Nivolumab + Chemoradiation in Stage II-IVB Nasopharyngeal Carcinoma (NPC)

PRIMARY OBJECTIVES:

I. To establish the feasibility of treatment completion of a combined
chemoradiation-nivolumab regimen followed by adjuvant nivolumab.

SECONDARY OBJECTIVES:

I. To determine the overall response rate at 1 year from completion of therapy, as determined
by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.

II. To determine the locoregional control rate at 1 year post-treatment. III. To determine
the distant metastasis rate at 1 year post-treatment. IV. To determine the overall survival
rate at 1 year post-treatment. V. To determine the rate of Epstein-Barr virus (EBV)
deoxyribonucleic acid (DNA) clearance at end of chemoradiation and at 1 year post-treatment.

VI. To assess patients' quality of life from baseline through 1 year post-treatment.

VII. To determine the acute and late toxicity rates according to Common Terminology Criteria
for Adverse Events (CTCAE) version (v.) 5, including immune-related adverse events (AEs).

OUTLINE:

Patients receive nivolumab intravenously (IV) over 60 minutes on day 1 of courses 1-5 and
7-12. Treatment repeats every 14 days for 11 courses in the absence of disease progression or
unacceptable toxicity. Beginning at course 2, patients undergo radiation therapy once daily
(QD) 5 days per week and receive cisplatin IV over 30-60 minutes on day 1. Treatment repeats
every 7 days for up to 3 courses in the absence of disease progression or unacceptable
toxicity.

After completion of study treatment, patients are followed up for 100 days, at 1, 3, 6, 9,
and 12 months for up to 1 year, and then every 3 months for 1 year.

Inclusion Criteria:

1. Males and females ≥18 years of age.

2. Histologically or cytologically confirmed nasopharyngeal carcinoma, stage II-IV by
American Joint Committee on Cancer (AJCC) 7th edition, endemic-type (defined as World
Health Organization (WHO) type 2a and 2b nonkeratinizing or undifferentiated subtypes,
excluding WHO type I keratinizing subtype) performed on a biopsy that occurred within
90 days of registration.

3. Positron emission tomography-computed tomography (PET-CT) (preferred) or a CT of
chest, abdomen, and pelvis within 60 days of registration showing radiographic stage
II to IVB nasopharyngeal cancer.

4. No distant metastasis as verified by one of the study investigators.

5. Documentation that the patient is a candidate for chemoradiation of their
nasopharyngeal cancer by one of the study investigators.

6. Ability to tolerate radiation therapy (e.g. lie flat and hold position for treatment).

7. Measurable disease as defined by RECIST v1.1.

8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

9. Lack of contraindications to systemic immunotherapy (see list of exclusions below).

10. Resolution of all acute toxic effects of any prior chemotherapy, radiotherapy or
surgical procedures to NCI CTCAE Version 4.0 grade 1.

11. Adequate hepatic, hematologic, and renal indices permitting administration of
cisplatin and nivolumab (within 14 days of registration):

Hepatic Function:

Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × upper limit
of normal (ULN); Total bilirubin ≤ 1.5 × ULN (except subjects with Gilbert Syndrome,
who can have total bilirubin < 3.0 mg/dL)

Adequate bone marrow function:

White blood cells (WBC) ≥ 2000/μL Neutrophils ≥ 1500/μL Platelet ≥ 100 x103/μL
Hemoglobin > 9.0 g/dL

Adequate renal function:

Serum creatinine ≤ 1.5 × upper limit of normal (ULN) OR Creatinine clearance (CrCl) >
40 mL/min (if using the Cockcroft-Gault formula below): Female CrCl = (140 - age in
years) x weight in kg x 0.85 72 x serum creatinine in mg/dL Male CrCl = (140 - age in
years) x weight in kg x 1.00 72 x serum creatinine in mg/dL

12. Women of childbearing potential must have a negative serum pregnancy test within 24
hours prior to the first dose of study treatment and agree to use appropriate highly
effective methods of contraception, during the study and for 5 months following
completion of study treatment; A "Woman of childbearing potential" is defined as any
female who has experienced menarche and who has not undergone surgical sterilization
(hysterectomy or bilateral oophorectomy) or who is not postmenopausal. Menopause is
defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of
other biological or physiological causes. In addition, women under the age of 62 must
have a documented serum follicle stimulating hormone (FSH) level less than 40
milli-international units per milliliter (mIU/mL).

Female Subjects:

Women of child bearing potential are expected to use one of the highly effective
methods of contraception listed in the protocol.

Male Subjects:

Male subjects must inform their female partners who are women of child bearing
potential of the contraceptive requirements and are expected to adhere to using
contraception with their partner. Female partners of male subjects, who are women of
child bearing potential, are expected to use one of the highly effective methods of
contraception listed in the protocol. In addition, male subjects are expected to use a
condom as noted in the protocol.

13. Men with a female partner of childbearing potential must agree to use highly effective
methods of contraception or any contraceptive method with a failure rate of less than
1% per year during the study and for 7 months following completion of study treatment.

14. Ability to sign informed consent.

Exclusion Criteria:

1. Active second malignancy, i.e. patient known to have potentially fatal hematologic
malignancy or another solid primary tumor present for which he/she may be (but not
necessarily) currently receiving treatment. Patients with a prior or concurrent
malignancy whose natural history or treatment does not have the potential to interfere
with the safety or efficacy assessment of the investigational regimen are allowed to
enroll in this trial. For example, patients with early-stage skin cancers, prostate
cancer under surveillance with non-rising prostate-specific antigen (PSA), or
meningioma or thyroid papillary cancers which are under surveillance are eligible. For
determinations of a specific clinical condition, please consult with the Principal
Investigator.

2. Active, untreated central nervous system (CNS) metastases;

3. Prior treatment with any other anti-programmed cell death protein-1 (anti-PD-1), or PD
Ligand-1 (PD-L1) or PD Ligand-2 (PD-L2), anti-cytotoxic T-lymphocyte-associated
protein-4 (CTLA-4) antibody, or any other antibody or drug specifically targeting
T-cell costimulation or immune checkpoint pathways, or cancer vaccine;

4. Prior systemic cytotoxic therapy, antineoplastic biologic therapy, or major surgery
within 28 days of first dose of study medication;

5. Severe hypersensitivity reaction to treatment during prior administration of a
monoclonal antibody (mAb) or history of allergy to any study drug component;

6. Has received a live-virus vaccination within 30 days of planned treatment start;

7. Condition requiring systemic treatment with either corticosteroids (> 10 mg daily
prednisone equivalents) or other immunosuppressive medications within 14 days of study
drug administration; Inhaled or topical steroids and adrenal replacement doses > 10 mg
daily prednisone equivalents are permitted in the absence of active autoimmune
disease.

8. Any evidence of current interstitial lung disease (ILD) or pneumonitis or a prior
history of ILD or pneumonitis requiring oral or IV glucocorticoids;

9. Active, known, or suspected autoimmune disease or any autoimmune condition that has
required systemic treatment in the past 2 years (replacement therapies for hormone
deficiencies are allowed); Subjects are permitted to enroll if they have vitiligo,
type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only
requiring hormone replacement, psoriasis not requiring systemic treatment, or
conditions not expected to recur in the absence of an external trigger.

10. Clinically active diverticulitis, intra-abdominal abscess, gastrointestinal (GI)
obstruction, or abdominal carcinomatosis (known risks factors for bowel perforation);

11. Signs or symptoms of infection within 2 weeks prior to first day of study treatment.

12. Received therapeutic oral or IV antibiotics within 2 weeks prior to first day of study
treatment:

Patients receiving prophylactic antibiotics (eg, to prevent a urinary tract infection
or chronic obstructive pulmonary disease exacerbation) are eligible.

13. Known positive test for human immunodeficiency virus (HIV);

14. Known active hepatitis B or hepatitis C virus (HBV or HCV):

Patients with past or resolved HBV infection (defined by a negative hepatitis B
surface antigen [HBsAg] test and a positive anti-hepatitis B core antigen (HBc)
antibody test) are eligible. HBV DNA must be obtained in these patients prior to first
day of study treatment.

Patients who have been recently discovered to have HBV with positive HBsAg test and
positive anti HBc antibody test but who have been started on antiretroviral treatment
with nondetectable HBV DNA are eligible. HBV DNA must be obtained in these patients
prior to first day of study treatment.

15. Patients with known active hepatitis C virus ribonucleic acid (HCV antibody)
indicating acute or chronic infection:

Patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA.

16. Prior radiation therapy of any type within 7 days of first dose of study medication;

17. Prior radiation therapy to head and neck region that would overlap with intended
radiation treatment for nasopharyngeal carcinoma;

18. Medical contraindication to radiation treatment (e.g. active systemic sclerosis, other
uncontrolled autoimmune condition)

19. Treatment with prohibited medications (including concurrent anticancer therapy
including chemotherapy, radiation, hormonal treatment [except corticosteroids and
megestrol acetate] ≤ 14 days prior to treatment.

20. Pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the study;

21. Active, uncontrolled psychiatric disorders or substance (drug/alcohol) abuse that
interfere with patient's safety, ability to provide informed consent, or ability to
comply with the protocol.

22. Persons who are incarcerated or otherwise under compulsory detention by an authority
are not eligible.