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

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ClinicalTrials.gov Identifier: NCT03575598
Recruitment Status : Recruiting
First Posted : July 2, 2018
Last Update Posted : September 5, 2018
Sponsor:
Collaborator:
Mirati Therapeutics Inc.
Information provided by (Responsible Party):
University Health Network, Toronto

Tracking Information
First Submitted Date  ICMJE June 11, 2018
First Posted Date  ICMJE July 2, 2018
Last Update Posted Date September 5, 2018
Actual Study Start Date  ICMJE August 30, 2018
Estimated Primary Completion Date August 30, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 28, 2018)
  • Pharmacodynamic effects with biomarker analyses [ Time Frame: 2 years ]
    Tumor PD-L1 expression by IHC
  • Immune effects with biomarker analyses [ Time Frame: 2 years ]
    Density of immune cell population in the tumor and/or peripheral blood, including T-cell subsets, NK cells and myeloid-derived cell subsets
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03575598 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 28, 2018)
  • Toxicities as per NCI CTCAE v5.0 [ Time Frame: 2 years ]
  • Rate of completion of surgery within the initially planned window [ Time Frame: 2 years ]
  • Rate of post-operative complications [ Time Frame: 2 years ]
  • Rate of disease progression as per RECIST v1.1 during the pre-operative treatment period [ Time Frame: 2 years ]
  • Pathologic treatment effect in tumor and/ or lymph nodes [ Time Frame: 2 years ]
  • Rate of nodal extracapsular extension and positive margins [ Time Frame: 2 years ]
  • Analysis of plasma Sitravatinib concentration before and after Nivolumab therapy [ Time Frame: 2 years ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: June 28, 2018)
  • Dynamic changes in immune cell activation and/or suppression using flow cytometry, DNA/RNA sequencing, and FACS sorting [ Time Frame: 2 years ]
    Tumor and immune cell genome and trascriptome analysis
  • Dynamic changes in intratumoral hypoxia with pre-operative Sitravatinib and Nivolumab therapy using 18FAZA PET [ Time Frame: 2 years ]
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Sitravatinib (MGCD516) and Nivolumab in Oral Cavity Cancer Window Opportunity Study
Official Title  ICMJE Sitravatinib (MGCD516) and Nivolumab in Oral Cavity Cancer Window Opportunity Study (SNOW)
Brief Summary This is a 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 drugs, Sitravatinib and Nivolumab.
Detailed Description

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Early Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Squamous Cell Carcinoma, Head And Neck
  • Squamous Cell Carcinoma Mouth
  • Squamous Cell Carcinoma of the Oral Cavity
Intervention  ICMJE
  • Drug: Sitravatinib
    Sitravatinib (MGCD516) is an orally-available, potent small molecule inhibitor of a closely related spectrum of tyrosine kinases, which has shown antitumor activity in a variety of in vitro and in vivo model systems.
    Other Name: MGCD516
  • Biological: Nivolumab
    Nivolumab (OPDIVO®) is a human IgG4 kappa immunoglobulin that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response.
    Other Name: OPDIVO®
Study Arms  ICMJE Experimental: Sitravatinib and Nivolumab

Patients will start therapy with sitravatinib within 10 days of study enrollment. Sitravatinib will be given at 120mg once daily on a continuous basis until 48 hours before planned surgery, or for a maximum period of 28 days.

Nivolumab will be given as a single infusion at a dose of 240mg, over a period of 30 minutes on Day 15 of the study.

Interventions:
  • Drug: Sitravatinib
  • Biological: Nivolumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 28, 2018)
15
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE August 30, 2020
Estimated Primary Completion Date August 30, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Signed written and voluntary informed consent.
  2. Patient must be willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures.
  3. Age > 18 years, male or female.
  4. 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).
  5. 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.
  6. No anti-neoplastic treatment is allowed between the time from obtaining baseline tumor specimen and enrollment.
  7. ECOG performance status 0-1.
  8. 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.

  9. 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.
  10. 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:

  1. 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.

  2. Patients with any prior history of clinically significant bleeding related to the current head and neck cancer.
  3. Patients with a history of gross hemoptysis (bright red blood of ½ teaspoon or more per episode of coughing) < 3 months prior to enrollment.
  4. Prior or concurrent radiation therapy to tumor at site of planned resection.
  5. 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.

  6. 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).
  7. 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.
  8. History of primary immune deficiency.
  9. History of stroke or transient ischemic attack within the previous 6 months.
  10. History of uncontrolled hypertension (> 150 mm Hg systolic or > 100 mm Hg diastolic) on multiple observations despite standard of care treatment.
  11. Any of the following cardiac abnormalities:

    • Unstable angina pectoris,
    • Congestive heart failure ≥ NYHA Class 3,
    • QTc >480 milliseconds,
    • Left ventricular ejection fraction (LVEF) < 50.
  12. Concomitant medication known to cause prolonged QT that cannot be discontinued or changed to a different medication prior to enrollment.
  13. History of organ transplant that requires use of immunosuppressive medications.
  14. Known allergy or reaction to any components of Sitravatinib and/or Nivolumab formulation.
  15. Subjects who are known to be human immunodeficiency (HIV) positive.
  16. 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.
  17. Female patients who are pregnant or breast-feeding.
  18. 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.
  19. 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.
  20. Any previous treatment with a PD1 or PD-L1 inhibitor, including Nivolumab.
  21. 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.
  22. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of study medications.
  23. Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE >Grade 1.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Lillian Siu, MD 416-946-4501 ext 2911 lillian.siu@uhn.ca
Contact: Kendra Ross 416-946-4501 ext 7754 kendra.ross@uhn.ca
Listed Location Countries  ICMJE Canada
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03575598
Other Study ID Numbers  ICMJE SNOW-001
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party University Health Network, Toronto
Study Sponsor  ICMJE University Health Network, Toronto
Collaborators  ICMJE Mirati Therapeutics Inc.
Investigators  ICMJE
Principal Investigator: Lillian Siu, MD University Health Network, Toronto
PRS Account University Health Network, Toronto
Verification Date August 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP