Nivolumab Plus Pemetrexed for Head and Neck Squamous Cell Carcinoma

The purpose of this study is to find out what effects the combination of Nivolumab and Pemetrexed has on you and your cancer. The safety of this combination and the effectiveness of this treatment will be studied.

The treatment of patients with SCCHN is challenging, and represents an area of high unmet need. Treatment options within this patient population are limited, and inadequately treated disease may cause high morbidity, negatively impacting quality of life and leading to increased costs for supportive care. To address the unmet needs of these patients, this exploratory trial combining pemetrexed with standard-of-care nivolumab, with an investigational plan to study clinical and health services outcomes is being proposed.

Eligibility Criteria:
Inclusion Criteria:

1. Patients must be 18 years of age or older.
2. Patients must have a diagnosis of histologically confirmed squamous cell carcinoma of the head and neck not amenable to curative intent therapy (surgery or radical chemoradiation).
3. Patients with squamous cell cancer of the head and neck (SCCHN) who either have a recurrence within 6 months of potentially curative neoadjuvant/adjuvant platinum-based therapy or recurrence after receiving plantium based therapy in a non-curative setting, and who have a good performance status. Nivolumab may also be considered for patients who are ineligible for a platinum-based chemotherapy.
4. Patients presenting with a diagnosis of HPV-related (p16+) squamous cell carcinoma without an unknown primary will be eligible for enrolment if the investigator deems a head and neck primary to be the most likely primary source.
5. Patients must be capable of providing consent to enrolment and treatment.
6. Patients with a performance status of ECOG 0-2(15) will be eligible for enrolment (see appendix 1).
7. Measurable disease must be present according to RECIST criteria V1.1(16) (see appendix 5).
8. Women of child bearing potential (WOCBP) must have a negative serum (or urine) pregnancy test at the time of screening. WOCBP is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy or bilateral salpingectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea in a woman over age 45 years in the absence of other biological or physiological causes.
9. Patients (men and women) of childbearing / reproductive potential should use highly effective birth control methods, as defined by the investigator, during the study treatment period and for a period of 6 months after the last dose of study drug. A highly effective method of birth control is defined as those that result in low failure rate (i.e. less than 1% per year) when used consistently and correctly.

   * Note: abstinence is acceptable if this is established and preferred contraception for the patient and is accepted as a local standard.
10. Female patients who are breast-feeding should discontinue nursing prior to the first dose of study treatment and until 30 days after the last dose of study drug.
11. Male patients should agree to not donate sperm during the study and for a period of at least 6 months after last dose of study drug.
12. Absence of any condition hampering compliance with the study protocol and follow- up schedule; those conditions should be discussed with the patient before registration in the trial.
13. The following adequate organ function laboratory values must be met:

Hematological:

* Absolute neutrophil count (ANC) \>1.5 x109/L
* Platelet count \>100 x109/L
* Hemoglobin \>9 g/dL (may have been transfused)

Renal:

-Estimated creatinine clearance ≥ 45 mL/min according to the Cockcroft-Gault formula (or l-ocal institutional standard method)

Hepatic:

* Total serum bilirubin \<1.5x ULN
* AST and ALT \<2.5x ULN (or ≤ 5 x ULN for patients with documented metastatic disease to the liver)

Exclusion Criteria:

1. History of pneumonitis requiring treatment with steroids.
2. History of active interstitial lung disease.
3. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (\< 6 months prior to enrollment), myocardial infarction (\< 6 months prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication.
4. History of another malignancy or a concurrent malignancy;

   -Exceptions include patients who have been disease-free for 3 years, or patients with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible, for example cervical cancer in situ.
5. Active brain metastases or leptomeningeal disease.

   -Patients with treated brain metastases that are stable for 6 weeks will be eligible for enrolment.
6. Current use of immunosuppressive medication, EXCEPT for the following: a. intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection); b. Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent; c. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
7. Prior organ transplantation including allogeneic stem-cell transplantation.
8. Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible.
9. Active infection requiring systemic therapy.
10. Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (CTCAE v4.03 Grade ≥ 3).
11. Other severe acute or chronic medical conditions including inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
12. Persisting toxicity related to prior therapy (NCI CTCAE v. 4.03 grade \> 1); however, alopecia, sensory neuropathy ≤ grade 2, or other toxicities ≤ grade 2 not constituting a safety risk based on investigator's judgment are acceptable.