Study Of Induction Checkpoint Blockade For Untreated Stage I-IIIA Non-Small Cell Lung Cancers Amenable For Surgical Resection

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to 1 of 3
study groups based on when you join the study.

If you are in the first 44 participants to join the study, you will be randomly assigned (as
in the flip of a coin) to either Group A or Group B. This is done because no one knows if one
study group is better, the same, or worse than the other group. Up to 22 participants will be
enrolled in Group A, and up to 22 in Group B.

After enrollment in Groups A and B is complete (44 total participants), if you join the study
after that, you will be assigned to Group C. Up to 22 participants will be enrolled in Group
C.

If you are in Group A, you will receive nivolumab alone.

If you are in Group B, you will receive ipilimumab and nivolumab.

If you are in Group C, you will receive one of these combinations, depending on what type of
NSCLC you have:

- nivolumab, cisplatin, and docetaxel

- nivolumab, cisplatin, and pemetrexed

Study Drug Administration:

If you are in Group A, you will receive nivolumab by vein over 60 minutes on Days 1, 15, and
29.

If you are in Group B, you will receive nivolumab by vein over 60 minutes on Days 1, 15, and
29. You will also receive ipilimumab by vein over 90 minutes on Day 1.

If you are in Group C, and depending on which treatment you are assigned within this group
based on your type of NSCLC, you will receive nivolumab, cisplatin, and either docetaxel or
pemetrexed as follows.

On Days 1, 22, and 43, you wll receive nivolumab by vein over about 30 minutes. You will
receive cisplatin by vein over about 2 hours. If you receive docetaxel, you will receive it
by vein over about 1 hour. If you receive pemetrexed, you will receive it by vein over about
10 minutes.

Length of Treatment:

You may receive 3 doses of nivolumab before your scheduled surgery. However, in some cases
fewer than 3 doses of nivolumab may be allowed before surgery.

If you are in Group B, you may receive 1 dose of ipilimumab.

If you are in Group C, you may receive either 3 doses of cisplatin and docetaxel or 3 doses
of cisplatin and pemetrexed.

Your surgery to remove the disease will most likely be performed at least 21 days after the
last dose of nivolumab or nivolumab plus platinum-based chemotherapy. You will sign a
separate consent form that explains the procedure and its risks.

Your participation on the study will be over after the follow-up.

Study Visits:

Within 7 days before your Day 15 and Day 29 nivolumab doses if you are in Groups A or B, or
nivolumab plus platinum-based chemotherapy doses if you are in Group C:

- You will have a physical exam.

- Blood (about 5½ tablespoons) will be drawn for routine and biomarker testing.

At least 14 days after the last nivolumab dose or nivolumab plus platinum-based chemotherapy
dose on Day 29:

- You will have a PET-CT scan and a CT scan of the chest.

- Blood (about 4 tablespoons) will be drawn for biomarker testing.

- You will have lung function tests.

- You will provide a stool sample for biomarker testing.

Leftover tissue removed during surgery (normal tissue, tumor tissue, and lymph tissue) will
be collected and stored at MD Anderson for use in future biomarker testing. No extra tissue
will be removed, as it is tissue that would be removed anyway for surgery and to check the
status of the disease. A research bank will be created so that biomarker testing can be
performed for as long as needed.

Your samples will be given a code number. No identifying information will be directly linked
to your samples. Only the researcher in charge of the bank will have access to the code
numbers and be able to link the samples to you. This is to allow medical data related to the
samples to be updated as needed.

End-of-Treatment Visit:

Within 8 weeks after surgery:

- You will have a physical exam.

- Blood (about 4 tablespoons) will be drawn for biomarker testing.

Follow-Up:

After the end-of-treatment visit, your medical record will be reviewed or you (or family
members or other people that you choose) will be called, contacted by mail, or e-mailed to
check on your health. If you are called, these calls should last about 5 minutes. You may
also be asked these questions during regularly scheduled clinic visits.

The follow-up period will last for as long as the study doctor thinks the information is
needed (to collect long-term information about the study).

Inclusion Criteria:

1. Age >/= 18 years

2. Histologically or cytologically confirmed previously untreated non-small cell lung
cancer. If a diagnostic biopsy is available, a pre-treatment biopsy is not required.
Patients with a suspected lung cancer are eligible, but pathology must be confirmed
prior to initiating treatment on study. Neuroendocrine carcinomas are not eligible.
Carcinomas with neuroendocrine differentiation are eligible

3. Patients with stage IA or stage IB < 4 cm (according to AJCC 7th edition) are eligible
for randomization into arms A and B only. Patients with stage IB >/= 4cm, IIA, IIB, or
IIIA disease (according to AJCC 7th edition) are eligible for randomization into arms
A, B, and C

4. Patients with stage IIIA must not have more than one mediastinal lymph node station
involved by tumor

5. All patients must have lymph node evaluation of contralateral stations 2 and/or 4 to
exclude N3 disease

6. The patient must be a suitable candidate for surgery, in the opinion of the treating
physician

7. Signed and dated written informed consent must be provided by the patient prior to
admission to the study in accordance with ICH-GCP guidelines and to the local
legislation

8. ECOG performance status score 0-1

9. Patients must have organ and marrow function as defined below: (Hematologic) Absolute
neutrophil count (ANC) >/= 1.5 X 10^9/L , Hemoglobin >/= 8.0 g/dL, Platelets >/= 100 X
10^9/L, (Hepatic) Total bilirubin who can have total bilirubin < 3.0 mg/dL), (Renal) Creatinine Calculated creatinine clearance >/= 50 mL/min using Cockcroft-Gault formula for
creatinine clearance calculation: For Female CrCL= (140 - age in years) x weight in kg
x 0.85 divided by 72 x serum creatinine in mg/dL; For Male CrCL = (140 - age in years)
x weight in kg x 1.00 divided by 72 x serum creatinine in mg/dL OR 24-hour urine
creatinine clearance >/= 50 mL/min

Exclusion Criteria:

1. Prior systemic therapy or radiation therapy for treatment of the current lung cancer

2. Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy, or
biologic therapy) or investigational anti-cancer drug

3. Pregnant or lactating female: Women of childbearing potential (WOCB) must have a
negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent
units of HCG) within 72 hours prior to the start of nivolumab; Women of childbearing
potential is defined as any female who has experienced menarche and who has not
undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is
not postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a
woman over 45 in the absence of other biological or physiological causes

4. Unwillingness or inability to follow the procedures required in the protocol

5. Patients with pre-existing peripheral neuropathy NCI CTC grade 2 or worse

6. Patients with a history of severe hypersensitivity reaction to Taxotere and or
polysorbate 80 must be excluded

7. Any serious or uncontrolled medical disorder that, in the opinion of the investigator,
may increase the risk associated with study participation or study drug
administration, impair the ability of the subject to receive protocol therapy, or
interfere with the interpretation of study results

8. Prior malignancy active within the previous 2 years. Patients with locally curable
cancers that have been apparently cured, such as basal or squamous cell skin cancer,
superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast
with local control measures (surgery, radiation) are eligible

9. Subjects with active, known or suspected autoimmune disease. Subjects with 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 are permitted
to enroll

10. Subjects with 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. Subjects are permitted to use topical, ocular, intra-articular,
intranasal, and inhalational corticosteroids (with minimal systemic absorption).
Physiologic replacement doses of systemic corticosteroids are permitted, even if > 10
mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxis (eg,
contrast dye allergy) or for treatment of non-autoimmune conditions (eg, delayed-type
hypersensitivity reaction caused by contact allergen) is permitted

11. Prior treatment with an anti-PD-1, anti-PD-L1 or anti-CTLA-4 antibody

12. Known positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C
virus ribonucleic acid indicating acute or chronic infection

13. Known history of testing positive for human immunodeficiency virus or known acquired
immunodeficiency syndrome

14. History of severe hypersensitivity reaction to any monoclonal antibody and/or to study
drug components

15. Serious illness or concomitant non-oncological disease such as neurologic,
psychiatric, infectious disease or laboratory abnormality that may increase the risk
associated with study participation or study drug administration and in the judgment
of the investigator would make the patient inappropriate for entry into the study

16. Patients who are sexually active, with preserved reproductive capacity, and unwilling
to use a medically acceptable method of contraception (e.g. such as implants,
injectables, combined oral contraceptives, some intrauterine devices or vasectomized
partner for participating females, condoms for participating males) during and after
the trial as detailed below:

17. This is a continuation of 16): WOCBP should use an adequate method to avoid pregnancy
for 23 weeks after the last dose of investigational drug(s); 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 31 weeks after the last dose of
investigational product; Women who are not of childbearing potential as well as
azoospermic men do not require contraception

18. Psychological, familial, sociological or geographical factors potentially hampering
compliance with the study protocol and follow-up schedule