called PD-1. Nivolumab can block PD-1 and may be able to re-activate the immune response to kill head and neck cancer cells.

Also known as: Opdivo

Arm B: Nivolumab

Combination 5-azacytidine and nivolumab DRUG

The primary objective of the study is to determine whether exposure to the demethylating agent 5-azacytidine will sensitize HPV-associated oropharynx cancer to nivolumab by induction of interferon response, neoantigen expression, and augmentation of lymphocyte infiltration of the tumor microenvironment.

Also known as: Vidaza and Opdivo

Arm C: Combination 5-azacytidine and Nivolumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with resectable histologically or cytologically confirmed squamous cell carcinoma of the oropharynx.
• T1-T3, N0-N2, M0 stage by AJCC 8th edition for HPV-initiated oropharynx cancer.
• Resectability confirmed by a surgical co-investigator; evaluation may include operative endoscopy to discover second primaries and map tumor extent with biopsy
• In addition to diagnostic biopsies, biopsies in clinic or at the time of operative endoscopy are required to yield primary tumor for research purposes equivalent to or greater than 3mm cup forceps biopsies X 3. Prior biopsies for research obtained with informed consent for the Yale Biosample Repository Protocol are acceptable if they meet the volume requirements above.
• HPV-association confirmed by institutional p16 testing (CINtec antibody demonstrating strong and diffuse nuclear and cytoplasmic staining in at least 70% of tumor cells).
• Age \> or equal to 18 years. 5-azacytidine and nivolumab are tolerated in the elderly and there is no upper age limit for patients with adequate performance status.
• Males and females are eligible.
• ECOG performance status 0 or 1.
• Absolute neutrophil count (ANC) \> or equal to 1500/microliter, absolute lymphocyte count (ALC) \> or equal to 1000/microliter, hemoglobin \> or equal to 9 g/dl, platelets \> or equal to 100,000/microliter.
• AST and ALT \< 2.5 x upper limit of normal. Bilirubin \< 1.5 x upper limit of normal.
• Albumin \> or equal to 3.0 g/dl.
• Creatinine \< or equal to 1.5 x upper limit of normal.
• Women of child-bearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) within 24 hours prior to the start of study treatment. An extension up to 72 hours prior to the start of study treatment is permissible in situations where results cannot be obtained within the standard 24-hour window.
• Willing and able to provide written informed consent. Informed consent is required prior to research-related activities, including biopsy. However, if written informed consent for participation in the biosample repository protocol has been obtained, tissue obtained under that consent can be used to meet eligibility criterion 4.

You may not qualify if:

• Medical contraindication to transoral surgery.
• Full dose anticoagulation.
• Concomitant invasive malignancy, or malignancy within 2 years except for hormonally responsive breast or prostate cancer, resected non-melanoma skin cancer, resected uterine cervical carcinoma or meningioma.
• Inability to give informed consent.
• Prior systemic therapy, radiation, or gross resection for the tumor under study.
• Women may not be pregnant or breast-feeding.
• Patients with active autoimmune disease, supraphysiologic systemic corticosteroid use within 7 days, and/or allergies/contraindications to the study drugs are excluded.

Sponsors & Collaborators

• Barbara Burtness: lead
• National Institute of Dental and Craniofacial Research (NIDCR): collaborator

Study Sites (1)

Yale University

New Haven, Connecticut, 06511, United States

RECRUITING

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MeSH Terms

Conditions

Squamous Cell Carcinoma of Head and Neck

Interventions

Nivolumab; Azacitidine

Condition Hierarchy (Ancestors)

Carcinoma, Squamous Cell; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Head and Neck Neoplasms; Neoplasms by Site

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• Barbara Burtness, MD

  Yale University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Carole Ramm

CONTACT

(203) 785-4095; carole.ramm@yale.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor of Medicine, Medical Oncology

Model Details: This Phase 2 study is a 3-arm window trial, randomizing patients to pre-operative treatment with 5-azacytidine alone, to nivolumab alone, or the combination of 5-azacytidine and nivolumab.

Study Record Dates

• First Submitted: March 29, 2022
• First Posted: April 7, 2022
• Study Start: March 23, 2023
• Primary Completion (Estimated): June 30, 2028
• Study Completion (Estimated): November 30, 2028
• Last Updated: January 12, 2026

Record last verified: 2025-12

Locations

US (1)