Docetaxel + Plinabulin Compared to Docetaxel + Placebo in Patients With Advanced NSCLC

Lung cancer is the leading cause of cancer-related mortality worldwide. A report published by
the WHO in February 2014, estimated there were 1.83 million new cases and 1.59 million deaths
worldwide in 2012. The American Lung Association reports 399,431 Americans living with lung
cancer, with an estimated 221,200 new cases predicted to be diagnosed in 2015; of those cases
158,040 patients will die of their lung cancer which accounts for approximately 29% of all
cancer deaths in the U.S. Similarly, lung cancer is the most frequent cancer in China and is
among the 1.96 million estimated annual cancer related deaths. Non-small cell lung cancer
(NSCLC) accounts for about 85% of lung cancer in China, and approximately half of the
patients present with advanced disease at the time of diagnosis.

The prognosis for patients with advanced or metastatic NSCLC, either at initial diagnosis or
recurrence, remains grim. The mainstay of standard of care has been chemotherapy with agents
including platinum analogs, taxanes, vinca alkaloids, pemetrexed, vascular endothelial growth
factor (VEGF) inhibitors. For patients with appropriate disease genotypes, first line therapy
has also included, epidermal growth factor receptor (EGFR) inhibitors or anaplastic lymphoma
kinase (ALK) inhibitors.

In both China and the US, first-line chemotherapy consists of a regimen based on one of two
platinum-based drugs (etoposide cisplatin and etoposide carboplatin). The platinum analogs
are commonly combined with paclitaxel, docetaxel, gemcitabine and vinorelbine while other
drugs such as irinotecan, etoposide and vinblastine are also used.

For those patients intolerant to platinum-containing regimen, platinum-free double-agent
chemotherapy regimens are used as an alternative. For those patients with ECOG score as 2 or
the elderly patients, single-agent or double-agent regimens are recommended. The chemotherapy
of cisplatin plus vinorelbine may recombine human endostatin. China has approved that
single-agent gefitinib may be used in first-line treatment of locally advanced or metastatic
NSCLC patients with sensitive mutation of epidermal growth factor receptor tyrosine kinase
gene.

Second-line Chemotherapy: In both China and the US, the drugs used for second-line treatment
include docetaxel, pemetrexed and the targeted drug EGFR-TKI.

Several drugs [docetaxel, pemetrexed, erlotinib, gefitinib (outside U.S and in China), and
ramucirumab combined with docetaxel] have been approved as single agents or combination for
second line therapy for locally advanced or metastatic NSCLC, but with limited efficacy, that
is, limited clinical significant improvement or overall survival.

Docetaxel, a taxane, binds to and stabilizes tubulin, thereby inhibiting microtubule
disassembly resulting in cell cycle arrest at the G2/M phase and cell death. In patients with
NSCLC previously treated with a platinum-based chemotherapy, second line therapy with
docetaxel afforded a median overall survival (OS) in the range from 5.7 to 7.5 months. The
most common adverse reactions included infections, neutropenia, anemia, febrile neutropenia,
hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia,
nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis,
alopecia, skin reactions, and myalgia. Since the approval of docetaxel in 1999 as the second
line treatment for advanced or metastatic NSCLC, other drugs, namely pemetrexed, erlotinib,
have been approved in the same indication. However, despite the availability of newer
treatment, patient survival did not demonstrably improve over docetaxel. The OS from these
trials remained in the range of 5.6-8.3 months.

With the advent of molecular profiling, it became possible to select patients based on
disease genomic characteristics and match disease genotype with appropriate treatment. EGFR
TKIs were found to be particularly effective in patients with EGFR mutation, and similarly
crizotinib was highly effective in patients with ALK translocation. However, NSCLC patients
with EGFR mutation or ALK translocation are the minority. For the 80-90% of patients in the
U.S. without EGFR mutation, chemotherapy with docetaxel is the standard of care for the
second line of treatment. As recently reported from the TAILOR trial, docetaxel demonstrated
a statistically significant survival improvement compared to erlotinib. The median overall
survival was 8.2 months (95% CI 5.8-10.9) with docetaxel versus 5.4 months (4.5-6.8) with
erlotinib (adjusted hazard ratio [HR] 0.73, 95% CI 0.53-1.00; p=0.05).

As discussed below, a retrospective analysis of the plinabulin phase II study suggests that
plinabulin prolongs progression and survival in NSCLC patients with measurable lung tumors.
Tumor size is a well known prognostic factor for survival in NSCLC; patients with large
tumors have a shorter survival than patients with smaller tumors. Among patients with
recurrent or metastatic disease, especially those wildtype for EGFR or ALK, the presence of
large lesions carries particularly grim prognosis, and treatment of these tumors represents
an unmet medical need.

Large tumors carry a rich tumor vasculature which may make them more susceptible to drugs
such as plinabulin. Plinabulin inhibits angiogenesis, disrupts existing tumor vasculature as
well as induces cancer cell apoptosis.

This study investigates the efficacy and safety of plinabulin and docetaxel combination in
patients with wild type NSCLC and large tumors requiring 2nd line therapy for advanced or
metastatic disease after failing a platinum-containing regimen. The primary endpoint is
overall survival (OS) with docetaxel alone as active comparator.

INCLUSION CRITERIA:

1. ECOG performance status ≤ 2.

2. Histopathologically or cytologically confirmed NSCLC.

3. Disease progression during or after treatment with one or two treatment regimen(s)
Treatment regimens can be chemotherapy, targeted therapy, biological therapy, or
immunotherapy for advanced (Stage IIIB) or metastatic disease (Stage IV). Modification
of a regimen to manage toxicity with a different drug does not constitute a new
regimen. Maintenance therapy following platinum-based chemotherapy is not considered
as a separate regimen. Adjuvant or neoadjuvant chemotherapy and/or chemo-radiation for
early stage disease do not count as prior systemic therapy. Prior radiation therapy is
not exclusionary. Prior immunotherapy with a PD-1/PD-L1 inhibitor is not exclusionary.
Prior treatment for advanced or metastatic disease must have included a platinum-based
regimen. (Treatment of early stage disease [Stage IIIA or earlier] with a
platinum-containing therapy does not count).

4. At least 1 lesion ≥10 mm in longest diameter in lung parenchyma.

5. patients with nonsquamous NSCLC must have been tested for EGFR exon 19 deletion and
Exon 21 L858R substitution mutation. Only patients without EGFR sensitizing mutations
are eligible, and they must have progressed on platinum-based chemotherapy. Patients
with known ALK-rearrangements should be treated with an appropriate tyrosine kinase
inhibitor (TKI) before entering the study. The TKI regimen would count as a line of
treatment

6. Patients with active brain metastasis or leptomeningeal involvement with brain
metastases who are asymptomatic, and whose lesions by imaging are at least stable and
without interim development of new lesions for at least 4 weeks may be enrolled.

7. All AE's of prior systemic therapy, surgery, or radiotherapy, must have resolved to
CTCAE v 4.03 Grade ≤2, except for neurological AE's that must have resolved to Grade
≤1.

8. The following laboratory results ≤14 days prior to study drug admin:

Hgb ≥9 g/dL independent of transfusion or growth factor support; absolute neutrophil
count 1.5x10^9/L independent of growth factor support; platelet count ≥100x10^9/L
independent of transfusion or growth factor support; Serum total bilirubin ≤ ULN,
unless the patient has a diagnosis of Gilbert's disease then serum bilirubin 3.0 times
ULN;

9. AST & ALT ≤2.5 x ULN(≤1.5 x ULN if alkaline phosphatase is > 2.5 x ULN), and serum
creatinine ≤1.5 x ULN.

10. Life expectancy >12 weeks.

11. Female patients of childbearing potential have a negative pregnancy test at baseline.

12. Signed informed consent.

EXCLUSION CRITERIA: Patients with any of the following:

1. Administration of chemo, biological, immunotherapy, radiotherapy or investigational
agent (therapeutic or diagnostic) ≤3 weeks prior to receipt of study medication. Major
surgery, other than diagnostic surgery, ≤4 weeks before first study drug admin.

2. Significant cardiac history:

History of myocardial infarction or ischemic heart disease ≤1 year before 1st study
drug administration; uncontrolled arrhythmia; history of congenital QT prolongation;
ECG findings consistent with acute ischemic heart disease; NYHA Class III-IV cardiac
disease; & uncontrolled hypertension: BP consistently >150 mm Hg systolic & 100 mm Hg
diastolic in spite of antihypertensive medication

3. Patients who have received prior treatment with docetaxel.

4. Prior transient ischemic attack or cerebrovascular accident with in the past year.
Neurologic toxicities ≥Grade 2 within 3 weeks of randomization.

5. 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.

6. Active uncontrolled bacterial, viral, or fungal infection requiring systemic therapy.

7. Known infection with human immunodeficiency virus (HIV) or active hepatitis A, B, or
C.

8. Known prior hypersensitivity reaction to any product containing polysorbate 80,
Polyoxyethylene 15 hydroxystearate/Macrogol 15 Hydroxystearate (Solutol HS 15).

9. Female subject who is pregnant or lactating

10. Second malignancy unless in remission for >5 years. (Non-melanoma skin cancer or
carcinoma in situ of the cervix treated with curative intent is not exclusionary.)

11. Medical conditions that would impose excessive patient risk. Examples: uncontrolled
diabetes, infection requiring parenteral anti infective treatment, liver failure,
altered mental status or psychiatric condition that would interfere with the
understanding of the informed consent.

12. Unwilling or unable to comply with protocol.