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

Barbara Burtness

Status and phase: Enrolling; Early Phase 1

Conditions: Squamous Cell Carcinoma of Head and Neck

Treatments: Drug: Nivolumab; Drug: 5-azacytidine; Drug: Combination 5-azacytidine and nivolumab

Study type: Interventional

Funder types: Other

Identifiers

NCT05317000

2000025632

Details and patient eligibility

About

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.

Full description

This Phase 0 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.

Enrollment: 50 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Patients with resectable histologically or cytologically confirmed squamous cell carcinoma of the oropharynx.
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 equivalent to or greater than 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. Males and females are eligible.
8. ECOG performance status 0 or 1.
9. Absolute neutrophil count (ANC) > 1500/microliter, absolute lymphocyte count (ALC) > 1000/microliter, hemoglobin > 9 g/dl, platelets > 100,000/microliter.
10. AST and ALT < 2.5 x upper limit of normal. Bilirubin < 1.5 x upper limit of normal.
11. Albumin > 3.0 g/dl.
12. Creatinine < 1.5 x upper limit of normal.
13. 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.
14. Willing and able to provide written informed consent.

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

---

50 participants in 3 patient groups

Arm A: 5-azacytidine

Active Comparator group

Description:

Patients will receive 5-azacytidine 75mg/m2 IV daily x 5. Treatment must begin on a Monday. 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. Dexamethasone will be reserved for patients who are not controlled by the initial regimen. A single cycle of 5-azacytidine will be administered and the patient scheduled for surgery in the period of day 16 through day 18.

Treatment:

Drug: 5-azacytidine

Arm B: Nivolumab

Active Comparator group

Description:

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.

Treatment:

Drug: Nivolumab

Arm C: Combination 5-azacytidine and Nivolumab

Experimental group

Description:

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.

Treatment:

Drug: Combination 5-azacytidine and nivolumab