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.
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. The primary endpoint is immune-related pathologic response, employing the quantitative immune-related pathologic response criteria (ir-PRC) of Cottrell et al. The 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. Secondary endpoints are objective response by modified RECIST, change in Ki-67, change in caspase activity, toxicity and hyperprogression. Patients are eligible 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 A receive 5-azacytidine 75mg/m2 IV once daily day 1-5. Patients on Arm B receive nivolumab 240 mg IV days 1 and 15. Patients on Arm C receive 5-azacytidine as described above and receive nivolumab 240 mg IV days 2 and 16. On arms A and 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 will enroll 8 patients to 5-azacytidine monotherapy and 20 patients per arm to nivolumab or 5-azacytidine/nivolumab combination and has an 80% power to detect a significant difference in immune-related pathologic response, according to the criteria of Cottrell, between the combination arm and each of the monotherapy arms considered separately, using a one-sided Fisher's exact test at a significance level of 0.10.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
50
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.
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.
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.
Yale University
New Haven, Connecticut, United States
RECRUITINGIncreased response for combination therapy compared with either monotherapy
As assessed by the ir-PRC of Cottrell.
Time frame: Day 16-18
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.
Time frame: 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.
Time frame: Screening pre-treatment specimen Day - 8 through day -1; post treatment specimen Day 16-18
Secondary correlative evidence of disease control
As measured by the HPV ctDNA with the NavDx assay
Time frame: baseline; 14-30 days prior to surgery, 30 and 90 days post resection surgery
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 frame: Time of 1st treatment to 30 days post
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