Nivolumab in Treating Patients With Advanced Metastatic Non-small Cell Lung Cancer

PRIMARY OBJECTIVE:

I. To study the sustained proliferation of programmed cell death protein (PD)-1+Ki-67+cluster
of differentiation(CD)8 T cells as a predictive biomarker of response to nivolumab by
comparing the response rates to nivolumab treatment between two groups of patients (positive
vs negative) stratified by the status of PD-1+Ki-67+CD8 T cells.

SECONDARY OBJECTIVES:

I. Characterize phenotype of proliferating T cells in peripheral blood in the setting of
nivolumab therapy.

II. Perform gene expression profiling of activated T cells from peripheral blood.

III. Perform T cell receptor (TCR) sequencing of activated T cells from peripheral blood and
tumor infiltrating T cells (TILs).

IV. Assess pre-treatment biopsies and biopsies at the time of disease progression for tumor
infiltrating lymphocytes.

V. Determine progression free survival (PFS) and overall survival (OS).

OUTLINE:

Patients receive nivolumab intravenously (IV) over 30 minutes on day 1. Courses repeat every
2 weeks in the absence of disease progression or unexpected toxicity.

After completion of study treatment, patients are followed up at 30 and 90 days and then
every 3 months for up to 3 years.

Inclusion Criteria:

- Subjects must have signed and dated an Institutional Review Board (IRB)/Independent
Ethics Committee (IEC) approved written informed consent form in accordance with
regulatory and institutional guidelines; this must be obtained before the performance
of any protocol related procedures that are not part of normal subject care

- Subjects must be willing and able to comply with scheduled visits, treatment schedule,
laboratory tests, and other requirements of the study

- Histologically confirmed stage IV or recurrent non-small cell lung cancer (NSCLC) per
the 7th International Association for the Study of Lung Cancer classification with
squamous or non-squamous histology

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2; patients
with PS 2 are being included as the primary endpoint of the study is correlation of
blood based biomarkers with response; nivolumab is currently approved for both
squamous and non-squamous NSCLC

- Disease progression following frontline platinum doublet therapy given for metastatic
or recurrent disease; there is no restriction on prior lines of therapy following
receipt of initial platinum doublet therapy

- Continuation maintenance therapy following platinum-based chemotherapy will not
be considered as a separate line of therapy

- Prior platinum-containing adjuvant, neoadjuvant, or definitive chemoradiation
therapy given for locally advanced disease is considered first-line platinum
therapy only if recurrent disease developed within 6 months of completing therapy

- Patients with activating epidermal growth factor receptor (EGFR) mutations must
have received an EGFR tyrosine kinase inhibitor directed therapy prior to
platinum therapy

- Patients with anaplastic lymphoma kinase (ALK) translocations must have received
an ALK tyrosine kinase inhibitor directed therapy prior to platinum therapy

- Prior systemic chemotherapy or other investigational therapy must have been completed
at least two weeks prior to administration of nivolumab

- Measurable disease by computed tomography (CT) or magnetic resonance imaging (MRI) per
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria

- Subject willing to undergo biopsy prior to treatment with investigational therapy for
fresh tissue immune cell analysis and would consider biopsy at disease progression
(progression biopsy is not mandated); biopsy should be obtained with core needle; fine
needle aspirates are not sufficient; if prior archival tissue is available, it should
be submitted

- Prior palliative radiotherapy must have been completed at least 2 weeks prior to
registration; subjects with symptomatic tumor lesions at baseline that may require
palliative radiotherapy within 4 weeks of randomization are strongly encouraged to
receive palliative radiotherapy prior to randomization

- White blood cell (WBC) ≥ 2000/µL

- Neutrophils ≥ 1500/µL

- Platelets ≥ 100 x 10³/µL

- Hemoglobin > 9.0 g/dL

- Serum creatinine ≤ 2 x upper limit of normal (ULN) or creatinine clearance (CrCl) ≥ 40
mL/min (if using the Cockcroft-Gault formula)

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 3 x ULN

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

- Women of childbearing potential (WOCBP) must use appropriate method(s) of
contraception; WOCBP should use an adequate method to avoid pregnancy for 5 months (30
days plus the time required for nivolumab to undergo five half-lives) after the last
dose of investigational drug

- Women of childbearing potential must have a negative serum or urine pregnancy test
(minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin
[HCG]) within 24 hours prior to the start of nivolumab

- Women must not be breastfeeding

- Men who are sexually active with WOCBP must use any contraceptive method with a
failure rate of less than 1% per year; men receiving nivolumab and who are sexually
active with WOCBP will be instructed to adhere to contraception for a period of 7
months after the last dose of investigational product; women who are not of
childbearing potential (i.e. who are postmenopausal or surgically sterile) as well as
azoospermic men do not require contraception

- Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP
on the importance of pregnancy prevention and the implications of an unexpected
pregnancy; investigators shall advise WOCBP and male subjects who are sexually active
with WOCBP on the use of highly effective methods of contraception; highly effective
methods of contraception have a failure rate of < 1% when used consistently and
correctly

- At a minimum, subjects must agree to the use of two methods of contraception, with one
method being highly effective and the other method being either highly effective or
less effective as listed below:

- HIGHLY EFFECTIVE METHODS OF CONTRACEPTION

- Hormonal methods of contraception including combined oral contraceptive
pills, vaginal ring, injectables, implants and intrauterine devices (IUDs)
by WOCBP subject or male subject's WOCBP partner

- Nonhormonal IUDs

- Tubal ligation

- Vasectomy

- Complete abstinence: Complete abstinence is defined as complete avoidance of
heterosexual intercourse and is an acceptable form of contraception for all
study drugs; subjects who choose complete abstinence are not required to use
a second method of contraception, but female subjects must continue to have
pregnancy tests; acceptable alternate methods of highly effective
contraception must be discussed in the event that the subject chooses to
forego complete abstinence

- LESS EFFECTIVE METHODS OF CONTRACEPTION

- Diaphragm with spermicide

- Cervical cap with spermicide

- Vaginal sponge

- Male condom without spermicide

- Male condoms with spermicide

- Progestin only pills by WOCBP subject or male subject's WOCBP partner

- Female condom: A male and female condom must not be used together

Exclusion Criteria:

- Subjects with untreated central nervous system (CNS) metastases or carcinomatous
meningitis are excluded

- Subjects with CNS metastases are only eligible if the CNS metastases are treated with
radiotherapy and/or surgery and subjects are neurologically returned to baseline
(except for residual signs or symptoms related to the CNS treatment); in addition,
subjects must be either off corticosteroids, or on a stable or decreasing dose of ≤ 10
mg daily prednisone (or equivalent)

- Subjects must have recovered from the effects of major surgery or significant
traumatic injury at least 14 days before registration

- Other active malignancy requiring concurrent intervention; a history of prior
malignancy will not be an exclusion factor as long as the patient is not currently
requiring treatment for this malignancy

- Subjects with an active, known or suspected autoimmune disease; subjects with type I
diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders
(such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or
conditions not expected to recur in the absence of an external trigger are permitted
to enroll

- Subjects with a condition requiring systemic treatment with either corticosteroids (>
10 mg daily prednisone equivalent) or other immunosuppressive medications within 14
days of registration; inhaled or topical steroids, and adrenal replacement steroid
doses > 10 mg daily prednisone equivalent, are permitted in the absence of active
autoimmune disease

- Subjects with interstitial lung disease that is symptomatic or may interfere with the
detection or management of suspected drug-related pulmonary toxicity

- Known history of testing positive for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome (AIDS)

- Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-cytotoxic
T-lymphocyte-associated protein (CTLA)-4 antibody, or any other antibody or drug
specifically targeting T-cell co-stimulation or checkpoint pathways

- Any positive test for hepatitis B virus or hepatitis C virus indicating acute or
chronic infection

- Ongoing or planned administration of anti-cancer therapies other than nivolumab

- Use of corticosteroids or other immunosuppressive medications per exclusion criteria

- Anti-cancer therapy, including an investigational agent, less than 14 days prior to
the first dose of nivolumab

- Prisoners or subjects who are involuntarily incarcerated

- Any other serious or uncontrolled medical disorder, active infection, physical exam
finding, laboratory finding, altered mental status, or psychiatric condition that, in
the opinion of the investigator, would limit a subject's ability to comply with the
study requirements, substantially increase risk to the subject, or impact the
interpretability of study results

- Drugs with a predisposition to hepatoxicity should be used with caution