Plinabulin vs. Pegfilgrastim in Patients With Solid Tumors Receiving Docetaxel Myelosuppressive Chemotherapy

This is a multicenter, double-blind, randomized study with a phase 2 portion and a phase 3
portion. Approximately 190 patients will be enrolled in this study.

All patients will receive docetaxel at a dose of 75 mg/m2.

In Phase 2, patients only with advanced or metastatic NSCLC after failing platinum based
therapy will be enrolled.

In Phase 3, patients with one of the following will be enrolled: advanced or metastatic
breast cancer, who have failed ≥ 1 but < 5 prior lines of chemotherapy; locally advanced or
metastatic NSCLC after platinum therapy failure; or hormone refractory (androgen independent)
metastatic prostate cancer.

The eligibility of all patients will be determined during a 28-day screening period.

Phase 2:

Approximately 40 patients with advanced and metastatic NSCLC will be enrolled. Patients are
randomly assigned, with 10 patients enrolled in each arm, with the arm designation and
planned intervention as follows:

Arm 1: Docetaxel (75 mg/m2) + pegfilgrastim (6 mg)

Arm 2: Docetaxel (75 mg/m2) + plinabulin (20 mg/m2)

Arm 3: Docetaxel (75 mg/m2) + plinabulin (10 mg/m2)

Arm 4: Docetaxel (75 mg/m2) + plinabulin (5 mg/m2)

The study will be temporarily closed to enrollment when 40 patients have been enrolled and
completed at least 1 treatment cycle in each arm in phase 2. The Sponsor will notify the
study sites when this occurs.

Once the study is temporarily closed to enrollment in phase 2, a PK/PD analysis will be
performed to determine the RP3D. The PK/PD analysis will be done by an independent party at
the time 40 patients in Phase 2 have completed at least Cycle 1. This analysis will be
blinded to the study team.

Phase 3:

Phase 3 will not begin until RP3D has been determined based on the phase 2 PK/PD analysis as
mentioned above; the RP3D will be the only plinabulin dose administered in Phase 3. A fixed
dose of 40 mg has been selected as the RP3D.

Approximately 150 patients are planned to be enrolled in the Phase 3 with one of the
following diagnosis: advanced or metastatic breast cancer, who have failed ≥ 1 but < 5 prior
lines of chemotherapy; locally advanced or metastatic NSCLC after platinum therapy failure;
or hormone refractory (androgen independent) metastatic prostate cancer. Each eligible
patient will be stratified according to his or her diagnosis (advanced or metastatic breast
cancer, NSCLC, or HRPC). Patients will be randomly assigned with equal probability (1:1
ratio) or 75:75, with the arm designation and planned intervention as follows:

Arm 1: Docetaxel (75 mg/m2) + pegfilgrastim (6 mg) + placebo matching plinabulin

Arm 2: Docetaxel (75 mg/m2) + plinabulin (40 mg) + placebo matching pegfilgrastim

In order to facilitate balanced treatment arms with respect to cancer type, once either arm
reaches at least 1/3 (of total) of patients with that cancer type, it will be closed to that
cancer type and enrollment will continue for patients with the other cancer types, up to the
planned maximum number of patients.

Data from all patients receiving the RP3D plinabulin dose in Phase 2 and Phase 3 will not be
pooled for assessing the primary and secondary study endpoints, but analyzed separately.

Inclusion Criteria:

1. At least ≥ 18 years of age (male or female) at the time of signing the informed
consent form.

2. ECOG performance status of 0 to 1.

3. Patients with:

Phase 2 only:

- Advanced or metastatic NSCLC failing platinum based therapy

Phase 3 only:

- Advanced or metastatic breast cancer, who have failed of chemotherapy

- Locally advanced or metastatic NSCLC after platinum therapy failure

- Hormone refractory (androgen independent) metastatic prostate cancer (HRPC).

4. Pathology confirmation of cancer is required.

5. Patients with ≥ 1 of the following risk factors, at the initiation of docetaxel
chemotherapy, that would require neutropenia prophylaxis per National Comprehensive
Cancer Network (NCCN) guidelines (version 2, 2016) Myeloid Growth Factors (refer to
Appendix C):

- Prior chemotherapy or radiation treatment

- Bone marrow involvement by tumor

- Surgery and/or open wounds within 4 weeks of first administration of study drug

- Age > 65 years of age and receiving full chemotherapy dose intensity

6. Life expectancy of 3 months or more.

7. The following laboratory results provided by the central laboratory within 14 days
prior to study drug administration:

- Hemoglobin >/= 9 g/dL independent of transfusion or growth factor support

- Absolute neutrophil count >/= 1.5 x 10**9/L independent of growth factor support

- Serum total bilirubin patient has a diagnosis of Gilbert's disease in which case direct bilirubin < t
1.5 times ULN of the direct bilirubin. Aspartate aminotransferase (AST) and
alanine aminotransferase (ALT) phosphatase is > 2.5 x ULN)

- Serum creatinine
Note: Results are from the central laboratory. Local laboratory results may be
accepted on a case by case basis after discussion with the Medical Monitor, however in
this case central laboratories must also be taken within the screening time window.

8. Prothrombin time (PT)/International Normalized Ratio (INR) ≤ 1.5 × upper limit of
normal (ULN), activated partial thromboplastin time (PTT) ≤ 1.5 × ULN, based on
central laboratory results.

9. Female subjects of childbearing potential have a negative pregnancy test at screening.
Females of childbearing potential are defined as sexually mature women without prior
hysterectomy or who have had any evidence of menses in the past 12 months. However,
women who have been amenorrhoeic for 12 or more months are still considered to be of
childbearing potential if the amenorrhea is possibly due to prior chemotherapy,
anti-estrogens, or ovarian suppression.

- Women of childbearing potential (i.e., menstruating women) must have a negative
urine pregnancy test (positive urine tests are to be confirmed by serum test)
documented within the 24-hour period prior to the first dose of study drug.

- Sexually active women of childbearing potential enrolled in the study must agree
to use two forms of accepted methods of contraception during the course of the
study and for 3 months after their last dose of study drug. Effective birth
control includes (a) intrauterine device (IUD) plus one barrier method; (b) on
stable doses of hormonal contraception for at least 3 months (e.g., oral,
injectable, implant, transdermal) plus one barrier method; (c) 2 barrier methods.
Effective barrier methods are male or female condoms, diaphragms, and spermicides
(creams or gels that contain a chemical to kill sperm); or (d) a vasectomized
partner.

- For male patients who are sexually active and who are partners of premenopausal
women: agreement to use two forms of contraception during the treatment period
and for at least 3 months after the last dose of study drug.

Exclusion Criteria:

1. History of myelogenous leukemia, myelodysplastic syndrome or concomitant sickle cell
disease.

2. Received chemotherapy within 4 weeks prior to the first dose of study drug.

3. Received prior docetaxel treatment, except if docetaxel received as adjuvant therapy
for breast cancer > 1 year before the first dose of study drug.

4. Received no prior chemotherapy or >/= 5 lines of cytotoxic chemotherapy for advanced
or metastatic breast cancer (adjuvant chemotherapy will count as one line of
chemotherapy, and any hormonal or biological, non conjugate therapy [e.g.,
trastuzumab] will not count as a line of therapy).

5. Current use of strong cytochrome P450 (CYP) 3A4 inhibitors, within 3 days of the first
administration of study drug, and 7 days after treatment with taxanes OR requires use
of strong CYP3A4 inhibitors (refer to Section 11.6.2)

6. Received an investigational agent or tumor vaccine within 2 weeks before the first
dose of study drug; patients must have recovered from toxicity of prior treatment and
have no > Grade 1 treatment emergent AEs.

7. Receiving any concurrent anticancer therapies.

8. Received a prior bone marrow or stem cell transplant.

9. Has a co-existing active infection or received systemic anti-infective treatment
within 72 hours before the first dose of study drug.

10. Prior radiation therapy within the 4 weeks before the first dose of study drug.

11. Prior use of pegfilgrastim or filgrastim within 4 weeks before the first dose of study
drug.

12. Presence of any serious or uncontrolled illness including, but not limited to:
uncontrolled diabetes, ongoing or active infection, symptomatic congestive heart
failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, uncontrolled
arterial thrombosis, symptomatic pulmonary embolism, or psychiatric illness that would
limit compliance with study requirements, or any other conditions that would preclude
the patient from study treatment as per the discretion of the Investigator.

13. Significant cardiovascular history:

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

- Uncontrolled arrhythmia;

- History of congenital QT prolongation;

- Electrocardiogram (ECG) findings consistent with active ischemic heart disease;

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

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

14. 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.

15. Any other malignancy requiring active therapy.

16. Known human immunodeficiency virus (HIV) seropositivity.

17. Active Hepatitis B virus (HBV) infection which requires antiviral treatment. Patients
with detectable Hepatitis B surface Antigen (HBsAg) may be eligible provided the
patient has a negative viral load. Patients with a positive HBsAg must have a negative
viral load before each chemotherapy administration. Hepatitis B surface antibody (anti
HBs) without detectable HBsAg does NOT exclude patients from the study. Hepatitis C
infection (Hepatitis C antibody reactive) which requires treatment also excludes
patients from the study.

18. Female subject who is pregnant or lactating.

19. Unwilling or unable to comply with procedures required in this protocol