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Squamous Cell Carcinoma of Head and NeckPhase 2NCT05317000

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

A Phase 2 study testing Combination 5-azacytidine and nivolumab and Nivolumab in people with Squamous Cell Carcinoma of Head and Neck, run by Barbara Burtness at 1 site in United States.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Squamous Cell Carcinoma of Head and Neck
What is being tested?
Combination 5-azacytidine and nivolumab and Nivolumab
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
50 participants
Where
1 siteUnited States
Study dates
23 Mar 2023to 30 Nov 2028
Phase
Phase 2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
  • 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 > 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 > 18 years. 5-azacytidine and nivolumab are tolerated in the elderly and there is no upper age limit for patients with adequate performance status.
Show all 13Show fewer
  • ECOG performance status 0 or 1.
  • Absolute neutrophil count (ANC) > 1500/microliter, absolute lymphocyte count (ALC) > 1000/microliter, hemoglobin > 9 g/dl, platelets > 100,000/microliter.
  • AST and ALT < 2.5 x upper limit of normal. Bilirubin < 1.5 x upper limit of normal.
  • Albumin > 3.0 g/dl.
  • Creatinine < 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

Who cannot join

  • 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.

Trial locations and contacts

1 site in 1 country. Contact the study team or a site near you to ask about taking part.

Carole Ramm contact

(203) 785-4095

carole.ramm@yale.edu

United States1 site, 1 recruiting

  • Yale University

    New Haven, Connecticut, 06511

    Sharon Huie, sharon.huie@yale.edu

    Barbara Burtness, MD, (203) 737-7636, barbara.burtness@yale.edu

    Recruiting

Other trials in United States

About this study

Official title: 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.

Read the 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.

Being tested
Combination 5-azacytidine and nivolumab, Nivolumab
Keywords
HPV- Associated Head and Neck Squamous Cell Cancer
Medical subject headings
Squamous Cell Carcinoma of Head and Neck

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Combination 5-azacytidine and nivolumabDrug

    Also called Vidaza and Opdivo

    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.

  • NivolumabDrug

    Also called Opdivo

    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.

Study groups in NCT05317000
Study groupRoleWhat they receive
Arm B: NivolumabActive comparatorNivolumab 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.
Receives: Drug: Nivolumab
Arm C: Combination 5-azacytidine and NivolumabExperimentalPatients 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.
Receives: Drug: Combination 5-azacytidine and nivolumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Increased response for combination therapy compared with either monotherapy

    As assessed by the ir-PRC of Cottrell.

    Measured: Day 16-18

Secondary outcomes (4)

  1. 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.

    Measured: Day 16-18

  2. Secondary correlative evidence of anti-tumor response

    As captured with tumoral Ki-67 and caspase staining on pre- and post-treatment specimens.

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

  3. Secondary correlative evidence of disease control

    As measured by the HPV ctDNA with the NavDx assay

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

  4. Occurrence of toxicity

    Adverse Events occurrence (Common Toxicity Criteria for Adverse Events), Immune-related adverse events of special interest, and hyperprogression will be captured.

    Measured: Time of 1st treatment to 30 days post

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted7 Apr 2022
  2. Study start23 Mar 2023
  3. Primary completion30 Jun 2028 (estimated)
  4. Study completion30 Nov 2028 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
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.
Masking
None (open label)
Enrolment
50 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05317000
Sponsor's protocol ID
2000025632
Other IDs
1P50DE030707-01
Status last verified
Jun 2026
First submitted
29 Mar 2022
Last updated
10 Jun 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tan PF, Westra WH, Chung CH, Jordan RC, Lu C, Kim H, Axelrod R, Silverman CC, Redmond KP, Gillison ML. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010 Jul 1;363(1):24-35. doi: 10.1056/NEJMoa0912217. Epub 2010 Jun 7.

    PubMed 20530316

  • Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, Harrington K, Kasper S, Vokes EE, Even C, Worden F, Saba NF, Iglesias Docampo LC, Haddad R, Rordorf T, Kiyota N, Tahara M, Monga M, Lynch M, Geese WJ, Kopit J, Shaw JW, Gillison ML. Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med. 2016 Nov 10;375(19):1856-1867. doi: 10.1056/NEJMoa1602252. Epub 2016 Oct 8.

    PubMed 27718784

  • Cohen EEW, Soulieres D, Le Tourneau C, Dinis J, Licitra L, Ahn MJ, Soria A, Machiels JP, Mach N, Mehra R, Burtness B, Zhang P, Cheng J, Swaby RF, Harrington KJ; KEYNOTE-040 investigators. Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet. 2019 Jan 12;393(10167):156-167. doi: 10.1016/S0140-6736(18)31999-8. Epub 2018 Nov 30.

    PubMed 30509740

  • Burtness B, Harrington KJ, Greil R, Soulieres D, Tahara M, de Castro G Jr, Psyrri A, Baste N, Neupane P, Bratland A, Fuereder T, Hughes BGM, Mesia R, Ngamphaiboon N, Rordorf T, Wan Ishak WZ, Hong RL, Gonzalez Mendoza R, Roy A, Zhang Y, Gumuscu B, Cheng JD, Jin F, Rischin D; KEYNOTE-048 Investigators. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet. 2019 Nov 23;394(10212):1915-1928. doi: 10.1016/S0140-6736(19)32591-7. Epub 2019 Nov 1.

    PubMed 31679945

  • Vos JL, Elbers JBW, Krijgsman O, Traets JJH, Qiao X, van der Leun AM, Lubeck Y, Seignette IM, Smit LA, Willems SM, van den Brekel MWM, Dirven R, Baris Karakullukcu M, Karssemakers L, Klop WMC, Lohuis PJFM, Schreuder WH, Smeele LE, van der Velden LA, Bing Tan I, Onderwater S, Jasperse B, Vogel WV, Al-Mamgani A, Keijser A, van der Noort V, Broeks A, Hooijberg E, Peeper DS, Schumacher TN, Blank CU, de Boer JP, Haanen JBAG, Zuur CL. Neoadjuvant immunotherapy with nivolumab and ipilimumab induces major pathological responses in patients with head and neck squamous cell carcinoma. Nat Commun. 2021 Dec 22;12(1):7348. doi: 10.1038/s41467-021-26472-9.

    PubMed 34937871

  • Uppaluri R, Campbell KM, Egloff AM, Zolkind P, Skidmore ZL, Nussenbaum B, Paniello RC, Rich JT, Jackson R, Pipkorn P, Michel LS, Ley J, Oppelt P, Dunn GP, Barnell EK, Spies NC, Lin T, Li T, Mulder DT, Hanna Y, Cirlan I, Pugh TJ, Mudianto T, Riley R, Zhou L, Jo VY, Stachler MD, Hanna GJ, Kass J, Haddad R, Schoenfeld JD, Gjini E, Lako A, Thorstad W, Gay HA, Daly M, Rodig SJ, Hagemann IS, Kallogjeri D, Piccirillo JF, Chernock RD, Griffith M, Griffith OL, Adkins DR. Neoadjuvant and Adjuvant Pembrolizumab in Resectable Locally Advanced, Human Papillomavirus-Unrelated Head and Neck Cancer: A Multicenter, Phase II Trial. Clin Cancer Res. 2020 Oct 1;26(19):5140-5152. doi: 10.1158/1078-0432.CCR-20-1695. Epub 2020 Jul 14.

    PubMed 32665297

  • Schoenfeld JD, Hanna GJ, Jo VY, Rawal B, Chen YH, Catalano PS, Lako A, Ciantra Z, Weirather JL, Criscitiello S, Luoma A, Chau N, Lorch J, Kass JI, Annino D, Goguen L, Desai A, Ross B, Shah HJ, Jacene HA, Margalit DN, Tishler RB, Wucherpfennig KW, Rodig SJ, Uppaluri R, Haddad RI. Neoadjuvant Nivolumab or Nivolumab Plus Ipilimumab in Untreated Oral Cavity Squamous Cell Carcinoma: A Phase 2 Open-Label Randomized Clinical Trial. JAMA Oncol. 2020 Oct 1;6(10):1563-1570. doi: 10.1001/jamaoncol.2020.2955.

    PubMed 32852531

  • Cannataro VL, Gaffney SG, Sasaki T, Issaeva N, Grewal NKS, Grandis JR, Yarbrough WG, Burtness B, Anderson KS, Townsend JP. APOBEC-induced mutations and their cancer effect size in head and neck squamous cell carcinoma. Oncogene. 2019 May;38(18):3475-3487. doi: 10.1038/s41388-018-0657-6. Epub 2019 Jan 15.

    PubMed 30647454

  • Hajek M, Sewell A, Kaech S, Burtness B, Yarbrough WG, Issaeva N. TRAF3/CYLD mutations identify a distinct subset of human papillomavirus-associated head and neck squamous cell carcinoma. Cancer. 2017 May 15;123(10):1778-1790. doi: 10.1002/cncr.30570. Epub 2017 Mar 13.

    PubMed 28295222

  • Cancer Genome Atlas Network. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 2015 Jan 29;517(7536):576-82. doi: 10.1038/nature14129.

    PubMed 25631445

  • Biktasova A, Hajek M, Sewell A, Gary C, Bellinger G, Deshpande HA, Bhatia A, Burtness B, Judson B, Mehra S, Yarbrough WG, Issaeva N. Demethylation Therapy as a Targeted Treatment for Human Papillomavirus-Associated Head and Neck Cancer. Clin Cancer Res. 2017 Dec 1;23(23):7276-7287. doi: 10.1158/1078-0432.CCR-17-1438. Epub 2017 Sep 15.

    PubMed 28916527

  • 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.

    PubMed 31422205

  • Cristescu R, Mogg R, Ayers M, Albright A, Murphy E, Yearley J, Sher X, Liu XQ, Lu H, Nebozhyn M, Zhang C, Lunceford JK, Joe A, Cheng J, Webber AL, Ibrahim N, Plimack ER, Ott PA, Seiwert TY, Ribas A, McClanahan TK, Tomassini JE, Loboda A, Kaufman D. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science. 2018 Oct 12;362(6411):eaar3593. doi: 10.1126/science.aar3593.

    PubMed 30309915

  • Glimelius B, Lahn M. Window-of-opportunity trials to evaluate clinical activity of new molecular entities in oncology. Ann Oncol. 2011 Aug;22(8):1717-25. doi: 10.1093/annonc/mdq622. Epub 2011 Jan 13.

    PubMed 21239400

  • Zandberg DP, Ferris RL. Window Studies in Squamous Cell Carcinoma of the Head and Neck: Values and Limits. Curr Treat Options Oncol. 2018 Oct 27;19(12):68. doi: 10.1007/s11864-018-0587-0.

    PubMed 30367283

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Combination 5-azacytidine and nivolumab and Nivolumab in people with Squamous Cell Carcinoma of Head and Neck, run by Barbara Burtness at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 13 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 10 Jun 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Carole Ramm ((203) 785-4095, carole.ramm@yale.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Increased response for combination therapy compared with either monotherapy (time frame: Day 16-18). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05317000, which also lists 19 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Jun 2026.

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