Phase II Clinical Trial of NIVO-IPI-TAXANE in Untreated Metastatic NSCLC

This is an open-label, non-randomized, phase II clinical research study designed to assess
the safety and efficacy of nivolumab and ipilimumab in combination with paclitaxel in
patients with treatment naïve NSCLC.

Patients with histologically confirmed stage IV or recurrent non curable NSCLC of squamous or
non-squamous histology, with no prior systemic anticancer chemotherapy or immunotherapy given
as primary treatment for advanced or metastatic disease may be eligible to participate in
this study.

Patients enrolled into the study will be given the study drugs, nivolumab (360 mg) (Day 1)
every 3 weeks, ipilimumab 1 mg/kg (Day 1) every 6 weeks, and paclitaxel 80mg/m2 on days 1 and
8 of each 21- day study treatment cycle. Paclitaxel will be stopped after a total of 4-6
cycles of treatment. Blood samples and possibly a small piece of tissue may be removed the
patient's lung to see what type of lung cancer cells that she or he may have. Patients will
also have other tests, exams, and procedures for study purposes and their standard of care.
Subject participation in the study will last for up to approximately 48 months after the
start of the study drug or until their condition worsens or they experience intolerable
adverse events as deemed by the study doctor.

There are possible patient risk to this study that include but are not limited to diarrhea,
itching, rash and a feeling of weakness.

Inclusion Criteria:

- Histologically confirmed Stage IV or recurrent Non-small cell lung cancer squamous or
non-squamous histology (Stage IV as diagnosed using the 7th edition of Lung Cancer
Stage Classification), with no prior systemic anticancer therapy given as primary
therapy for advanced or metastatic disease. Prior adjuvant chemotherapy, neoadjuvant
chemotherapy, or chemoradiotherapy is permitted as long as the last administration of
the prior regimen occurred at least 6 months prior to study enrollment. Patients with
EGFR, ALK, or ROS1 alterations must have received one prior TKI.

- A core needle biopsy or surgical specimen must be available for submission.

- At least one site of disease that is measurable by Response Evaluation Criteria in
Solid Tumors (RECIST) Version 1.1 that has not been previously irradiated; if the
patient has had previous radiation to the marker lesion(s), there must be evidence of
progression since the radiation.

- Age ≥ 18 years with ability and willingness to provide informed consent.

- ECOG performance status 0 or 1.

- Negative pregnancy test done ≤72 hours (or per institutional policy) prior to
treatment, for women of childbearing potential only. Female subjects should be using
highly effective contraceptive measures, and must have a negative pregnancy test or
must have evidence of non-child-bearing potential by fulfilling one of the following
criteria at screening:

1. Post-menopausal defined as aged more than 50 years and amenorrheic for at least
12 months following cessation of all exogenous hormonal treatments.

2. Women under 50 years old would be consider postmenopausal if they have been
amenorrheic for 12 months or more following cessation of exogenous hormonal
treatments and with LH and FSH levels in the post-menopausal range for the
institution

3. Documentation of irreversible surgical sterilization by hysterectomy, bilateral
oophorectomy or bilateral salpingectomy but not tubal ligation

- Men and women of childbearing potential must agree to use medically accepted barrier
methods of contraception (e.g. male or female condom) at the time of pregnancy test
(women of childbearing potential only), during the course of the study and for 90 days
after the last dose of study drug, even if oral contraceptives are also used. All
subjects of reproductive potential must agree to use both a barrier method and a
second method of birth control during the course of study and for 90 days after the
last dose of study drug.

- A concurrent diagnosis of a separate malignancy is allowed if clinically stable and
does not require tumor-directed therapy.

- Provision of written informed consent including HIPAA according to institutional
guidelines prior to any study-specific procedures

- Patients must agree to research blood sampling to participate in study;

- Adequate organ and marrow function as defined by the following:

1. Creatinine clearance ≥ 50 cc/min or serum Cr < 1.5 x institutional ULN

2. Total bilirubin ≤ 1.5 x upper limit of normal (ULN)

3. AST/ALT ≤ 2 x ULN without liver metastasis; ≤ 5 x ULN with liver metastasis

4. Absolute neutrophil count (ANC) ≥ 1500 µl

5. Hemoglobin (Hgb) ≥ 9 g/dL

6. Platelets ≥ 100,000/µl

Exclusion Criteria:

- Subjects with known EGFR mutations which are sensitive to available targeted inhibitor
therapy and must have received treatment with at least one prior tyrosine kinase
inhibitor (TKI).

- Subjects with known ALK or ROS1 translocations which are sensitive to available
targeted inhibitor therapy must have received treatment with at least one prior TKI.

- Radiation therapy within 14 days prior to day 1 of study drug.

- Experimental agents within 28 days prior to day 1 of study drug.

- Intolerance of nivolumab or other PD-1/PD-L1 axis drug(s), or any other antibody or
drug specifically targeting T-cell co-stimulation or immune checkpoint pathways,
including prior therapy with anti-tumor vaccines or other immune-stimulatory
anti-tumor agents.

- Known auto-immune conditions requiring systemic immune suppression therapy other than
prednisone < 10 mg daily (or equivalent).

- History of interstitial pneumonitis from any cause.

- Concurrent severe and/or uncontrolled medical conditions which may compromise
participation in the study, including impaired heart function or clinically
significant heart disease.

- Pregnant or breast feeding.

- Not willing to use an effective method of birth control medically accepted barrier
methods of contraception (e.g. male or female condom) at the time of pregnancy test
(women of childbearing potential only), during the course of the study and for 90 days
after the last dose of study drug.

- Current use of medications specified by the protocol as prohibited for administration
in combination with the study drugs. This includes patients with a condition requiring
systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents)
or other immunosuppressive medications within 14 days prior to day 1 of study drug.
Inhaled or topical steroids and adrenal replacement doses >10 mg daily prednisone
equivalents are permitted in the absence of active autoimmune disease.

- Current active infectious disease requiring systemic antibiotics, antifungal, or
antiviral treatment on day 1 of study drug. Patients receiving prophylactic
antibiotics (e.g., for prevention of urinary tract infection or chronic obstructive
pulmonary disease) are eligible.

- Known active CNS metastases which are symptomatic. Eligible if metastases have been
locally treated 14 days prior to cycle 1 day 1, are clinically controlled, or
asymptomatic on cycle 1 day

- Steroid dose must be equivalent of <10 mg prednisone daily or equivalent dose steroid.
Untreated, asymptomatic brain metastases allowed if subject does not require
corticosteroids or anticonvulsant therapy.

- History of myocardial infarction, NYHA class III or IV congestive heart failure, or
unstable angina, cardiac or other vascular stenting, angioplasty, or surgery within 6
months prior to study enrollment.

- Known history of HIV seropositivity or known acquired immunodeficiency syndrome
(AIDS), hepatitis C virus (allowed if received curative therapy), acute or chronic
active hepatitis B infection, or other serious chronic infection requiring ongoing
treatment.

- Inability to comply with protocol or study procedures.