Squamous Cell Carcinoma of Head and Neck
Conditions
Keywords
HPV- Associated Head and Neck Squamous Cell Cancer
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.
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
DRUGCombination 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.
DRUGNivolumab
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.
Sponsors
Barbara Burtness
National Institute of Dental and Craniofacial Research (NIDCR)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Increased response for combination therapy compared with either monotherapy | Day 16-18 | As assessed by the ir-PRC of Cottrell. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Increased activated T cell infiltration in 5-Aza containing arms compared to Nivolumab monotherapy arm | Day 16-18 | As confirmed by quantitative immunofluorescence for CD3+ cells and granzyme B expression. |
| Secondary correlative evidence of anti-tumor response | Screening pre-treatment specimen Day - 8 through day -1; post treatment specimen Day 16-18 | As captured with tumoral Ki-67 and caspase staining on pre- and post-treatment specimens. |
| Secondary correlative evidence of disease control | baseline; 14-30 days prior to surgery, 30 and 90 days post resection surgery | As measured by the HPV ctDNA with the NavDx assay |
| Occurrence of toxicity | Time of 1st treatment to 30 days post | Adverse Events occurrence (Common Toxicity Criteria for Adverse Events), Immune-related adverse events of special interest, and hyperprogression will be captured. |
Countries
United States
Contacts
CONTACTCarole Ramm
PRINCIPAL_INVESTIGATORBarbara Burtness, MD
Yale University
Outcome results
None listed