Nab-paclitaxel and Carboplatin Followed by Response-Based Local Therapy in Treating Patients With Stage III or IV HPV-Related Oropharyngeal Cancer

PRIMARY OBJECTIVES:

I. To determine the 2-year progression-free survival (PFS).

SECONDARY OBJECTIVES:

I. Clinical complete response rate (nab-paclitaxel based induction, compared to European Prospective Investigation into Cancer and Nutrition [EPIC] induction [paclitaxel based]).

II. Response rate (nab-paclitaxel based induction, compared to EPIC induction [paclitaxel based]).

III. Proportion of patients with >= 50% shrinkage by Response Evaluation Criteria In Solid Tumors (RECIST) (nab-paclitaxel based induction, compared to EPIC induction, paclitaxel based).

IV. Toxicity (nab-paclitaxel based induction, compared to EPIC induction [paclitaxel based]).

V. To assess swallowing function and speech at 6 months (mos) and 12 mos post therapy.

VI. To determine the rates of late toxicity with chemoradiation following surgery as determined by xerostomia, dental decay, osteroradionecrosis, G-tube dependency, tracheostomy placement and dysphagia.

VII. 2-year overall survival (OS) in patients treated on the Low-Risk, Intermediate-Risk Arm, and High-Risk Arms.

VIII. 2-year PFS in patients treated on the Low-Risk, Intermediate-Risk Arm, and High-Risk Arms - early and late toxicities.

IX. Evaluate need for post radiotherapy/chemoradiotherapy (RT/CRT) surgery on low- and intermediate-risk arms based on response from induction chemotherapy.

X. Evaluate in a descriptive manner the role of transoral robotic surgery (TORS) resection/lymph node dissection (LND) when integrated into a de-escalation trial.

TERTIARY OBJECTIVES:

I. To evaluate pathologic/histologic appearance of tumor after induction chemotherapy and after CRT.

II. Translational research on blood and tissue samples. III. To profile tumors genetically and immunologically in order to assess in a descriptive manner genetic or immunological features characteristic of clinical behavior.

OUTLINE:

INDUCTION CHEMOTHERAPY: All patients receive paclitaxel albumin-stabilized nanoparticle formulation intravenously (IV) over 60 minutes on days 1, 8, and 15 and carboplatin IV over 30-60 minutes on day 1. Treatment repeats every 21 days for 3 courses in the absence of disease progression or unacceptable toxicity.

Patients are then assigned to 1 of 3 treatment groups based on response to induction chemotherapy.

GROUP A (LOW-DOSE ARM): Patients undergo radiation therapy once daily for 5 weeks.

GROUP B (INTERMEDIATE-DOSE ARM): Patients receive hydroxyurea orally (PO) twice daily (BID) on days 0-5, fluorouracil IV continuously on days 1-5, and paclitaxel IV over 60 minutes on day 1. Patients also receive low-dose radiation therapy BID on days 1-5. Treatment repeats every 14 days for 3 courses in the absence of disease progression or unacceptable toxicity.

GROUP C (STANDARD-DOSE ARM): Patients receive hydroxyurea PO BID on days 0-5, fluorouracil IV continuously on days 1-5, and paclitaxel IV over 60 minutes on day 1. Patients also receive standard-dose radiation therapy BID on days 1-5. Treatment repeats every 14 days for up to 5 courses in the absence of disease progression or unacceptable toxicity.*

*NOTE: At the discretion of the principal investigator (PI), patients may receive cisplatin IV over 1-3 hours every 3 weeks during radiation therapy instead of paclitaxel and undergo daily radiation therapy.

After completion of study treatment, patients are followed up for 30 days, every 3 months for 1 year, every 6 months for 2 years, and then annually for 2 years.

Inclusion criteria

• Patients must have pathologically confirmed HPV-positive squamous cell carcinoma
• HPV testing must follow the following criteria

• HPV testing using an E6/E7 based assay is preferred, and does not require any validation (e.g. HPV in situ hybridization [ISH] or HPV E6/E7 polymerase chain reaction [PCR])
• For oropharyngeal tumors p16 immunohistochemistry (IHC) positivity is sufficient to enroll and initiate treatment (p16 IHC interpretation to follow guidelines by Jordan/Lingen et al 2012); it is recommended that p16 IHC positivity is validated at a later point (during or after treatment) using an E6/E7 based test at the University of Chicago and provided slides will be used
• For non-operative (OP) tumors accurate HPV testing (i.e. ISH, or E6/E7 based testing) is required for enrollment and treatment initiation
• Availability of >= 10 unstained 5 micron slides
• Patients with American Joint Committee on Cancer (AJCC) (7th edition, 2010) nodal stage N2 or N3 or a T4 primary tumor
• The primary and nodal involvement must be assessable on clinical exam (mucosal and lymph node exam)
• The primary and nodal involvement must have been defined bi- or uni-dimensional measurements measurable by RECIST
• No previous radiation or chemotherapy for a head and neck cancer
• No 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 of the tumor is acceptable)
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (Karnofsky >= 70%)
• Leukocytes >= 3000/mm^3
• Platelets >= 100,000/mm^3
• Absolute neutrophil count >= 1,500
• Hemoglobin > 9.0 gm/dL
• Albumin > 2.9 gm/dL
• Total bilirubin =< 1.5 mg/dl
• Creatinine clearance > 45 mL/min (or serum creatinine [SCr] =< 1.5 mg/dL), normal within 2 weeks prior to start of treatment
• The standard Cockcroft and Gault formula or the measured glomerular filtration rate must be used to calculate creatinine clearance (CrCl) for enrollment or dosing
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 X upper limit of normal (ULN)
• Alkaline phosphatase =< 2.5 X ULN
• 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

Exclusion criteria

• Unequivocal demonstration of distant metastases (M1 disease)
• Intercurrent medical illnesses which would impair patient tolerance to therapy or limit survival; including but 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
• Pregnant and nursing women are excluded; men and women of child-bearing potential are eligible but must consent to using effective contraception during therapy and for at least 3 months after completing therapy; women with child-bearing potential must have a negative serum or urine beta-human chorionic gonadotropin (B-hCG) pregnancy test at screening
• Other coexisting malignancies or malignancies diagnosed within the previous 3 years no evidence of disease for at least 3 years; exceptions to this include non-melanoma skin cancer, cervical cancer in situ, well differentiated thyroid cancer or prostate cancer; other cancers that per assessment of the PI are not prognosis limiting can be allowed after review by the PI
• Prior surgical therapy other than incisional or excisional biopsy and organ-sparing procedures such as debulking of airway-compromising tumors or neck dissection in a patient with an unknown primary tumor; residual tumor is required for enrollment on study
• Patients receiving other investigational agents
• Peripheral neuropathy >= grade 1