De-Escalation Therapy for Human Papillomavirus Negative Disease

Study Overview
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Brief Summary
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This study is looking to see if nivolumab, an immunotherapy drug, given with carboplatin and paclitaxel (2 chemotherapy agents) during induction therapy in advanced stage HPV negative patients can significantly shrink the subject's cancer.

Official Title
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A Phase II Trial of Carboplatin, Paclitaxel, and Nivolumab Induction Therapy Followed by Response-stratified Locoregional Therapy for Patients With Locally Advanced, HPV-negative Head and Neck Cancer. The DEPEND Trial.

Conditions
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Human Papilloma Virus, Squamous Cell Carcinoma, Squamous Cell Carcinoma of the Head and Neck, HPV-Related Squamous Cell Carcinoma, HNSCC

Intervention / Treatment
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* Drug: Carboplatin
* Drug: Paclitaxel
* Drug: Nivolumab
* Radiation: Radiation
* Drug: Hydroxyurea Pill
* Drug: 5-fluorouracil
* Drug: Filgrastim Injection
* Drug: Cisplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have pathologically confirmed locally advanced, non-metastatic, HPV-negative head and neck squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, nasopharynx, larynx, or sinuses. Stage IV disease with the exception of nasopharyngeal tumor-3, node-2 (stage III) based of American Joint Committee on Cancer staging 8th edition If a primary oropharyngeal squamous cell carcinoma is diagnosed, HPV must be ruled out by immunohistochemistry. Availability of ≥10 unstained 5 micron slides. Patients who cannot fulfill this requirement will need to undergo a new biopsy prior to enrollment on study. Patients must be at least 18 years of age. Measurable disease (either primary site and/or nodal disease) by RECIST criteria. No previous radiation or chemotherapy for a head and neck cancer. No complete surgical resection for a head and neck cancer within 8 weeks of enrollment (although lymph node biopsy including excision of an individual node with presence of residual nodal disease, or surgical biopsy/excision of the tumor with residual measurable disease is acceptable.) No surgical procedures or biopsies will occur after baseline scans are performed and measurable lesions are identified. Eastern Cooperative Oncology Group performance status 0-1 Normal Organ Function Leukocytes ≥ 3000/mm3 Platelets ≥ 100,000/mm3 Absolute neutrophil count ≥ 1,500 Hemoglobin ≥ 9.0 gm/dL Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤ 2.5x upper limit of normal Alkaline phosphatase ≤ 2.5x upper limit of normal Albumin > 2.9 gm/dL Total bilirubin ≤ 1.5 mg/dL Creatinine clearance > 45 mL/min, normal within 2 weeks prior to start of treatment (Of note, the standard Cockcroft and Gault formula must be used to calculate creatinine clearance (CrCl) for enrollment or dosing) Patients must sign a study-specific informed consent form prior to study entry. Patients should have the ability to understand and the willingness to sign a written informed consent document. Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug Women must not be breastfeeding Women of childbearing potential must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug(s) plus 6 months after completing chemoradiation or receiving the last dose of consolidative nivolumab, whichever occurs latest. Men who are sexually active with women of childbearing potential must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug(s) plus 6 months after completing chemoradiation or receiving the last dose of consolidative nivolumab, whichever occurs latest. Exclusion Criteria: Unequivocal demonstration of distant metastatic disease (M1 disease). Unidentifiable primary site. Inter-current medical illnesses which would impair patient tolerance to therapy or limit survival. This includes but is not limited to ongoing or active infection, immunodeficiency, symptomatic congestive heart failure, pulmonary dysfunction, cardiomyopathy, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance. Patients with clinically stable and/or chronically managed medical illnesses that are not symptomatic and/or are not expected to impact treatment on protocol are still eligible (conditions to be reviewed by the PI to confirm eligibility) Prior surgical therapy other than incisional/excisional biopsy or organ-sparing procedures such as debulking of airway-compromising tumors. Residual measurable tumor is required for enrollment as discussed above. Patients receiving other investigational agents. Diagnosis of immunodeficiency or is receiving systemic steroid therapy in excess of physiologic dose or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. Known history of active tuberculosis (Bacillus Tuberculosis infection). Hypersensitivity to nivolumab or any other drug used in this protocol. Prior systemic anti-cancer treatment within the last 8 weeks. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer or any tumors that are not likely to influence life expectancy in the subsequent 3 years without active treatment. Has active autoimmune disease that has required systemic therapy in the past year (i.e. with steroids or immunosuppressive drugs). Replacement therapy e.g. levothyroxine, insulin, or physiologic corticosteroid doses for adrenal or pituitary insufficiency, etc. are not considered a form of systemic treatment. Has known history of, or any evidence of active, non-infectious pneumonitis. Has a history of HIV. Has known active Hepatitis B or hepatitis C. If eradicated, patient is eligible. Has received a live vaccine within 28 days of planned start of study therapy.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ARM 1<br>Induction Therapy | Drug: Carboplatin<br>* Carboplatin will be given through IV infusions for 30-60 minutes on day 1 of each cycle. Each cycle will last 21 days. There will be 3 cycles.<br>Drug: Paclitaxel<br>* During Induction Therapy Paclitaxel (100 mg) will be given through IV infusions on days 1, 8 and 15 of each 21 day cycle. There will be 3 cycles. During Radiotherapy, paclitaxel will be given after a dose of radiation by IV infusion for 60 minutes after day 1 of radiotherapy.<br>Drug: Nivolumab<br>* Nivolumab will be given through IV infusions at 360 mg on day 1 every 21 days for 3 cycles.<br>|
| Experimental: ARM 2<br>Radiation therapy with chemotherapy | Drug: Paclitaxel<br>* During Induction Therapy Paclitaxel (100 mg) will be given through IV infusions on days 1, 8 and 15 of each 21 day cycle. There will be 3 cycles. During Radiotherapy, paclitaxel will be given after a dose of radiation by IV infusion for 60 minutes after day 1 of radiotherapy.<br>Radiation: Radiation<br>* Patients will receive 4.5-5 cycles of radiation depending on response. Those with a positive response will receive radiation for 4.5 cycles with a total radiation dose of 66 Gy. Patients with a moderate or no response will receive 5 cycles with a total radiation dose of 70-75 Gy. 2 times a day for days 1-5 followed by a rest period for days 6-13<br>Drug: Hydroxyurea Pill<br>* One dose of hydroxyurea pill by mouth at start of 5-FU infusion during radiotherapy cycle<br>Drug: 5-fluorouracil<br>* 5-FU will be given by IV infusion continuously for 5 days during radiotherapy cycles<br>* Other names: 5-FU;Drug: Filgrastim Injection<br>* Filgrastim shot will be given if patient has certain side effects during radiotherapy cycle on days 6-12.<br>* Other names: Filgrastim shot;Drug: Cisplatin<br>* Radiotherapy may also be given with a different chemotherapy agent called cisplatin. This is the traditional standard of care chemotherapy regimen. In this case, the radiotherapy will be given once daily for 5 days per week. Cisplatin will be administered via IV once every 21 days for 2 or 3 cycles.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Deep Response Rate (DRR) | DRR is 50% or greater response to induction therapy based on RECIST criteria. The objective is to intensify induction chemotherapy with the addition of an immune checkpoint inhibitor aimed at increasing the proportion of patients achieving a deep tumor response in order to subsequently allow risk-adapted definitive chemoradiotherapy in advanced stage HPV negative head and neck squamous cell cancer patients. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival rate (PFS) | Progression free survival at 24 months after completing chemoradiation. PFS will be defined as the time from registration to the date of the first documented disease progression, clinical progression, or death due to any cause, whichever occurs first. | 24 months | 
| Overall Survival rate (OS) | Overall survival will be defined as the time between the date of registration and the date of death. | 24 months | 
| Locoregional control after completing chemoradiation | assess disease control in all patients receiving induction chemoimmunotherapy and compare disease control between radiation arms. | 24 months | 
| Distant control after completing chemoradiation | Distant control will be defined as the time from registration to the date of the first documented disease progression below the clavicles. Comparison between the two radiation arms will be made. | 24 months |