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

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

Overview

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.

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.

Interventions

• 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.
• 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.

Primary outcome measures

• Increased response for combination therapy compared with either monotherapy [Time frame: Day 16-18]

Secondary outcome measures (4)

• Increased activated T cell infiltration in 5-Aza containing arms compared to Nivolumab monotherapy arm [Time frame: Day 16-18]
• Secondary correlative evidence of anti-tumor response [Time frame: Screening pre-treatment specimen Day - 8 through day -1; post treatment specimen Day 16-18]
• Secondary correlative evidence of disease control [Time frame: baseline; 14-30 days prior to surgery, 30 and 90 days post resection surgery]
• Occurrence of toxicity [Time frame: Time of 1st treatment to 30 days post]

Eligibility criteria

Inclusion criteria

• 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.
• 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

Exclusion criteria

• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• Yale University — New Haven

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. PMID 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. E PMID 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): PMID 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 metas PMID 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, d PMID 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 PMID 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-Labe PMID 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. PMID 30647454

Identifiers

NCT: NCT05317000 · 2000025632 · 1P50DE030707-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗