Nivolumab in Combination With Plinabulin in Patients With Metastatic Non-Small Cell Lung Cancer (NSCLC)

Plinabulin is a microtubule destabilizing agent (MDA) that inhibits the polymerization of
tubulin monomers with resultant vascular disrupting properties. Plinabulin inhibits tumor
growth by targeting both angiogenesis and tumor vasculature as well as directly by inducing
apoptosis via the Ras-JNK pathway. It also may activate anti-tumor immunity via inducing
maturation of dendritic cells (DC) and triggering release of pro-inflammatory cytokines.
Plinabulin could therefore have a synergic anti-tumor effect when combined with
immune-checkpoint inhibitors. This hypothesis has been confirmed in a murine model bearing
subcutaneous MC38 colon cancers using other MDAs, including ansamitocin P3, which induces DC
maturation similar to that of plinabulin. Plinabulin has been tested in a randomized phase 2
trial in combination of docetaxel and showed similar response rate to that of docetaxel
alone, but with a significantly longer duration of response.

Nivolumab is an inhibitor of the programmed cell death receptor-1 checkpoint pathway (PD-1)
that has superior activity in NSCLC, regardless of tumor histology, comparing to standard of
care. In this study, we plan to combine nivolumab with escalating doses of plinabulin to
determine the maximum tolerated dose (MTD) and /or recommended Phase 2 dose (RP2D) of the
combination. An expansion cohort will be enrolled at RP2D to further assess toxicities and to
evaluate preliminary anti-tumor activity.

This is a single-center, phase 1 dose finding trial of plinabulin, combining with FDA
approved dose of nivolumab, using a 3+3 design in patients with metastatic NSCLC who
progressed after chemotherapy, including a platinum-containing regimen. Patients will receive
plinabulin at escalating doses in combination with nivolumab. Doses of plinabulin and
nivolumab will be administered as intravenous infusions in 4-week cycles. Patients will
receive both medications on Days 1 and 15 and additional dose of plinabulin on Day 8.
Plinabulin will be administered 60 minutes after the completion of nivolumab.

Inclusion Criteria:

- Subjects with histologically or cytologically-confirmed metastatic NSCLC whose disease
progressed during/after treatment with at least one platinum-containing chemotherapy
regimen.

- At least 1 prior systemic therapy for metastatic disease. Adjuvant chemotherapy or
concurrent chemoradiation for early stage disease does not count as prior therapy
unless patients progressed within 6 months of completion of chemotherapy

- Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1

- Life expectancy ≥ 12 weeks

- Must have at least 1 measurable lesion per Response Evaluation Criteria in Solid
Tumors (RECIST).

- Adequate hematopoietic, electrolyte, hepatic, and renal laboratory findings.

- Prior chemotherapy must have been completed at least 4 weeks or at least 5 half-lives
(whichever is longer) before study drug administration, and all adverse events have
either returned to baseline or stabilized

- Prior treated brain metastases are allowed. However, prior treated brain metastases
must be without MRI evidence of progression for at least 4 weeks and off systemic
steroids for at least 2 weeks before study drug administration

- Prior definitive radiation therapy must have been completed at least 4 weeks before
study drug administration. Prior palliative radiotherapy should be completed at least
2 weeks before study drug administration. Whole brain radiation therapy (WBRT),
stereotactic radiosurgery (SRS) and focal radiation to the sites of pain or bronchial
obstruction will be considered palliative. No radiopharmaceuticals (strontium,
samarium) within 8 weeks before study drug administration

- Prior major surgery must be completed at least 4 weeks before study drug
administration. Prior minor surgery must be completed at least 1 week before study
drug administration and subjects should be recovered. Percutaneous biopsies should be
completed at least 10 days prior to study drug administration;

- A negative serum pregnancy test at screening for women of childbearing potential.

Exclusion Criteria:

- History of grade 3 or above hypersensitivity reactions to other monoclonal antibodies

- Subjects with a history of a cardiovascular illness.

- Uncontrolled hypertension, SBP> 160 or DBP>100

- Symptomatic or untreated brain metastases

- Presence of leptomeningeal disease

- Pulmonary conditions, which in the PI's opinion would increase the risk of
immunotherapy-related pulmonary toxicity.

- Has active, non-infectious pneumonitis

- Presence of a second malignancy, excluding non-melanomatous skin cancer unless in
remission for 3 years

- Subjects with any active, known, or suspected autoimmune disease.

- History of ileus or other significant gastrointestinal disorder known to predispose to
ileus or chronic bowel hypomotility.

- Prior therapy with microtubule destabilizing agents for NSCLC (ie. Vinorelbine)

- Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody (or
any other antibody targeting T cell co-stimulation pathways);

- Known history of Human Immunodeficiency Virus;

- Active infection requiring therapy, positive tests for Hepatitis B surface antigen or
Hepatitis C ribonucleic acid (RNA)

- Underlying medical conditions that, in the Investigator's opinion, will make the
administration of study drug hazardous or obscure the interpretation of toxicity
determination or adverse events

- Concurrent medical condition requiring the use of immunosuppressive medications, or
systemic steroids.

- Use of other investigational drugs within 28 days or at least 5 half-lives before
study drug administration

- Pregnant or nursing