Evaluation of the Efficacy and Safety of Nivolumab Neoadjuvant Treatment of Patients With Locally Advanced Oral Squamous Cell Carcinoma

NOCANO: Nivolumab as Neoadjuvant Immunotherapy for Patients With Oral CANcer and Identification of Response-predictive Biomarkers in Tumour Draining Lymph NOdes

This is a Phase II, single-centre, non-randomized, single-arm clinical trial to investigate the efficacy and safety of neoadjuvant nivolumab therapy in adult participants with resectable, locoregionally advanced Oral Squamous Cell Carcinoma (OSCC) tumors. Identification of predictive molecular biomarkers of tumor response to treatment will also be performed.

Patients 18 years old and above, any gender, naïve to immunotherapy, and with histologically confirmed T2-4 N0-3 M0 resectable Oral Squamous Cell Carcinoma tumors will be eligible for this clinical trial. Enrolled patients must be fit and eligible for the primary treatment of curative surgery at the primary tumor site with sentinel node identification and removal. Total 60 patients fulfilling eligibility criteria will be included during the period of three years and will receive a total of 2 doses (240 mg per dose) of nivolumab at day 1 and day 15 prior to the curative standard of care surgery. After the study treatment and standard of care surgery, the study participants will be offered evidence-based adjuvant therapy, such as radiotherapy, chemoradiotherapy and checkpoint inhibitors or combination treatments, according to the existing evidence.

The study duration per participant after inclusion is approximately 27 weeks including two study-related follow-up visits at 3 and 6 months after the second nivolumab dose. Survival status and disease status of every participant will be also reviewed in medical records at 1, 2, 3 and 5 years after the second nivolumab dose.

Inclusion Criteria:

• The subject is willing to participate and has given their written and dated consent to participate in the trial.

• Naïve to immunotherapy.

  ≥ 18 years of age at the time of signing the informed consent.

• Primary histologically or cytologically confirmed Oral Squamous Cell Carcinoma classified according to the ICD-10 classification.

• Stage T2-4 N0-3 M0.

• The subject is planned for curative surgery as the primary treatment.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

Exclusion Criteria:

• Distant metastases (pathologically proven, radiologic or clinical evidence of distant metastatic disease). This includes all diseases below the clavicles, as well as disease metastatic to the bone, brain, or in the spinal canal.
• Active malignancy requiring concurrent treatment or history of another primary malignancy.
• History of radio- and/or chemotherapy.
• Pregnant, breastfeeding, planning pregnancy or refusal to use highly effective contraception method during the treatment period and for at least 5 months after the last dose.
• History of systemic treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways.
• Prior organ transplantation.
• Treatment with a live (attenuated) vaccine within 4 weeks before Screening visit.
• Initiation of allergen immunotherapy within 3 months prior Screening visit or a plan to begin therapy during the trial.
• Known or suspected systemic hypersensitivity to the active substance nivolumab including any of the OPDIVO™ excipients.
• History of systemic hypersensitivity or anaphylaxis to other monoclonal antibodies including any excipient.
• Active, known, or suspected autoimmune disease or inflammatory disease (e.g. lupus, inflammatory bowel disease [e.g. colitis or Crohn's disease]), diverticulitis, rheumatoid arthritis, Sarcoidosis, Wegener syndrome, Grave's disease, uveitis, etc.) that has required systemic treatment with immune modifying agents in the last 2 years (e.g. replacement therapy such as thyroxine, insulin or physiological corticosteroids is not an exclusion criteria).*The subject may enroll if they have vitiligo, alopecia, 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.
• Presence of condition requiring systemic treatment with corticosteroids (> 10 mg daily prednisolone equivalents) or other immunosuppressive medication within 14 days before the start of nivolumab therapy.
• Severe asthma exacerbation requiring the admission to hospital with systemic corticosteroids within 4 weeks before Screening visit.
• Known significant respiratory disease, including, but not limited to, pneumonitis, interstitial lung disease (ILD), chronic obstructive pulmonary disease, cystic fibrosis.
• Prior history or evidence of active ILD or non-infectious pneumonitis that required steroids
• Known or suspected condition that affects your nervous system, such as myasthenia gravis or Guillain-Barré syndrome.
• Recent history of myocardial infarction, cardiac arrhythmia, unstable angina pectoris, transient ischemic attack, or a known history of a hypercoagulable disease.
• Known hepatitis B virus (HBV) and/or hepatitis C virus (HCV) acute or chronic infection. If suspected, tests for hepatitis B surface antigen (HBs Ag) and/or HCV antibody (HCV Ab) confirmed by HCV ribonucleic acid (RNA) are required.
• Known human immunodeficiency virus (HIV) infection or known acquired immunodeficiency syndrome (AIDS) or positive HIV 1/2 serology test result if suspected.
• Active tuberculosis (TB), non-tuberculous mycobacterial infection, a history of incompletely treated TB. TB test if suspected.
• Known or suspected immunodeficiency, including history of invasive opportunistic infections (e.g. TB, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystosis or aspergillosis) despite infection resolution, or otherwise recurrent infections of abnormal frequency or prolonged duration suggesting a compromised immune system status, as judged by the Investigator.
• Uncontrolled concurrent medical disorder affecting organ function and in the opinion of the Investigator may increase the risk for the subject or may interfere with the treatment and thus affect the study results or assessment.
• Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study.
• Known or suspected heavy drinking and/or drug use.
• In the opinion of the Investigator, the subject is unfit or unsuitable to receive neoadjuvant nivolumab, whatever the reason, including medical or clinical condition.
• Any mental inability (e.g. dementia), reluctance or language difficulties that result in difficulty understanding the meaning of participation in the clinical trial and following the study protocol and instructions.
• Lack of adherence to the study protocol and instructions given by the Investigator.
• Premature withdrawal by the Investigator/Sponsor due to safety or any other reason.
• Revoked consent.