Carboplatin, Paclitaxel, and Nivolumab Induction Therapy followed by Chemoradiation for the Treatment of Locally Advanced, HPV Negative Head and Neck Cancer, DEPEND Trial
This trial studies how well carboplatin, paclitaxel, and nivolumab induction therapy works followed by chemoradiation for the treatment of human papillomavirus (HPV) negative head and neck cancer that has spread to nearby tissue or lymph nodes (locally advanced). Drugs used in chemotherapy, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving carboplatin, paclitaxel, and nivolumab as induction therapy may shrink the cancer and reduce the total amount of radiation needed during treatment.
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 T3N2 (stage III) based of American Joint Committee on Cancer (AJCC) 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 (to be provided to human tissue resource center [HTRC] at the University of Chicago). Patients who cannot fulfill this requirement will need to undergo a new biopsy prior to enrollment on study
- Measurable disease (either primary site and/or nodal disease) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 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 (ECOG) performance status 0-1
- Leukocytes >= 3000/mm^3
- Platelets >= 100,000/mm^3
- 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 human chorionic gonadotropin [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 5 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 7 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
- Intercurrent 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 principal investigator [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 human immunodeficiency virus (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
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT03944915.
PRIMARY OBJECTIVE:
I. 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.
SECONDARY OBJECTIVES:
I. Assess survival outcomes in all patients receiving induction chemoimmunotherapy and compare survival between radiation arms.
II. Assess disease control in all patients receiving induction chemoimmunotherapy and compare disease control between radiation arms.
EXPLORATORY OBJECTIVES:
I. Assess long-term/late toxicities including enteral tube dependence in all patients receiving induction chemoimmunotherapy.
II. Assess acute and long-term toxicity in patients who received risk-adapted chemoradiotherapy after deep response to induction chemoimmunotherapy.
III. Evaluate quality of life in patients who receive dose-reduced chemoradiotherapy after a deep response to induction therapy.
IV. Interrogate and understand the immune micro-environment at baseline and 2-3 weeks into induction therapy with extensive immunohistological and serum biomarkers.
OUTLINE:
INDUCTION: Patients receive carboplatin intravenously (IV) over 30-60 minutes on day 1, paclitaxel IV on days 1, 8 and 15 and nivolumab IV over 30-60 minutes on day 1. Treatment repeats every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity.
Patients are assigned to 1 of 2 arms depending on the extent of response.
ARM I: Patients receive cisplatin IV over 3-4 hours on days 1 or 2, 22 or 23 and 43 or 44 then undergo radiation therapy (RT) once daily (QD) for 5 days per week in the absence of disease progression or unacceptable toxicity.
ARM II: Patients receive hydroxyurea orally (PO) on days 1-5 and fluorouracil IV via continuous infusion on days 1-5. Beginning day 2, they also undergo RT twice daily (BID) on days 2-5 and receive paclitaxel IV over 60 minutes. Patients may receive filgrastim subcutaneously (SC) daily on days 6-12. Treatment repeats every 14 days for up to 4.5-5 cycles (completion of RT) in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for 1 year, every 6 months for 2 years, hen annually for 2 years.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationUniversity of Chicago Comprehensive Cancer Center
Principal InvestigatorEverett E. Vokes
- Primary IDIRB19-0162
- Secondary IDsNCI-2020-00015
- ClinicalTrials.gov IDNCT03944915