Chemotherapy and Locoregional Therapy Trial (Surgery or Radiation) for Patients With Head and Neck Cancer

A phase II trial in human papillomavirus (HPV)-positive oropharyngeal squamous cell cancer
(as determined by p16 immunohistochemistry with confirmatory ISH or PCR) to determine
radiologic response to induction chemotherapy with nivolumab. Patients will undergo
evaluation by a multidisciplinary team prior to risk assessment. The patients will be
assigned to high or low risk groups based on tumor size, lymph node involvement, and smoking
history. Patients will be assigned to treatment with induction chemotherapy with carboplatin,
nab-paclitaxel, and nivolumab. Radiologic response to induction chemotherapy according to
RECIST measurement of tumor shrinkage will then be used for therapeutic stratification of
locoregional therapy, consisting of either transoral robotic surgery (TORS) or radiation with
or without chemotherapy. Patients with low risk disease (see table above) and small volume
tonsillar/BOT disease (T1-2 primary, non-bulky N2A-N2B nodal status) who have ≥50% reduction
by RECIST following induction chemotherapy will undergo TORS for primary site resection and
selective nodal dissection as a definitive treatment if technically feasible with adjuvant
radiation for adverse pathologic features. Patients with other low risk tumors e.g. with
higher volume disease, or who refuse surgery, who also have ≥50% reduction by RECIST
following induction chemotherapy will be given de-intensified treatment with radiation alone
to 50 Gy (no chemotherapy). Patients with low risk features and <50% but ≥30% reduction OR
high risk features (T4, bulky N2B or N2C-N3, >10 pack-years tobacco use) with ≥50% reduction
will receive de-intensified chemoradiation with concurrent cisplatin-RT to 50 Gy (5 weeks) or
TFHX to 45 Gy (3 cycles/6 weeks). Patients with low risk features and <30% reduction OR high
risk disease with <50% reduction or any patients with progressive disease during induction
chemotherapy will undergo chemoradiotherapy with concurrent cisplatin-RT to 70 Gy (7 weeks)
or TFHX to 75 Gy (5 cycles/10 weeks). Patients with both high and low risk features who have
≥50% reduction will receive locoregional therapy targeting the pre-chemotherapy extent of
disease only. Adjuvant nivolumab will be offered to all patients for 6-months post completion
of definitive therapy (7 doses given as a flat dose of 480mg, every four weeks).

Inclusion Criteria:

- Patients must have pathologically confirmed HPV-positive head and neck squamous cell
carcinoma of the oropharynx. Confirmed HPV-positive disease of other subsites are
uncommon but also eligible.

- HPV testing must be compliant with the following criteria:

- p16 IHC positivity is sufficient to enroll and initiate treatment (p16 IHC
interpretation to follow guidelines by Jordan and Lingen et al89).

- p16 IHC positivity is to be validated using an HPV PCR during the induction phase.
This is essential as HPV genotype influences treatment arm allocation, with non-HPV16
HPV strains being considered high risk.

- Availability of ≥10 unstained 5 micron slides (to be provided to HTRC at the
University of Chicago). 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.

- Patients with AJCC (7th edition, 2010) N2-N3 nodal disease or T3-T4 primary tumor.

- Measurable disease (either primary site and/or nodal disease) by 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 disease
is acceptable).

- ECOG performance status 0-1 (Karnofsky greater than or equal to 80%).

- Normal Organ Function

- Leukocytes ≥3000/mm3,

- platelets ≥100,000/mm3,

- absolute neutrophil count ≥1,500,

- hemoglobin >9.0 gm/dL,

- AST and ALT <2.5 X ULN

- alkaline phosphatase <2.5 X ULN

- albumin >2.9 gm/dL, 29 Version Date: 12/28/2016

- total bilirubin ≤1.5 mg/dl,

- creatinine clearance >45 mL/min (or 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 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.

- Age, Sex, and Reproductive Status:

1. Men and women, ages > 18.

2. Women of childbearing potential (WOCBP=premenopausal woman capable of becoming
pregnant) 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.

3. Women must not be breastfeeding.

4. WOCBP must agree to follow instructions for method(s) of contraception for the
duration of treatment with study drug(s) plus 5 half-lives of study drug(s) plus
30 days (duration of ovulatory cycle) for a total of 23 weeks post-treatment
completion.

5. Men who are sexually active with WOCBP must agree to follow instructions for
method(s) of contraception for the duration of treatment with study drug(s) plus
5 half-lives of study drug(s) plus 90 days (duration of sperm turnover) for a
total of 31 weeks post treatment completion.

6. Azoospermic males and WOCBP who are continuously not heterosexually active are
exempt from contraceptive requirements. However, they must still undergo
pregnancy testing as described in this section.

- Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP
on the importance of pregnancy prevention and the implications of an unexpected
pregnancy. Investigators shall advise WOCBP and male subjects who are sexually active
with WOCBP on the use of highly effective methods of contraception. Highly effective
methods of contraception have a failure rate of <1% when used consistently and
correctly.

- At a minimum subjects must agree to the use of one method of highly effective
contraception as listed below:

HIGHLY EFFECTIVE METHODS OF CONTRACEPTION

- Hormonal methods of contraception including combined oral contraceptive pills, vaginal
ring, injectables, implants and intrauterine devices (IUDs) such as Mirena® by WOCBP
subject or male subject's WOCBP partner

- IUDs, such as ParaGard®

- Tubal ligation

- Vasectomy 30 Version Date: 12/28/2016

- Complete Abstinence*

- *Complete abstinence is defined as complete avoidance of heterosexual intercourse
and is an acceptable form of contraception for all study drugs. Female subjects
must continue to have pregnancy tests. Acceptable alternate methods of highly
effective contraception must be discussed in the event that the subject chooses
to forego complete abstinence.

Subjects are encouraged to use two methods of contraception, with one method being highly
effective and the other method being either highly effective or less effective as listed
below:

LESS EFFECTIVE METHODS OF CONTRACEPTION

- Diaphragm with spermicide

- Cervical cap with spermicide

- Vaginal sponge

- Male condoms and spermicide

- Male condom without spermicide

- Progestin only pills by WOCBP subject or male subject's WOCBP partner

- Female condom*

- *A male and female condom must not be used together

Exclusion Criteria:

- Unequivocal demonstration of distant metastases (M1 disease).

- Unidentifiable primary site.

- 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 because of the potential teratogenic effects
and potential unknown effects on nursing newborns (please see above paragraph under
inclusion criteria regarding WOCBP) 31 Version Date: 12/28/2016

- 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 on study as outlined above

- Patients receiving other investigational agents.

- Peripheral neuropathy >grade 1

- Has a 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.

- Has a known history of active tuberculosis (Bacillus Tuberculosis infection)

- Has hypersensitivity to nivolumab or any other drug used in this protocol.

- Has had a 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 live expectancy in the subsequent 3 years
without active treatment (e.g. low grade prostate cancer in absence of therapy).

- Has active autoimmune disease that has required systemic treatment in the past year
(i.e. with use of 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) (HIV 1/2 antibodies).

- Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
[qualitative] is detected). However, if eradicated patient is eligible.

- Has received a live vaccine within 28 days of planned start of study therapy. o Note:
Seasonal influenza vaccines for injection are generally inactivated flu vaccines and
are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live
attenuated vaccines, and are not allowed within 28 days prior to initiation of
treatment.