Neoadjuvant Nivolumab in Resectable Non-Small-Cell Lung Cancer
Neoadjuvant Nivolumab in Resectable Non-Small-Cell Lung Cancer
The proposed study will evaluate the safety and feasibility of preoperative administration
 nivolumab in patients with high-risk resectable NSCLC, and will facilitate a comprehensive
 exploratory characterization of the tumor immune milieu and circulating immune cells and
 soluble factors in these patients. Data obtained in this study will provide valuable
 information for planning further prospective clinical trials of anti-PD-1 and other
 immunotherapies in NSCLC, both in the peri-operative and advanced disease setting.
The proposed study will evaluate the safety and feasibility of preoperative administration
 nivolumab in patients with high-risk resectable NSCLC, and will facilitate a comprehensive
 exploratory characterization of the tumor immune milieu and circulating immune cells and
 soluble factors in these patients. Data obtained in this study will provide valuable
 information for planning further prospective clinical trials of anti-PD-1 and other
 immunotherapies in NSCLC, both in the peri-operative and advanced disease setting.
 Ultimately, it is highly desirable to discover prospective biomarkers of response and
 toxicity to allow patients with NSCLC who are most likely to derive benefit to receive
 anti-PD-1 treatment, and conversely to minimize the risk of toxicity and ineffective
 treatment for patients who are unlikely to benefit.
Inclusion Criteria:

 -  Histologically proven non-small-cell lung cancer (core biopsy required).

 -  Squamous or non-squamous histology.

 -  Diagnostic core biopsy specimens must be reviewed by a faculty pathologist at The
 Second Affiliated Hospital Zhejiang University School of Medicine.

 -  Either a formalin fixed paraffin block or a minimum of fifteen 5-micron tissue
 sections (slides) of tumor biopsy sample must be available for biomarker
 evaluation (study pathologist must review for adequacy of sampling). This can be
 obtained from archived tissues, or from a new biopsy if needed.

 -  Stage - High risk NSCLC with resection option for potential cure, as assessed by a
 faculty surgeon at The Second Affiliated Hospital Zhejiang University School of
 Medicine. This may include clinical stage IA3 (≥2cm), II and IIIA(see Appendix A).
 Subjects with N3 nodal involvement are not included.

 -  ECOG performance status 0-1.

 -  Adequate organ function as follows:

 -  Leukocytes ≥ 2,000/mm3.

 -  Absolute neutrophil count (ANC) ≥ 1000/mm3.

 -  Platelet count ≥ 100,000/mm3.

 -  Hemoglobin ≥ 9 g/dL.

 -  Creatinine ≤ 1.5 x 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.

 -  Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total
 bilirubin < 3.0 mg/dL).

 -  AST(SGOT), ALT(SGPT), and alkaline phosphatase ≤ 3 times the upper limit of normal.

 -  Subjects must have adequate lung function to permit surgical resection determined
 by pre-enrollment pulmonary function tests to include DLCO.

 -  The effects of nivolumab on the developing human fetus are unknown. For this reason,
 women of child-bearing potential (WOCBP) and men must agree to use adequate
 contraception (hormonal or barrier method of birth control; abstinence) prior to study
 entry and for the duration of study participation and for up to 23 weeks after the
 last dose of nivolumab. Should a woman become pregnant or suspect she is pregnant
 while she or her partner is participating in this study, she should inform her
 treating physician immediately. Sexually active fertile men must use effective barrier
 birth control if their partners are WOCBP for up to 31 weeks after the last dose of
 nivolumab. WOCBP must have a negative serum or urine pregnancy test (minimum
 sensitivity 25 IU/L or equivalent units of HCG) within two weeks of registration.
 Women must not be breastfeeding.

 -  Patient understands the study regimen, its requirements, risks and discomforts and is
 able and willing to sign the informed consent form. Voluntary signed and dated IRB/IEC
 approved written informed consent form in accordance with regulatory and institutional
 guidelines must be obtained before the performance of any protocol related procedures
 that are not part of normal patient care. Subjects must be competent to report AEs,
 understand the drug dosing schedule and use of medications to control AEs.

 Exclusion Criteria:

 -  Subjects are excluded if they have an active, known or suspected autoimmune disease.
 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.

 -  Subjects are excluded if they have a 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. As there is potential for
 hepatic toxicity with nivolumab or nivolumab/ipilimumab combinations, drugs with a
 predisposition to hepatoxicity should be used with caution in patients treated with
 nivolumab-containing regimen.

 -  Administration of chemotherapy or any other cancer therapy in the pre-operative
 period.

 -  Subjects with active concurrent malignancies are excluded i.e. cancers other than
 NSCLC (except non melanoma skin cancers, in situ bladder, gastric, breast, colon or
 cervical cancers/dysplasia).

 -  Subjects with brain metastasis are excluded from this study, and all patients should
 have brain imaging (either MRI brain or CT brain with contrast) prior to enrollment.

 -  Subjects with a history of symptomatic interstitial lung disease.

 -  Active systemic infection requiring therapy, positive tests for Hepatitis B surface
 antigen or Hepatitis C ribonucleic acid (RNA).

 -  Known positive history or positive test for Human Immunodeficiency Virus or

 -  Acquired ImmunoDeficiency Syndrome (AIDS).

 -  History of allergy to study drug components.

 -  Women who are pregnant or nursing.

 -  Men with female partners (WOCBP) that are not willing to use contraception.

 -  Prior therapy with an anti-PD-1, anti-PD-L1, anti-PDL-2, or anti-CTLA-4 antibody (or
 any other antibody targeting T cell co-regulatory pathways).

 -  Underlying medical conditions that, in the Investigator's opinion, will make the
 administration of study drug hazardous or obscure the interpretation of toxicity or
 adverse events.

 -  Prisoners or subjects who are involuntarily incarcerated or compulsorily detained for
 treatment of either a psychiatric or physical (e.g. infectious disease) illness.