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

A Window Trial of 5-Azacytidine or Nivolumab or Combination Nivolumab Plus 5-Azacytidine in Resectable HPV-Associated Head and Neck Squamous Cell Cancer

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.

Study Overview

• Status: Recruiting
• Conditions: Squamous Cell Carcinoma of Head and Neck
• Intervention / Treatment: Drug: Nivolumab; Drug: Combination 5-azacytidine and nivolumab

Detailed Description

This Phase 2 study is a 3-arm window trial, randomizing patients to pre-operative treatment with nivolumab or the combination of 5-azacytidine and nivolumab. The primary endpoint is immune-related pathologic response, employing the quantitative immune- related pathologic response criteria (irPRC) of Cottrell et al. The main secondary endpoint is augmentation of tumor infiltration of the tumor microenvironment as determined by a quantitative immunofluorescence score (QIF) measuring CD3+ lymphocytes and granzyme B expression. Additional secondary and exploratory endpoints are change in Ki-67, change in caspase activity, change in HPV ctDNA levels, toxicity and hyperprogression, and response according to modified RECIST. Eligible patients are those with T1-3, N0-2, M0 p16-positive squamous cell carcinoma of the oropharynx deemed resectable by a surgical co-investigator. Patients must have normal absolute lymphocyte count, adequate end organ function, and not require full dose anticoagulation. Patients must be capable of providing, and provide, written informed consent. Patients on Arm B will receive nivolumab 240 mg IV at days 1 and 15. Patients on Arm C will receive 5-azacytidine 75 mg/m2 once daily day 1-5 and receive nivolumab 240 mg IV days 2 and 16. On Arm B, surgery is performed during the period of days 16 to 18, and on Arm C during the period of days 17 to 18. The study previously enrolled 5 patients to 5-azacytidine monotherapy, but this arm (Arm A) was discontinued after neoadjuvant PD-1 inhibition entered the standard of care. The trial will enroll 17 patients per arm to nivolumab and to 5-azacytidine/nivolumab combination. The study has an 81.9% power to detect a 33% difference in immune-related pathologic response, according to the criteria of Cottrell, between the combination arm and the nivolumab monotherapy arm.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Carole Ramm; Phone Number: (203) 785-4095; Email: carole.ramm@yale.edu

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06511
      • Recruiting
      • Yale University
      • Principal Investigator: Barbara Burtness, MD
      • Contact: Barbara Burtness, MD; Phone Number: (203) 737-7636; Email: barbara.burtness@yale.edu
      • Contact: Sharon Huie; Email: sharon.huie@yale.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients with resectable squamous cell carcinoma of the oropharynx. Histologic or cytologic confirmation from either a biopsy/aspirate of the oropharyngeal primary lesion and/or a regional lymph node is required.
2. T1-T3, N0-N2, M0 stage by AJCC 8th edition for HPV-initiated oropharynx cancer.
3. Resectability confirmed by a surgical co-investigator; evaluation may include operative endoscopy to discover second primaries and map tumor extent with biopsy
4. In addition to diagnostic biopsies, biopsies in clinic or at the time of operative endoscopy are required to yield primary tumor for research purposes > 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.
5. HPV-association confirmed by institutional p16 testing (CINtec antibody demonstrating strong and diffuse nuclear and cytoplasmic staining in at least 70% of tumor cells).
6. Age > 18 years. 5-azacytidine and nivolumab are tolerated in the elderly and there is no upper age limit for patients with adequate performance status.
7. ECOG performance status 0 or 1.
8. Absolute neutrophil count (ANC) > 1500/microliter, absolute lymphocyte count (ALC) > 1000/microliter, hemoglobin > 9 g/dl, platelets > 100,000/microliter.
9. AST and ALT < 2.5 x upper limit of normal. Bilirubin < 1.5 x upper limit of normal.
10. Albumin > 3.0 g/dl.
11. Creatinine < 1.5 x upper limit of normal.
12. 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.
13. 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

Exclusion Criteria:

1. Medical contraindication to transoral surgery.
2. Full dose anticoagulation.
3. 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.
4. Inability to give informed consent.
5. Prior systemic therapy, radiation, or gross resection for the tumor under study.
6. Women may not be pregnant or breast-feeding.
7. Patients with active autoimmune disease, supraphysiologic systemic corticosteroid use within 7 days, and/or allergies/contraindications to the study drugs are excluded.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm B: Nivolumab; 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; 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.; Other Names: Opdivo
Experimental: Arm C: Combination 5-azacytidine and Nivolumab; 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; 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.; Other Names: Vidaza and Opdivo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Increased response for combination therapy compared with either monotherapy	As assessed by the ir-PRC of Cottrell.	Day 16-18

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Increased activated T cell infiltration in 5-Aza containing arms compared to Nivolumab monotherapy arm	As confirmed by quantitative immunofluorescence for CD3+ cells and granzyme B expression.	Day 16-18
Secondary correlative evidence of anti-tumor response	As captured with tumoral Ki-67 and caspase staining on pre- and post-treatment specimens.	Screening pre-treatment specimen Day - 8 through day -1; post treatment specimen Day 16-18
Occurrence of toxicity	Adverse Events occurrence (Common Toxicity Criteria for Adverse Events), Immune-related adverse events of special interest, and hyperprogression will be captured.	Time of 1st treatment to 30 days post
Secondary correlative evidence of disease control	As measured by the HPV ctDNA with the NavDx assay	baseline; 14-30 days prior to surgery, 30 and 90 days post resection surgery

Collaborators and Investigators

• Sponsor: Barbara Burtness
• Collaborators: National Institute of Dental and Craniofacial Research (NIDCR)
• Investigators: Principal Investigator: Barbara Burtness, MD, Yale University

Publications and helpful links

General Publications

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• Faden DL, Ding F, Lin Y, Zhai S, Kuo F, Chan TA, Morris LG, Ferris RL. APOBEC mutagenesis is tightly linked to the immune landscape and immunotherapy biomarkers in head and neck squamous cell carcinoma. Oral Oncol. 2019 Sep;96:140-147. doi: 10.1016/j.oraloncology.2019.07.020. Epub 2019 Jul 30.
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Study record dates

Study Major Dates

• Study Start (Actual): March 23, 2023
• Primary Completion (Estimated): June 30, 2028
• Study Completion (Estimated): November 30, 2028

Study Registration Dates

• First Submitted: March 29, 2022
• First Submitted That Met QC Criteria: March 29, 2022
• First Posted (Actual): April 7, 2022

Study Record Updates

• Last Update Posted (Actual): June 10, 2026
• Last Update Submitted That Met QC Criteria: June 8, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: HPV- Associated Head and Neck Squamous Cell Cancer
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Head and Neck Neoplasms; Neoplasms, Glandular and Epithelial; Carcinoma; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Amino Acids, Peptides, and Proteins; Proteins; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleic Acids, Nucleotides, and Nucleosides; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Aza Compounds; Nucleosides; Ribonucleosides; Nivolumab; Azacitidine
• Other Study ID Numbers: 2000025632; 1P50DE030707-01 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No