Cisplatin/Carboplatin and Etoposide With or Without Nivolumab in Treating Patients With Extensive Stage Small Cell Lung Cancer

PRIMARY OBJECTIVES:

I. To evaluate the progression-free survival (PFS) of patients with extensive stage small
cell lung cancer (ED-SCLC) treated with cisplatin/carboplatin and etoposide (CE) or CE with
nivolumab (CEN) as front-line treatment.

SECONDARY OBJECTIVES:

I. To estimate overall survival of patients with ED-SCLC treated with cisplatin/carboplatin
and etoposide (CE) or CE with nivolumab (CEN) as front-line treatment.

II. To assess best overall response rate after treatment with CE with or without nivolumab as
first line treatment.

III. To evaluate the toxicity profile of nivolumab with CE.

TERTIARY OBJECTIVES:

I. To evaluate immune biomarkers and biomarkers correlatives. II. To evaluate serial
circulating tumor deoxyribonucleic acid (DNA) and explore whether clinical outcome is
associated with fluctuations in DNA levels following the administration of therapy.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1, carboplatin IV
over 30-60 minutes on day 1 or cisplatin IV over 60-120 minutes on day 1, and etoposide IV
over 60-120 minutes on days 1-3. Treatment repeats every 21 days for up to 4 courses in the
absence of disease progression or unacceptable toxicity. Patients continue to receive
nivolumab IV over 30 minutes every 2 weeks for up to 2 years.

ARM B: Patients receive carboplatin IV over 30-60 minutes on day 1 or cisplatin IV over
60-120 minutes on day 1, and etoposide IV over 60-120 minutes on days 1-3. Treatment repeats
every 21 days for up to 4 courses in the absence of disease progression or unacceptable
toxicity.

After completion of study treatment, patients are followed up every 3 months if the patient
is less than 2 years from registration, every 6 months if the patient is 2-3 years from
registration, and yearly for up to 5 years from study enrollment.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed extensive stage small
cell lung cancer and must be a candidate for systemic therapy; NOTE: The extensive
disease SCLC classification for this protocol includes all patients with disease sites
not defined as limited stage; limited stage disease category includes patients with
disease restricted to one hemithorax with regional lymph node metastases, including
hilar, ipsilateral and contralateral mediastinal, and/or ipsilateral supraclavicular
nodes; extensive disease patients are defined as those patients with extrathoracic
metastatic disease, malignant pleural effusion, bilateral or contralateral
supraclavicular adenopathy; patients with locally recurrent SCLC who are not eligible
for curative intent chemoradiation are eligible

- Patients must have measurable disease based on Response Evaluation Criteria in Solid
Tumors (RECIST) 1.1

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

- Absolute neutrophil count >= 1,500/mm^3 must be obtained =< 7 days prior to protocol
registration

- Platelets >= 100,000/mm^3 must be obtained =< 7 days prior to protocol registration

- Leukocytes >= 3000/mm^3 must be obtained =< 7 days prior to protocol registration

- Hemoglobin >= 9 g/dL must be obtained =< 7 days prior to protocol registration

- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (except subjects
with Gilbert syndrome, who can have total bilirubin < 3 mg/dL) must be obtained =< 7
days prior to protocol registration

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 3 X
institutional upper limit of normal (ULN) (=< 5 X if liver function test [LFT]
elevations due to known liver metastases) must be obtained =< 7 days prior to protocol
registration

- Serum creatinine =< 1.5 x ULN or calculated creatinine clearance > 50 mL/min (using
the Cockcroft-Gault formula) must be obtained =< 7 days prior to protocol registration

- Patients are eligible if central nervous system (CNS) metastases are adequately
treated and neurological symptoms have returned to baseline or are controlled for at
least 2 weeks prior to enrollment; in addition, subjects must be either off
corticosteroids, or on a stable or decreasing dose of =< 10 mg daily prednisone (or
equivalent); patients with untreated CNS metastases are eligible if they are not
symptomatic and the lesions are less than 1 cm in size

- Patients cannot have had prior chemotherapy or biologic therapy for small cell lung
cancer for front line treatment; patients receiving prior whole brain radiation cannot
register within 7 days after completion of radiation, and must have resolved adverse
events attributed to radiation to =< grade 1; a 1-week washout is permitted for
palliative radiation (=< 2 weeks of radiotherapy) to non-CNS disease

- Patients who have received prior chemoradiation treatment with chemotherapy regimen
including cisplatin or carboplatin/etoposide for limited-stage SCLC are eligible if
treated with curative intent at least 6 months since last treatment from diagnosis of
extensive-stage SCLC

- Patients may not be receiving any other investigational agents while on study

- Patients must not have history of allergic reactions attributed to compounds of
similar chemical or biologic composition to nivolumab or other agents used in the
study

- Women must not be pregnant or breast-feeding; breastfeeding must be discontinued or
the subject is not eligible for the study; all females of childbearing potential must
have a blood test or urine study, with a minimum sensitivity 50 mlU/L or equivalent
units of human chorionic gonadotropin (HCG), within 14 days prior to registration to
rule out pregnancy; a female of childbearing potential is any woman, regardless of
sexual orientation or whether they have undergone tubal ligation, who meets the
following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or
2) has not been naturally postmenopausal for at least 24 consecutive months (i.e. has
had menses at any time in the preceding 24 consecutive months)

- Women of childbearing potential (WOCBP) and males who are sexually active with WOCBP
must use an accepted and effective method of contraception or abstain from sexual
intercourse for at least one week prior to the start of treatment, and continue for 5
months after the last dose of protocol treatment for women of childbearing potential
and 7 months after the last dose of protocol treatment for males who are sexually
active with WOCBP

- No prior or current invasive malignancy (except non-melanomatous skin cancer,
localized bladder and prostate cancer) unless disease free for a minimum of 2 years
(for example, carcinoma in situ of the breast, oral cavity, or cervix are all
permissible);

- No prior systemic treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4
antibody, or any other antibody or drug specifically targeting T-cell costimulation or
immune checkpoint pathways;

- Patient must not have leptomeningeal disease

- No patients with an active, known or suspected autoimmune disease and neuromuscular
paraneoplastic syndromes including but not limited to myasthenia gravis, Lambert-Eaton
myasthenic syndrome, limbic encephalitis, myositis, Guillain-Barre; 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

- No patients with a condition requiring systemic treatment with either corticosteroids
(> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 7
days of randomization; inhaled or topical steroids, and adrenal replacement steroid
doses > 10 mg daily prednisone equivalent, are permitted in the absence of active
autoimmune disease

- No patients with interstitial lung disease that is symptomatic or may interfere with
the detection or management of suspected drug-related pulmonary toxicity

- Patients must NOT have uncontrolled intercurrent illness including, but not limited
to, ongoing or active infection, symptomatic congestive heart failure, unstable angina
pectoris, uncontrolled cardiac arrhythmia, or psychiatric illness/social situations
that would limit compliance with study requirements

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible

- Any positive test for hepatitis B virus or hepatitis C virus indicating acute or
chronic infection, patients are excluded

- Patients are ineligible if administration of a live, attenuated vaccine within 4 weeks
before randomization

- No history of severe hypersensitivity reaction to any monoclonal antibody or allergy
to study drug components;