Sitravatinib (MGCD516) and Nivolumab in Oral Cavity Cancer Window Opportunity Study

This is a single center, open-label, non-randomized, pre-operative window of opportunity study for patients with resectable squamous cell carcinoma of the oral cavity who are considered suitable for curative-intent surgical resection, with pre-operative Sitravatinib and Nivolumab. A total of 12 patients who are evaluable for correlative studies, are planned for enrollment.

This study will involve treatment with Sitravatinib and Nivolumab, tests and procedures done for safety and the collection of blood samples for biomarker research. Tissue samples (fresh biopsy or archival tissue) will also be collected for biomarker research and evaluation.

Inclusion criteria

• Signed written and voluntary informed consent.
• Patient must be willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures.
• Age > 18 years, male or female.
• Patient must be diagnosed with histologically confirmed squamous cell carcinoma of the oral cavity (SCCOC) (floor of mouth, anterior 2/3 tongue, buccal mucosa, upper and lower gingiva, retromolar trigone and hard palate) previously untreated, considered resectable by the head and neck treating surgeon (T2-4a, N0-2, or T1 - greater than 1 cm - N2, M0; without evidence of distant metastasis).
• Patient must be willing and able to provide 2 fresh tumor biopsies for histopathological and biomarker evaluation: one at baseline and one after treatment with Sitravatinib but prior to treatment with Nivolumab. Archival tissue sample will be requested if available.
• No anti-neoplastic treatment is allowed between the time from obtaining baseline tumor specimen and enrollment.
• ECOG performance status 0-1.
• Patient must have adequate organ function as determined by the following:

• Renal function: i. Serum creatinine < 1.5 ULN (upper limit of normal range) or a calculated creatinine clearance of > 50mL/min using the following formula:

Creatinine clearance = [(140-age) x wt (kg) x Constant*] / creatinine (umol/L)

*Constant = 1.23 for men, and 1.04 for women

• Bone marrow function (without hematopoietic growth factors or transfusion): i. Absolute neutrophil count (ANC) > 1.0 x 109/L ii. Leukocytes > 2.0 x 109/L iii. Hemoglobin > 90 g/L or > 9g/dL iv. Platelets > 100 x 109/L

• Liver function: i. Total bilirubin ≤ 1.5 x ULN or ≤ 3 x ULN for patients with Gilbert Syndrome. ii. Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) < 2.5 x ULN

• Cardiac function: i. A normal left ventricular ejection fraction (LVEF) of ≥50% by a MUGA scan performed within 4 weeks of the study commencement.
• Evidence of post-menopausal status, or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:

• Women <50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
• Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy). Women of child-bearing potential (WOCBP) or men whose partner is a WOCBP agrees to use contraception while participating in this study, and for a period of 6 months following termination of study treatment.
• Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.

Exclusion criteria

• Primary site of head and neck carcinoma unknown, lip, skin, or outside the oral cavity.

• Patients with tumors that invade major vessels or are within ≤ 3 mm of the carotid artery as shown unequivocally by imaging studies.
• Patients with any prior history of clinically significant bleeding related to the current head and neck cancer.
• Patients with a history of gross hemoptysis (bright red blood of ½ teaspoon or more per episode of coughing) < 3 months prior to enrollment.
• Prior or concurrent radiation therapy to tumor at site of planned resection.
• Any concurrent chemotherapy, biologic, immunologic or hormonal therapy for cancer treatment.

• Concurrent use of hormones for non-cancer-related conditions (eg, insulin for diabetes and hormone replacement therapy) is acceptable.
• Current or prior use of immunosuppressive medication within 14 days prior to starting dosing. The following are exceptions to this criteria:

• Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular injection).
• Adrenal replacement steroid > 10 mg daily prednisone equivalent are permitted in the absence of active autoimmune disease.
• Steroids as premedication for hypersensitivity reactions (eg, computed tomography scan premedication).
• Active or documented history of autoimmune disease within 2 years before screening, including:

• Active or prior documented inflammatory bowel disease (eg. Crohn's disease, ulcerative colitis).
• Patients with vitiligo, resolved childhood asthma/atopy, type I diabetes mellitus, Grave's disease, Hashimoto's disease, or psoriasis not requiring systemic steroids and/or immunosuppressive agents within the past 2 years, are not excluded.
• History of primary immune deficiency.
• History of stroke or transient ischemic attack within the previous 6 months.
• History of uncontrolled hypertension (> 150 mm Hg systolic or > 100 mm Hg diastolic) on multiple observations despite standard of care treatment.
• Any of the following cardiac abnormalities:

• Unstable angina pectoris,
• Congestive heart failure ≥ NYHA Class 3,
• QTc >480 milliseconds,
• Left ventricular ejection fraction (LVEF) < 50.
• Concomitant medication known to cause prolonged QT that cannot be discontinued or changed to a different medication prior to enrollment.
• History of organ transplant that requires use of immunosuppressive medications.
• Known allergy or reaction to any components of Sitravatinib and/or Nivolumab formulation.
• Subjects who are known to be human immunodeficiency (HIV) positive.
• Has a known history of or is positive for active hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (defined as HCV RNA [qualitative] is detected).

• HBV DNA must be undetectable and HBsAg negative at Screening Visit.
• Participants who have had definitive treatment for HCV are permitted if HCV RNA is undetectable at Screening Visit.
• Female patients who are pregnant or breast-feeding.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active clinically significant infection requiring parenteral antibiotics, unstable cardiac arrhythmia, active peptic ulcer disease or gastritis, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring adverse events from Sitravatinib or Nivolumab, or compromise the ability of the subject to give written informed consent.
• Any condition that, in the opinion of the Investigator, would interfere with evaluation of the study regimen or interpretation of patient safety or study results.
• Any previous treatment with a PD1 or PD-L1 inhibitor, including Nivolumab.
• History of another primary malignancy, except for:

• Malignancy treated with curative intent and with no known active disease ≥3 years before the first dose of study drug and of low potential risk for recurrence,
• Adequately treated non-melanoma skin cancer without evidence of disease,
• Adequately treated carcinoma in situ without evidence of disease.
• Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of study medications.
• Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE >Grade 1.