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