Nivolumab and Plinabulin in Treating Patients With Stage IIIB-IV, Recurrent, or Metastatic Non-small Cell Lung Cancer

PRIMARY OBJECTIVES:

I. To determine the safety and tolerability of the combination of nivolumab and plinabulin.
(Phase I)

II. To determine the overall response rate (ORR) of treatment with nivolumab with the
addition of plinabulin in the treatment of advanced stage non-small cell lung cancer in the
second line setting. (Phase II)

SECONDARY OBJECTIVES:

I. To determine the progression free survival (PFS), disease control rate (DCR), duration of
response (DOR) and overall survival (OS) of patients treated with nivolumab in combination
with plinabulin.

II. To determine the safety and tolerability of the combination of plinabulin and nivolumab.

TERTIARY OBJECTIVES:

I. Patients who have a pre-treatment and/or post cycle one biopsy will have flow cytometry of
their tissue to identify infiltration of immune cells, rates of expression of programmed cell
death 1 (PD-1), programmed cell death 2 (PD-2) and programmed cell death 1 ligand 1 (PDL1).

OUTLINE: This is a phase I, dose-escalation study of plinabulin followed by a phase II study.

Patients receive plinabulin intravenously (IV) over 30 minutes and nivolumab IV over 60
minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression
or unacceptable toxicity.

After completion of study treatment, patients are followed up at 28 days.

Inclusion Criteria:

- Subjects must have histologically or cytologically-documented stage IIIB or stage IV,
recurrent, or metastatic non-small cell lung cancer (NSCLC)

- Subjects must have received prior platinum doublet based treatment

- Up to 2 lines of prior systemic therapy for metastatic disease are permitted

- Adjuvant chemotherapy or concurrent chemoradiation for early stage disease does
not count as prior therapy unless subject progressed within 6 months of
completion of regimen

- Patients with known activating mutations in epidermal growth factor receptor
(EGFR), or known translocation in anaplastic lymphoma kinase (ALK) or ROS-1 are
eligible provided they have progressed on or were intolerant to Food and Drug
Administration (FDA) approved targeted therapy

- Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status of
0 to 2

- Subjects, including those in the dose-escalation portion of the study, must have
measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
criteria; imagining must be within 28 days of trial enrollment

- Target lesions may be located in a previously irradiated field if there is
documented (radiographic) disease progression in that site prior to trial
enrollment

- Absolute neutrophil count (ANC) >= 1000/mm^3

- Platelets >= 75,000/dL

- Hemoglobin >= 9 g/dL

- Total bilirubin =< 1.5 mg/dL x upper limit of normal (ULN) (except subjects with
Gilbert syndrome who can have total bilirubin =< 3.0 mg/dL)

- Serum creatinine =< 1.5 mg/dL or creatinine clearance >= 60 mL/min

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 times the
upper limit of normal if no liver involvement or =< 5 times the upper limit of normal
with liver involvement

- For women of child bearing potential, documented negative pregnancy test within two
weeks of study entry and agreement to acceptable birth control throughout the trial
starting with the screening visit through 120 days after the last dose of study
medication

- Abstinence is an acceptable method of birth control

- Male subjects with a female partner(s) of child-bearing potential must agree to use
acceptable birth control throughout the trial starting with the screening visit
through 120 days after the last dose of study medication

- Capability to understand and comply with the protocol requirements as and signed
informed consent documents

Exclusion Criteria:

- Systemic anticancer therapy within 21 days of the first dose of study drug

- All adverse events from prior systemic therapy must have either stabilized or
returned to baseline

- Prior treatment with nivolumab or any other PD1/PDL1 checkpoint inhibitor

- Major medical conditions that might affect study participation (e.g. uncontrolled
pulmonary, renal, or hepatic dysfunction, uncontrolled serious infection, cardiac
disease)

- Significant cardiac history:

- History of myocardial infarction or ischemic heart disease within 1 year before
first study drug administration;

- Uncontrolled arrhythmia;

- History of congenital QT prolongation;

- New York Heart Association class III or IV cardiac disease;

- Uncontrolled hypertension: blood pressure consistently greater than 150 mm Hg
systolic and 100 mm Hg diastolic in spite of antihypertensive medication

- History of hemorrhagic diarrhea, inflammatory bowel disease or active uncontrolled
peptic ulcer disease; (concomitant therapy with ranitidine or its equivalent and/or
omeprazole or its equivalent is acceptable); history of ileus or other significant
gastrointestinal disorder known to predispose to ileus or chronic bowel hypomotility

- Subjects with untreated symptomatic central nervous system (CNS) metastases are
excluded

- Subjects are eligible if symptomatic CNS metastases are treated and subjects have
neurologically returned to baseline (except for residual signs and symptoms
related to CNS treatment) for at least 7 days prior to first dose of study
treatment

- Subjects must be off corticosteroids for at least 7 days prior to first dose
of study treatment

- Subjects with leptomeningeal disease are excluded

- Subjects with planned radiation therapy to a target lesion will be excluded

- Radiation therapy within 14 days of the first dose of study drug

- Subjects who are pregnant or breastfeeding are excluded

- Subjects who are unable or unwilling to abide by the study protocol or cooperate fully
with the investigator or designee are excluded

- Pulmonary conditions such as sarcoidosis, silicosis, idiopathic pulmonary fibrosis, or
hypersensitivity pneumonitis are excluded

- Subject who have active non-infectious pneumonitis

- Subjects who have a diagnosis of immunodeficiency or are receiving systemic steroid
therapy or any other form of immunosuppressive therapy within 7 days prior to the
first dose of study treatment

- Subjects with any 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 asthma that require intermittent use of bronchodilators, inhaled
steroids, or local steroid injections would not be excluded from the study

- Subjects on chronic systemic steroids for any reason would be excluded from the
study; the use of topical steroids is allowable

- Any known additional malignancy (with exception of non-melanoma skin cancer, in-situ
breast cancer or a malignancy diagnosed >= 3 years ago and with no evidence of
requiring active treatment)

- Patients with known active hepatitis B, or hepatitis C will be excluded

- Patients with risk factors for bowel obstruction or bowel perforation (e.g., acute
diverticulitis) will be excluded

- Has any serious or uncontrolled active infection