Clinical trial NCT04345900
Conditions: Chemotherapy-induced Neutropenia
Sponsor: BeyondSpring Pharmaceuticals Inc.
Start date: 2017-04-05; Completion date: 2018-04-20
Enrollment: 55 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To assess the duration of severe neutropenia (DSN) in treatment Cycle 1 in patients treated with docetaxel (75 mg/m2) + plinabulin (5, 10, or 20 mg/m2) or with docetaxel (75 mg/m2) + pegfilgrastim (6 mg). Neutrophils count was to be assessed at baseline (prior to Cycle 1 docetaxel dose) and during Cycle 1 on Days 1, 2, 6, 7, 8, 9, 10, and 15 (pre-dose on dosing days; times equivalent to pre dose on other days).

Detailed description:
55 patients with advanced and metastatic NSCLC have been randomized 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/m\^2) Arm 3: Docetaxel (75 mg/m2) + plinabulin (10 mg/m\^2) Arm 4: Docetaxel (75 mg/m2) + plinabulin (5 mg/m\^2)

Arms: arm 1: 75 mg/m\^2 Docetaxel + 20 mg/m\^2 Plinabulin arm 2: 75 mg/m\^2 Docetaxel + 10 mg/m\^2 Plinabulin arm 3: 75 mg/m\^2 Docetaxel + 5 mg/m\^2 Plinabulin arm 4: 75 mg/m\^2 Docetaxel + 6 mg Pegfilgrastim
Interventions: intervention 1: Plinabulin intervention 2: Pegfilgrastim
Intervention descriptions: intervention 1: a synthetic, low molecular weight, new chemical entity that belongs to the diketopiperazine class of compounds. Plinabulin is intended for intravenous (IV) infusion and is diluted in D5W and administered for 30 minutes (± 5 minutes). intervention 2: PEGFILGRASTIM is a long-acting granulocyte colony-stimulating factor that stimulates the growth of neutrophils, to reduce the incidence of fever and infection in patients with certain types of cancer who are receiving chemotherapy that affects the bone marrow.

Protocol documents:
Prot_000.pdf: 
Document Cover Page 
Official Title: A Phase 2/3, Multicenter, Randomized, Double Blind Study to Evaluate 
Duration of Severe Neutropenia with Plinabulin Versus Pegfilgrastim in Patients with Solid 
Tumors Receiving Docetaxel Myelosuppressive Chemotherapy (Protective 1)  
NCT Number: NCT04345900 
Document Date: 30 May 2017


Protocol BPI-2358-105 
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Protocol Amendment 3 Date: 
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TITLE PAGE 
Protocol Title: 
A Phase 2/3, Multicenter, Randomized, Double Blind 
Study to Evaluate Duration of Severe Neutropenia with 
Plinabulin Versus Pegfilgrastim in Patients with Solid 
Tumors Receiving Docetaxel Myelosuppressive 
Chemotherapy (Protective 1) 
Protocol Number: 
BPI-2358-105 
Date of Protocol: 
05 December 2016 
Date of Protocol Amendment 1: 
14 January 2017 
Date of Protocol Amendment 2: 
10 February 2017 
Date of Protocol Amendment 3: 
30 May 2017 
IND No: 
131490 
EUDRACT No: 
Not applicable 
Study Phase: 
2/3 
Sponsor: 
BeyondSpring Pharmaceuticals, Inc. 
28 Liberty Street, 39th Floor 
New York, New York 10005 
Confidentiality Statement 
This protocol is the confidential information of BeyondSpring Pharmaceuticals Inc. and is 
intended solely for the guidance of the clinical study. This protocol may not be disclosed to 


Protocol BPI-2358-105 
 
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parties not associated with the study or used for any purpose without the prior written consent of 
BeyondSpring Pharmaceuticals Inc. 


Protocol BPI-2358-105 
 
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A. SUMMARY OF AMENDMENT 1 
Changes found in Amendment 1.0 Protocol BPI-2358-105 have been made to respond to 
FDA’s Information Request dated 12 January 2017.  In addition, headers and footers were 
changed to reflect the amendment number and dates.  
 
 
 
Changes to the protocol are shown as follows: 
 
• General changes to terms, abbreviations, spelling, and formatting have been made for 
consistency throughout the document and are not detailed here. 
• In response to FDA’s first information request, protocol pages 5, 9, 37, 43 and 48 the 
following language was added to the Rescue Treatment sections: 
  
 
“If the patient develops an FN event on subsequent cycles, the patient should be  
 
 
discussed with the medical monitor and either treated with a lower dose of  
 
 
docetaxel, or taken off study at the discretion of the investigator. Febrile   
 
 
neutropenia should be treated with antibiotics per institutional standard of care” 
• In response to FDA’s second information request, protocol pages 5, 44 and 50 the 
following language was revised:  
 
 
From “(with the exception of hypertension and neutropenia)”,  
 
 
To language in this Amendment 1 version “(with the exception of neutropenia)”. 
• In response to FDA’s third information request, protocol page 6 Protocol Inclusion 
criteria format for item 3 was corrected by exchanging bullet points for item numbers.  
• The protocol title on page 1 includes the short title (Protective 1). 
• The protocol title page includes “Amendment 1      17 January 2017”. 
• Page 45 section 11.1.2 and page 46 section 11.2 the following sentence was added: 
 
 
“Instructions for pharmacy drug preparation can be found in the study Pharmacy 
 
Manual.” 
 
• Page 64 section 12.5.2 was changed: 
 
From “Hepatitis B/C serologic markers and viral load”,  
 
To “Hepatitis B/C serologic markers”. 
 
B. SUMMARY OF AMENDMENT 2 
Changes found in Amendment 2.0 Protocol BPI-2358-105 have been made primarily to 
present separate analyses for Phase 2 and 3 (rather than pooled analysis of both phases).  In 
addition, headers and footers were changed to reflect the amendment number and dates.  
 
 
Changes to the protocol are shown as follows: 
 
• General changes to terms, abbreviations, spelling, and formatting have been made for 
consistency throughout the document and are not detailed here. 
• Specific secondary objectives for Phase 2 (related to pharmacokinetics, 
exposure-response relationships, and exposure-safety relationships) have been added. 
• Efficacy objectives that we previously assigned as being for Phase 2 and 3 combined are 
now assigned to Phase 3 alone. 


Protocol BPI-2358-105 
 
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• Endpoint sections amended in line with changes to objectives detailed above. 
• Sample size for Phase 3 increased from 130 to 150 patients; sample size rationale 
amended. 
• Timing of plinabulin dose relative to docetaxel dose clarified. 
• Definition of intent-to-treat analysis amended, such that it includes only patients that 
have received at least one dose of study medication (previously it included all 
randomized patients, regardless of whether they had received treatment or not). 
• Analysis sections restructured to separate Phase 2 and 3 analyses where they were 
previously combined into a pooled analysis. 
• Added details of type of analysis for primary endpoint. 
• Section on pharmacokinetic and pharmacodynamics analyses added for Phase 2. 
• Interim analyses section has been completely revised to allow stopping of the study (was 
previously for sample size adjustment). 
• Additional pharmacokinetic sample added for Day 2 at 24 hours post-Day 1 dose in 
Phase 2. 
• Day 2 electrocardiogram (ECG) added for Phase 2, and additional ECG time points 
added for Phase 3 to match those of Phase 2. 
• Clarified the timing and methods for vital signs, and resolved inconsistencies in the study 
assessment flow charts. 
• Study assessment flow charts also amended to add ECOG performance status and Day 2 
pharmacokinetic samples, other minor clarifications made. 
• Noted that analysis of CD34+ can only be performed in selected countries. 
• In the overview section (Section 7.1), a figure presenting absolute neutrophil count nadir 
levels has been added. 
• Clarified when central laboratory will be used for analysis. 
• Throughout, amended ‘platinum therapy’ to ‘platinum-based therapy’. 
 
C. SUMMARY OF AMENDMENT 3 
Changes found in Amendment 3.0 Protocol BPI-2358-105 have been made primarily to 
change the Phase 2 portion to open label, to remove all Day 5 assessments, to change 
semi-continuous blood pressure and ECG monitoring from 6 hours to 4.5 hours after the 
start of plinabulin/placebo infusion, to reduce the time from the start of docetaxel infusion to 
start of plinabulin infusion to 30 minutes, and to clarify inconsistent wording. 
In addition, headers and footers were changed to reflect the amendment number and dates. 
 
Changes to the protocol are as follows: 
 
• Phase 2 portion of the study changed to open label. 
• Matching placebo removed from Phase 2 portion. 
• Latin America added to list of countries (Latin America, North America, Europe, 
Asia Pacific, and Australia). 
• Pharmacodynamic endpoint definitively identified as duration of severe 
neutropenia  


Protocol BPI-2358-105 
 
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30 May 2017 
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• Quality of life and disease progression data collection added as exploratory 
objectives. 
• All Day 5 assessments removed. 
• A Day 6 assessment added for CD34+. 
• In the Phase 2 portion, bone pain assessment on days 2 and 3 of Cycle 2 removed. 
• In the Phase 3 portion, breast cancer eligibility changed to reflect that patients 
without previous chemotherapy for recurrent cancer are eligible 
• For Cycles 2 to 4, serum chemistry added to Day 8. 
• Body weight is now included as a separate assessment (and not as part of the 
physical examination) in the schedules of assessment; for Cycle 1, additional 
measurements have been added, on Days 2 and 6. 
• Requirement for rescue kit for FN removed.  If FN develops on cycle 1, blinding 
is broken (if Phase 3), and plinabulin patients treated with pegfilgrastim. 
• Semi-continuous blood pressure and ECG collection to last 4.5 hours. 
• Inclusion criterion 8 clarified to confirm prothrombin time (PT) and International 
Normalized Ratio (INR) should be assessed. 
• Exclusion criteria 3 and 4 amended for clarity. 
• Exclusion criterion 11 wording in main body amended to be consistent with 
synopsis wording. 
• Reference to an ICON Safety Manual removed. 
• Quality of life appendices updated with versions without watermarks. 
• Sections 13.1.1.2 and 13.2.2.1 changed to reflect updated adverse event reporting 
procedures. 
• IVRS removed.  
• Reduced the time from the start of docetaxel infusion to start of plinabulin 
infusion to 30 minutes. 
• Added 5-minute window to duration of docetaxel dosing. 
• Clarified timing of neutrophil count, vital signs, and ECG assessments. 
• Clarified in the text that CD34+, urinalysis, and height assessments are performed 
at screening (not at baseline). 
• Added a window up to 18 days less than 1 year to exclusion criterion related to 
history of myocardial infarction or ischemic heart disease within 1 year. 
• Timing of follow-up made consistent throughout protocol. 
• Amended instructions regarding anti-emetic prophylaxis and diarrhea. 
• Pharmacokinetic sample moved from 6 hours to 4.5 hours after the start of 
plinabulin/placebo infusion. 
• Clarified that docetaxel/pegfilgrastim will only be supplied by the Sponsor if not 
available at study sites. 
• Language on replacement of withdrawals modified. 
• References to prostate cancer removed from schedule of assessments for Phase 2. 
• Reduced some duplication regarding follow-up to report of a serious adverse 
event in Section 13.2.2.1. 
• Instructions for the preparation of prescribed doses replaced by reference to 
Pharmacy Manual. 
• Section ‘Other Statistical Issues’ has been removed. 


Protocol BPI-2358-105 
 
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• Clarified that DSMB will review (but not perform) interim statistical analysis. 
• Removed mention of sample size re-estimation from interim analysis. 
• Removed some repetition in the protocol, for example text relating to rescue 
treatment. 
 
 


Protocol BPI-2358-105 
 
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1. 
PROTOCOL SYNOPSIS 
Compound No.: BPI-2358 (Formerly NPI-2358) 
Name of Active Ingredient(s): plinabulin 
Study Protocol Title 
A Phase 2/3, Multicenter, Randomized, Double Blind Study to Evaluate Duration of Severe Neutropenia with 
Plinabulin Versus Pegfilgrastim in Patients with Solid Tumors Receiving Docetaxel Myelosuppressive 
Chemotherapy 
Number of Sites 
Investigational sites (to be determined) in Latin America, North America, Europe, Asia Pacific, and Australia. 
Study Period and Phase of Development 
Patients will be on study for approximately 5 months, including screening, on treatment, and follow-up. 
Phase 2/3 
Objectives  
Phase 2 (Open Label) Objectives 
Plinabulin pharmacokinetic (PK) and pharmacodynamic (PD) assessments will be made to enable a 
PK/PD analysis.  
Primary objective:   
• 
To establish the Recommended Phase 3 Dose (RP3D) based on PK/PD analysis. 
Primary efficacy pharmacodynamic (PD) objective:   
• 
To assess duration of severe neutropenia (DSN) in treatment Cycle 1 in patients treated with 
docetaxel (75 mg/m2) + plinabulin (5, 10 or 20 mg/m2) or with docetaxel (75 mg/m2) + 
pegfilgrastim (6 mg). Neutrophils count will be assessed at baseline (prior to Cycle 1 docetaxel 
dose) and during Cycle 1 on Days 1, 2, 6, 7, 8, 9, 10, 15 (pre-dose on dosing days; times equivalent 
to pre-dose on other days) 
Primary Safety Pharmacodynamic Objective: 
• 
To assess blood pressure semi-continuously with 15-minute intervals, starting 15 minutes 
pre-plinabulin dose and lasting 4.5 hours after start of infusion with plinabulin (Arms 2 to 4) or for 
4.75 hours starting 15 minutes after the end of docetaxel infusion (Arm 1). 
Secondary Objectives 
• 
To characterize the pharmacokinetic profile of plinabulin and docetaxel  
• 
To characterize the exposure-response relationships between measures of plinabulin exposure and 
the pharmacodynamic endpoint DSN. 
• 
To characterize the exposure-safety relationships between measures of plinabulin exposure and 
safety events of interest.  
Exploratory Objectives: 
• 
To assess CD34+ at screening, and on Days 2, 6, and 8 in Cycle 1 and Day 1 in Cycle 2 
• 
Health-related QoL questionnaire evaluated with EORTC QLQ-C30 (Appendix A) and EQ-5D-5L 
(Appendix D) 
• 
To collect data on disease progression 
 
Safety Objectives 
 
• 
Incidence, occurrence, and severity of adverse events (AEs)/serious adverse events (SAEs)  


Protocol BPI-2358-105 
 
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• 
Incidence, occurrence and severity of bone pain (Appendix B)  
• 
Systemic tolerance (physical examination and safety laboratory assessments) 
Phase 3 (Double Blind) Objectives 
Primary Objective 
• 
To assess DSN in treatment Cycle 1 in patients with advanced or metastatic breast cancer, who have 
failed < 5 prior lines of chemotherapy; advanced or metastatic non-small cell lung cancer (NSCLC) 
after failing platinum-based therapy; or hormone refractory (androgen independent) metastatic 
prostate cancer (HRPC) treated with docetaxel (75 mg/m2) + plinabulin (RP3D) versus docetaxel 
(75 mg/m2) + pegfilgrastim (6 mg). Neutrophils count will be assessed at baseline (prior to Cycle 1 
docetaxel dose) and during Cycle 1 on Days 1, 2, 6, 7, 8, 9, 10, 15 (pre-dose on dosing days; times 
equivalent to pre-dose on other days). 
Secondary Objectives 
• 
To assess the effects of docetaxel (75 mg/m2) + plinabulin (RP3D) versus docetaxel (75 mg/m2) + 
pegfilgrastim (6 mg) in patients with advanced or metastatic breast cancer, who have failed < 5 prior 
lines of chemotherapy; advanced or metastatic NSCLC after failing platinum-based therapy; or 
hormone refractory (androgen independent) metastatic prostate cancer: 
o 
Incidence of Grade 4 neutropenia (absolute neutrophil count [ANC] < 0.5 × 109/L) on 
Days 8 and 15 in Cycle 1 and on Day 8 in Cycles 2 to 4 
o 
Incidence of febrile neutropenia (FN) (ANC <0.5 × 109/L and body temperature ≥ 38.3°C) 
in Cycles 1 to 4 
o 
Neutrophil nadir during Cycle 1 
o 
Incidence of documented infections in Cycles 1 to 4 
o 
Incidence and duration of hospitalizations due to FN in Cycles 1 to 4 
o 
Health-related Quality of Life (QoL) questionnaire evaluated with European Organization 
for Research and Treatment of Cancer (EORTC) QLQ-C30 (Appendix A) and EQ-5D-5L 
(Appendix D)  
o 
Incidence of use of pegfilgrastim or filgrastim as treatment for neutropenia 
o 
Incidence of antibiotic use 
o 
Incidence of docetaxel dose delay, dose reduction, and/or dose discontinuation 
 
Exploratory Objective: 
• 
To collect data on disease progression 
 
Safety Objectives 
• 
Incidence, occurrence, and severity of adverse events (AEs)/serious adverse events (SAEs)  
• 
Incidence, occurrence and severity of bone pain (Appendix B)  
• 
Systemic tolerance (physical examination and safety laboratory assessments) 
Study Design 
This is a multicenter, randomized study with an open label phase 2 portion and a double blind phase 3 portion. 
Approximately 190 patients will be enrolled in this study.  
The decision to complete the Phase 2 portion of the study as open label was made to reduce the unnecessary 
complexities of study conduct (such as placebo infusions and injections). All patients will receive docetaxel at a 
dose of 75 mg/m2.  
In Phase 2, only patients with advanced or metastatic NSCLC after failing platinum-based therapy will be 
enrolled.   
In Phase 3, patients with one of the following diagnosis will be enrolled: advanced or metastatic breast cancer, 
who have failed < 5 prior lines of chemotherapy; advanced or metastatic NSCLC after failing platinum-based 
therapy; or hormone refractory (androgen independent) metastatic prostate cancer.  
The eligibility of all patients will be determined during a 28-day screening period.   


Protocol BPI-2358-105 
 
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Phase 2 (Open Label): 
Approximately 40 patients with advanced or metastatic NSCLC will be enrolled.  Patients are randomly assigned 
with approximately 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 (Pharsight/Certara) at the time 40 patients in 
Phase 2 have completed at least Cycle 1.     
Phase 3 (Double Blind):   
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.  
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 < 5 prior lines of chemotherapy; advanced or metastatic 
NSCLC after failing platinum-based therapy; or hormone refractory (androgen independent) metastatic prostate 
cancer. Each eligible patient will be stratified according to his or her diagnosis (breast cancer or NSCLC or 
HRPC). Patients will be randomly assigned within each stratum (diagnosis) 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 (RP3D) + placebo matching pegfilgrastim 
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. 
Treatments Administered: 
Both Phase 2 and Phase 3, Cycles 1 to 4, will consist of docetaxel 75 mg/m2 administered by intravenous (IV) 
infusion on Day 1 over 60 minutes (±5 minutes) every 21 days.  In the phase 2 portion, on Day 1 of each cycle, 
1.5 hours (± 10 minutes) after the start time of docetaxel infusion (i.e., approximately 30 minutes after the end of 
docetaxel infusion), patients assigned to a plinabulin arm (arms 2-4) will get a single intravenous infusion of 
plinabulin at their assigned dose over 30 minutes (± 5 minutes). Thus, the wait time between end of docetaxel 
infusion and start of the plinabulin infusion is approximately 30 minutes. On Day 2 of each cycle, ≥24 hours after 
completing chemotherapy, patients assigned to pegfilgrastim (arm 1) will receive a single dose of pegfilgrastim 
(6 mg) (subcutaneous injection).  
In the phase 3 portion, on Day 1 of each cycle, 1.5 hours (± 10 minutes) after the start time of docetaxel infusion 
(i.e., approximately 30 minutes after the end of docetaxel infusion), patients will get a single dose of plinabulin or 
placebo intravenously over 30 minutes (± 5 minutes).  On Day 2 of each cycle, ≥24 hours after completing 
chemotherapy, patients will receive a single dose of pegfilgrastim (6 mg) or placebo (subcutaneous injection).   
If a chemotherapy cycle is delayed by more than 3 weeks, the patient will be withdrawn from the study.  If a 
critical AE (refer to Section 10.5) occurs during the cycle, the dosage of docetaxel may be reduced 20% in the 
next cycle.  Only 1 docetaxel dose reduction is allowed (refer to Taxotere® (Prescribing Information)).  No dose 
reductions are allowed with plinabulin or pegfilgrastim. 
All patients, including patients who withdraw from the study early, will complete a safety follow-up visit 30 days 
(± 7 days) after the last dose of study drug.  Follow-up visits will be required to monitor for ongoing 
treatment-related AEs.  All patients experiencing drug-related toxicities of Grade ≥ 2 at the End of Treatment 
visit should be followed-up at least monthly until the AE(s) resolves to Grade ≤ 1, the event is considered to be 
chronic, or the patient receives other anti-cancer therapy.  The method of follow-up assessment will be at the 
Investigator’s discretion (for example, patient site visit or telephone call).  All deaths which occur within 30 days 
of study drug administration regardless of relationship to the study drug must be reported to the Sponsor 
immediately and within 24 hours of becoming aware of the event. 


Protocol BPI-2358-105 
 
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Laboratory test results (hematology and serum chemistry) will be collected via a central laboratory.  Safety 
laboratory tests are required prior to treatment on Day 1 of each cycle and can be collected by a local laboratory; 
however, all other scheduled blood samples as per the schedule assessments and procedure table must also be 
obtained for central laboratory assessment.  Urinalysis will be performed at screening only.  CD34+ counts will 
be established through a fluorescence-activated cell sorting (FACS) method as described in Table 6 and Table 7. 
Stopping Rules  
During the phase 2 study if at any given cohort, 3 patients or more have Grade 4 or 5 toxicity not related to 
underlying disease (with the exception of neutropenia), accrual to that cohort will be halted and the study will be 
continued at the lower dose cohorts in phase 2 (for example if 3 patients at the 20 mg/m2 cohort develop Gr. 4 
toxicity the accrual to that cohort will be stopped and the study will continue as planned with the accrual of the 
two remaining open cohorts). Interactive web response system (IWRS) will be utilized to assign patients to a 
lower dose cohort in phase 2. Study sites will be instructed to call IWRS when a Grade 4 or 5 toxicity event 
occurs. 
Number of Patients 
Approximately 40 patients will be enrolled in Phase 2 and approximately 150 patients are planned to be enrolled 
in Phase 3. 


Protocol BPI-2358-105 
 
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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 < 5 prior lines of chemotherapy (Note that 
study treatment may be the first chemotherapy treatment for advanced or metastatic cancer) 
• 
Advanced or metastatic NSCLC failing platinum-based therapy 
• 
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): 
a. 
Prior chemotherapy or radiation treatment  
b. Bone marrow involvement by tumor 
c. 
Surgery and/or open wounds within 4 weeks of first administration of study drug 
d. 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 109/L independent of growth factor support 
• 
Serum total bilirubin ≤ 1.5 times the upper limit normal (ULN), unless the patient has a diagnosis of 
Gilbert’s disease in which case direct bilirubin < 1.5 times ULN of the direct bilirubin.   
• 
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN (≤ 1.5 x ULN if 
alkaline phosphatase is > 2.5 x ULN) 
• 
Serum creatinine ≤ 1.5 x ULN 
8. Prothrombin time (PT) and 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 


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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, except adjuvant docetaxel given > 1 year prior to first dose of study drug. 
4. Phase 3 only: Received ≥ 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 10.6.2) 
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 (within a window of up to 
18 days less than 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. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection requiring treatment. 
18. Female subject who is pregnant or lactating. 
19. Unwilling or unable to comply with procedures required in this protocol 
Study Treatments 
Phase 2 (approximately 10 patients per arm with advanced or metastatic NSCLC after failing 
platinum-based therapy): 
Arm 1: Docetaxel (75 mg/m2) + pegfilgrastim (6 mg)  


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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)  
Phase 3 (a planned 75 patients per arm with advanced or metastatic breast cancer, who have failed 
< 5 prior lines of chemotherapy; advanced or metastatic NSCLC after failing platinum-based therapy; or 
hormone refractory [androgen independent] metastatic prostate cancer): 
Arm 1: Docetaxel (75 mg/m2) + pegfilgrastim (6 mg) + placebo matching plinabulin 
Arm 2: Docetaxel (75 mg/m2) + plinabulin (RP3D) + placebo matching pegfilgrastim 
All patients should be pre-medicated with oral corticosteroids such as dexamethasone 16 mg per day (e.g., 8 mg 
bid) for 3 days starting 1 day prior to docetaxel administration in order to reduce the incidence and severity of 
fluid retention as well as the severity of hypersensitivity reactions (refer to Taxotere® (Prescribing Information)). 
For hormone-refractory metastatic prostate cancer, given the concurrent use of prednisone, the recommended 
premedication regimen is oral dexamethasone 8 mg, at 12 hours, 3 hours and 1 hour before the docetaxel infusion 
(refer to Taxotere® (Prescribing Information)). 
Rescue Treatment: 
Patients who experience an FN event in Cycle 1 should be discussed with the medical monitor.  The blinding will 
be broken (if Phase 3), and patients assigned to plinabulin will receive pegfilgrastim in subsequent cycles.   If a 
patient was originally assigned to the pegfilgrastim arm, patients should be treated at a lower dose of docetaxel, 
or taken of study at the discretion of the investigator.  
If the patient develops an FN event on subsequent cycles, the patient should be discussed with the medical 
monitor and either treated with a lower dose of docetaxel, or taken off study at the discretion of the investigator. 
Febrile neutropenia should be treated with antibiotics per institutional standard of care (refer to Section 10.6.1). If 
a patient is hospitalized, the procedure for reporting Serious Adverse Events (Section 13.2) should also be 
followed. 
Duration of Treatment 
Patients will receive treatment with study drug for up to 4 cycles in this study, a treatment cycle is 21 days; 
thereafter, patients may continue receiving docetaxel and pegfilgrastim at the Investigator’s discretion.  After 
completion of 4 cycles, patients will complete a safety follow-up visit 30 days (± 7 days) after the last dose of 
study drug (see Table 6 and Table 7 Study Assessments and Procedures Schedule). 
Treatment up to 4 cycles of study drug in this study will continue until any 1 of the following occurs: 
• 
Dose limiting toxicity or critical adverse event as described in the docetaxel package insert (Taxotere® 
(Prescribing Information)) 
• 
Need for a protocol-prohibited dose reduction or study drug delay greater than 21 days 
• 
Initiation of a protocol-prohibited concomitant medication or non-protocol chemo/biological therapy for 
treatment of his or her disease 
• 
Development of a AE/SAE, illness, or condition that may interfere with the patient’s participation or 
require treatment discontinuation 
• 
Investigator opinion 
• 
Sponsor decision 
• 
Voluntary withdrawal of consent 
Concomitant Drug/Therapy 
Institutional guidelines should be followed in the event of infusion/hypersensitivity reaction.  Diphenhydramine 
and dexamethasone infusion may be administered in the event of infusion reaction. 
All patients should be premedicated with oral corticosteroids (see below for HRPC) such as dexamethasone 
16 mg per day (e.g., 8 mg twice daily) for 3 days starting 1 day before the docetaxel administration in order to 
reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions (refer to 
Taxotere® (Prescribing Information)). 
For HRPC, given the concurrent use of prednisone, the recommended premedication regimen is oral 
dexamethasone 8 mg at 12 hours, 3 hours, and 1 hour before docetaxel infusion (refer to Taxotere® (Prescribing 


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Information)).  
The prophylactic use of antibiotics is allowed at the discretion of the Investigator.  The use of antibiotics will be 
recorded by patient and summarized by treatment arm (refer to Table 5 for prohibited medications). 
Corticosteroids (except as described for premedication) and non-steroidal anti-inflammatory drugs (NSAIDs) are 
prohibited except for the treatment of AEs and as premedication. 
The use of strong CYP3A4 inhibitors as concomitant medications will be prohibited because docetaxel exposure 
increases by approximately 2-fold (Section 10.6.2) with the use of strong CYP3A4 inhibitors. 
Docetaxel is low emetic risk (10% to 30% frequency of emesis) and appropriate anti-emetic prophylaxis should 
be given prior to study medication per institutional policy.  In this study, dexamethasone is used as anti-emetic 
prophylaxis as well as to minimize docetaxel associated fluid retention.  
If “breakthrough” emesis (e.g. emesis and nausea after Day 1) occurs, the general strategy is to add one agent 
from a different drug class to the “rescue” anti-emesis regimen.  Useful anti-emetic agents for rescue include the 
benzodiazepines, cannabinoids (e.g. dronabinol or nabilone), haloperidol, metoclopramide, scopolamine, the 
phenothiazines (e.g. prochlorperaxine or promethazine) and 5HT3 receptor agonists. If a 5HT3 receptor agonist is 
needed, palonosetron (which is not known to prolong QT/QTc intervals) is safest and must be chosen over other 
5HT3 receptor agonists.   
Because of the potential interference with QT/QTc interval, in Cycle 1 between Day 1 and Day 2, the 5HT3 
receptor agonists ondansetron, granisetron and dolenasetron,  and the atypical antipshycotic olanzapine, are 
prohibited until the triplicate ECGs are completed.  After Cycle 1, triplicate ECGs are not obtained, and therefore 
no restrictions in the use of anti-emetics apply in those cycles, thus any 5HT3 receptor agonist can be used.  
If nausea and /or vomiting of Grade 2 and higher occurs, it must be treated with “rescue” anti-emetics during 
mid-cycle, and on subsequent cycles, the prophylactic anti-emetic regimen should be modified. 
If diarrhea of Grade 1 and higher occurs, it must be treated. Grade 1 diarrhea is less than 4 bowel movements a 
days without any signs of hypotention, dehydration. 
Antidiarrheals such as loperamide (or diphenoxylate/atropine) must be prescribed for diarrhea. Suggested 
loperamide use: 4 mg orally after first loose stool, then 2 mg after each stool not to exceed 16 mg in 24 hours.  
The use of anti-emetics and anti-diarrheals will need to be recorded on the CRF.   
Patients who have FN should receive antibiotics per standard of care (refer to Rescue Treatment section and 
Table 5 for prohibited medications).  The use of granulocyte colony-stimulating factor (G-CSF) as a treatment 
option during hospitalization for FN is strongly discouraged, since G-CSF is not approved for the treatment of 
FN, and is not likely to be effective.  If, however, G-CSF treatment for FN is considered, the Investigator should 
contact the Medical Monitor prior to its use.  FN is defined as single temperature ≥ 38.3°C orally or ≥ 38.0°C 
over 1 hour; neutropenia < 500 neutrophils/mcL or < 1000 neutrophils/mcL and a predicted decline to 
≤ 500/neutrophils/mcL over the next 48 hours (NCCN guidelines).   
Pharmacokinetics 
Non-compartmental pharmacokinetic analyses will be used to calculate plasma concentrations of plinabulin 
following doses of 5 mg/m2, 10 mg/m2, and 20 mg/m2 and docetaxel in cycle 1 of the phase 2 portion of the 
study.  
Sparse PK sampling for plinabulin in Phase 3 will be collected from all patients, and the sampling schedule will 
be based on the PK results of Phase 2. 
Pharmacodynamics 
Patients in phase 2 will participate in the PD assessments.  The PD assessments include blood pressure and DSN 
in cycle 1 of the phase 2 portion of the study.  
Statistical Methods 
Note: Patients will be stratified using the strata by tumor type in Phase 3. 
Study Endpoints  
Phase 2 (Open Label) 
Plinabulin pharmacokinetic (PK) and pharmacodynamic (PD) assessments will be made to enable a PK/PD 
analysis.  


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Primary Endpoint:   
• 
The primary endpoint is to establish the Recommended Phase 3 Dose (RP3D) based on PK/PD 
analysis 
Primary Efficacy Pharmacodynamic Endpoint 
• 
DSN in treatment Cycle 1 in patients treated with docetaxel (75 mg/m2) + plinabulin (5, 10 or 
20 mg/m2) or with docetaxel (75 mg/m2) + pegfilgrastim (6 mg). Neutrophils count will be assessed 
at baseline (prior to Cycle 1 docetaxel dose) and during Cycle 1 on Days 1, 2, 6, 7, 8, 9, 10, 15 
(pre-dose on dosing days; times equivalent to pre-dose on other days).  
Primary Safety Pharmacodynamic Endpoint 
• 
To assess blood pressure semi-continuously with 15-minute intervals, starting 15 minutes 
pre-plinabulin dose and lasting 4.5 hours after start of infusion with plinabulin (Arms 2 to 4) or for 
4.75 hours starting 15 minutes after the end of docetaxel infusion (Arm 1). 
Secondary Endpoints: 
• 
To characterize the pharmacokinetic profile of plinabulin and docetaxel  
• 
To characterize the exposure-response relationships between measures of plinabulin exposure and 
the pharmacodynamic endpoint DSN. 
• 
To characterize the exposure-safety relationships between measures of plinabulin exposure and 
safety events of interest.  
Exploratory Endpoints 
• 
To assess CD34+ at screening, and on Days 2, 6 and 8 in Cycle 1 and Day 1 in Cycle 2  
• 
Health-related QoL questionnaire evaluated with EORTC QLQ-C30 (Appendix A) and EQ-5D-5L 
(Appendix D) 
• 
Data collection on disease progression   
 
Safety Endpoints 
• 
Incidence, occurrence, and severity of AEs/SAEs  
• 
Incidence, occurrence, and severity of bone pain (Appendix B) 
• 
Systemic tolerance (physical examination and safety laboratory assessments) 
 
Phase 3 (Double Blind) 
Primary Efficacy Endpoint 
• 
DSN in treatment Cycle 1 in patients treated with docetaxel (75 mg/m2) + plinabulin (RP3D) compared with 
patients treated with docetaxel (75 mg/m2) + pegfilgrastim (6 mg). Neutrophils count will be assessed at 
baseline (prior to Cycle 1 docetaxel dose) and during Cycle 1 on Days 1, 2, 6, 7, 8, 9, 10, 15 (pre-dose on 
dosing days; times equivalent to pre-dose on other days).  
Secondary Efficacy Endpoints  
• 
To assess the effects of docetaxel (75 mg/m2) + plinabulin RP3D versus docetaxel + pegfilgrastim (6 mg),: 
• 
Incidence of Grade 4 neutropenia (ANC < 0.5 × 109/L) on Days 8 and 15 in Cycle 1 and on Day 8 in 
Cycles 2 to 4 
• 
Incidence of FN (ANC < 0.5 × 109/L and body temperature ≥ 38.3°C) in Cycles 1 to 4 
• 
Neutrophil nadir during Cycle 1 
• 
Incidence of documented infections Cycles 1 to 4 
• 
Incidence and duration of hospitalizations due to FN in Cycles 1 to 4 
• 
Health-related QoL questionnaire evaluated with EORTC QLQ-C30 (Appendix A) and EQ-5D-5L 
(Appendix D) 


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• 
Incidence of use of pegfilgrastim or filgrastim as treatment for neutropenia 
• 
Incidence of antibiotic use 
• 
Incidence of docetaxel dose delay, dose reduction, and/or dose discontinuation. 
 
Exploratory Endpoint 
• 
Data collection on disease progression  
 
Safety Endpoints 
• 
Incidence, occurrence, and severity of AEs/SAEs  
• 
Incidence, occurrence, and severity of bone pain (Appendix B) 
• 
Systemic tolerance (physical examination and safety laboratory assessments) 
Missing data will not be imputed for the primary and key secondary endpoints. Though, sensitivity analyses will 
be performed to examine the potential impact of the missing data, by assigning worst case, best case and average 
case scenarios. Repeated measures mixed-effects models, weighted estimating equations and multiple-imputation 
models will also be used to determine the potential impact of missing data.  
 
Analysis Sets Phase 2 
Intent-to-Treat Analysis Sets 
The intent-to-treat analysis set for Phase 2 is comprised of all Phase 2 patients that have been randomized in the 
study and have received at least one dose of study medication. 
The analysis of all endpoints, unless noted otherwise, will be conducted on the intent-to-treat analysis set. 
Safety Analysis Set 
The safety analysis set will be the same as the intent-to-treat analysis set for Phase 2.  
Efficacy Analyses 
Primary Efficacy Pharmacodynamic Analyses 
PK/PD analysis will determine the RP3D of plinabulin which will be used during the phase 3 of study treatment.  
In addition, exploratory analysis to assess DSN in treatment Cycle 1 in patients treated with docetaxel (75 mg/m2) 
+ plinabulin (5,10 or 20 mg/ m2) or with docetaxel (75 mg/m2) + pegfilgrastim (6 mg) will be performed, using 
the Jonckheere-Terpstra Test for Ordered Alternatives (Hollander, Wolfe, and Chicken 2013). With this statistical 
procedure the null hypothesis of equality among treatment group means will be tested (μj's, j = 1, 2, 3, 4) 
H0: μ1 = μ2 = μ3 = μ4  
against the alternative in which order is specified 
H1: μ1 ≥ μ2 ≥ μ3 ≥ μ4, 
where at least one of the inequalities is strict. The mean indices have the following interpretation: 1 = docetaxel 
(75 mg/m2) + pegfilgrastim (6 mg), 2 = docetaxel (75 mg/m2) + plinabulin (5 mg/m2), 3 = docetaxel (75 mg/m2) + 
plinabulin (10 mg/m2), and 4 = docetaxel (75 mg/m2) + plinabulin (20 mg/m2). The statistically significant 
rejection of the null hypothesis will be interpreted, that there is an ordered alternative of responses as indicated by 
the alternative hypothesis H1. 
Exploratory analyses 
Continuous variables and proportions will be analyzed using exact t-tests.  Categorical data will be analyzed 
using non-parametric statistical methods.  
Pharmacokinetic and Pharmacodynamic Analyses 
Plasma plinabulin and docetaxel concentrations will be measured using validated methods and PK parameters 
will be summarized using descriptive statistics.   Individual and mean serum plinabulin and docetaxel 
concentration versus time profiles will be plotted on both linear and logarithmic scales. 
Exploratory graphical and statistical techniques, including linear, nonlinear, and logistic regression, etc., will be 
used to explore potential relationships between pharmacokinetic parameters of interest and efficacy endpoints, 
pharmacodynamic variables and safety events of interest.  These exposure-response analyses will support the 
RP3D of plinabulin which will be used during the phase 3 of study treatment.   Full methodology will be 


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documented with the final results of the analyses, potentially as a separate report. 
 
 
Analysis Sets Phase 3  
Intent-to-Treat Analysis Sets 
The intent-to-treat analysis set for Phase 3 is comprised of all Phase 3 patients that have been randomized in the 
study, and have received at least one dose of study medication. The analysis of all endpoints, unless noted 
otherwise, will be conducted on the intent-to-treat analysis set. 
 
Safety Analysis Set 
For each part of the study, the safety analysis set will be the same as the intent-to-treat analysis set for Phase 3.  
 
Efficacy Analyses 
Primary efficacy analysis 
DSN was not measured in the previous Phase 2 study ([Study NPI-2358-101] in which patients received 
treatment with either plinabulin (30 mg/m2 [n=50] or 20 mg/m2 [n=40] + docetaxel or docetaxel alone [n=73]).  
DSN was obtained using the following methods (described below) for generation of ANC data and the observed 
neutrophil values on Day 8/Cycle 1 in the Phase 2 study.  Day 8 neutrophil values were shown to approximately 
coincide with the nadir of neutrophil counts after docetaxel treatment (Blackwell et al, 2015).  The study will 
assume that the shape of the time/neutrophil recovery curve in plinabulin-treated patients is indistinguishable 
from the time/neutrophil recovery curve for filgrastim and its biosimilars. 
In a study with filgrastim and its biosimilar, time course of ANC in Cycle 1 for the Per Protocol dataset was 
published by Blackwell et al, 2015.  Mean values and standard deviations of ANC during the 21-day follow-up 
period were readily available.  This information was used to write a computer simulation program that would 
generate random ANC data that asymptotically has the same means and standard deviations for the 21-day 
follow-up period as the publication.  The simulation would then also generate the projected number of days with 
severe neutropenia, (i.e., the DSN). 
Deming regression (Deming, 1943) was used to calculate the linear relationship between simulated nadir and 
DSN.  The rank correlation between simulated nadir and DSN was used to calculate the DSN with plinabulin 
(+ docetaxel) and docetaxel alone.  In the Phase 2 study, neutrophil counts were obtained on Day 8, which 
approximately coincides with the time that the neutrophil nadir occurs after docetaxel administration.  The 
observed Day 8 neutrophil (nadir) values were computed into the linear relationship (Deming regression), 
mentioned above to calculate DSN for each patient.  Using these methods, calculated mean DSN was 0.065 days 
for the plinabulin+ docetaxel arm, and 1.076 days for the docetaxel alone.  Based on published data with 
filgrastim in patients receiving docetaxel (Alexopoulos K et al, 1999), the assumption is that Grade 4 neutropenia 
in Cycle 1 would occur in a 2 times higher frequency with G-CSF+docetaxel versus plinabulin+docetaxel, 
resulting in a presumed mean DSN of 0.13 days for the G-CSF+ docetaxel combination.  
This non-inferiority trial design will utilize a difference (arm 2 minus arm 1) of 0.65 days (non-inferiority 
margin) in DSN in Cycle 1 as the largest acceptable difference between plinabulin and pegfilgrastim.  The 
non-inferiority test will evaluate the null hypothesis H0: true difference (arm 2 minus arm 1) ≥ 0.65 against the 
alternative hypothesis H1: true difference (arm 2 minus arm 1) < 0.65.  Plinabulin will be considered non-inferior 
to pegfilgrastim if in Cycle 1, the upper limit of the 2-sided 95% confidence interval for the true difference in 
mean duration of Grade 4 neutropenia was < 0.65 days.  A sample size of patients was based on sample size 
considerations as outlined.  
Data suggest (http://www.neulastahcp.com/risk/duration-of-severe-neutropenia/) that FN is correlated with 
DSN.  The frequency of FN with docetaxel monotherapy (100 mg/m2) + G-CSF was reported to be 1% in 
Cycle 1.  FN frequency in Cycle 1 with docetaxel combined with doxorubicin and G-CSF was ~ 3 % (Aarts M et 
al, 2013), which would translate into a DSN of 1 day according to Holmes FA, et al, 2002.  Based on these data, 
it is assumed that the median DSN for docetaxel monotherapy + G-CSF will be approximately 1 day. 
The frequency of FN with docetaxel monotherapy (without G-CSF) has been reported to be 11% in Cycle 1 (17% 
over all cycles) docetaxel dose of 100 mg/m2 (Vogel et al, 2005) and 19.8% over all cycles at a lower docetaxel 
dose of 60 mg/m2 (Yoh K et al, 2016).  Hanna N et al, 2004 reported an FN percentage of 12.7% with 75 mg/m2 


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docetaxel.   Based on this range of FN, the relationship established by Meza et al, 2002 between FN and DSN, we 
make the assumption that, with docetaxel monotherapy at a dose of 75 mg/m2 without G-CSF, the median DSN 
is estimated to be 4-5 days. 
In the Zarxio® briefing document, 2015, the margin was selected based on the fact that 
Taxotere/Adriamycin/cyclophosphamide (TAC) chemotherapy is known to induce a median DSN of 7 days in 
breast cancer patients receiving no G-CSF treatment (Nabholtz, 2001), while G-CSF treatment reduces the mean 
DSN for this chemotherapy to 1.4 days (95% CI: 1.07 - 1.69) as shown in pegfilgrastim (Neulasta®) Study 
20020778 (Kaufman et al, 2004).  Based on this a non-inferiority limit of 1 day was derived.  
As an extension of this reasoning, it is argued for our study, a non-inferiority margin of 0.65 would be reasonable 
and correspond to approximately a median of 4.5 days of DSN, as a ratio of 1 day to 7 days of DSN in the 
Zarxio® briefing document, 2015. 
A non-inferiority margin of 0.65 days can also be justified, because a difference of 0.65 days is not considered to 
be clinically meaningful.   
Since it is expected that the distribution of the primary endpoint (DSN) will contain a large number of zeros, the 
primary endpoint will be analyzed using a two-sided two-sample zero-inflated Poisson model with treatment as 
the only covariate (Johnson et al. 1992). 
 
Secondary efficacy analyses 
For endpoints other than Grade 4 neutropenia, analyses will be based on conventional methods (i.e., assuming 
asymptotic normality) for calculating 95% confidence intervals (CIs) and hypothesis testing.  ANC nadir, a 
secondary endpoint, will be analyzed using the Wilcoxon rank sum test. 
Continuous variables and proportions will be analyzed using exact t-tests.  Categorical data will be analyzed 
using non-parametric statistical methods. 
Exploratory analyses 
Continuous variables and proportions will be analyzed using exact t-tests.  Categorical data will be analyzed 
using non-parametric statistical methods.  
 
Safety analyses 
Continuous variables and proportions will be analyzed using exact t-tests.  Categorical data will be analyzed 
using non-parametric statistical methods. 
 
Interim Analyses 
The study design is group sequential with 1 interim analysis (after 50 patients in each treatment arm have 
completed at least 1 cycle in each of the treatment arms docetaxel + plinabulin (RP3D) versus docetaxel + 
pegfilgrastim, with matching placebos) and 1 final analysis at the completion of the study. These results assume 
that 2 sequential tests are made using the O'Brien-Fleming spending function to determine the test boundaries. 
If non-inferiority is determined from the statistical testing, then also the hypothesis of superiority will be tested, 
and if it is concluded that the plinabulin treatment is superior to the pegfilgrastim treatment, with respect to DSN, 
then the study will be stopped. Since the design allows for stopping for inferiority, it might be decided at that 
occasion that the study will be stopped. Since this is a hierarchical testing procedure no penalty with respect to 
overall significance will be paid. 
 
The statistical testing will be performed and will be reviewed by an independent Data Safety Monitoring Board 
(DSMB) at the interim analysis. 


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Sample Size Rationale 
Phase 2 (Open Label) 
In the Phase 2 (40 patients; approximately 10 patients per arm), patients with advanced or metastatic NSCLC will 
be enrolled.   
Phase 3 (Double blind) 
Approximately 150 patients are planned to be enrolled with 1 of the following diagnoses: advanced or metastatic 
breast cancer, NSCLC, or HRPC.  A sample size of 75 patients in each of the treatment arms docetaxel + 
plinabulin (RP3D) versus docetaxel + pegfilgrastim, with matching placebos achieve at least a 90% power to 
reject the null hypothesis of 0.65 day of inferiority in DSN between the treatment means with standard deviations 
of 0.75, at a significance level (alpha) of 0.05 two-sided two-sample zero-inflated Poisson model.   
The software PASS version 15.0.1 has been used for the calculations referencing Chow et al. 2003, Lan and 
DeMets 1983, O'Brien and Fleming 1979.  
Timing of Statistical Analysis 
 
Number of Patients in Phase 2 
Arm 1: Docetaxel + Pegfilgrastim 6 mg 
10 
Arm 2: Docetaxel + Plinabulin 20 mg/m2 
10 
Arm 3: Docetaxel + Plinabulin 10 mg/m2  
10 
Arm 4: Docetaxel + Plinabulin 5 mg/m2 
10 
 
PK/PD Analysis (to determine RP3D) 
 
Number of patients in Phase 3 
Arm 1: Docetaxel + Pegfilgrastim 6 mg 
50 
75 
Arm 2: Docetaxel + Plinabulin (RP3D) 
50 
75 
 
Interim Analysis 
Final Analysis 
 
 


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2. 
TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
1. 
PROTOCOL SYNOPSIS .............................................................................................7 
2. 
TABLE OF CONTENTS ...........................................................................................20 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................26 
4. 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE 
PROCEDURES ..........................................................................................................28 
4.1. 
Regulatory Authority Approval ..................................................................................28 
4.2. 
Investigator Responsibilities .......................................................................................28 
4.2.1. 
Good Clinical Practice ................................................................................................28 
4.2.2. 
Ethical Conduct of the Study and Ethics Approval ....................................................28 
4.2.3. 
Informed Consent .......................................................................................................29 
5. 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE .................30 
6. 
INTRODUCTION ......................................................................................................31 
6.1. 
Overview .....................................................................................................................31 
6.1.1. 
Pharmacokinetics and Drug Disposition in Humans ..................................................38 
6.2. 
Study Rationale ...........................................................................................................38 
6.2.1. 
Rationale for the use of Plinabulin in the Prevention of Chemotherapy 
Induced Neutropenia ...................................................................................................38 
7. 
STUDY OBJECTIVES ..............................................................................................40 
7.1. 
Phase 2 (Open Label) Objectives ...............................................................................40 
7.2. 
Phase 3 (Double Blind) Objectives.............................................................................41 
8. 
STUDY DESIGN .......................................................................................................42 
8.1. 
Summary of Study Design ..........................................................................................42 
9. 
STUDY POPULATION .............................................................................................45 
9.1. 
Inclusion Criteria ........................................................................................................45 
9.2. 
Exclusion Criteria .......................................................................................................46 
9.3. 
Removal of Patients from Therapy or Assessments ...................................................47 
10. 
STUDY TREATMENTS............................................................................................49 
10.1. 
Study Treatment ..........................................................................................................49 
10.1.1. 
Treatments Administered ............................................................................................49 
10.1.2. 
Identity of Study Drugs ..............................................................................................51 


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10.2. 
Study Drug Preparation and Dispensation ..................................................................52 
10.2.1. 
Packaging and Labeling ..............................................................................................52 
10.2.2. 
Handling and Storage .................................................................................................52 
10.2.3. 
Compliance and Accountability .................................................................................53 
10.2.4. 
Disposal and Destruction ............................................................................................53 
10.3. 
Patient Numbering and Treatment Assignment ..........................................................53 
10.3.1. 
Patient Numbering ......................................................................................................53 
10.3.2. 
Treatment Assignment ................................................................................................53 
10.3.3. 
Treatment Allocation ..................................................................................................54 
10.4. 
Dosage and Administration ........................................................................................54 
10.4.1. 
Plinabulin or Matching Placebo ..................................................................................54 
10.4.2. 
Pegfilgrastim or Matching Placebo ............................................................................54 
10.4.3. 
Docetaxel ....................................................................................................................55 
10.5. 
Dose Interruptions and Modifications ........................................................................56 
10.5.1. 
Criteria for Premature Withdrawal .............................................................................57 
10.6. 
Concomitant Medications and Non-drug Therapies ...................................................58 
10.6.1. 
Permitted Medications ................................................................................................58 
10.6.2. 
Prohibited Medications ...............................................................................................58 
10.6.3. 
Anti-emetics, Antidiarrheals, and Bowel Maintenance Regimens .............................59 
10.6.4. 
Other Concomitant Medications .................................................................................60 
11. 
STUDY ASSESSMENTS ..........................................................................................62 
11.1. 
Study Flow and Visit Schedule...................................................................................62 
11.2. 
General Study Procedures ...........................................................................................71 
11.2.1. 
Demographics .............................................................................................................71 
11.2.2. 
Medical History ..........................................................................................................71 
11.2.3. 
Baseline Characteristics ..............................................................................................71 
11.2.4. 
Vital Signs ..................................................................................................................71 
11.2.5. 
Temperature ................................................................................................................73 
11.2.6. 
Physical Examinations, Height, and Weight ..............................................................73 
11.2.7. 
Performance Status .....................................................................................................73 
11.2.8. 
Electrocardiogram .......................................................................................................74 
11.2.9. 
Health-Related Quality of Life Questionnaire Evaluated with EORTC QLQ-
C30 and EQ-5D-5L .....................................................................................................75 


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11.2.10. 
Bone Pain Inventory (Short Form) .............................................................................75 
11.3. 
Efficacy .......................................................................................................................75 
11.3.1. 
Disease Progression ....................................................................................................75 
11.4. 
Safety ..........................................................................................................................76 
11.4.1. 
Adverse Events ...........................................................................................................76 
11.4.2. 
Concomitant Medications ...........................................................................................76 
11.5. 
Laboratory Evaluations ...............................................................................................76 
11.5.1. 
Pregnancy Testing ......................................................................................................77 
11.5.2. 
Hepatitis B/C Testing .................................................................................................78 
11.5.3. 
HIV Testing ................................................................................................................78 
11.5.4. 
Exploratory Markers ...................................................................................................78 
11.6. 
End of Treatment Assessment ....................................................................................78 
11.7. 
Safety Follow-up/End of Study Assessment ..............................................................78 
11.8. 
Pharmacokinetics ........................................................................................................78 
11.9. 
Appropriateness of Measurements .............................................................................79 
12. 
DATA HANDLING AND QUALITY ASSURANCE ..............................................80 
12.1. 
Data Collection ...........................................................................................................80 
12.2. 
Data Management/Coding ..........................................................................................80 
12.3. 
Quality Assurance .......................................................................................................80 
13. 
SAFETY MONITORING AND REPORTING .........................................................81 
13.1. 
Adverse Events ...........................................................................................................81 
13.1.1. 
Definitions and Reporting ...........................................................................................81 
13.1.1.1. 
Assessment of Severity ...............................................................................................81 
13.1.1.2. 
Relationship to Study Drug ........................................................................................81 
13.1.1.3. 
Follow-Up of Adverse Events and Serious Adverse Events ......................................82 
13.1.2. 
Laboratory Test Abnormalities ...................................................................................83 
13.2. 
Serious Adverse Events ..............................................................................................83 
13.2.1. 
Definitions ..................................................................................................................83 
13.2.2. 
Reporting ....................................................................................................................84 
13.2.2.1. 
Timeframes for Submitting Serious Adverse Events .................................................84 
13.3. 
Pregnancies .................................................................................................................84 
13.4. 
Independent Data Safety Monitoring Board ...............................................................85 
14. 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN .......................86 


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14.1. 
Study Endpoints ..........................................................................................................86 
14.1.1. 
Phase 2 Endpoints .......................................................................................................86 
14.1.2. 
Phase 3 Endpoints .......................................................................................................87 
14.2. 
Statistical Analysis ......................................................................................................88 
14.2.1. 
Analysis Sets of Phase 2 .............................................................................................88 
14.2.1.1. 
Intent-to-Treat Analysis Set ........................................................................................88 
14.2.1.2. 
Safety Analysis Set .....................................................................................................88 
14.2.1.3. 
Pharmacokinetic Analysis Set ....................................................................................88 
14.2.1.4. 
Pharmacodynamic Analysis Set .................................................................................88 
14.2.2. 
Analysis Sets of Phase 3 .............................................................................................88 
14.2.2.1. 
Intent-to-Treat Analysis Set ........................................................................................88 
14.2.2.2. 
Safety Analysis Set .....................................................................................................88 
14.2.3. 
Patient Disposition ......................................................................................................88 
14.2.4. 
Demographics and Other Baseline Characteristics .....................................................89 
14.2.5. 
Prior and Concomitant Therapy ..................................................................................89 
14.2.6. 
Efficacy Analyses .......................................................................................................89 
14.2.6.1. 
Phase 2 Efficacy Analyses ..........................................................................................89 
14.2.6.2. 
Phase 3 Efficacy Analyses ..........................................................................................90 
14.2.7. 
Pharmacokinetic and Pharmacodynamic Analyses (Phase 2) ....................................92 
14.3. 
Safety Analyses ..........................................................................................................92 
14.3.1. 
Deaths .........................................................................................................................92 
14.3.2. 
Extent of Exposure .....................................................................................................92 
14.3.3. 
Adverse Events ...........................................................................................................92 
14.3.4. 
Laboratory Analyses ...................................................................................................93 
14.3.5. 
Vital Signs ..................................................................................................................93 
14.3.6. 
Electrocardiogram .......................................................................................................93 
14.4. 
Sample Size Considerations .......................................................................................93 
14.4.1. 
Phase 2 ........................................................................................................................93 
14.4.2. 
Phase 3 ........................................................................................................................93 
14.5. 
Interim Analysis ..........................................................................................................93 
14.6. 
Withdrawal .................................................................................................................94 
14.7. 
Independent Data Safety Monitoring Board Interim Safety Review..........................94 
15. 
ADMINISTRATIVE PROCEDURES .......................................................................95 


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15.1. 
Investigator Reporting Requirements .........................................................................95 
15.2. 
Confidentiality ............................................................................................................95 
15.3. 
Case Report Forms .....................................................................................................95 
15.4. 
Drug Accountability ...................................................................................................95 
15.5. 
Protocol Compliance ..................................................................................................95 
15.6. 
Protocol Modifications ...............................................................................................95 
15.7. 
Study Report and Publications....................................................................................96 
15.8. 
Study Discontinuation ................................................................................................96 
15.9. 
Records Retention and Study Files .............................................................................96 
15.9.1. 
Study Files and Retention of Records ........................................................................96 
15.9.2. 
Source Documents and Background Data ..................................................................97 
15.10. 
Provision of Study Results and Information to Investigators .....................................97 
15.11. 
Information Disclosure and Inventions ......................................................................97 
15.11.1. 
Access to Information for Monitoring ........................................................................97 
15.11.2. 
Access to Information for Auditing or Inspections ....................................................97 
16. 
REFERENCES ...........................................................................................................98 
17. 
APPENDICES ..........................................................................................................101 
APPENDIX A. EORTC QLQ-C30 ...........................................................................................102 
APPENDIX B. BONE PAIN INVENTORY (SHORT FORM) ...............................................105 
APPENDIX C. NCCN GUIDELINES VERSION 2.2016 .......................................................109 
APPENDIX D. EQ-5D-5L ........................................................................................................110 
APPENDIX E. CTCAE VERSION 4.03 ..................................................................................114 
18. 
SIGNATURES .........................................................................................................115 
Signature of Investigator ..............................................................................................................115 
Signature of Chief Medical Officer .............................................................................................116 
 
LIST OF TABLES 
Table 1: 
Summary of Docetaxel Dose Reductions and G-CSF Use (NPI-2358-101, 
Phase 2 ........................................................................................................................37 
Table 2: 
Treatments Administered for Phase 2 .........................................................................50 
Table 3: 
Treatments Administered for Phase 3 .........................................................................51 
Table 4: 
Dose Modifications for Docetaxel ..............................................................................57 


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Table 5: 
Strong Inhibitors of CYP3A4, as Docetaxel Exposure Increases by 
Approximately 2-fold .................................................................................................59 
Table 6: 
Study Assessments and Procedures Schedule for Phase 2 
(Open-Label)/Cycles 1 through 4, End of Treatment, Safety Follow-up, and 
Early Termination Visits .............................................................................................63 
Table 7: 
Study Assessments and Procedures Schedule for Phase 3 (Double 
Blind)/Cycles 1 through 4, End of Treatment, Safety Follow-up, and Early 
Termination Visits ......................................................................................................67 
Table 8: 
Vital Signs Assessments .............................................................................................72 
Table 9: 
ECOG Performance Status .........................................................................................73 
Table 10: Schedule for ECG Collection (Phase 2) .....................................................................74 
Table 11: Schedule for ECG Collection (Phase 3) .....................................................................75 
Table 12: Clinical Laboratory Tests (Central Laboratory) .........................................................77 
Table 13: Plinabulin Pharmacokinetic Sampling Schedule (Cycle 1) ........................................79 
Table 14: Docetaxel Pharmacokinetic Sampling Schedule (Cycle 1, Day 1) .............................79 
Table 15: Timing of Statistical Analyses ....................................................................................94 
 
LIST OF FIGURES 
 
Figure 1: 
Grade 4 Neutropenia for Docetaxel Plus Plinabulin and Docetaxel Alone by 
21-day Cycles (NPI-2358, Phase 2)............................................................................34 
Figure 2: 
Grade 4 Neutropenia on Cycle 1 Day 8 ......................................................................35 
Figure 3: 
Absolute Neutrophil Count at Day 8 Only (Prior to the Second Dose of 
Plinabulin) After a Single Dose of 20 mg/m2 Plinabulin per Cycle and 
Absolute Neutrophil Count Nadir Observed in all Samples Taken in Cycles 
1 to 3 ...........................................................................................................................36 
 


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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate aminotransferase 
CBC 
Complete blood count 
CI 
Confidence intervals 
CRF 
Case report form 
CRO 
Contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
D5W 
Dextrose 5% in distilled water 
DEHP 
di(2-ethylhexyl)phthalate 
DSMB 
Data safety monitoring board 
DSN 
ECOG 
Duration of severe neutropenia 
Eastern Cooperative Oncology Group 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EORTC 
European Organization for Research and Treatment of Cancer 
FACS 
Fluorescence-activated cell sorting 
FDA 
Food and Drug Administration 
FN 
Febrile neutropenia 
G-CSF 
Granulocyte colony-stimulating factor 
HBcAb 
Hepatitis B core antibody 
HBsAb 
Hepatitis B surface antibody 
HBsAG 
Hepatitis B surface antigen reactive 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HRPC 
Hormone refractory prostate cancer 
ICH 
International Council on Harmonisation 
IEC 
Institutional Ethical Committee 
IND 
Investigational New Drug Application 
INR 
International Normalized Ratio 


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Abbreviation 
Definition 
IRB 
Institutional Review Board 
IV 
Intravenous 
IWRS 
Interactive web response system 
JSCO 
Japanese Society of Clinical Oncology 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute  
NSAID 
Non-steroidal anti-inflammatory drug 
NSAIDs 
Non-steroidal anti-inflammatory drugs 
NSCLC 
Non-small cell lung cancer 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PT 
Prothrombin Time, preferred term 
PTT 
Partial thromboplastin time 
PVC 
Polyvinyl chloride 
QoL 
Quality of life 
RBC 
Red blood cell 
RP2D 
Recommended Phase 2 dose 
RP3D 
Recommended Phase 3 dose 
SAE 
Serious adverse events 
SAP 
Statistical Analysis Plan 
SOC 
System organ class 
SOP 
Standard Operating Procedure 
TAC 
Taxotere/Adriamycin/cyclophosphamide 
TEAE 
Treatment emergent adverse event 
ULN 
Upper limit of normal 
US 
United States 
WHO 
World Health Organization 


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4. 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE 
PROCEDURES 
4.1. 
Regulatory Authority Approval 
The sponsor will obtain approval to conduct the study from the appropriate regulatory agency in 
accordance with any applicable country-specific regulatory requirements before the study is 
initiated at a study center in that country. 
4.2. 
Investigator Responsibilities 
4.2.1. 
Good Clinical Practice 
The Investigator will ensure that this study is conducted in full conformance with the principles 
of the “Declaration of Helsinki” (as amended in Tokyo, Venice, Hong Kong, South Africa, and 
Edinburgh) or with the laws and regulations of the country in which the research is conducted, 
whichever affords the greater protection to the individual.  The study must fully adhere to the 
principles outlined in “Guideline for Good Clinical Practice” International Council on 
Harmonisation (ICH) Tripartite Guideline (January 1997) or with local law if it affords greater 
protection to the patient.  For studies conducted in the United States (US) or under US 
Investigational New Drug Application (IND), the Investigator will additionally ensure that the 
basic principles of “Good Clinical Practice” as outlined in the current version of 21 Code of 
Federal Regulations, subchapter D, part 312, “Responsibilities of Sponsors and Investigators”, 
part 50, “Protection of Human Patients”, and part 56, “Institutional Review Boards”, are adhered 
to. 
In other countries where “Guideline for Good Clinical Practice” exists the Sponsor and the 
Investigators will strictly ensure adherence to the stated provisions. 
4.2.2. 
Ethical Conduct of the Study and Ethics Approval 
This Protocol and any accompanying material provided to the patient (such as patient 
information sheets or descriptions of the study used to obtain informed consent) as well as any 
advertising or compensation given to the patient, will be submitted by the Investigator to an 
Institutional Review Board (IRB)/Institutional Ethics Committee (IEC).  Approval from the 
Committee must be obtained before starting the study, and should be documented in a letter to 
the Investigator specifying the date on which the committee met and granted the approval. 
Any modifications made to the Protocol after receipt of the IEC approval must also be submitted 
by the Investigator to the Committee in accordance with local procedures and regulatory 
requirements. 
When no local review board exists, the Investigator is expected to submit the Protocol to a 
regional committee.  If no regional committee exists, the Sponsor will assist the Investigator in 
submitting the Protocol to an appropriate Ethics Review Committee. 
It is the understanding of the Sponsor that this Protocol (and any modifications) as well as 
appropriate consent procedures will be reviewed and approved by an IRB.  This board must 


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operate in accordance with the current Federal Regulations.  A letter or certificate of approval 
will be sent by the Investigator to the Sponsor before initiation of the study, and also whenever 
subsequent modifications to the Protocol are made. 
4.2.3. 
Informed Consent 
It is the responsibility of the Investigator, or a person designated by the Investigator (if 
acceptable by local regulations), to obtain written informed consent from each patient 
participating in this study, after adequate explanation of the aims, methods, anticipated benefits, 
and potential hazards of the study.  For patients not qualified or incapable of giving legal 
consent, written consent must be obtained from the legally acceptable representative.  In the case 
where both the patient and his/her legally acceptable representative are unable to read, or unable 
to understand due to language barriers, an impartial witness should be present during the entire 
informed consent discussion.  After the patient and representative have orally consented to 
participation in the study, the witness’ signature on the form will attest that the information in the 
consent form was accurately explained and understood.  The Investigator or designee must also 
explain that the patients are completely free to refuse to enter the study or to withdraw from it at 
any time, for any reason.  The Case Report Forms (CRFs) for this study contain a section for 
documenting informed patient consent, and this must be completed appropriately.  If new safety 
information results in significant changes in the risk/benefit assessment, the consent form should 
be reviewed and updated if necessary.  All patients (including those already being treated) should 
be informed of the new information, given a copy of the revised form and give consent to 
continue in the study.  No study related activities should be conducted on a patient until after 
obtaining informed consent. 


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5. 
INVESTIGATORS AND STUDY ADMINISTRATIVE 
STRUCTURE 
This study will be conducted at sites in Latin America, North America, Europe, Asia Pacific, and 
Australia (to be determined). 
The name, telephone and fax numbers of the medical monitor and other contact personnel at the 
Sponsor are listed in the regulatory binder provided to each site. 
 


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6. 
INTRODUCTION 
6.1. 
Overview  
Myelosuppression is the primary toxicity of many chemotherapy regimens which often limits 
applicability.  Both the duration of Grade 4 neutropenia and the depth of the neutrophil nadir 
have been correlated to severe and life-threatening infections (Pizzo et al, 1993; Holmes FA, et 
al, 2002; Crawford et al, 2004).  As a result, the prevention of neutropenia is a major goal for 
oncology practitioners for both safety and cost-efficiency (Green et al., 2004). 
Neutropenia is a frequent and potentially life-threatening complication of cytotoxic 
myelosuppressive chemotherapy.  Research has shown that patients who develop neutropenia are 
more susceptible to infections which often required treatment with antibiotics and in severe cases 
require hospitalization.  Moreover, severe neutropenia often necessitates modification of the 
chemotherapy regimen, thereby compromising the ultimate success of the anticancer treatment 
plan (Waller et al., 2010). 
Febrile neutropenia (FN) is a potentially life-threatening condition characterized by the 
development of fever (≥ 38.3 °C) and chemotherapy-induced neutropenia (absolute neutrophil 
count [ANC] < 0.5 × 109/L).  The risk of severe neutropenia including FN is mitigated by 
reducing chemotherapy dosages or extending the dosing interval of the agents.  However, 
research has shown these measures are directly correlated to lower long-term survival rates 
because of the relative reduction in the dose intensity of the chemotherapy.  Therefore, 
granulocyte colony-stimulating factor (G-CSF) also known as filgrastim (Neupogen®) or 
pegfilgrastim (Neulasta®), is given as standard of care to manage chemotherapy-induced severe 
neutropenia and to allow chemotherapy to be administered more effectively.  Guidelines for the 
use of G-CSF based on the risk of FN have been established by several groups worldwide such 
as the National Cancer Institute (NCI) Network, American Society of Clinical Oncology, 
National Comprehensive Cancer Network (NCCN), European Organization for Research and 
Treatment of Cancer, and Japanese Society of Clinical Oncology (JSCO).  According to these 
guidelines, prophylactic G-CSF use is recommended for patients at significant risk of FN based 
on the chemotherapy regimen and patient specific risk factors (Kosaka et al., 2015).  However, 
the prophylactic use of G-CSF has some significant limitations in terms of safety, cost and 
convenience of use.  Treatment should not be administered within 14 days of chemotherapy 
initiation.  Moreover, G-CSF therapy cannot be initiated until 24 hours after the last dose of 
chemotherapy for each treatment cycle and is generally administered once per chemotherapy 
cycle (requires baseline complete blood count [CBC] and platelet count during therapy).  The 
concern with administering G-CSF on the day of chemotherapy is that increasing growth of 
myeloid cells may increase sensitivity to cytotoxic chemotherapy agents.  Since cytotoxic 
chemotherapy causes the most damage to rapidly growing cells, giving an agent that causes 
myeloid cells to grow faster while chemotherapy is present may cause more toxicity.  Duration 
of G-CSF therapy is to attenuate chemotherapy-induced neutropenia and is dependent on the 
myelosuppressive potential of chemotherapy regimen employed.  Patients are required to either 
self-administer the drug or return to the center for treatment and evaluation which is often 
difficult and costly for the patient.  Cost constraints in health care have been reported to be factor 
in access to filgrastim and pegfilgrastim for some patients.  In countries in which patients are 


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required to contribute to treatment costs, high drug prices have resulted in reduced compliance.  
In Europe, the availability of filgrastim biosimilars (which are more cost effective) have been 
accompanied by increased use suggesting physicians are more likely to use a cost-effective 
product (Blackwell et al, 2015). 
Warnings and precautions for pegfilgrastim include splenic rupture, acute respiratory distress 
syndrome, allergic reactions including anaphylaxis, fatal sickle cell crisis, glomerulonephritis, 
capillary leak syndrome, and leukocytosis.  The most common adverse reactions are bone pain 
and pain in an extremity which occurred in 31% and 9% of patients, respectively. Additional 
notable adverse events include acute febrile neutrophilic dermatosis, cutaneous vasculitis and 
injection site reactions (Neulasta® Package Insert). 
Plinabulin has the potential to offer a new treatment option that would ameliorate 
chemotherapy-related severe neutropenia (including FN) as well as have a better safety profile 
(much less bone pain) and be more convenient for the patient by reducing the number of required 
patient visits and potentially also reducing the burden to the healthcare system.  Most 
importantly, plinabulin can be given 1 hour after a chemotherapy cycle as opposed to 24 hours 
after the completion of the cycle (as prescribed by pegfilgrastim).   
Two clinical studies with plinabulin have been conducted to date, a Phase 1 monotherapy study 
(Study NPI-2358-100) and a Phase 1/2 combination study (Study NPI-2358-101) with docetaxel.  
A total of 141 patients with solid tumors received plinabulin. Laboratory data did not uncover 
any clinically significant deleterious changes in hematology or chemistry laboratory parameters; 
however, there was a significantly lower incidence of neutropenia in patients receiving 
plinabulin plus docetaxel compared with the docetaxel monotherapy arm. 
Plinabulin (BPI-2358) is a synthetic, low molecular weight, new chemical entity originally 
developed (previous name NPI-2358) by Nereus Pharmaceuticals, Inc., and now by 
BeyondSpring Pharmaceuticals, Inc.  It belongs to the diketopiperazine class of compounds.   
The chemical name of plinabulin is 2, 5-piperazinedione, 3-[[5-(1,1-dimethylethyl)-1H-imidazol-
4-yl]methylene]-6-(phenylmethylene)-,(3Z,6Z).   
Plinabulin is a yellow to orange solid and the clinical drug product is supplied as a solution in 
40% Kolliphor HS 15 (formerly known as polyoxyl 15 hydroxystearate, or Solutol HS-15)®/60% 
propylene glycol in an amber vial containing 80 mg in 20 mL (4 mg/mL). Each vial is designated 
for single use.  
Plinabulin is intended for intravenous (IV) infusion and is diluted with dextrose 5% in distilled 
water (D5W) and given over 30 minutes (± 5 minutes) at an initial dose of 30 mg/m2. 
Plinabulin which inhibits the polymerization of tubulin monomers, also has multiple mechanisms 
of action that inhibit tumor growth. Plinabulin targets angiogenesis and the existing tumor 
vasculature and also directly induces cancer cell apoptosis via the JNK pathway (Nicholson et al, 
2006; Singh et al, 2011; Kennedy et al, 2003).  Plinabulin stimulates the tumor-related immune 
system by means of dendritic cell maturation and enhances the antitumor activity of checkpoint 
inhibitors in an immune-competent mouse model (Lloyd et al, 2016).  Based on the nonclinical 
and clinical studies conducted to date, plinabulin has several advantages compared to agents that 
target existing tumor vasculature, including inhibition of angiogenesis, induction of tumor cell 
apoptosis, sustained suppression of tumor growth after treatment, inhibition of tubulin 


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dimerization and thus new microtubule formation without alteration of microtubule dynamic 
instability (reducing the risk of peripheral neuropathies associated with taxanes) (Gornstein, 
2014).  The safety profile of plinabulin appears to be superior to that of other agents with 
immune-oncology effects, such as checkpoint inhibitors (e.g., nivolumab), providing a major 
advantage in cancer therapy.  Thus, plinabulin may prove to be efficacious in the management of 
cancers such as advanced non-small cell lung cancer (NSCLC).  A Phase 3 global trial with 
plinabulin in combination with docetaxel is underway in NSCLC patients. (Study NPI-2358-
103). 
The mechanism by which plinabulin exerts its beneficial effect in neutropenia is still under 
investigation.  Preclinical evidence shows that plinabulin induces maturation of dendritic cells, 
resulting in the release of the cytokines interleukin (IL)-1β, IL-6 and IL-12 from 
monocytes/dendritic cells (Lloyd et al, 2016).  In particular IL-6 is mediated in the prevention of 
neutrophil apoptosis (Asensi et al, 2004) and IL-1β with increased neutrophil count (Dinarello, 
2011). 
Phase 1 (Study NPI-2358-100) and Phase 1/2 (Study NPI-2358-101) studies with plinabulin have 
been completed. Study NPI-2358-100 was a Phase 1, open-label, dose-escalation study to 
determine the maximum-tolerated dose and/or recommended Phase 2 dose (RP2D) of plinabulin 
monotherapy in patients with advanced solid tumor malignancies or lymphoma, whose disease 
had progressed after treatment with standard approved treatments.  Plinabulin was administered 
once per week as an IV infusion for 3 successive weeks in repeating 4-week cycles.  Doses 
ranged from 2 to 30 mg/m2.  A total of 38 patients received plinabulin monotherapy.  
Study NPI-2358-101 was a Phase 1/2, open-label study to evaluate plinabulin in combination 
with docetaxel in patients with advanced NSCLC that had progressed after treatment with at least 
1 chemotherapy regimen.  In the Phase 1 part of the study, patients received escalating doses of 
plinabulin (13.5 mg/m2 to 30 mg/m2) in combination with a standard dose of docetaxel 
(75 mg/m2). No drug-drug interaction was detected between plinabulin and docetaxel.  The 
RP2D of plinabulin administered with docetaxel was determined to be 30 mg/m2. 
In the Phase 2 part, patients were randomized to receive either docetaxel in combination with 
plinabulin or docetaxel alone (active control group).  A docetaxel dose of 75 mg/m2 was 
administered to all patients.  The study was stratified into 2 segments.  A stratum that compared 
plinabulin 30 mg/m2 plus docetaxel (study arm DN) to docetaxel alone (study arm D) followed 
by a second stratum of plinabulin 20 mg/m2 plus docetaxel (DN arm) to docetaxel alone (D arm). 
Study drug was administered by IV infusion on Day 1 (docetaxel plus plinabulin) and Day 8 
(plinabulin) of each 3-week cycle.  A total of 103 patients receive plinabulin plus docetaxel and 
73 patients received docetaxel alone. 
Improvement in Neutropenia 
In the Phase 2 clinical trial, patients were randomized to receive docetaxel 75 mg/m2 alone 
(n=73) or docetaxel 75 mg/m2 followed by plinabulin (Study NPI-2358-101) at 30 mg/m2 (n=50) 
or at 20 mg/m2 (n=40), repeated every 3 weeks (clinicaltrials.gov NCT00630110).  Plinabulin 
was given by a 30-minute intravenous (IV) infusion, starting 1 hour after administration of 
docetaxel.  The primary efficacy endpoint was median overall survival.  Secondary endpoints 
included safety assessments, such as complete blood count measurements, on Days 1, 8, and 15 
of each cycle. 


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In Figure 1, plinabulin and docetaxel combination has a much lower incidence of Grade 4 
neutropenia versus docetaxel alone (4% versus 33% in the first cycle, based on hematological 
laboratory values) for both the 20 mg/m2 and 30 mg/m2 plinabulin cohorts combined, and a 
benefit in neutropenia prevention was maintained over Cycles 2, 3, and 4. 
 
Figure 1: 
Grade 4 Neutropenia for Docetaxel Plus Plinabulin and Docetaxel Alone by 21-
day Cycles (NPI-2358, Phase 2) 
 
 
In Figure 2, the percentage of patients with Grade 4 neutropenia (absolute neutrophil count 
[ANC] < 0.5 x109/L) on Day 8 of Cycle 1, in the patients receiving docetaxel monotherapy 
without plinabulin (“Docetaxel”), docetaxel +20 mg/m2 plinabulin, and docetaxel+ 30 mg/m2 
plinabulin are shown.  The reduction in Grade 4 neutropenia with either plinabulin dose was 
statistically highly significant, and this reduction was comparable for the 20 and 30 mg/m2 
plinabulin dose. 


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Figure 2: 
Grade 4 Neutropenia on Cycle 1 Day 8 
 
Docetaxel (n=65) vs plinabulin 20 mg/m2 (n=39): p = 0.00026  
Docetaxel (n=65) vs plinabulin 30 mg/m2 (n=47): p = 0.00018  
Plinabulin 20 mg/m2 (n=39) vs plinabulin 30 mg/m2 (n=47): p = 0.68  
The benefit in Grade 4 neutropenia reduction on Day 8 in Cycle 1 was observed prior to patients 
receiving their plinabulin dose on Day 8, which provides evidence that a single plinabulin dose 
per cycle, given on Day 1 after docetaxel administration, is sufficient to achieve the neutropenia 
benefit.  Further evidence that a single 20 mg/m2 dose of plinabulin after each dose of docetaxel 
is sufficient to prevent myelosuppressive regimens-induced neutropenia is demonstrated in 
Figure 3 in which the nadir following a single dose (measured on Day 8 prior to the second dose 
of plinabulin) is similar to that measured in all blood samples in a cycle. 


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Figure 3: 
Absolute Neutrophil Count at Day 8 Only (Prior to the Second Dose of 
Plinabulin) After a Single Dose of 20 mg/m2 Plinabulin per Cycle and 
Absolute Neutrophil Count Nadir Observed in all Samples Taken in Cycles 1 
to 3 
 
Abbreviations: ANC = absolute neutrophil count; D = docetaxel; DN = docetaxel plus plinabulin. 
 
There were 10% of patients (5 of 50 patients) in the plinabulin 30 mg/m2 plus docetaxel 
treatment arm who required docetaxel dose reductions and 18.2% of patients (10 of 55 patients) 
in the docetaxel arm who required dose reductions.  In the 20 mg/m2 cohort, similar findings 
were observed, in which a lower proportion of patients required docetaxel dose reductions when 
treated with the combination (2.5%) than the companion docetaxel arms (22.2%) (refer to 
Table 1). 
 
 
D N  2 0  m g /m
2 N a d ir a ll s a m p le s
D N 2 0  m g /m
2 L o w e s t D 8
A ll  D
0
1
2
3
4
5
A N C  N a d ir L e v e ls  in  C y c le s  1 -3
C o m p a ris o m  o f N a d ir A N C  fo r A ll S a m p le s
to  th e  L o w e s t D a y  8  R e a d in g  P rio r to  P lin a b u lin  D o s e
S tu d y  N P I-2 3 5 8 -1 0 1  P 2
A N C  L o w e s t D 8  (1 0 3 c e lls /m m 3)
N S
p < 0 .0 0 0 1
p < 0 .0 0 0 1
D N 2 0  n a d ir a ll s a m p le s n = 4 0
D N 2 0  D 8  m g /m
2 n = 3 8
A ll  D  n = 6 5


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Table 1: 
Summary of Docetaxel Dose Reductions and G-CSF Use (NPI-2358-101, 
Phase 2 
 
 
30 mg/m2 Cohort 
20 mg/m2 Cohort 
DN arm  
N=50 
D arm  
N=55 
DN arm  
N=40 
D arm  
N=18 
Docetaxel dose reductions (n [%]) 
5 (10.0%) 
10 (18.2%) 
1 (2.5%) 
4 (22.2%) 
G-CSF use (n [%]) 
7 (14%) 
16 (29.1%) 
2 (5%) 
6 (33.3%) 
Abbreviations: D = docetaxel; DN = docetaxel plus plinabulin; G-CSF = granulocyte colony stimulating factor. 
Note:  G-CSF included the following concomitant medications: pegfilgrastim, filgrastim, Neupogen, and Neulasta. 
P = 0.0013 (G-CSF use % in combined DN arm versus combined D arm). 
The Phase 2 data suggest that a single dose of 20 mg/m2 plinabulin per cycle is highly effective 
in preventing docetaxel-induced neutropenia, and that the 20 mg/m2 plinabulin dose appears 
equally effective as the 30 mg/m2 group for the prevention of docetaxel-induced neutropenia. 
Consistent with the benefit of neutropenia prevention, in the plinabulin groups fewer patients 
required G-CSF treatment, and fewer patients required docetaxel dose reductions. 
Safety Conclusions 
The safety profile of plinabulin was consistent with what has been reported in earlier Phase 1 
studies.  The combination appeared to have a similar adverse event (AE) profile as single-agent 
docetaxel.  Increases in both systolic and diastolic blood pressure were seen in 20% to 30 % of 
patients.  The incidence of hypertension in the 20 mg/m2 (9 patients, 22.5%; 5% with Grade 3) 
and 30 mg/m2 (16 patients, 32.0%; 20% with grade 3) cohorts was higher compared with the 
docetaxel group (1 patient 5.6% and 2 patients, 3.6%), respectively.  These events typically 
resolved within 2 hours after plinabulin infusion.  No events of Grade 4 hypertension had 
occurred.  Grade 3 hypertension had occurred in 2 cases with the 20 mg/m2 dose and 7 cases 
with the 30 mg/m2 dose.  In both cases, the patients had a previous medical history of 
hypertension, which makes a causal relationship with plinabulin unlikely.  In the 30 mg/m2, there 
were 7 cases with Grade 3 hypertension, of which 4 cases had a prior medical history of 
hypertension; a causal relationship with plinabulin could not be determined in these 4 cases.  
Hypertension typically resolved within 2 hours after the plinabulin infusion.  Ileus and intestinal 
obstruction were also reported as AEs.  It was not clear if they were a direct effect of plinabulin 
or caused by some concomitant medications such as opioids. 
Overall, plinabulin + docetaxel appeared to have a more favorable safety profile at the 20 mg/m2 
plinabulin dose versus the 30 mg/m2 plinabulin dose, as demonstrated by a smaller proportion of 
patients who discontinued treatment due to a treatment emergent adverse event ([TEAE] 
3 patients, 7.5% versus 11 patients, 22.0%) and a smaller proportion experienced 1 or more 
serious adverse events ([SAEs] 14 patients, 35.0% versus 31 patients, 62.0%).   
The proportion of patients in the plinabulin plus docetaxel 20 mg/m2 arm who discontinued 
treatment due to a TEAE and experienced 1 or more SAEs was similar to that reported for the 
combined docetaxel alone arms (4 patients, 5.5% and 23 patients, 31.5%, respectively), thus the 
20 mg/m2 plinabulin dose appears to represent a safe plinabulin dose.  
Laboratory data did not uncover any clinically significant deleterious changes in hematology or 
chemistry laboratory parameters; however, there was a lower incidence of neutropenia in patients 


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in the DN 30 mg/m2 and 20 mg/m2 arm compared with its companion docetaxel arm as 
discussed above. 
Adverse events of concern were atrial fibrillation, ileus/intestinal obstruction, and reversible 
posterior leukoencephalopathy syndrome (Plinabulin Investigator Brochure 2016). 
In specific therapeutic settings as described by the NCCN guidelines, docetaxel is an accepted 
treatment regimen for breast cancer, NSCLC, and hormone refractory prostate cancer (HRPC) 
(https://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site). 
6.1.1. 
Pharmacokinetics and Drug Disposition in Humans 
The pharmacokinetics (PK) of plinabulin was evaluated in a Phase1 monotherapy clinical study 
in advanced solid tumor malignancies or lymphoma.  Compartment-independent PK analysis 
revealed a linear increase in systemic exposure (AUCtot) with increasing dose of plinabulin.  
Inter-patient variability in AUCtot was large, suggesting individual differences in metabolism of 
the parent drug.  Maximal plasma concentration was observed at the end of infusion for most 
patients.  Distributive volumes (Vz and Vss) were similar for all patients, and were indicative of 
the drug reaching deep compartments or being stored in peripheral compartments.  
There was no evidence of any interaction between plinabulin and docetaxel with regard to 
plasma levels in the Phase 1b portion of Study NPI-2358-101. 
Pharmacokinetic analysis of plinabulin indicated Cmax and AUC were dose proportional over the 
range of 2 to 30 mg/m2 without evidence of drug accumulation.  The mean t½ is 6.35 hours, the 
mean CL is 31 L/hour, and the mean Vz is 208 L for plinabulin as a single agent.  
6.2. 
Study Rationale 
6.2.1. 
Rationale for the use of Plinabulin in the Prevention of Chemotherapy Induced 
Neutropenia 
Plinabulin is a small molecule with tumor-inhibiting and immune-enhancing effects.  Plinabulin 
induces dendritic cell maturation and cytokines interleukin-1β (IL-1β), IL-6, and IL-12 
production, all of which are important in neutrophil survival.  In preclinical studies, plinabulin 
prevented docetaxel- or cyclophosphamide-induced neutropenia via a mechanism of action 
different from that of G-CSF analogues.  In Phase 1 and 2 solid tumor trials of plinabulin, which 
included >140 patients, routine safety laboratory assessments revealed an unexpected protective 
effect against neutropenia.  
Compared to docetaxel treatment alone, the addition of plinabulin to docetaxel significantly 
(p < 0.0003) reduced the proportion of patients with Grade 4 neutropenia from 33.3% to 4.6% in 
Cycle 1.  Figure 2 shows the proportions of patients with Grade 4 neutropenia (absolute 
neutrophil count [ANC] < 0.5x109/L) on Day 8, the approximate day after docetaxel 
administration corresponding to the largest reduction in neutrophil count (Blackwell et al, 2015).  
Plinabulin also reduced the clinical sequelae associated with docetaxel-induced neutropenia 
(sepsis, infections, hospitalizations, need for docetaxel dose reductions, and G-CSF use). Bone 
pain was reported in 4% of patients receiving plinabulin.  Plinabulin had a favorable safety 
profile; the most prominent finding was Grade 3 transient hypertension in 20% and 5% of 
patients receiving 30 mg/m2 and 20 mg/m2 plinabulin, respectively (Blayney D, et al, 2016).  


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Plinabulin is a novel small molecule that is being developed for the mitigation of 
chemotherapy-induced neutropenia.  Administered by IV infusion on the same day of 
(approximately 1 hour after) chemotherapy, plinabulin will be given in a single dose to be 
determined per cycle.  Plinabulin has the potential to be an effective, safe (with much less bone 
pain), cost-effective, and convenient alternative to G-CSF for the prevention of 
chemotherapy-induced neutropenia. 


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7. 
STUDY OBJECTIVES  
7.1. 
Phase 2 (Open Label) Objectives 
Plinabulin pharmacokinetic (PK) and pharmacodynamic (PD) assessments will be made to 
enable a PK/PD analysis.  
Primary objective:   
• To establish the Recommended Phase 3 Dose (RP3D) based on PK/PD analysis. 
Primary efficacy pharmacodynamic objective:  
• To assess DSN in treatment Cycle 1 in patients treated with docetaxel (75 mg/m2) + 
plinabulin (5, 10 or 20 mg/m2) or with docetaxel (75 mg/m2) + pegfilgrastim (6 mg). 
Neutrophils count will be assessed at baseline (prior to Cycle 1 docetaxel dose) and 
during Cycle 1 on Days 1, 2, 6, 7, 8, 9, 10, 15 (pre-dose on dosing days; times 
equivalent to pre dose on other days). 
Primary Safety Pharmacodynamic objective: 
• To assess blood pressure semi-continuously with 15-minute intervals, starting 
15 minutes pre-plinabulin dose and lasting 4.5 hours after start of infusion with 
plinabulin (Arms 2 to 4) or for 4.75 hours starting 15 minutes after the end of 
docetaxel infusion (Arm 1). 
Secondary objectives:   
• To characterize the pharmacokinetic profile of plinabulin and docetaxel 
• To characterize the exposure-response relationships between measures of plinabulin 
exposure and the pharmacodynamic endpoint duration of severe neutropenia (DSN). 
• To characterize the exposure-safety relationships between measures of plinabulin 
exposure and safety events of interest. 
Exploratory objectives: 
• To assess CD34+ at screening, and on Days 2, 6, and 8 in Cycle 1 and Day 1 in 
Cycle 2 
• Health-related QoL questionnaire evaluated with EORTC QLQ-C30 (Appendix A) 
and EQ-5D-5L (Appendix D) 
• To collect data on disease progression 
Safety objectives: 
• 
Incidence, occurrence, and severity of AEs/SAEs 
• 
Incidence, occurrence and severity of bone pain (Appendix B) 
• 
Systemic tolerance (physical examination and safety laboratory assessments) 
 


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7.2. 
Phase 3 (Double Blind) Objectives 
Primary objective:   
• To assess DSN in treatment Cycle 1 in patients with advanced or metastatic breast 
cancer, who have failed < 5 prior lines of chemotherapy; advanced or metastatic non-
small cell lung cancer (NSCLC) after failing platinum-based therapy; or hormone 
refractory (androgen independent) metastatic prostate cancer treated with docetaxel 
(75 mg/m2) + plinabulin (RP3D) versus docetaxel (75 mg/m2) + pegfilgrastim (6 mg).  
Neutrophils count will be assessed at baseline (prior to Cycle 1 docetaxel dose) and 
during Cycle 1 on Days 1, 2, 6, 7, 8, 9, 10, 15 (pre-dose on dosing days; times 
equivalent to pre dose on other days). 
Secondary objectives: 
• To assess the effects of docetaxel (75 mg/m2) + plinabulin (RP3D) versus docetaxel 
(75 mg/m2) + pegfilgrastim (6 mg) in patients with advanced or metastatic breast 
cancer, who have failed < 5 prior lines of chemotherapy; advanced or metastatic 
NSCLC after failing platinum-based therapy; or hormone refractory (androgen 
independent) metastatic prostate cancer: 
− Incidence of Grade 4 neutropenia (ANC < 0.5 × 109/L) on Days 8 and 15 in 
Cycle 1 and on Day 8 in Cycles 2 to 4 
− Incidence of FN (ANC<0.5 × 109/L and body temperature ≥38.3°C) in 
Cycles 1 to 4 
− Neutrophil nadir during Cycle 1 
− Incidence of documented infections in Cycles 1 to 4 
− Incidence and duration of hospitalizations due to FN in Cycles 1 to 4 
− Health-related Quality of Life (QoL) questionnaire evaluated with European 
Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 
(Appendix A) and EQ-5D-5L (Appendix D)  
− Incidence of use of pegfilgrastim or filgrastim as treatment for neutropenia 
− Incidence of antibiotic use 
− Incidence of docetaxel dose delay, dose reduction, and/or dose discontinuation 
Exploratory objective: 
• To collect data on disease progression 
Safety objectives 
• 
Incidence, occurrence, and severity of AEs/SAEs 
• 
Incidence, occurrence and severity of bone pain (Appendix B) 
• 
Systemic tolerance (physical examination and safety laboratory assessments) 


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8. 
STUDY DESIGN 
8.1. 
Summary of Study Design 
This is a multicenter, randomized study with an open label phase 2 portion and a double blind 
phase 3 portion. Approximately 190 patients will be enrolled in this study. 
The decision to complete the Phase 2 portion of the study as open label was made to reduce the 
unnecessary complexities of study conduct (such as placebo infusions and injections). 
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 < 5 prior lines of chemotherapy; advanced or metastatic NSCLC after 
failing platinum-based therapy; or hormone refractory (androgen independent) metastatic 
prostate cancer. 
The eligibility of all patients will be determined during a 28-day screening period.   
Phase 2 (Open Label): 
Approximately 40 patients with advanced and metastatic NSCLC will be enrolled.  Patients are 
randomly assigned, with approximately 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 
(Pharsight/Certara) at the time 40 patients in Phase 2 have completed at least Cycle 1.     
   
Phase3 (Double Blind): 
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.  
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 < 5 prior lines of 


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chemotherapy; advanced or metastatic NSCLC after failing platinum-based therapy; 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 (RP3D) + placebo matching pegfilgrastim 
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.  
 
Treatment Administration: 
In Phase 2 and Phase 3, Cycles 1 to 4 will consist of docetaxel 75 mg/m2 administered by IV 
infusion on Day 1 over 60 minutes (±5 minutes) every 21 days.   
In the phase 2 portion,  on Day 1 of each cycle, 1.5 hours (± 10 minutes) after the start time of 
docetaxel infusion (i.e., approximately 30 minutes after the end of docetaxel infusion), patients 
assigned to a plinabulin arm (arms 2-4) will get a single intravenous infusion of plinabulin at 
their assigned dose over 30 minutes (± 5 minutes).  Thus the wait time between end of docetaxel 
infusion and start of the plinabulin infusion is approximately 30 minutes. On Day 2 of each 
cycle, ≥24 hours after completing chemotherapy, patients assigned to pegfilgrastim (arm 1) will 
receive a single dose of pegfilgrastim (6 mg) (subcutaneous injection).  
In the phase 3 portion, on Day 1 of each cycle, 1.5 hours (± 10 minutes) after the start time of 
docetaxel infusion (i.e., approximately 30 minutes after the end of docetaxel infusion), patients 
will get a single dose of plinabulin or placebo intravenously over 30 minutes (± 5 minutes).  On 
Day 2 of each cycle, ≥24 hours after completing chemotherapy, patients will receive a single 
dose of pegfilgrastim (6 mg) or placebo (subcutaneous injection).   
If a chemotherapy cycle is delayed by more than 3 weeks, the patient will be withdrawn from the 
study.  If a critical AE occurs during the cycle, the dosage of docetaxel may be reduced 20% in 
the next cycle.  Only 1 docetaxel dose reduction is allowed (refer to Taxotere® (Prescribing 
Information)).  No dose reductions are allowed with plinabulin or pegfilgrastim. 
All patients, including patients who withdraw from the study early, will complete a safety 
follow-up visit 30 days (± 7 days) after the last dose of study drug.  Follow-up visits will be 
required to monitor for ongoing treatment-related AEs.  All patients experiencing drug-related 
toxicities of Grade ≥ 2 at the End of Treatment visit should be followed-up at least monthly until 
the AE(s) resolves to Grade ≤ 1, the event is considered to be chronic, or the patient receives 
other anti-cancer therapy.  The method of follow-up assessment will be at the Investigator’s 
discretion (for example, patient site visit or telephone call).  All deaths which occur within 
30 days of study drug administration regardless of relationship to the study drug must be 
reported to the Sponsor immediately and within 24 hours of becoming aware of the event. 
Laboratory test results (hematology and serum chemistry) will be collected via a central 
laboratory.  Safety laboratory tests are required prior to treatment on Day 1 of each cycle and can 
be collected by a local laboratory; however, all other scheduled blood samples as per the 


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schedule assessments and procedure table must also be obtained for central laboratory 
assessment.  Urinalysis will be performed at screening only.  CD34+ counts will be established 
through a fluorescence-activated cell sorting (FACS) method as described in Table 6 and 
Table 7. 
The schedule of assessments is presented in Table 6 and Table 7. 


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9. 
STUDY POPULATION 
9.1. 
Inclusion Criteria 
Patients may be entered in the study only if they meet all of the following 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 < 5 prior lines of chemotherapy 
(Note that study treatment may be the first chemotherapy treatment for advanced or 
metastatic cancer);  
• advanced or metastatic NSCLC failing platinum-based therapy, or  
• hormone refractory (androgen independent) metastatic prostate 
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 NCCN guidelines 
(version 2, 2016) (refer to Appendix C): 
a. Prior chemotherapy or radiation treatment  
b. Bone marrow involvement by tumor 
c. Surgery and/or open wounds within 4 weeks of first administration of study drug 
d. 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 109/L independent of growth factor support 
• Serum total bilirubin ≤ 1.5 times the upper limit normal (ULN), unless the patient has 
a diagnosis of Gilbert’s disease, in which case direct bilirubin less than or equal to 
1.5 x ULN of the direct bilirubin.  
• AST and ALT ≤ 2.5 x ULN (≤ 1.5 x ULN if alkaline phosphatase is > 2.5 x ULN) 
• Serum creatinine ≤ 1.5 x ULN  


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8. Prothrombin time (PT) and International Normalized Ratio (INR) ≤ 1.5 × 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. 
9.2. 
Exclusion Criteria 
Patients will not be entered in the study if they meet any of the following 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, except adjuvant docetaxel given > 1 year prior to first dose of 
study drug. 
4. Phase 3 only: Received ≥ 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 10.6.2) 
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 CTCAE (v4.03) treatment emergent adverse events.  


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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 (within a 
window of up to 18 days less than 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. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection requiring treatment. 
18. Female subject who is pregnant or lactating. 
19. Unwilling or unable to comply with procedures required in this protocol. 
 
9.3. 
Removal of Patients from Therapy or Assessments 
Patients will receive treatment with study drug up to 4 cycles in this study; thereafter patients 
may continue receiving docetaxel and pegfilgrastim at the Investigator’s discretion.  Patients will 
complete a safety follow-up visit 30 days (± 7 days) after the last dose of study drug. 


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Treatment up to 4 cycles of study drug in this study will continue until any 1 of the following 
occurs: 
• Dose limiting toxicity or critical adverse events as described in the docetaxel package 
insert (refer to Taxotere® (Prescribing Information) and Section 10.5, Table 4). 
• Need for a protocol-prohibited dose reduction or study drug delay greater than 
21 days 
• Initiation of a protocol-prohibited concomitant medication or non-protocol 
chemo/biological therapy for treatment of his or her disease 
• Development of a AE/SAE, illness or condition that may interfere with the patient’s 
participation or require treatment discontinuation 
• Investigator opinion 
• Sponsor decision 
• Voluntary withdrawal of consent 


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10. 
STUDY TREATMENTS 
10.1. 
Study Treatment  
The study drugs under evaluation are plinabulin and pegfilgrastim.  Placebo-matching plinabulin 
and pegfilgrastim will also be used as part of the study design. 
10.1.1. 
Treatments Administered 
Patients will be included in either Phase 2 or Phase 3 parts of the study (Table 2 and Table 3): 
Phase 2 (Open Label) (approximately 10 patients per arm with advanced or metastatic 
NSCLC after failing platinum-based therapy): 
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)  
In the phase 2 portion, on Day 1 of each cycle, 1.5 hours (± 10 minutes) after the start time of 
docetaxel infusion (i.e., approximately 30 minutes after the end of docetaxel infusion), patients 
assigned to a plinabulin arm (arms 2-4) will get a single intravenous infusion of plinabulin at 
their assigned dose over 30 minutes (± 5 minutes).  Thus the wait time between end of docetaxel 
infusion and start of the plinabulin infusion is approximately 30 minutes. On Day 2 of each 
cycle, ≥24 hours after completing chemotherapy, patients assigned to pegfilgrastim (arm 1) will 
receive a single dose of pegfilgrastim (6 mg) (subcutaneous injection).  
 
Phase 3 (Double Blind) (a planned 75 patients per arm with advanced or metastatic breast 
cancer, who have failed < 5 prior lines of chemotherapy; advanced or metastatic NSCLC 
after failing platinum-based therapy; or hormone refractory [androgen independent] 
metastatic prostate cancer): 
Arm 1: Docetaxel (75 mg/m2) + pegfilgrastim (6 mg) + placebo matching plinabulin 
Arm 2: Docetaxel (75 mg/m2) + plinabulin (RP3D) + placebo matching pegfilgrastim 
All patients with HRPC also are given prednisone 5 mg orally twice daily continuously in 
addition to docetaxel (see Taxotere® (Prescribing Information) as well as other assigned study 
drugs. 
In the phase 3 portion, on Day 1 of each cycle, 1.5 hours (± 10 minutes) after the start time of 
docetaxel infusion (i.e., approximately 30 minutes after the end of docetaxel infusion), patients 
will get a single dose of plinabulin or placebo intravenously over 30 minutes (± 5 minutes).  On 
Day 2 of each cycle, ≥24 hours after completing chemotherapy, patients will receive a single 
dose of pegfilgrastim (6 mg) or placebo (subcutaneous injection).   
 


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Rescue Treatment: 
Patients who experience an FN event in Cycle 1 should be discussed with the medical monitor.  
The blinding will be broken (if Phase 3), and patients assigned to plinabulin will receive 
pegfilgrastim in subsequent cycles.   If a patient was originally assigned to the pegfilgrastim arm, 
patients should be treated at a lower dose of docetaxel, or taken of study at the discretion of the 
investigator.  
If the patient develops an FN event on subsequent cycles, the patient should be discussed with 
the medical monitor and either treated with a lower dose of docetaxel, or taken off study at the 
discretion of the investigator. Febrile neutropenia should be treated with antibiotics per 
institutional standard of care (refer to Section 10.6.1). If a patient is hospitalized, the procedure 
for reporting Serious Adverse Events (Section 13.2) should also be followed. 
 
Treatments Administered: 
 
Table 2: 
Treatments Administered for Phase 2 
 
Cycles 1 to 4, Day 1 of each 
21 Day Cycle 
 
 
 
Docetaxel 
Cycles 1 to 4, Day 1 of each 
21 Day Cycle 
30 minutes after the end of the 
docetaxel infusion 
 
Plinabulin  
Cycles 1 to 4, Day 2 of 
each 
21 Day Cycle 
≥ 24 hours post docetaxel 
 
Pegfilgrastim  
Arm 1 
docetaxel (75 mg/m2) 
60-minute IV infusion 
 
pegfilgrastim (6 mg) 
SC single dose 
Arm 2 
docetaxel (75 mg/m2) 
60-minute IV infusion 
plinabulin (20 mg/m2) 
30-minute IV infusion 
 
Arm 3 
docetaxel (75 mg/m2) 
60-minute IV infusion 
plinabulin (10 mg/m2) 
30-minute IV infusion 
 
Arm 4 
docetaxel (75 mg/m2) 
60-minute IV infusion 
plinabulin (5 mg/m2) 
30-minute IV infusion 
 
Abbreviations:  IV = intravenous; SC = subcutaneous 
 


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Table 3: 
Treatments Administered for Phase 3 
 
Cycles 1 to 4, Day 1 of each 
21 Day Cycle 
 
 
 
Docetaxel 
Cycles 1 to 4, Day 1 of each 
21 Day Cycle 
30 minutes after the end of the 
docetaxel infusion 
 
Plinabulin or Placebo 
Cycles 1 to 4, Day 2 of 
each 
21 Day Cycle 
≥ 24 hours post 
docetaxel 
 
Pegfilgrastim or Placebo 
Arm 1 
docetaxel (75 mg/m2) 
60-minute IV infusion 
placebo matching plinabulin 
30-minute IV infusion 
pegfilgrastim (6 mg) 
SC single dose 
Arm 2 
docetaxel (75 mg/m2) 
60-minute IV infusion 
plinabulin (RP3D) 
30-minute IV infusion 
placebo matching 
pegfilgrastim 
SC single dose 
Abbreviations:  IV = intravenous; SC = subcutaneous 
 
Dose modifications for docetaxel for specific Grade 3/4 AEs are provided in Section 10.5, 
Table 4. 
Stopping Rules  
During the phase 2 study if at any given cohort, 3 patients or more have Grade 4 or 5 toxicity not 
related to underlying disease (with the exception of neutropenia), accrual to that cohort will be 
halted and the study will be continued at the lower dose cohorts in phase 2 (for example if 
3 patients at the 20 mg/m2 cohort develop Gr. 4 toxicity the accrual to that cohort will be stopped 
and the study will continue as planned with the accrual of the two remaining open cohorts). 
Interactive web response system (IWRS) will be utilized to assign patients to a lower dose cohort 
in phase 2. Study sites will be instructed to call IWRS when a Grade 4 or 5 toxicity event occurs. 
10.1.2. 
Identity of Study Drugs 
The Sponsor will supply plinabulin during the study treatment. If docetaxel/pegfilgrastim is not 
available at study sites, this will be supplied by the Sponsor. 
Refer to Taxotere® (Prescribing Information) and Neulasta® Package Insert for details on 
docetaxel and pegfilgrastim. 
Details are provided for plinabulin below. 
Instructions for pharmacy drug preparation can be found in the study Pharmacy Manual. 
Plinabulin 
Plinabulin (BPI-2358) is a synthetic, low molecular weight, new chemical entity originally 
developed (previous name NPI-2358) by Nereus Pharmaceuticals, Inc., and now by 
BeyondSpring Pharmaceuticals, Inc.  It belongs to the diketopiperazine class of compounds. 
Plinabulin is being developed as an anti-cancer agent for use in combination with docetaxel as a 
second-line and third-line treatment for patients with recurrent NSCLC and for the prevention of 
severe neutropenia in patients with non-myeloid malignancies receiving docetaxel monotherapy.  


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Investigator-initiated clinical trial of plinabulin with nivolumab in recurrent NSCLC has been 
initiated.  
Chemical Name, Structural Formula of Plinabulin 
• Study drug code: BPI-2358 (previous name NPI-2358) 
• Generic name: Plinabulin 
• Chemical name: 5-Piperazinedione, 3-[[5-(1,1-dimethylethyl)-1H-imidazol-4- 
yl]methylene]-6-(phenylmethylene)-, (3Z,6Z)  
• Molecular formula: C19H20N4O2  
• Molecular Weight: 336.4 g/mol 
• Structural Formula: 
 
 
10.2. 
Study Drug Preparation and Dispensation 
Details are provided for plinabulin only.  Refer to the Taxotere® (Prescribing Information) and 
Neulasta® Package Insert for details on docetaxel and pegfilgrastim.  
Instructions for pharmacy drug preparation can be found in the study Pharmacy Manual. 
10.2.1. 
Packaging and Labeling 
Plinabulin is supplied as a solution in 40% Kolliphor HS 15 (formerly known as polyoxyl 
15 hydroxystearate or Solutol HS-15®)/60% propylene glycol in amber vials containing 80 mg in 
20 mL (4 mg/mL).  Each vial is designated for single use.  The labeled storage condition for the 
drug product is stored between 15° and 25°C (59° and 77°F).  Vials contain 80 mg drug in 
20 mL (4 mg/mL) and are labeled with other information as per local regulatory requirements.  
The contents of the label will be in accordance with all applicable regulatory requirements. 
10.2.2. 
Handling and Storage 
The study drug will be dispatched to a study center only after receipt of the required documents 
in accordance with applicable regulatory requirements and the sponsor’s procedures. 
Vials of plinabulin should be stored at room temperature (between 15°C and 25°C [59° F and 
77°F]) and must be protected from light.  Protection from light must be maintained throughout 
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The stability of the drug meets all specifications under controlled room temperature storage 
conditions (25°C, 60% relative humidity).  Using a previous manufacturing process, drug 
product stability was demonstrated for up to, and including, 48 months.  Maintenance of 
plinabulin purity, potency, and impurity profile has been demonstrated at 6 months at elevated 
temperature and humidity (40°C/75% relative humidity) and after freeze-thaw cycles.  
Instructions for the preparation of prescribed doses are provided in the Pharmacy Manual. 
10.2.3. 
Compliance and Accountability 
Plinabulin will be provided by an agent of the Sponsor and shipped directly to the Investigator or 
the designated pharmacist.  If docetaxel/pegfilgrastim is not available at study sites, this will be 
supplied by the Sponsor.   
The Investigator or designated pharmacist will acknowledge receipt of the shipment and note 
content and condition of the shipment on the clinical material shipping form.  The Sponsor or its 
representatives will supply the appropriate forms.  
The pharmacist or person responsible for dispensing the study drug at the site will maintain an 
accurate and current record of all drug supplies received from the repository and dispensed to 
study patients.  The dispensing record should contain the protocol number and information 
regarding the amount/vial(s) dispensed; date dispensed, lot #, patient identifier number, patient 
initials, and the initials of the person dispensing the medication. 
10.2.4. 
Disposal and Destruction 
All partially used or empty vial drug counts should be verified by the Sponsor’s monitor.  The 
site will contact and discuss with the Sponsor the method of study drug destruction to determine 
whether the study drug will be shipped to a designated facility contracted by the Sponsor or 
destroyed at the study center according to the site’s Standard Operating Procedures (SOP).  If it 
is determined that the study drug will be destroyed on site, written confirmation of vial 
destruction and a copy of the institutional SOP must be provided to the Sponsor or its 
representative.   
At the end of the study, all expired or unused medication will be returned to the contract 
repository with an inventory of returned clinical materials or destroyed on site according to site 
procedures.  The Sponsor will be notified before shipment or destruction. 
10.3. 
Patient Numbering and Treatment Assignment 
10.3.1. 
Patient Numbering 
Patients will be identified by a patient number.   
10.3.2. 
Treatment Assignment 
Patients will be stratified based on his or her diagnosis.  Patients will be randomized using IWRS 
to 1 of the following treatment groups: 
Phase 2 (approximately 10 patients in each arm): 
Arm 1: Docetaxel (75 mg/m2) + pegfilgrastim (6 mg)   


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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)  
 
Phase 3 (75 patients enrolled in each arm): 
Arm 1: Docetaxel (75 mg/m2) + placebo matching plinabulin + pegfilgrastim (6 mg) 
Arm 2: Docetaxel (75 mg/m2) + plinabulin (RP3D) + placebo matching pegfilgrastim 
 
10.3.3. 
Treatment Allocation 
Phase 2 Open Label: 
During randomization, patients and all personnel involved in the conduct of the study and 
interpretation of results, including investigators, site personnel, and sponsor staff will be notified 
of treatment allocation.  A master list of all treatments and the patient numbers associated with 
the treatments will be maintained by the clinical supply vendor, the IWRS vendor, and the 
sponsor. 
Phase 3 Double Blind: 
During randomization, patients and all personnel involved with the conduct and interpretation of 
the study, including Investigators, site personnel, and sponsor staff will be blinded to the 
treatment codes.  Randomization data will be kept strictly confidential, filed securely by an 
appropriate group with the sponsor or contract research organization (CRO) and accessible only 
to authorized persons. 
A master list of all treatments and the patient numbers associated with the treatments will be 
maintained in a sealed envelope by the clinical supply vendor, the IWRS vendor, and the 
sponsor.  In the event that emergency conditions require knowledge of the study treatment given, 
the blind may be broken via the code breaker facility within the IWRS.  Emergency procedures 
for revealing drug codes are provided in the study manual.  If possible, before breaking the blind, 
the Investigator should consult with the sponsor to ascertain the necessity of breaking the code 
10.4. 
Dosage and Administration 
10.4.1. 
Plinabulin or Matching Placebo 
Plinabulin will be administered at a dose of 5 mg/m2, 10 mg/m2, and 20 mg/m2.  In the Phase 3 
portion of the study matching placebo will be administered in an equal volume. 
10.4.2. 
Pegfilgrastim or Matching Placebo 
Pegfilgrastim will be administered at a dose of 6 mg as a single dose syringe.  In the Phase 3 
portion of the study matching placebo will be administered in an equal volume. 
The Investigator and study site staff should be experienced in the use of pegfilgrastim and 
familiar with the pegfilgrastim prescribing information provided by the manufacturer.  


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Pegfilgrastim should be obtained from the institutional pharmacy and prepared per institutional 
protocol.  United States Food and Drug Administration (US FDA) approved source of 
pegfilgrastim is required for use in this study.  The recommended dosage of pegfilgrastim is a 
single subcutaneous injection of 6 mg administered once per chemotherapy cycle in adults.  Do 
not administer pegfilgrastim between 14 days before and 24 hours after administration of 
cytotoxic chemotherapy. Pegfilgrastim or matching placebo will be administered 24 hours after 
completing chemotherapy. Visually inspect parenteral drug products for particulate matter and 
discoloration prior to administration, whenever solution and container permit.  Do not administer 
pegfilgrastim if discoloration or particulates are observed.  NOTE: The needle cover on the 
single-use prefilled syringe contains dry natural rubber (latex); persons with latex allergies 
should not administer this product.  Follow institutional guideline/practice for 
prevention/assessment/management of hypersensitivity/infusion reaction with pegfilgrastim 
administration (refer to Neulasta® Package Insert for further details). 
10.4.3. 
Docetaxel 
Docetaxel will be administered at a dose of 75 mg/m2. 
As a standard approved chemotherapy agent, the Investigator and study site staff should be 
experienced in the use of docetaxel and familiar with the docetaxel prescribing information 
provided by the manufacturer.  Docetaxel should be obtained from the institutional pharmacy 
and prepared per institutional protocol.  US FDA approved source of docetaxel is required for 
use in this study.  Docetaxel may be provided by a distributer in some regions by agreement with 
the Sponsor.  Administration should be carried out with a 1-hour IV infusion per institutional 
protocol at the dose prescribed by this clinical study protocol (75 mg/m2).  Dexamethasone 
(16 mg per day administered as 8 mg twice daily, or as per institution standard) will be given on 
the day before, the day of (Day 1), and the day following docetaxel infusion (Day 2).  Follow 
institutional guideline/practice for prevention/assessment/management of 
hypersensitivity/infusion reaction with docetaxel administration- patients should be closely 
observed during docetaxel infusion with vital signs checked every 15 minutes especially for the 
first 2 cycles of administration (refer to Taxotere® (Prescribing Information) for further details). 
Docetaxel when given on a standard regimen (e.g., 75 mg/m2 IV every 3 weeks in non-small cell 
lung cancer) has an intermediate (10%-20%) risk of causing febrile neutropenia.  The NCCN 
guidelines recommend that physicians consider myeloid growth factor support in patients with 
≥1 risk factor with docetaxel treatment (see below).  Patients without risk factors may be 
observed for their initial treatment cycle. If the patient experiences an episode of febrile 
neutropenia or a dose limiting neutropenic event (a nadir or a day of treatment count impacting 
the planned dose of chemotherapy) during the previous treatment cycle, with the same dose and 
schedule planned for the current cycle, this patient is now in the high risk group and should be 
considered for myeloid growth factor support for subsequent cycles.  
Patient risk factors for developing febrile neutropenia when receiving docetaxel at dose and 
schedule used in the protocol (NCCN guidelines, version 2.2016) (Note: this list below is not 
identical to the risk-factor based inclusion criterion used to determine eligibility of patients 
[which is presented in Section 9.1]). 
• Prior chemotherapy or radiation therapy 


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• Persistent neutropenia 
• Bone marrow involvement by tumor 
• Recent surgery and/or open wounds 
• Liver dysfunction (bilirubin >2.0 mg/dL) 
• Renal dysfunction (creatinine clearance <50 mL/min) 
• Age >65 years receiving full chemotherapy dose intensity. 
10.5. 
Dose Interruptions and Modifications 
All adverse events should be assessed according to the Common Terminology Criteria for 
Adverse Events (CTCAE, v4.03). In the event of multiple toxicities, dose delays and 
modifications should occur in accordance with the highest adverse events observed. 
All patients, including patients who withdraw from the study early, will complete a safety 
follow-up visit 30 days (± 7 days) after the last dose of study drug.  Follow-up visits will be 
required to monitor for ongoing treatment-related AEs.  All patients experiencing drug-related 
toxicities of Grade ≥ 2 at the End of Treatment visit should be followed-up at least monthly until 
the AE(s) resolves to Grade ≤ 1, the event is considered to be chronic, or the patient receives 
other anti-cancer therapy.  The method of follow-up assessment will be at the Investigator’s 
discretion (for example, patient site visit or telephone call).  All deaths which occur within 
30 days of study drug administration regardless of relationship to the study drug must be 
reported to the Sponsor immediately and within 24 hours of becoming aware of the event. 
As described in Table 4, the occurrence of specific Grade 3 or 4 AEs during chemotherapy will 
require a dose reduction, delay, or discontinuation.  Only 1 docetaxel dose reduction is allowed 
(refer to Taxotere® (Prescribing Information) for further details). If a chemotherapy cycle is 
delayed by more than 3 weeks, the patient will be withdrawn from the study.     
No dose reductions are allowed with plinabulin or pegfilgrastim. 
Docetaxel 
Dose reduction and treatment delay for docetaxel will follow guidance described in docetaxel 
prescribing information as summarized in Table 4.  The use of blood cell growth factors 
according to the 2006 Update of American Society of Clinical Oncology (ASCO) Practice 
Guidelines Recommendation is permitted.   
Any delay of docetaxel dosing will result in the delay of plinabulin administration.  For each 
cycle, the dose of plinabulin is always administered 60 minutes after the docetaxel infusion.  If 
docetaxel is discontinued, plinabulin will also be discontinued.   
 
 


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Table 4: 
Dose Modifications for Docetaxel 
Condition 
Action 
Febrile neutropenia or 
ANC < 500 / mm3 for > 1 week or 
Grade 4 thrombocytopenia 
withhold docetaxel until ANC > 1500 / mm3 and 
platelets > 100,000 / mm3, then resume at 55 mg/m2 
Grade 3/4 skin reactions 
withhold docetaxel until resolution and then resume 
at 55 mg/m2 
Grade 3/4 non-hematologic docetaxel related 
toxicities 
withhold docetaxel until resolution and then resume 
at 55 mg/m2 
Grade 3/4 peripheral neuropathy 
discontinue docetaxel 
AST and/or ALT > 2.5 to ≤ 5 x ULN, or AST 
and/or ALT > 1.5 to ≤ 5 x ULN and AP > 2.5 to 
≤ 5 x ULN 
reduce docetaxel dose by 20% 
AST and/or ALT or AP > 5 x ULN 
discontinue docetaxel 
ALT=alanine aminotransferase; AP=alkaline phosphatase; AST=aspartate aminotransferase; ULN=upper limit of 
normal 
Dexamethasone  
If the patient has trouble sleeping, anxiety, stomach upset, nausea, vomiting, diarrhea, headache 
or swelling, they have the option to skip the 3rd day of dexamethasone (or steroid equivalent) 
dosing, on the day after the day of docetaxel infusion. On the day before and on the day of 
docetaxel infusion, the patient must take their dexamethasone (or steroid equivalent) as per 
institution standard. 
Stopping Rules  
During the phase 2 study if at any given cohort, 3 patients or more have Grade 4 or 5 toxicity not 
related to underlying disease (with the exception of neutropenia), accrual to that cohort will be 
halted and the study will be continued at the lower dose cohorts in phase 2 (for example if 
3 patients at the 20 mg/m2 cohort develop Gr. 4 toxicity the accrual to that cohort will be stopped 
and the study will continue as planned with the accrual of the two remaining open 
cohorts).IWRS will be utilized to assign patients to a lower dose cohort in phase 2. Study sites 
will be instructed to call IWRS when a Grade 4 or 5 toxicity event occurs. 
10.5.1. 
Criteria for Premature Withdrawal 
Patients have the right to withdraw from the study at any time for any reason.  The Investigator 
also has the right to withdraw patients from the study if it is in the best interest of the patient.  
The sponsor may also decide to withdraw a patient. All efforts should be made to complete and 
report the observations as thoroughly as possible as described in Section 11.6.  
Every reasonable effort should be made to determine as completely as possible the reason for the 
withdrawal, including contacting the patient either by telephone or through a personal visit, or 
contacting a responsible relative.  A complete final evaluation at the time of the patient’s 
withdrawal should be made with an explanation of why the patient is withdrawing from the 
study. 


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If the reason for removal of a patient from the study is an adverse event or an abnormal 
laboratory test result, the principal specific event or test will also be recorded on the eCRF. 
Patients with clearly documented progressive disease will be taken off treatment. 
10.6. 
Concomitant Medications and Non-drug Therapies 
10.6.1. 
Permitted Medications 
Institutional guidelines should be followed in the event of infusion/hypersensitivity reaction.  
Diphenhydramine and dexamethasone infusion may be administered in the event of infusion 
reaction. 
All patients should be premedicated with oral corticosteroids (see below for HRPC) such as 
dexamethasone 16 mg per day (e.g., 8 mg twice daily) for 3 days starting 1 day before docetaxel 
administration in order to reduce the incidence and severity of fluid retention as well as the 
severity of hypersensitivity reactions (refer to Taxotere® (Prescribing Information)). If the 
patient has trouble sleeping, anxiety, stomach upset, nausea, vomiting, diarrhea, headache or 
swelling, they have the option to skip the 3rd day of Dexamethasone (or steroid equivalent) 
dosing, on the day after the day of docetaxel infusion. On the day before and on the day of 
docetaxel infusion, the patient must take their dexamethasone (or steroid equivalent) as per 
institution standard. 
For HRPC, given the concurrent use of prednisone, the recommended premedication regimen is 
oral dexamethasone 8 mg at 12 hours, 3 hours and 1 hour before docetaxel infusion (refer to 
Taxotere® (Prescribing Information). 
The prophylactic use of antibiotics is allowed per discretion of the treating physician.  The use of 
antibiotics will be recorded per treatment arm (refer to Table 5 for prohibited medications). 
Corticosteroids (except as described for premedication) and non-steroidal anti-inflammatory 
drugs (NSAIDs) are prohibited except for the treatment of AEs and as premedication as 
described above. 
The use of strong CYP3A4 inhibitors as concomitant medications will be prohibited because 
docetaxel exposure increases by approximately 2-fold (Section 10.6.2) with the use of strong 
CYP3A4 inhibitors. 
Patients who have FN should receive antibiotics per standard of care (refer to Section 10.1.1 and 
Table 5 for prohibited medications).  The use of G-CSF as a treatment option during 
hospitalization for FN is strongly discouraged, since G-CSF is not approved for the treatment of 
FN, and is not likely to have efficacy.  If, however, G-CSF treatment for FN is considered, the 
Investigator should contact the Medical Monitor prior to its use.  FN is defined as single 
temperature ≥ 38.3°C orally or ≥ 38.0°C over 1 hour; neutropenia < 500 neutrophils/mcL or 
< 1000 neutrophils/mcL and a predicted decline to ≤ 500/neutrophils/mcL over the next 48 hours 
(NCCN guidelines).   
10.6.2. 
Prohibited Medications 
Corticosteroids (except as described in Section 10.6.1) and NSAIDs are prohibited except for the 
treatment of AEs. 


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Table 5: 
Strong Inhibitors of CYP3A4, as Docetaxel Exposure Increases by 
Approximately 2-fold 
Class/Therapeutic Areaa 
Drugs/Agents 
Antibiotics 
clarithromycin, telithromycin 
Antidepressant 
nefazodone 
Antifungals 
itraconazole, ketoconazole, posaconazole, 
voriconazole 
Antiretroviral 
ritonavir/lopinavir, ritonavir, saquinavir, 
indinavir, nelfinavir 
Antiviral 
boceprevir, telaprevir 
Miscellaneousa, b 
conivaptan, grapefruit juiceb, mibefradilc 
a Topical formulations of prohibited medication(s) are permitted. 
b The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-dependent.  
Studies have shown that it can be classified as a “strong CYP3A4 inhibitor” when a certain preparation was used 
(e.g., high dose, double strength) or as a “moderate CYP3A4 inhibitor” when another preparation was used (e.g., 
low dose, single strength). 
c Withdrawn from the US market. 
CYP = cytochrome P450 
 
Strong CYP3A4 inhibitors are not permitted as they may alter docetaxel exposure; consider 
therapeutic substitutions for these medications.  Approval from the Medical Monitor is required 
in these situations.  Please contact the Sponsor for review and approval if questions on any 
concomitant medication before patient enrollment or during the study treatment. 
10.6.3. 
Anti-emetics, Antidiarrheals, and Bowel Maintenance Regimens 
Docetaxel is low emetic risk (10% to 30% frequency of emesis) and appropriate anti-emetic 
prophylaxis should be given prior to study medication per institutional policy.  In this study, 
dexamethasone is used as anti-emetic prophylaxis as well as to minimize docetaxel associated 
fluid retention. 
If “breakthrough” emesis (e.g. emesis and nausea after Day 1) occurs, the general strategy is to 
add one agent from a different drug class to the “rescue” anti-emesis regimen.  Useful 
anti-emetic agents for rescue include the benzodiazepines, cannabinoids (e.g. dronabinol or 
nabilone), haloperidol, metoclopramide, scopolamine, the phenothiazines (e.g. prochlorperaxine 
or promethazine) and 5HT3 receptor agonists. If a 5HT3 receptor agonist is needed, palonosetron 
(which is not known to prolong QT/QTc intervals) is safest and must be chosen over other 5HT3 
receptor agonists. 
Because of the potential interference with QT/QTc interval, in Cycle 1 between Day 1 and 
Day 2, the 5HT3 receptor agonists ondansetron, granisetron and dolenasetron, and the atypical 
antipshycotic olanzapine, are prohibited until the triplicate ECGs are completed.  After Cycle 1, 
triplicate ECGs are not obtained, and therefore no restrictions in the use of anti-emetics apply in 
those cycles, thus any 5HT3 receptor agonist can be used.  


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If nausea and /or vomiting of Grade 2 and higher occurs, it must be treated with “rescue” 
anti-emetics during mid-cycle, and on subsequent cycles, the prophylactic anti-emetic regimen 
should be modified. 
Diarrhea: 
If diarrhea of Grade 1 and higher occurs, it must be treated. Grade 1 diarrhea is less than 4 bowel 
movements a days without any signs of hypotention, dehydration. 
Antidiarrheals such as loperamide (or diphenoxylate/atropine) must be prescribed for diarrhea. 
Suggested loperamide use: 4 mg orally after first loose stool, then 2 mg after each stool not to 
exceed 16 mg in 24 hours. 
Milk and milk products should be avoided, and other appropriate dietary interventions should be 
advised to patients. 
Patients should also be cautioned to avoid dehydration, and of the importance of drinking water 
and electrolyte containing fluids throughout the day when diarrhea occurs.  If IV fluids are 
needed, their administration must be recorded on the CRF. 
In patients who develop diarrhea, use of a motility enhancing agent such as metoclopramide as 
part of the anti-emetic regimen in subsequent treatment cycles should be avoided.   
Prophylaxis with bowel motility agents should follow institutional practice as applied to drugs 
such as vincristine, including the use of agents such as stool softeners, bulking agents, 
stimulating agents and/or dopamine antagonists.  The use of opiates should be limited to when 
clearly indicated and prophylaxis for opiate induced constipation with agents such as 
methylnaltrexone should be administered.  If significant constipation develops, it should be 
managed immediately and plinabulin administration should be delayed until resolution.  Careful 
observance for signs of ileus and early diagnostic evaluation with radiographic and/or ultrasound 
studies is recommended. 
Patients may receive hematopoietic growth factors or transfusion support during study; however, 
initiation of hematologic support, such as erythropoietin, darbopoetin, G-CSF, or platelet 
transfusions within 4 weeks of the first dose of study drug in order to meet entry criteria is not 
permitted.  
The use of anti-emetics and anti-diarrheals will need to be recorded on the CRF.   
10.6.4. 
Other Concomitant Medications 
If an increase in systolic blood pressure to > 160 mmHg is observed after administration of 
plinabulin or placebo, oral amlodipine 10 mg or an equivalent calcium channel blocker should be 
administered before each subsequent dose.  Increases in systolic blood pressure above 
200 mmHg should be managed with nitroprusside or similar regimen per institutional practice. If 
hypertension can be successfully managed, patient can continue in the study at the discretion of 
the investigator. The Investigator should be experienced in the use of docetaxel and familiar with 
the docetaxel prescribing information provided by the manufacturer.  According to the 
prescribing information for docetaxel, there have been no formal clinical studies to evaluate the 
drug interactions of docetaxel with other medications.  In vitro studies have shown that the 
metabolism of docetaxel may be modified by the concomitant administration of compounds that 
induce, inhibit, or are metabolized by CYP3A4, (refer to Table 5 for further details).  These 


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medications should be avoided when patients receive docetaxel as there is a potential for a 
significant interaction.  For patients receiving these medications before the study entry, these 
medications must be discontinued before docetaxel administration and sufficient time for drug 
clearance must be provided.  
Any other medication which is considered necessary for the patient’s welfare including 
bisphosphonates, and which is not expected to interfere with the evaluation of the study drug, 
may be given at the discretion of the Investigator.   
All medications will be recorded in an appropriate section of the CRF.  
No other cancer therapies or investigational agents are permitted during the entire duration of the 
study treatment (from 21 days before the first administration until the End of Treatment 
evaluation). 


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11. 
STUDY ASSESSMENTS 
11.1. 
Study Flow and Visit Schedule 
The study-specific assessments and procedures for Phase 2 and Phase 3 are shown in Table 6 and 
Table 7.   
 


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Table 6: 
Study Assessments and Procedures Schedule for Phase 2 (Open-Label)/Cycles 1 through 4, End of Treatment, 
Safety Follow-up, and Early Termination Visits 
Period 
Screening 
Period 
Treatment Period for Phase 2/Cycle 1 
Treatment Period for Phase 2 
Cycle 2, 3 and 4 
EOTa 
Early 
Discontinuation 
b 
30 Day  
Safety Follow-
upc 
Cycle Day 
-28 to -1 
-1 
1 
2 
3 
6 
7 
8 
9 
10 
15 
-1 
1 
2 
3 
 
8 
Post Cycle 4 
on Day 22 
(+7days) 
(± 21 days) 
± 7 days 
Cycle Week 
 
 
1 
2 
3 
1 
2 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographicsd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/ Baseline 
Characteristicse 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsf 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
X 
X 
X 
ECOG Performance 
Status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Temperatureg 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
X 
X 
X 
Physical examinationh 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Body weight 
X 
 
X 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
12-lead ECGi 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Hematologyj 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
X 
X 
X 
Serum Chemistryj 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
 
 
PT, INR, PTTk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exploratory Biomarker 
analysis CD34+l 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
Xm  
 
 
 
 
 
 
Urinalysisk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B/C testingn 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIVk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testo 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Period 
Screening 
Period 
Treatment Period for Phase 2/Cycle 1 
Treatment Period for Phase 2 
Cycle 2, 3 and 4 
EOTa 
Early 
Discontinuation 
b 
30 Day  
Safety Follow-
upc 
Cycle Day 
-28 to -1 
-1 
1 
2 
3 
6 
7 
8 
9 
10 
15 
-1 
1 
2 
3 
 
8 
Post Cycle 4 
on Day 22 
(+7days) 
(± 21 days) 
± 7 days 
PK sample collectionp 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease progression 
evaluationq 
 
Assessments of disease progression will be performed in accordance with standard medical 
practice per institution standard 
X 
 
 
Docetaxel  
Pre-Medication 
 
Xr 
X
r 
X
r 
 
 
 
 
 
 
 
Xr 
Xr 
Xr 
 
 
 
 
 
Docetaxel treatment 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Plinabulin s 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Pegfilgrastim s 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Bone Pain Inventory Short 
Formt 
X 
 
X
u  
X
u  
X 
 
X 
 
X 
 
 
 
Xv  
 
 
 
X 
 
 
Health-related QoL 
EORTC QLQ-C30 and 
EQ-5D-5L questionnairew 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
Concomitant medicationsx 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
Adverse eventsy 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
Abbreviations: ECG = electrocardiogram, EORTC = European Organization for Research and Treatment of Cancer, HIV = human immunodeficiency virus, QoL = Quality of 
Life. 
a. 
EOT is defined as the last assessment for the protocol-specified treatment post cycle 4 (Day 22 [+ 7 days]) of the study for an individual patient. 
b. 
If a patient discontinues the study, procedures should be performed within 21 days of the last dose of study drug. 
c. 
All patients, (including patients who withdraw from the study early), will complete a safety follow-up visit 30 (+7) days after the last dose.  Follow-up visits will be 
required to monitor for ongoing treatment-related adverse events.  All patients experiencing drug-related toxicities of Grade ≥ 2 at the End of Treatment visit should be 
followed-up at least monthly until the adverse event(s) resolves to Grade ≤ 1, the event is considered to be chronic or the patient receives other anti-cancer therapy.  The 
method of follow-up assessment will be at the Investigator’s discretion (for example, patient site visit or telephone call). All deaths which occur within 30 days of study 
drug administration regardless of relationship to the study drug must be reported the Sponsor immediately and within 24 hours of becoming aware of the event.  
d. 
Demographic data will include gender, date of birth (or age), and race/ethnicity. 
e. 
Background characteristics will include a history of disease and current disease status, bone marrow involvement, sites of disease, prior anticancer therapies, and prior 
medications/significant non-drug therapies. 
f. 
Patients must be in a supine position in a rested and calm state for at least 5 minutes before blood pressure is assessed.  If the patient is unable to be in the supine 
position, the patient should be in the most recumbent position possible.  The position selected for a patient, the same arm, and same blood pressure cuff should be kept 
the same throughout the study. 


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Two methods will be used to collect blood pressure. 
Method 1 in Phase 2 ONLY, Cycle 1 Day 1 ONLY,, using blood pressure devices provided by the sponsor (SpaceLabs 90217 ambulatory blood pressure 
monitor): 
• 
Day 1 (Arm 1): Blood pressure and heart rate will be measured semi-continuously starting at 15 minutes after completion of docetaxel infusion, and at every 
15 minutes thereafter for 4.5 hours. 
• 
Day 1 (Arms 2 to 4): Blood pressure and heart rate will be measured semi-continuously starting at 15 minutes before plinabulin infusion (15 minutes after 
completion of docetaxel infusion), and at every 15 minutes thereafter for 4.5 hours after start of infusion with plinabulin. 
 
Method 2 in Phase 2 in Cycles 1, 2, 3, and 4 as follows: 
A standard cuff will be used to measure blood pressure (heart rate will also be measured): 
• 
Cycle 1 (Arms 1 to 4): At screening, Day 1 (pre-docetaxel), Days 2, 6, 7, 8, 9, 10, and 15 (once, prior to blood draw). 
• 
Cycles 2 to 4 (Arm 1): Day 1 pre-docetaxel dose, and on Day 8 prior to blood draw 
• 
Cycles 2 to 4 (Arms 2 to 4): On Day 1 at pre-dose, 30 min, 1 hour, 2 hours post-infusion with plinabulin, and on Day 8 
g. 
Temperature is to be taken every time a blood draw is taken for neutrophil count and can be taken orally or in the ear; however, the same method (ear or oral) should be 
used throughout the study for each patient; thus if the ear method was used the first time for a given patient, the ear method should be used throughout the study for that 
patient.  
h. 
Height (cm) will be measured at screening. 
i. 
A single 12-lead ECG will be performed at screening, EOT, Early Discontinuation and 30 Day Safety Follow-Up. All other ECGs will be performed in triplicate. In 
Cycle 1 Day 1, ECG will be collected before docetaxel infusion, immediately before plinabulin infusion, 5-minutes before end of plinabulin infusion, 30 minutes and 
4.5 hours after start of infusion with plinabulin. In Cycle 1 Day 2, ECG will be performed in triplicate prior to the blood draws on Day 2 in Arms 2 to 4.  For Arm 1, the 
triplicate ECGs will not be performed.   
j. 
Laboratory test samples (hematology and serum chemistry) will be collected and sent to the protocol central laboratory. Safety laboratory tests are required prior to 
treatment on Day 1 of each cycle and can be collected by a local laboratory and will be used to determine docetaxel dosing; however, all other safety (e.g. protocol 
specified) blood samples as per the schedule assessments and procedure table must also be obtained for central laboratory assessment. In addition a central laboratory 
blood draw needs to be taken on the day of dosing on Day 1 of each cycle, prior to the docetaxel dosing. Neutrophils are to be collected on time points as indicated in this 
schedule; neutrophils must be collected at pre-dose on day 1 of each cycle. During Cycle 1, neutrophils count will be assessed at baseline (prior to Cycle 1 docetaxel 
dose), pre-dose on Day 1 and on Days 2, 6, 7, 8, 9, 10, and 15. 
k. 
Analyzed at a central laboratory. 
l. 
CD34+ will be analyzed using FACS via a central laboratory. 
m. Samples for CD34+ analysis to be collected at Day 1 Cycle 2 only. Do not collect at cycle 3 and 4 visits. 
n. 
Hepatitis B surface antigen reactive, hepatitis B core antibody, hepatitis B surface antibody, and hepatitis C antibodies 
o. 
Pregnancy tests will be done using urine samples in women of childbearing potential. Subject must have a negative urine pregnancy test documented within the 24-hour 
period prior to the first infusion. Confirm with serum testing (central laboratory) if urine sample is positive. 
p. 
Plasma samples (5 mL each) for plinabulin and docetaxel PK.  All patients will be sampled for PK via a central laboratory.  For PK collection schedule refer to Table 13 
and Table 14 (see Section 11.8).  During the phase 2 open label portion of the study patients randomized to pegfilgrastim will not have samples collected for plinabulin 
PK analysis. 
q. 
Investigator opinion of progression (yes/no) at End of Treatment (EOT) recorded in CRF. For example if the patient completes two cycles of docetaxel and study drug, 
and in the opinion of the investigator per institutional practice the cancer is growing and a new treatment is required, then the EOT evaluation will be performed as 
specified, and the “disease progression” will be scored as “yes.”  As an another example, if after four cycles of docetaxel and study drug, the cancer is stable or 
responding, and the patient receives further docetaxel, then the EOT evaluation will be completed as specified, and the “disease progression” will be scored as “no.”. 
r. 
Docetaxel infusion: 75 mg/m2 docetaxel will be administered via IV infusion over 1 hour on Day 1 of each cycle.  All patients should be premedicated with oral 
corticosteroids such as dexamethasone 16 mg per day (e.g., 8 mg bid) for 3 days starting 1 day prior to docetaxel administration in order to reduce the incidence and 
severity of fluid retention as well as the severity of hypersensitivity reactions (refer to Taxotere® Package Insert). 


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s. 
Cycles 1 to 4 will consist of docetaxel 75 mg/m2 administered by IV on Day 1 over 60 minutes (±5 minutes) each 21 day cycle.  Patients will get a single dose of 
plinabulin intravenously over 30 minutes (± 5 minutes) 30 minutes after the end of the docetaxel infusion if in arms 2-4.  On Day 2 of each cycle ≥ 24 hours after 
completing chemotherapy, patients will receive a single dose of pegfilgrastim (6 mg) if in arm 1. 
t. 
The bone pain questionnaire should be completed prior to docetaxel infusion and at the site if possible, if not the questionnaire needs to be returned to the site at the next 
scheduled visit. 
u. 
Bone pain questionnaire to be completed prior to pegfilgrastim and plinabulin pre dose, Cycle 1  
v. 
Bone pain questionnaire to be collected at Cycle 2: Pre-dose Day 1, only. Do not collect at Cycle 3 and 4 visits.  
w. Health-related QoL questionnaire evaluated with EORTC QLQ-C30 and EQ 5D-5L will be collected prior to docetaxel infusion on Day 1 of each cycle (Appendix A  
and Appendix D). 
x. 
All concomitant medicines (dose, schedule, and duration of treatment) and in particular analgesics as well as antibiotics should be entered in the eCRF. 
y. 
All hospitalizations should be entered in the eCRF. 


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Table 7: 
Study Assessments and Procedures Schedule for Phase 3 (Double Blind)/Cycles 1 through 4, End of Treatment, 
Safety Follow-up, and Early Termination Visits 
Period 
Screening 
Period 
Treatment Period for Phase 3/Cycle 1 
Treatment Period for Phase 3 
Cycle 2, 3 and 4 
EOTa 
Early 
Discontinuatio
nb 
30 Day  
Safety Follow-
upc 
Cycle Day 
-28 to -1 
 
1 
2 
3 
6 
7 
8 
9 
10 
15 
-1 
1 
2 
3 
 
8 
Post Cycle 4 
on Day 22 
(+ 7 days) 
(± 21 days) 
± 7 days 
Cycle Week 
 
 
1 
2 
3 
1 
2 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographicsd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/ 
Baseline 
Characteristicse 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsf 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
X 
X 
X 
ECOG Performance 
Status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Temperatureg 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
X 
X 
X 
Physical examinationh 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Body weight 
X 
 
X 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
12-lead ECGi 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Hematologyj 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
X 
X 
X 
Serum Chemistryj 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
 
 
PT, INR, PTTk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysisk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B/C testingl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIVk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testm 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Period 
Screening 
Period 
Treatment Period for Phase 3/Cycle 1 
Treatment Period for Phase 3 
Cycle 2, 3 and 4 
EOTa 
Early 
Discontinuatio
nb 
30 Day  
Safety Follow-
upc 
Cycle Day 
-28 to -1 
 
1 
2 
3 
6 
7 
8 
9 
10 
15 
-1 
1 
2 
3 
 
8 
Post Cycle 4 
on Day 22 
(+ 7 days) 
(± 21 days) 
± 7 days 
PK sample collectionn 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Period 
Screening 
Period 
Treatment Period for Phase 3/Cycle 1 
Treatment Period for Phase 3 
Cycle 2, 3 and 4 
EOTa 
Early 
Discontinuatio
nb 
30 Day  
Safety Follow-
upc 
Cycle Day 
-28 to -1 
 
1 
2 
3 
6 
7 
8 
9 
10 
15 
-1 
1 
2 
3 
 
8 
Post Cycle 4 
on Day 22 
(+ 7 days) 
(± 21 days) 
± 7 days 
Disease status 
evaluationo 
 
Assessments of disease progression will be performed in accordance with standard medical practice 
per institution standard 
X 
 
 
Docetaxel  
Pre-Medication 
 
Xp 
Xp 
Xp 
 
 
 
 
 
 
 
Xp 
Xp 
Xp 
 
 
 
 
 
Docetaxel treatmentq 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Plinabulin or placeboq 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Pegfilgrastim or 
placeboq 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Bone Pain Inventory 
Short Formr 
X 
 
Xs 
Xs 
X 
 
X 
 
X 
 
 
 
Xs 
Xs 
Xs 
 
X 
 
 
Health-related QoL 
EORTC QLQ-C30 
and EQ 5D-5L 
questionnairet 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
Concomitant 
medicationsu 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Adverse eventsv 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Abbreviations: ECG = electrocardiogram, EORTC = European Organization for Research and Treatment of Cancer, HIV = human immunodeficiency virus, QoL = Quality of 
Life. 
a. 
EOT is defined as the last assessment for the protocol-specified treatment post cycle 4 (Day 22 [+ 7 days]) of the study for an individual patient. 
b. 
If a patient discontinues the study, procedures should be performed within 21 days of the last dose of study drug.  
c. 
All patients, (including those who discontinued from the study) will complete a safety follow-up visit 30 (+7) days after the last dose.  Follow-up visits will be required 
to monitor for ongoing treatment-related adverse events.  All patients experiencing drug-related toxicities of Grade ≥ 2 at the End of Treatment visit should be followed-
up at least monthly until the adverse event(s) resolves to Grade ≤ 1, the event is considered to be chronic or the patient receives other anti-cancer therapy.  The method of 
follow-up assessment will be at the Investigator’s discretion (for example, patient site visit or telephone call). All deaths which occur within 30 days of study drug 
administration regardless of relationship to the study drug must be reported the Sponsor immediately and within 24 hours of becoming aware of the event. 
d. 
Demographic data will include gender, date of birth (or age), and race/ethnicity. 
e. 
Background characteristics will include a history of disease and current disease status, bone marrow involvement, sites of disease, prior anticancer therapies, and prior 
medications/significant non-drug therapies. 
f. 
Patients must be in a supine position in a rested and calm state for at least 5 minutes before blood pressure is assessed.  If the patient is unable to be in the supine 
position, the patient should be in the most recumbent position possible.  The position selected for a patient, the same arm, and same blood pressure cuff should be kept 
the same throughout the study. 
A standard cuff will be used to measure blood pressure (heart rate will also be measured): 


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• 
Cycle 1:  On Day 1 at pre-dose docetaxel, pre-dose plinabulin, 30 min, 1 hour, 2 hours post-infusion with plinabulin or placebo, and on Days 2, 6, 7, 8, 9, 10, and 15 
(once, prior to blood draw). 
• 
Cycles 2 to 4: On Day 1 at pre-dose docetaxel, pre-dose plinabulin, 30 min,1 hour, 2 hours post-infusion with plinabulin or placebo and on Day 8 
g. 
Temperature is to be taken every time a blood draw is taken for neutrophil count and can be taken orally or in the ear; however, the same method (ear or oral) should be 
used throughout the study for each patient; thus if the ear method was used the first time for a given patient, the ear method should be used throughout the study for that 
patient. 
h. 
Physical examination will include height (cm) at screening. 
i. 
A single 12-lead ECG will be performed at screening, EOT, Early Discontinuation and 30 Day Safety Follow-Up. All other ECGs will be performed in triplicate. In 
Cycle 1 Day 1, ECG will be collected before docetaxel infusion, immediately before plinabulin/placebo infusion, 5-minutes before end of plinabulin/placebo infusion, 
30 minutes and 4.5 hours after start of infusion with plinabulin/placebo. In Cycle 1 Day 2, ECG will be performed in triplicate prior to pegfilgrastim/placebo injection.  
j. 
Laboratory test samples (hematology and serum chemistry) will be collected and sent to the protocol central laboratory. Safety laboratory tests are required prior to 
treatment on Day 1 of each cycle and can be collected by a local laboratory and will be used to determine docetaxel dosing; however, all other safety (e.g. protocol 
specified) blood samples as per the schedule assessments and procedure table must also be obtained for central laboratory assessment. In addition a central laboratory 
blood draw needs to be taken on the day of dosing on Day 1 of each cycle, prior to the docetaxel dosing. Neutrophils are to be collected on time points as indicated in this 
schedule; neutrophils must be collected at pre-dose on day 1 of each cycle. During cycle 1, neutrophils count will be assessed at baseline (prior to Cycle 1 docetaxel 
dose), pre-dose on Day 1 and on Days 2, 6, 7, 8, 9, 10, 15. 
k. 
Analyzed at a central laboratory. 
l. 
Hepatitis B surface antigen reactive, hepatitis B core antibody, hepatitis B surface antibody, and hepatitis C antibodies 
m. Pregnancy tests will be done using urine samples in women of childbearing potential. Subject must have a negative urine pregnancy test documented within the 24-hour 
period prior to the first infusion. Confirm with serum testing (central laboratory) if urine sample is positive. 
n. 
Sparse PK sampling for plinabulin in Phase 3 will be collected from all patients, and the sampling schedule will be based on the PK results of Phase 2. 
o. 
Investigator opinion of progression (yes/no) at End of Treatment (EOT) recorded in CRF. For example if the patient completes two cycles of docetaxel and study drug, 
and in the opinion of the investigator per institutional practice the cancer is growing and a new treatment is required, then the EOT evaluation will be performed as 
specified, and the “disease progression” will be scored as “yes.”  As an another example, if after four cycles of docetaxel and study drug, the cancer is stable or 
responding, and the patient receives further docetaxel, then the EOT evaluation will be completed as specified, and the “disease progression” will be scored as “no.” 
p. 
Docetaxel infusion: 75 mg/m2 docetaxel will be administered via IV infusion over 1 hour on Day 1 of each cycle.  All patients should be premedicated with oral 
corticosteroids (see below for prostate cancer) such as dexamethasone 16 mg per day (e.g., 8 mg bid) for 3 days starting 1 day prior to docetaxel administration in order 
to reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions (refer to Taxotere® Package Insert). For hormone-refractory 
metastatic prostate cancer, given the concurrent use of prednisone, the recommended premedication regimen is oral dexamethasone 8 mg, at 12 hours, 3 hours and 1 hour 
before the docetaxel infusion (refer to Taxotere® Package Insert).  
q. 
Cycles 1 to 4 will consist of docetaxel 75 mg/m2 administered by IV on Day 1 over 60 minutes (±5 minutes) each 21 day cycle.  Patients will get a single dose of 
plinabulin or placebo intravenously over 30 minutes (± 5 minutes) 30 minutes after the end of the docetaxel infusion.  On Day 2 of each cycle ≥ 24 hours after 
completing chemotherapy, patients will receive a single dose of pegfilgrastim (6 mg) or placebo (subcutaneous injection). 
r. 
The bone pain questionnaire should be completed prior to docetaxel infusion and at the site if possible, if not the questionnaire needs to be returned to the site at the next 
scheduled visit. Bone pain questionnaire to be completed pre-dose  
s. 
Bone pain questionnaire to be collected at Cycle 2: Pre-dose Day 1, Day 2 and Day 3 only. Do not collect at Cycle 3 and 4 visits.  
t. 
Health-related QoL questionnaire evaluated with EORTC QLQ-C30 and EQ 5D-5L will be collected prior to docetaxel infusion on Day 1 of each cycle (Appendix A  
and Appendix D). 
u. 
All concomitant medicines (dose, schedule, and duration of treatment) and in particular analgesics as well as antibiotics should be entered in the eCRF. 
v. 
All hospitalizations should be entered in the eCRF. 
. 


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11.2. 
General Study Procedures 
11.2.1. 
Demographics 
Demographic data will include gender, date of birth (or age), and race/ethnicity 
11.2.2. 
Medical History 
Medical history findings (i.e., previous diagnoses, diseases, or surgeries) not pertaining to the 
study indication, started before signing the informed consent, and considered relevant for the 
patient’s study eligibility will be collected and captured in the eCRF. 
11.2.3. 
Baseline Characteristics 
Baseline characteristics will include a history of disease and current disease status, staging, bone 
marrow involvement, sites of disease, prior anticancer therapies, and prior 
medications/significant non-drug therapies will be collected. 
Information will also be collected regarding child-bearing potential and any other assessments 
that are done for the purpose of eligibility for inclusion into the study (physical examination, 
vital signs, hematology and blood chemistry, urinalysis, pregnancy test, and ECG).  For further 
details on eligibility assessments, see Table 6 and Table 7. 
11.2.4. 
Vital Signs 
The following measurements for vital signs must be performed: systolic/diastolic blood pressure, 
heart rate, and respiratory rate.  The patient must be in a supine position in a rested and calm 
state for at least 5 minutes before blood pressure assessments are conducted.  If the patient is 
unable to be in the supine position, the patient should be in the most recumbent position possible.  
The position selected for a patient, the same arm, and same blood pressure cuff should be the 
same throughout the study and documented on the vital signs CRF.   
Two methods will be used to collect blood pressure.  
• Method 1: using blood pressure devices provided by the sponsor (SpaceLabs 90217 
ambulatory blood pressure monitor) to measure blood pressure (heart rate will also be 
measured) 
• Method 2: using a standard cuff to measure blood pressure (heart rate will also be 
measured) 
Vital assessments will be performed as detailed in Table 8. 


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Table 8: 
Vital Signs Assessments 
Cycle 
Day 
Time Point(s) 
Method 
Phase 2 
- 
Screening 
- 
2 (standard cuff) 
Cycle 1 (all arms) 
Day 1 
Pre-docetaxel dose 
2 (standard cuff) 
Cycle 1 (Arm 1) 
Day 1 
Semi-continuously starting at 15 minutes 
after completion of docetaxel infusion, 
and at every 15 minutes thereafter for 4.5 
hours 
1 (ambulatory) 
Cycle 1 
(Arms 2 to 4) 
Day 1 
Semi-continuously starting at 15 minutes 
before plinabulin infusion (15 minutes 
after completion of docetaxel infusion), 
and at every 15 minutes thereafter for 4.5 
hours after start of infusion with 
plinabulin 
1 (ambulatory) 
Cycle 1 (all arms) 
Days 2, 6, 7, 8, 9, 10, and 15 
Time approximately equivalent to 
pre-dose on Day 1, before blood draws 
2 (standard cuff) 
Cycles 2 to 4 
(Arm 1) 
Day 1 
Pre-dose docetaxel 
2 (standard cuff) 
Cycles 2 to 4 
(Arms 2 to 4) 
Day 1 
Pre-dose docetaxel, pre-dose plinabulin, 
30 min, 1 hour, 2 hours post-infusion 
with plinabulin 
2 (standard cuff) 
Cycles 2 to 4 (all 
arms) 
Day 8 
Time approximately equivalent to 
pre-dose on Day 1, before blood draws 
2 (standard cuff) 
Phase 3 
- 
Screening 
- 
2 (standard cuff) 
Cycle 1 
(Arms 1 and 2) 
Day 1 
Pre-dose docetaxel, pre-dose plinabulin, 
30 min, 1 hour, 2 hours post-infusion 
with plinabulin or placebo 
2 (standard cuff) 
Cycle 1 
(Arms 1 and 2) 
Days 2, 6, 7, 8, 9, 10, and 15 
Time approximately equivalent to 
pre-dose on Day 1, before blood draws 
2 (standard cuff) 
Cycles 
2 to 4 
(Arms 1 and 2) 
Day 1 
Pre-dose docetaxel, pre-dose plinabulin, 
30 min, 1 hour, 2 hours post-infusion 
with plinabulin or placebo 
2 (standard cuff) 
Cycles 
2 to 4 
(Arms 1 and 2) 
Day 8 
Time approximately equivalent to 
pre-dose on Day 1, before blood draws 
2 (standard cuff) 
Phase 2 and 3 
All cycles 
End of Treatment, Early 
Discontinuation, and 30-Day 
Safety Follow-up 
- 
2 (standard cuff) 
 


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11.2.5. 
Temperature 
The temperature location (ear or oral) selected for a patient should be the same throughout the 
study and documented on the vital signs CRF.   
If abnormalities are found and they are considered an AE, record on the AE summary page. 
11.2.6. 
Physical Examinations, Height, and Weight 
Physical examinations (comprehensive [including neurological examination] or symptom 
directed) will be performed as described in Table 6 and Table 7.  A comprehensive physical 
examination will include evaluations of the head, eyes, ears, nose, throat, neck, chest (including 
heart and lungs), abdomen, limbs, skin, and a complete neurological examination.  A urogenital 
examination will only be required in the presence of clinical symptoms related to this region.  
Documentation of the physical examination will be included in the source documentation at the 
site.  Significant findings at the screening Visit will be recorded on the CRF.  Changes from the 
screening physical examination findings that meet the definition of an AE will be recorded on 
CRF. 
Height will be measured in centimeters once at screening.  Weight will be measured in kilograms 
at screening, prior to Day 1 dosing in all cycles and at the end of treatment (EOT) visit.  For 
Cycle 1, body weight will also be measured on Days 2 and 6.  The body weight measurements 
are made to enable the calculation of the plinabulin dose and to monitor for potential weight 
increase due to the docetaxel pre-medication. Both measurements will be performed without the 
patient wearing shoes.  
11.2.7. 
Performance Status 
Patients will be graded according to the ECOG Performance Status scale and criteria as 
described in Table 9.  
Table 9: 
ECOG Performance Status 
ECOG Scale 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature (e.g., office work or light house work) 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities; up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled; cannot perform any self-care; totally confined to bed or 
chair 
 


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11.2.8. 
Electrocardiogram 
A single 12-lead ECG will be performed at screening and triplicate ECGs will be taken for 
Phase 2 (Table 10) and Phase 3 (Table 11).  
ECGs are to be performed using a standardized method before blood draws or any other 
procedures.  The patient must be in a supine position in a rested and calm state for at least 
5 minutes before the ECG assessment is conducted.  If the patient is unable to be in the supine 
position, the patient should be in most recumbent position as possible.   
In Phase 2 and Phase 3, single safety ECGs will be obtained during screening, at the EOT, Early 
Discontinuation and at 30-day safety follow-up visit for all patients.  ECG in triplicate with 
2-3 minutes between measurements will be obtained in Phase 2 (Arms 2 to 4 only) and Phase 3 
on Cycle 1 Day 1 (in both arms) before docetaxel infusion, immediately before plinabulin 
infusion, 5 minutes before end of plinabulin infusion, 30 minutes and 4.5 hours after start of 
infusion with plinabulin or matching placebo. On Cycle 1 Day 2, ECG in triplicate will be 
obtained prior to blood draws in Arms 2 to 4 (Phase 2) or prior to pegfilgrastim/placebo injection 
in both arms (Phase 3).  
For Arm 1 of Phase 2, the triplicate ECGs will not be obtained; so the only assessments will be 
the single ECGs at screening, end of treatment, early discontinuation, and follow-up. 
The ECG must include the following measurements: heart rate, QRS, QT, and PR intervals.  
Table 10: 
Schedule for ECG Collection (Phase 2)  
Screening 
Day −28 to 
−1 
(All arms) 
Cycle 1 
Day 1 
Before 
docetaxel 
infusion 
(up to 
1-hour 
window) 
(Arms 
2 to 4) 
Cycle 1 Day 1 
Immediately 
before 
plinabulin 
infusion 
(-5 minutes 
window; must 
be before 
plinabulin 
infusion 
starts) 
(Arms 2 to 4) 
Cycle 1 
Day 1 
5-minutes 
before End 
of 
plinabulin 
infusion 
(Arms 
2 to 4) 
Cycle 1 Day 1 
Post-plinabulin 
infusion 
 
Cycle 1 Day 2 
Pre-blood 
draws 
(Arms 2 to 4) 
End-of 
Treatment, 
Early 
Discontinuation, 
and 30 Day 
Safety 
Follow-up 
(All arms) 
30 
minutes* 
(+ 15 
minutes 
window) 
(Arms 
2 to 4) 
4.5 
hours** 
(+ 15 
minutes 
window) 
(Arms 
2 to 4) 
Single 
Triplet# 
Triplet# 
Triplet# 
Triplet# 
Triplet# 
Triplet# 
Single 
* ECG measurement approximately 30 minutes after the end of the infusion with plinabulin. 
** ECG measurement approximately 4 hours after the end of the infusion with plinabulin. 
# Triplicate ECGs not performed for Arm 1 in Phase 2. 
 


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Table 11: 
Schedule for ECG Collection (Phase 3)  
Screening 
Day −28 to 
−1 
Cycle 1 
Day 1 
Before 
docetaxel 
infusion 
(up to 
1-hour 
window) 
Cycle 1 Day 1 
Immediately 
before 
plinabulin/ 
placebo 
infusion 
(-5 minutes 
window; must 
be before 
plinabulin/ 
placebo 
infusion 
starts) 
Cycle 1 
Day 1  
5-minutes 
before End 
of 
plinabulin/ 
placebo 
infusion  
Cycle 1 Day 1  
Post-
plinabulin/placebo 
infusion 
 
Cycle 1 Day 2 
Pre-
pegfilgrastim/ 
placebo 
injection 
End-of 
Treatment, 
Early 
Discontinuation, 
and 30 Day 
Safety 
Follow-up 
30 
minutes* 
(+ 15 
minutes 
window) 
4.5 
hours** 
(+ 15 
minutes 
window) 
Single  
Triplet  
Triplet  
Triplet  
Triplet 
Triplet  
Triplet 
Single 
* ECG measurement approximately 30 minutes after the end of the infusion with plinabulin/placebo. 
** ECG measurement approximately 4 hours after the end of the infusion with plinabulin/placebo. 
 
11.2.9. 
Health-Related Quality of Life Questionnaire Evaluated with EORTC QLQ-C30 
and EQ-5D-5L 
Health-related QoL questionnaire evaluated with EORTC QLQ-C30 and EQ-5D-5L is a 
validated questionnaire developed to assess the QoL of cancer patients (Appendix A and 
Appendix D). 
It is a copyrighted instrument, which has been translated and validated in over 90 languages and 
used in more than 3,000 studies worldwide.   
Refer to the study manual for specific module and how to administer. 
11.2.10. 
Bone Pain Inventory (Short Form) 
The incidence, occurrence, and severity of bone pain will be recorded through a validated 
questionnaire (Appendix B). The bone pain questionnaire should be completed prior to docetaxel 
infusion and at the site if possible, if not the questionnaire needs to be returned to the site at the 
next scheduled visit. 
11.3. 
Efficacy 
Efficacy assessments and the time when they will be performed are presented in Table 6 and 
Table 7.   
11.3.1. 
Disease Progression 
Patients will be evaluated for disease progression in accordance with institutional practice.  For 
example, the investigator may identify target lesions at screening, and at the EOT visit will 
assess the patient’s response to the docetaxel and study drug chemotherapy.  This will be 
designated the patient’s treatment response.  If no reliable target lesions are identifiable (e.g. 
patients with bone-only cancer metastases), institutional response criteria will be used for 
recording disease progression. 


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Investigators should exercise their clinical judgment in performing studies (including computed 
tomography and positron emission tomography scans) to assess disease progression, and can end 
study treatment if a patient is clearly having disease progression prior to the completion of the 
planned 4 cycles of chemotherapy.  If a patient is taken off-study prior to completing 4 cycles of 
docetaxel and study drug, the screening and end of study images, when clinically indicated, will 
be performed.  If the patient completes four cycles of docetaxel and study drug, and there is not 
disease progression and the docetaxel is continued, then the EOT assessment of disease 
progression will be recorded as “no.” 
The investigator will submit supporting documentation for the treatment response determination, 
which could include reports from cross-sectional imaging,  laboratory values, and performance 
status estimates (before and at the end of study treatment), and this data will support the 
investigator’s determination in the CRF as disease progression “yes” or “no”. Source documents 
supporting the investigator’s judgment of disease progression will be collected, but images will 
not be “over read” nor will the investigator’s determination be subject to review.   
 (Note: a requirement for a target lesion or for “measurable disease” is not required for study 
entry.) 
11.4. 
Safety 
Safety assessments should be performed at all visits to the study center and throughout the study.  
The list of events and the time when they will be performed are presented in Table 6 and Table 7.   
11.4.1. 
Adverse Events 
Adverse events observed by the Investigator or reported by the patient will be collected at all 
study visits starting with the first dose of study drug. 
Serious adverse events are collected from the time of signing the informed consent form to the 
end of the study. 
All AEs, SAEs, treatment emergent AEs, treatment emergent SAEs, and treatment emergent 
deaths regardless of the relationship to the study drug, will be collected. 
All hospitalizations should be documented in the eCRF. 
11.4.2. 
Concomitant Medications 
All concomitant medications and in particular all analgesics, pain medications, and antibiotics 
should be recorded with date of onset and discontinuation, dose, and frequency will be entered 
into the eCRF. 
11.5. 
Laboratory Evaluations 
Chemistry, coagulation tests, hematology, urinalysis, hepatitis serology, HIV, pregnancy testing 
confirmation will be performed using a central laboratory and will be used to determine 
docetaxel dosing.  Safety laboratory tests are required prior to treatment on Day 1 of each cycle 
and can be collected by a local laboratory; however, all other safety (e.g. protocol specified) 
blood samples as per the schedule of assessments (refer to Table 6 and Table 7) must also be 


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obtained for central laboratory assessment. In addition a central laboratory blood draw needs to 
be taken on the day of dosing on Day 1 of each cycle, prior to the docetaxel dosing. 
The Sponsor or the central laboratories will supply containers for sample collection, preparation, 
packaging, and shipping.  Detailed instructions for sample collection, processing, and shipping 
are provided in the central laboratory manual and/or the Sponsor will provide training materials.  
The date and time of sample collection will be recorded in the source documents at the site.  
Table 12 outlines the specific analytes that will be assessed during the study at time points 
outlined in the Schedule of Assessments (Table 6 and Table 7). 
Table 12: 
Clinical Laboratory Tests (Central Laboratory) 
Category 
Parameters 
Hematology 
Haptoglobin, hematocrit, hemoglobin, platelets, RBC count, WBC 
count with differential (bands, basophils, eosinophils, lymphocytes, 
monocytes, neutrophils), and ANC 
Chemistry 
 
 Electrolytes 
Bicarbonate, chloride, magnesium, potassium, sodium 
 Liver function tests 
Alanine aminotransferase, alkaline phosphatase, aspartate 
aminotransferase, direct bilirubin, total bilirubin 
 Renal function tests 
Blood urea/blood urea nitrogen, creatinine 
 Pregnancy test 
Subject must have a negative urine pregnancy test documented within 
the 24-hour period prior to the first infusion. Confirm with serum 
testing if urine sample is positive. 
 Coagulation 
PT, INR, PTT 
 Other 
Albumin, amylase, calcium, lactate dehydrogenase, lipase, 
phosphorus, total protein, uric acid, hepatitis B/C testing (HBsAb, 
hepatitis C antibody, HBsAG, HBcAb) 
Urinalysis 
glucose, ketones, pH, protein, RBCs, specific gravity 
Exploratory Biomarker 
 
 
CD34+ (in selected countries) 
Abbreviations: ANC= absolute neutrophil count, β hCG = beta-human chorionic gonadotropin, HBcAb = hepatitis B 
core antibody, HBsAb = hepatitis B surface antibody, HBsAG = Hepatitis B Surface Antigen Reactive, INR = 
International Normalized Ratio, PT = prothrombin time, PTT = partial thromboplastin time, RBC = red blood cells, 
WBC = white blood cells 
11.5.1. 
Pregnancy Testing 
Pregnancy tests will be done using urine samples in women of childbearing potential. Subject 
must have a negative urine pregnancy test documented within the 24-hour period prior to the first 
infusion. Confirm with serum testing if urine sample is positive.  


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11.5.2. 
Hepatitis B/C Testing 
Hepatitis B/C serologic markers hepatitis B surface antigen reactive (HBsAG), hepatitis B core 
antibody (HBcAb), hepatitis B surface antibody (HBsAb), and hepatitis C antibodies will be 
tested.  
11.5.3. 
HIV Testing 
HIV will be tested for using standard methodology. 
11.5.4. 
Exploratory Markers 
A blood sample for exploratory marker evaluation will be collected for CD34+ which will be 
established by FACS. This test will be performed in selected countries participating in the study, 
via central laboratory.  
11.6. 
End of Treatment Assessment 
EOT is defined as the last assessment for the protocol-specified treatment post Cycle 4 (Day 22 
[+ 7 days]) of the study for an individual patient (refer to Table 6 and Table 7 for details).  
11.7. 
Safety Follow-up/End of Study Assessment 
All patients, including patients who withdraw from the study early, should complete a safety 
follow-up visit 30 (+ 7) days after the last dose (refer to Table 6 and Table 7 for details).  All 
patients experiencing drug-related toxicities of Grade ≥ 2 at the End of Treatment visit should be 
followed-up at least monthly until the adverse event(s) resolves to Grade ≤ 1, the event is 
considered to be chronic, or the patient receives other anti-cancer therapy.  The method of 
follow-up assessment will be at the Investigator’s discretion (for example, patient site visit or 
telephone call).  All deaths which occur within 30 days of study drug administration regardless 
of relationship to the study drug must be reported the Sponsor immediately and within 24 hours 
of becoming aware of the event. 
11.8. 
Pharmacokinetics 
All patients in Phase 2 will participate in the PK assessments. Sparse PK sampling for plinabulin 
in Phase 3 will be collected from all patients, and the sampling schedule will be based on the PK 
results of Phase 2.  
 
Plinabulin Sampling 
All patients randomized to a plinabulin treatment arm will have samples taken for plinabulin PK 
on Cycle 1 for up to 24 hours after the start of the plinabulin infusion.  Patients randomized to 
pegfilgrastim during open label treatment will not have samples collected for plinabulin PK.   
 


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Table 13: 
Plinabulin Pharmacokinetic Sampling Schedule (Cycle 1) 
Day 
Day 1 
Day 2 
Time 
Pre-dose* 
 
End-of infusion  
(+/- 5 min) 
Post-dose 
60 minutes**  
(+/- 5 min) 
Post-dose 
4.5 hours***  
(+/- 15 min ) 
24 hours post 
Day 1 dose 
(+/- 6 hr) 
* Immediately before infusion, up to 1 hour window 
** Sample to be taken 30 minutes after the end of the 30-minute infusion. 
*** Sample to be taken 4 hours after the end of the 30-minute infusion. 
 
Docetaxel Sampling 
All patients will have samples taken for docetaxel PK on Cycle 1 Day 1 for up to 24 hours after 
the start of the docetaxel infusion. 
Table 14: 
Docetaxel Pharmacokinetic Sampling Schedule (Cycle 1, Day 1) 
Day 
Day 1 
Day 2 
Time  
End-of infusion  
(+/- 5 min) 
Post-dose 
1.5 hours*  
(+/- 5 min) 
Post-dose 
6.0 hours**  
(+/- 15 min) 
24 hours post 
Day 1 dose 
(+/- 6 hr) 
* Sample to be taken 30 minutes after the end of the 60-minute docetaxel infusion. 
** Sample to be taken 5 hours after the end of the 60-minute docetaxel infusion. 
 
11.9. 
Appropriateness of Measurements 
All safety assessments used in this study are standard, i.e., widely used and generally recognized 
as reliable, accurate, and relevant, either in clinical practice or specifically in cancer patients.  
Questionnaires for bone pain and health-related QoL questionnaire evaluated with EORTC 
QLQ-C30 and EQ-5D-5L are validated for use in this population.   


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12. 
DATA HANDLING AND QUALITY ASSURANCE 
Data management will be the responsibility of the Sponsor.  CRFs and edit checks will be 
designed and validated based on protocol requirements for data collection and with input from 
the statistical, data management and clinical operations staff.   
12.1. 
Data Collection 
Data will be captured by using an online Electronic Data Capture (EDC) system.  Data collected 
in patient source documents will be entered onto the eCRFs by site study staff, and subject to an 
audit trail of changes made to the eCRF.  For each patient enrolled, an eCRF must be completed 
and electronically signed by the principal investigator or authorized delegate from the study staff.  
The investigator should ensure the accuracy and completeness of the data reported to the 
sponsor/ CRO in the eCRFs.  Data will be stored in files that can be accessed through listing 
exports. 
12.2. 
Data Management/Coding 
A CRO will be responsible for data management, including quality checking of the data.  During 
the data entry and verification process, edit check programs will identify data discrepancies and, 
automatically generate queries.  Query reports will be sent to sites or to laboratories for 
resolution.  The sites will correct the data as needed to resolve the queries.  Any data captured 
electronically (such as laboratory results) will be transferred to the database electronically and 
edit checks will be programmed to search for missing and out of range data.  For electronically 
transferred data, the laboratory is expected to re-send the data transferred with the correction 
applied.  Per Sponsor’s or designee’s operating procedures, an audit trail will be maintained. 
Throughout the study, the Study Management Team will review data according to the Edit 
Specifications Document as described in the Data Management Plan. 
12.3. 
Quality Assurance  
The database will be audited for quality assurance by an outside vendor based on a predefined 
study audit plan to ensure acceptable accuracy and completeness.  


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13. 
SAFETY MONITORING AND REPORTING 
The investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an AE or SAE as provided in this protocol.  
13.1. 
Adverse Events 
13.1.1. 
Definitions and Reporting 
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment.  An AE can, therefore, be any unfavorable and unintended sign 
(including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.  Pre-existing conditions, which worsen during a study, are to be reported as 
AEs. 
All clinical AEs encountered during the clinical study will be reported on the AE page of the 
CRF.   
13.1.1.1. Assessment of Severity 
Whenever possible, the intensity of clinical AEs will be graded according to NCI Common 
Terminology Criteria for Adverse Events (CTCAE) (v 4.03) grading system.  Adverse events not 
listed on the NCI-CTCAE grading system will be graded on a 5-point scale (mild, moderate, 
severe, life-threatening, and death) as described below, and reported in detail as indicated on the 
CRF (Study Manual). 
Severity Grading for AEs not listed in NCI-CTCAE (v4.03) 
Grade 1: 
Mild – Transient or mild discomfort; no medical intervention or therapy required. 
Grade 2: 
Moderate – Moderate discomfort or limitation in activity – some assistance may 
be needed or minimal medical intervention or therapy required. 
Grade 3: 
Severe – Marked limitation in activity, some assistance required; medical 
intervention or therapy required; hospitalization possible. 
Grade 4: 
Life Threatening – Extreme limitation in activity; significant assistance required; 
significant medical intervention or therapy required; hospitalization probable. 
Grade 5: 
Death 
13.1.1.2. Relationship to Study Drug 
The investigator will assess the possible relationship of a AE or SAE to the use of study drug.  
An investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that the investigational product caused or contributed to an AE; generally, the facts 
(evidence) or arguments to suggest a causal relationship should be provided.   
The following grading of causality will be used for this study: 


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• Related: There is a reasonable causal relationship between the study drug and the event, 
and the event occurred within a plausible time relationship to drug administration, and the 
event cannot be explained by the condition under study, concurrent disease, other drugs 
or chemicals, or other circumstances. The event responds to withdrawal of study drug 
(dechallenge) and recurs with rechallenge (if clinically feasible to rechallenge). 
• Probable: There is reasonable causal relationship between the event and the study drug, 
the event occurred within plausible time relationship to drug administration, the event is 
unlikely to be attributed to the condition under study, concurrent disease, other drugs or 
chemicals, or other circumstances. The event follows a clinically reasonable response on 
withdrawal of study drug. 
• Possible: There is a reasonable causal relationship between the event and study drug, the 
event occurred within a plausible time relationship to study drug administration, but the 
event could also possibly be explained by the condition under study, concurrent disease, 
other drugs or chemicals, or other circumstances. Dechallenge information is lacking or 
unclear. 
• Unlikely: There is a temporal relationship of the event to study drug but not a reasonable 
causal relationship, or there is no temporal relationship to study drug administration or 
the condition under study, concurrent disease, other drugs or chemicals, or other 
circumstances provide a plausible explanation for the event. 
• Unrelated: There is no temporal relationship between the event and study drug 
administration (too early or late or study drug not administered). There is no reasonable 
causal relationship between the event and the study drug. The condition under study, 
concurrent disease, other drugs or chemicals, or other circumstances provides a plausible 
explanation for the event. 
For the purposes of regulatory reporting a casuality assessment of related, probable, or possible, 
will be treated as related. 
If the investigator’s causality assessment is “unknown but not related to investigational product”, 
this should be clearly documented on study records.   
In addition, if the investigator determines an SAE is associated with study procedures, the 
investigator must record this causal relationship in the source documents and CRF and report 
such an assessment in accordance with the SAE reporting requirements. 
13.1.1.3. Follow-Up of Adverse Events and Serious Adverse Events 
For the purpose of this study, AEs irrespective of causality will be collected from first study drug 
administration (Study Day 1) and all SAEs irrespective of causality will be collected from the 
time the Informed Consent Form is signed.  AEs and SAEs will be collected until 30 days after 
the last infusion of study treatment or initiation of another anti-cancer therapy.  Thereafter, all 
SAEs which are considered to be drug-related should be reported, regardless of time elapsed 
since the last dose of study drug (even if the study has stopped).  


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13.1.2. 
Laboratory Test Abnormalities 
Laboratory test results will be recorded on the laboratory results pages of the eCRF.  Laboratory 
test value abnormalities as such should not be reported on the AE page of the CRF as AEs unless 
they result in a clinically significant condition as judged by the investigator. 
13.2. 
Serious Adverse Events 
13.2.1. 
Definitions 
The definition and reporting requirements of International Council on Harmonisation (ICH) 
Guideline for Clinical Safety Data Management, Definitions and Standards for Expedited 
reporting, Topic E2 will be adhered to. 
An SAE is any experience that suggests a significant hazard, contraindication, side effect or 
precaution.  With respect to human clinical experience, this includes any experience which: 
• is fatal, 
• is life-threatening, 
• requires in-patient hospitalization or prolongation of existing hospitalization, 
• results in persistent or significant disability/incapacity, 
• is a congenital anomaly/birth defect, or 
• is considered medically significant by the investigator or requires intervention to 
prevent 1 or other of the outcomes listed above, 
Medical and scientific judgment should be exercised in deciding whether expedited reporting to 
the Sponsor is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the patient 
or may require intervention to prevent 1 of the outcomes listed in the definitions above.  These 
situations should also usually be considered serious. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasia or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse.  The term severe is a measure of intensity, thus 
an SAE is not necessarily serious.  For example, nausea of several hours’ duration may be rated 
as severe, but may not be clinically serious.  
All relevant information, either initial or follow-up, has to be reported on the SAE report forms. 
For serious and all other AEs, the following must be assessed and recorded on the AE page of 
the CRF: event, intensity, relationship to test substance, action taken, and outcome to date.   
The Investigator must notify the Ethics Review Committee/IRB of such an event in writing 
as soon as is practical and in accordance with international and local laws and regulations. 


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13.2.2. 
Reporting 
13.2.2.1. Timeframes for Submitting Serious Adverse Events 
ANY CLINICAL AE OR ABNORMAL LABORATORY TEST VALUE THAT IS 
SERIOUS (INCLUDING DEATH OR CONGENITAL ANOMALY) OCCURRING 
DURING THE COURSE OF THE STUDY, IRRESPECTIVE OF THE TREATMENT 
RECEIVED BY THE PATIENT, MUST BE REPORTED TO THE SPONSOR OR 
DESIGNEE WITHIN ONE WORKING DAY OF THE SITE LEARNING OF THE 
EVENT (EXPEDITED REPORTING).  
Please contact the sponsor or designee to report all SAEs within 24 hours of learning of the SAE. 
• Please complete an SAE Report Form and scan the form and any supporting 
documentation (which includes laboratory data, hospital records and the results of 
relevant tests).  The form and supporting documentation must be e-mailed to: 
ICON-Safety-CentralReceipt@iconplc.com within 24 hours.  
• The preferred method for receiving SAEs is via email.  In cases where submission 
through email is not possible, the site may report the SAEs through the following 
alternative numbers: 
For Australia and China: 
Fax No.: +6565657939 
For the US: 
Fax No.: +1 215 616 3096 
For EU: 
Fax No.: +44 (0)208 100 5005 
• If an ongoing SAE changes in intensity or causal relationship to the investigational 
product, or if new information becomes available, a follow-up SAE report should be 
sent to ICON within 24 hours using the same procedure used for transmitting the 
initial SAE report. 
• All SAEs should be followed-up until resolution, improvement, or stabilization.  
The definition and reporting requirements of ICH Guideline for Clinical Safety Data 
Management, Definitions and Standards for Expedited reporting, Topic E2 will be adhered to. 
13.3. 
Pregnancies 
A female patient of child-bearing potential must be instructed to immediately inform the 
Investigator if she becomes pregnant during the study.  Pregnancies occurring up to 90 days after 
final administration of study drug must also be reported to the Investigator.  The Investigator 
should report all pregnancies within 24 hours to the Sponsor.  The Investigator should counsel 
the patient; discuss the risks of continuing with the pregnancy and the possible effects on the 
fetus. Monitoring of the patient should continue until conclusion of the pregnancy.  Patients who 
become pregnant while on study will be discontinued from the study treatment and all End of 


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Treatment visit procedures will be performed.  If the patient is a man who is capable of fathering 
a child, he must agree to use adequate birth control beginning immediately after he enrolls on 
this study until 3 months after his last dose of study drug.  Pregnancy occurring in the partner of 
a patient participating in the study should also be immediately reported to the Investigator and 
the Sponsor.  The partner should be counseled and followed as described above.  
Pregnancy is not an SAE; however, the outcome of a pregnancy must be reported to detect a 
potential SAE (congenital anomaly, premature birth, or birth defect).  All pregnancies must be 
initially reported and follow-up information must be reported on the pregnancy follow-up form.  
The reporting timeframe to report a pregnancy to the Sponsor is from start of study drug up to 
90 days after the last dose of study drug.  Procedures and policies at the site and at the Sponsor, 
regarding pregnancies, will be followed to ensure that the safety and well-being of the study 
patient and fetus are appropriately followed through the pregnancy to birth.  In the event that a 
pregnancy occurs in the female partner of a male patient, the Investigator will then (and only 
then) also be required to obtain her consent so that the Sponsor can hold her data on file.  If the 
female partner is unwilling to sign the consent her data may not be held in the safety database.  
However, this will not affect the ability of the male patient to continue in the study. 
13.4. 
Independent Data Safety Monitoring Board 
An independent DSMB will be assembled and be governed by a DSMB charter, which will 
specify membership, frequency of meetings, and potential sample size adjustment. 
 


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14. 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN 
All statistical analyses will be performed by the sponsor or designee after the study is completed 
included in a separate statistical analysis plan (SAP). 
Patients will be stratified using the strata by tumor type in Phase 3. 
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. 
14.1. 
Study Endpoints 
14.1.1. 
Phase 2 Endpoints  
Plinabulin pharmacokinetic (PK) and pharmacodynamic (PD) assessments will be made to 
enable a PK/PD analysis.  
Primary Endpoint:   
• To establish the Recommended Phase 3 Dose (RP3D) based on PK/PD analysis 
Primary Efficacy Pharmacodynamic Endpoint: 
• DSN in treatment Cycle 1 in patients treated with docetaxel (75 mg/m2) + plinabulin 
(5,10 or 20 mg/ m2) or with docetaxel (75 mg/m2) + pegfilgrastim (6 mg). 
Neutrophils count will be assessed at baseline (prior to Cycle 1 docetaxel dose) and 
during Cycle 1 on Days 1, 2, 6, 7, 8, 9, 10, 15 (pre-dose on dosing days; times 
equivalent to pre dose on other days).  
Primary Safety Pharmacodynamic Endpoint: 
• To assess blood pressure semi-continuously with 15-minute intervals, starting 
15 minutes pre-plinabulin dose and lasting 4.5 hours after start of infusion with 
plinabulin (Arms 2 to 4) or for 4.75 hours starting 15 minutes after the end of 
docetaxel infusion (Arm 1). 
Secondary Endpoints:   
• To characterize the pharmacokinetic profile of plinabulin and docetaxel  
• To characterize the exposure-response relationships between measures of plinabulin 
exposure and the pharmacodynamic endpoint DSN. 
• To characterize the exposure-safety relationships between measures of plinabulin 
exposure and safety events of interest. 
Exploratory Endpoints: 
• To assess CD34+ at screening, and on Days 2, 6, and 8 in Cycle 1 and Day 1 in 
Cycle 2. 
• Health-related QoL questionnaire evaluated with EORTC QLQ-C30 (Appendix A) 
and EQ-5D-5L (Appendix D) 


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• Data collection on disease progression  
Safety Endpoints 
• 
Incidence, occurrence, and severity of AEs/SAEs  
• 
Incidence, occurrence and severity of bone pain (Appendix B) 
• 
Systemic tolerance (physical examination and safety laboratory assessments) 
14.1.2. 
Phase 3 Endpoints  
Primary Efficacy Endpoint:  
• DSN in treatment Cycle 1 in patients treated with docetaxel + plinabulin (RP3D) 
compared with patients treated with docetaxel + pegfilgrastim. Neutrophils count will 
be assessed at baseline (prior to Cycle 1 docetaxel dose) and during Cycle 1 on 
Days 1, 2, 6, 7, 8, 9, 10, 15.  
Secondary Efficacy Endpoints: 
• To assess the effects of docetaxel + plinabulin RP3D versus docetaxel + pegfilgrastim, 
using the following endpoints: 
− Incidence of Grade 4 neutropenia (ANC < 0.5 × 109/L) on Days 8 and 15 in 
Cycle 1 and on Day 8 in Cycles 2 to 4 
− Incidence of FN (ANC < 0.5 × 109/L and body temperature ≥ 38.3°C) in Cycles 1 
to 4 
− Neutrophil nadir during Cycle 1 
− Incidence of documented infections Cycles 1 to 4 
− Incidence and duration of hospitalizations due to FN in Cycles 1 to 4 
− Health-related QoL questionnaire evaluated with EORTC QLQ-C30 and EQ-5D-
5L (Appendix A) and EQ-5D-5L (Appendix D) 
− Incidence of use of pegfilgrastim or filgrastim as treatment for neutropenia 
− Incidence of antibiotic use 
− Incidence of docetaxel dose delay, dose reduction, and/or dose discontinuation 
Exploratory Endpoint 
• 
Data collection on disease progression   
Safety Endpoints 
• 
Incidence, occurrence, and severity of AEs/SAEs  
• 
Incidence, occurrence and severity of bone pain (Appendix B) 
• 
Systemic tolerance (physical examination and safety laboratory assessments) 


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14.2. 
Statistical Analysis 
14.2.1. 
Analysis Sets of Phase 2 
14.2.1.1. Intent-to-Treat Analysis Set 
The intent-to-treat analysis set for Phase 2 is comprised of all Phase 2 patients that have been 
randomized in the study and have received at least one dose of study medication.  
The analysis of all endpoints, unless noted otherwise, will be conducted on the intent-to-treat 
analysis set. 
14.2.1.2. Safety Analysis Set 
The safety analysis set will be the same as the intent-to-treat analysis set for Phase 2.  
14.2.1.3. Pharmacokinetic Analysis Set 
All subjects who received at least 1 dose of plinabulin or docetaxel and had at least 1 PK sample 
collected will be included in the PK analysis set.  These subjects will be evaluated for PK unless 
significant protocol deviations affect the data analysis or if key dosing, dosing interruption, or 
sampling information is missing. For phase 3, PK samples may be collected with a schedule of 
collection based on the emerging data from Phase 2.  Population pharmacokinetic modeling will 
be utilized to analyze the PK data, and optimal sampling approaches will be used to determine 
the PK time points for Phase 3. 
14.2.1.4. Pharmacodynamic Analysis Set 
All patients who had blood pressure and DSN collected at any time during the study will be 
included in the PD analysis set. For phase 3, PD data may be collected with a schedule of 
collection to be confirmed based on the emerging data to be determined.  Exploratory PK/PD and 
exposure-response analyses will be conducted to evaluate the effects of plinabulin on safety and 
efficacy endpoints.  Details of these analyses will be summarized in the statistical analysis plan, 
and may be reported outside of the main clinical study report. 
14.2.2. 
Analysis Sets of Phase 3 
14.2.2.1. Intent-to-Treat Analysis Set 
The intent-to-treat analysis set for Phase 3 is comprised of all Phase 3 patients that have been 
randomized in the study and have received at least one dose of study medication.  
The analysis of all endpoints, unless noted otherwise, will be conducted on the intent-to-treat 
analysis set. 
14.2.2.2. Safety Analysis Set 
The safety analysis set will be the same as the intent-to-treat analysis set for Phase 3.  
14.2.3. 
Patient Disposition 
Descriptive summaries will be generated to describe the disposition of all enrolled patients. 


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14.2.4. 
Demographics and Other Baseline Characteristics 
Demographic and other baseline characteristics will be described, but no hypothesis testing will 
be done. 
14.2.5. 
Prior and Concomitant Therapy 
Concomitant medications will be assigned an 11-digit code using the World Health Organization 
(WHO) Drug dictionary codes. 
14.2.6. 
Efficacy Analyses 
Data will be tabulated by treatment group, with data listings provided for all data captured in the 
eCRF as well as laboratory data. On treatment data, will be assessed descriptively as both 
observed values and as changes from pretreatment.  When tabulated, data will be presented using 
descriptive statistics (e.g., mean, median, standard deviation, and range for continuously scaled 
parameters, and as number and percent for categorically scaled parameters).  Statistical Analysis 
System Version 9.4 or higher will be used to perform the majority of the analyses; other software 
(e.g., NCSS) may be utilized to generate graphics or perform other analysis.  A detailed 
statistical analysis plan (SAP) will be written and approved before unblinding the treatment 
allocation codes.  Analyses will be performed based on observed data, and missing values will 
not be imputed unless otherwise stated in the SAP.  
Inferential assessment of treatment effects will be performed for efficacy outcomes.  For 
continuously scaled parameters, methods of longitudinal assessment using mixed models will be 
applied.  Overall treatment effects will be estimated (over the course of the treatment period) as 
will pairwise effects at individual time points.  For categorically scaled parameters, chi square or 
other statistics will be applied as appropriate.  More details will be given in the SAP. 
14.2.6.1. Phase 2 Efficacy Analyses 
14.2.6.1.1. Primary Efficacy Pharmacodynamic Analysis 
PK/PD analysis will determine the RP3D of plinabulin which will be used during the phase 3 of 
study treatment. 
In addition, exploratory analysis to assess DSN in treatment Cycle 1 in patients treated with 
docetaxel (75 mg/m2) + plinabulin (5,10 or 20 mg/ m2) or with docetaxel (75 mg/m2) + 
pegfilgrastim (6 mg) will be performed, using the Jonckheere-Terpstra Test for Ordered 
Alternatives (Hollander, Wolfe, and Chicken, 2013). With this statistical procedure, the null 
hypothesis of equality among treatment group means will be tested (μj's, j = 1, 2, 3, 4) 
H0: μ1 = μ2 = μ3 = μ4 
against the alternative in which order is specified 
H1: μ1 ≥ μ2 ≥ μ3 ≥ μ4, 
where at least one of the inequalities is strict. The mean indices have the following interpretation: 
1 = docetaxel (75 mg/m2) + pegfilgrastim (6 mg), 2 = docetaxel (75 mg/m2) + plinabulin 
(5 mg/m2), 3 = docetaxel (75 mg/m2) + plinabulin (10 mg/m2), and 4 = docetaxel (75 mg/m2) + 
plinabulin (20 mg/m2). The statistically significant rejection of the null hypothesis will be 


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interpreted, that there is an ordered alternative of responses as indicated by the alternative 
hypothesis H1. 
14.2.6.1.2. Exploratory Analyses 
Continuous variables and proportions will be analyzed using exact t-tests.  Categorical data will 
be analyzed using non-parametric statistical methods. 
14.2.6.2. Phase 3 Efficacy Analyses 
14.2.6.2.1. Primary Efficacy Analysis 
DSN was not measured in the previous Phase 2 study ([Study NPI-2358-101] in which patients 
received treatment with either plinabulin (30 mg/m2 [n=50] or 20 mg/m2 [n=40] plinabulin + 
docetaxel or docetaxel alone [(n=73]).  DSN was obtained using the following methods 
(described below) for generation of ANC data and the observed neutrophil values on Day 8 
in the Phase 2 study.  Day 8 neutrophil values were shown to approximately coincide with 
the nadir of neutrophil counts after docetaxel treatment (Blackwell et al, 2015). The study will 
assume that the shape of the time/neutrophil recovery curve in plinabulin-treated patients is 
indistinguishable from the time/neutrophil recovery curve for filgrastim and its biosimilars. 
In a study with filgrastim and its biosimilar, time course of ANC in Cycle 1 for the Per 
Protocol dataset was published by Blackwell et al, 2015.  Mean values and standard deviations of 
ANC during the 21-day follow-up period were readily available.  This information was used to 
write a computer simulation program that would generate random ANC data that asymptotically 
has the same means and standard deviations for the 21-day follow-up period as the publication.  
The simulation would then also generate the projected number of days with severe neutropenia 
(i.e., the DSN). 
Deming regression (Deming, 1943) was used to calculate the linear relationship between 
simulated nadir and DSN.  The rank correlation between simulated nadir and DSN was used to 
calculate the DSN with plinabulin (+ docetaxel) and docetaxel alone.  In the Phase 2 study, 
neutrophil counts were obtained on Day 8, which approximately coincides with the time that the 
neutrophil nadir occurs after docetaxel administration.  These observed Day 8 neutrophil (nadir) 
values were computed into the linear relationship (Deming regression), mentioned above to 
calculate DSN for each patient.  Using these methods, calculated mean DSN was 0.065 days for 
the plinabulin+ docetaxel arm, and 1.076 days for the docetaxel alone. Based on published data 
with filgrastim in patients receiving docetaxel (Alexopoulos K et al, 1999), the assumption is that 
Grade 4 neutropenia in Cycle 1 would occur in a 2 times higher frequency with G-
CSF+docetaxel versus plinabulin+docetaxel, resulting in a presumed mean DSN of 0.13 days for 
the G-CSF+ docetaxel combination. 
This non-inferiority trial design will utilize a difference (arm 2 minus arm 1) of 0.65 days 
(non-inferiority margin) in DSN in Cycle 1 as the largest acceptable difference between 
plinabulin and pegfilgrastim.  The non-inferiority test will evaluate the null hypothesis H0: true 
difference (arm 2 minus arm 1) ≥ 0.65 against the alternative hypothesis H1: true difference (arm 
2 minus arm 1) < 0.65.  Plinabulin will be considered non-inferior to pegfilgrastim if in Cycle 1, 
the upper limit of the 2-sided 95% confidence interval for the true difference in mean duration of 


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Grade 4 neutropenia was < 0.65 days.  A sample size of patients was based on sample size 
considerations as outlined. 
Data suggest (http://www.neulastahcp.com/risk/duration-of-severe-neutropenia/) that FN is 
correlated with DSN.  The frequency of FN with docetaxel monotherapy (100 mg/m2) + G-CSF 
was reported to be 1% in cycle 1.  FN frequency in Cycle 1 with docetaxel combined with 
doxorubicin and G-CSF was ~ 3 % (Aarts M et al, 2013), which would translate into a DSN of 
1 day according to Holmes FA, et al, 2002. Based on this data, it is assumed that the median 
DSN for docetaxel monotherapy + G-CSF will be approximately 1 day. 
The frequency of FN with docetaxel monotherapy (without G-CSF) has been reported to be 11% 
in cycle 1 (17% over all cycles) docetaxel dose of 100 mg/m2 (Vogel et al, 2005) and 19.8% over 
all cycles at a lower docetaxel dose of 60 mg/m2 (Yoh K et al, 2016). Hanna et al., 2004 reported 
a FN percentage of 12.7% with 75 mg/m2 docetaxel.  Based on this range of FN, the relationship 
established by Meza et al, 2002 between FN and DSN, we make the assumption that, with 
docetaxel monotherapy at a dose of 75 mg/m2 without G-CSF, the median DSN is estimated to 
be 4-5 days. 
In the Zarxio® briefing document, 2015, the margin was selected based on the fact that TAC 
chemotherapy is known to induce a median DSN of 7 days in breast cancer patients receiving no 
G-CSF treatment (Nabholtz, 2001), while G-CSF treatment reduces the mean DSN for this 
chemotherapy to 1.4 days (95% CI: 1.07 - 1.69) as shown in pegfilgrastim (Neulasta®) Study 
20020778 (Kaufman et al, 2004). Based on this a non-inferiority limit of 1 day was derived. 
As an extension of this reasoning, it is argued for our study, a non-inferiority margin of 0.65 
would be reasonable and correspond to approximately a median of 4.5 days of DSN, as a margin 
of 1 day to 7 days of DSN in the Zarxio® briefing document, 2015. 
A non-inferiority margin of 0.65 days can also be justified, because a difference of 0.65 days is 
not considered to be clinically meaningful. 
Since it is expected that the distribution of the primary endpoint (DSN) will contain a large 
number of zeros, the primary endpoint will be analyzed using a two-sided two-sample zero-
inflated Poisson model with treatment as the only covariate (Johnson et al. 1992). 
14.2.6.2.2. Secondary Efficacy Analysis 
For endpoints other than Grade 4 neutropenia, analyses will be based on conventional methods 
(i.e., assuming asymptotic normality) for calculating 95% CIs and hypothesis testing.  ANC 
nadir, a secondary endpoint will be analyzed using the Wilcoxon rank sum test. 
Continuous variables and proportions will be analyzed using exact t-tests.  Categorical data will 
be analyzed using non-parametric statistical methods. 
14.2.6.2.3. Exploratory Efficacy Analyses 
Continuous variables and proportions will be analyzed using exact t-tests.  Categorical data will 
be analyzed using non-parametric statistical methods.  


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14.2.7. 
Pharmacokinetic and Pharmacodynamic Analyses (Phase 2) 
Plasma plinabulin and docetaxel concentrations will be measured using validated methods and 
PK parameters will be summarized using descriptive statistics.  Individual and mean serum 
plinabulin and docetaxel concentration versus time profiles will be plotted on both linear and 
logarithmic scales. 
Exploratory graphical and statistical techniques, including linear, nonlinear, and logistic 
regression, etc., will be used to explore potential relationships between pharmacokinetic 
parameters of interest and efficacy endpoints, pharmacodynamic variables, and safety events of 
interest.  These exposure-response analyses will support the RP3D of plinabulin which will be 
used during the phase 3 of study treatment.  Full methodology will be documented with the final 
results of the analyses, potentially as a separate report. 
14.3. 
Safety Analyses 
Medical history and AE data will be coded by system organ class (SOC) and preferred term (PT), 
using the Medical Dictionary for Regulatory Activities (MedDRA) dictionary.  Concomitant 
medication data will be coded by drug class and indication, using the WHO Drug dictionary.  
All treatment emergent AEs will be graded according to NCI CTCAE version 4.03, and grouped 
by the MedDRA Preferred Term and System Organ Class, and summarized by worst grade 
severity per patient. 
Treatment emergent AEs are those events that occur after first administration of any study 
therapy through 30 days post last dose of any study therapy, and/or any treatment-related AEs, 
regardless of the onset date.  Dose delays, dose modifications and/or dose discontinuation of 
docetaxel due to safety concerns will be summarized for the 2 treatment groups. 
Continuous variables and proportions will be analyzed using exact t-tests.  Other categorical data 
will be analyzed using non-parametric statistical methods. 
14.3.1. 
Deaths 
Treatment emergent deaths are those deaths within 30 days of last dose of any study therapy. 
Early deaths are those deaths within 60 days of the first dose of study therapy. 
Treatment emergent and/or early deaths will be tabulated and summarized by treatment groups. 
14.3.2. 
Extent of Exposure 
Refer to the SAP for details. 
14.3.3. 
Adverse Events 
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using MedDRA.  AEs will be coded to MedDRA 
(Version 18.1 or higher) lower level term closest to the verbatim term.  The linked MedDRA 
preferred term (PT) and primary system organ class (SOC) are also captured in the database. 


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14.3.4. 
Laboratory Analyses 
Continuous variables and proportions will be analyzed using exact t-tests.  Other categorical data 
will be analyzed using non-parametric statistical methods.  
14.3.5. 
Vital Signs 
Descriptive statistics and shift tables will be used for the evaluations. 
14.3.6. 
Electrocardiogram 
Electrocardiogram assessments will be provided in a listing. 
14.4. 
Sample Size Considerations   
14.4.1. 
Phase 2 
In the Phase 2 (approximately 40 patients; approximately 10 patients per arm), patients with 
advanced or metastatic NSCLC will be enrolled. 
14.4.2. 
Phase 3 
Approximately 150 patients are planned to be enrolled with 1 of the following diagnoses: 
advanced or metastatic breast cancer, NSCLC, or HRPC.  A sample size of 75 patients in each of 
the treatment arms docetaxel + plinabulin (RP3D) versus docetaxel + pegfilgrastim, with 
matching placebos achieve at least a 90% power to reject the null hypothesis of 0.65 day of 
inferiority in DSN between the treatment means with standard deviations of 0.75, at a 
significance level (alpha) of 0.05 two-sided two-sample zero-inflated Poisson model.   
The software PASS version 15.0.1 has been used for the calculations referencing Chow et al. 
2003, Lan and DeMets 1983, O'Brien and Fleming 1979. 
14.5. 
Interim Analysis 
The study design is group sequential with 1 interim analysis (after 50 patients in each treatment 
arm have completed at least 1 cycle in each of the treatment arms docetaxel + plinabulin [RP3D] 
versus docetaxel + pegfilgrastim, with matching placebos) and 1 final analysis at the completion 
of the study (Table 15). These results assume that 2 sequential tests are made using the O'Brien-
Fleming spending function to determine the test boundaries. 
If non-inferiority is determined from the statistical testing, then also the hypothesis of superiority 
will be tested, and if it is concluded that the plinabulin treatment is superior to the pegfilgrastim 
treatment, with respect to DSN, then the study will be stopped. Since the design allows for 
stopping for inferiority, it might be decided at that occasion that the study will be stopped. Since 
this is a hierarchical testing procedure no penalty with respect to overall significance will be 
paid. 
The statistical testing will be performed and will be reviewed by an independent DSMB at the 
interim analysis.   


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Table 15: 
Timing of Statistical Analyses 
 
Number of Patients in Phase 2 (approximate) 
Arm 1: Docetaxel + Pegfilgrastim 6 mg 
10 
Arm 2: Docetaxel + Plinabulin 20 mg/m2 
10 
Arm 3: Docetaxel + Plinabulin 10 mg/m2  
10 
Arm 4: Docetaxel + Plinabulin 5 mg/m2 
10 
 
PK/PD Analysis (to determine RP3D) 
 
Number of patients in Phase 3 (approximate) 
Arm 1: Docetaxel + Pegfilgrastim 6 mg 
50 
75 
Arm 2: Docetaxel + Plinabulin (RP3D) 
50 
75 
 
Interim Analysis 
Final Analysis 
 
14.6. 
Withdrawal 
During the phase 2 and phase 3 portions, randomized patients who withdraw before receiving the 
first dose will be replaced.   
14.7. 
Independent Data Safety Monitoring Board Interim Safety Review 
An independent DSMB will be utilized in this study and will be comprised of individuals who 
are not members of the clinical study team.  At least 2 independent oncologists (external to the 
sponsor) will serve on the committee.  The objective of the DSMB will be to ensure objective 
medical and/or statistical review of safety and/or efficacy issues in order to protect the ethical 
and safety interests of subjects and to protect the scientific validity of the study.  See details in 
Section 14.5.  


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15. 
ADMINISTRATIVE PROCEDURES 
15.1. 
Investigator Reporting Requirements 
As indicated in periodic safety updates and notifications are the responsibility of the investigator 
and not of the sponsor. 
15.2. 
Confidentiality 
The Investigator must assure that patients’ anonymity will be maintained and that his or her 
identities are protected from unauthorized parties.  On CRFs or other documents submitted to the 
Sponsor, patients should not be identified by his or her names, but by an identification code.  The 
Investigator should keep a patient enrollment log showing codes, names and addresses.  The 
Investigator should maintain documents not for submission to the Sponsor (e.g., patients’ written 
consent forms, in strict confidence). 
15.3. 
Case Report Forms 
For each patient enrolled, an eCRF must be completed and electronically signed by the Principal 
Investigator or authorized delegate from the study staff.  Once a patient has signed informed 
consent and any study related procedures are performed, an eCRF must be completed.  If a 
patient is withdrawn from the study because of a treatment-limiting AE, thorough efforts should 
be made to clearly document the outcome.  The Investigator should ensure the accuracy, 
completeness, legibility, and timeliness of the data reported to the Sponsor in the CRFs and in all 
required reports. 
15.4. 
Drug Accountability 
The investigator or designee (i.e., pharmacist) is responsible for ensuring adequate accountability 
of all used and unused study drug.  This includes acknowledgment of receipt of each shipment of 
study product (quantity and condition), patient dispensing records and returned or destroyed 
study product. 
15.5. 
Protocol Compliance 
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol. 
15.6. 
Protocol Modifications 
Protocol modifications to ongoing studies must be made only after consultation between an 
appropriate representative of the Sponsor and the Investigator.  Protocol modifications must be 
prepared by a representative of the Sponsor and initially reviewed and approved by Chief 
Medical Officer. 
All protocol modifications must be submitted to the appropriate IEC or IRB for information and 
approval in accordance with local requirements and to Regulatory Agencies if required.  
Approval must wait before any changes can be implemented, except for changes necessary to 


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eliminate an immediate hazard to study patients, or when the change(s) involves only logistical 
or administrative aspects of the study (e.g. change in Monitor(s), change of telephone number(s). 
15.7. 
Study Report and Publications 
The results of this study may be published or presented at scientific meetings.  The Investigators 
agree to submit all manuscripts or abstracts to the Sponsor before submission.  This allows the 
Sponsor to protect proprietary information and to provide comments based on information from 
other studies that may not yet be available to the Investigator. 
Because this is a multicenter study, individual investigators may not publish the results of the 
study based on information from his or her sites until the complete study has been published in 
full (not abstract) form.  If a joint publication has not been submitted within 8 months after the 
study has been completed or terminated at all sites, then individual sites may publish subject to 
the requirement to submit to the Sponsor before publication. 
The Sponsor will prepare a clinical study report upon completion or termination of the study. 
15.8. 
Study Discontinuation 
Both the Sponsor and the Investigator reserve the right to terminate the study at any time.  
Should this be necessary, both parties will arrange the procedures on an individual study basis 
after review and consultation.  In terminating the study, the Sponsor and the Investigator will 
assure that adequate consideration is given to the protection of the patient’s interests. 
15.9. 
Records Retention and Study Files 
15.9.1. 
Study Files and Retention of Records 
The Investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified.  These documents should 
be classified into 2 different separate categories 1) Investigator’s Study File, and 2) patient 
clinical source documents. 
The Investigator’s Study File will contain the Protocol/Amendments, sample CRFs, patient 
screening and enrollment logs, Independent Ethics Committee/IRB and governmental approval 
with correspondence, sample informed consent, study-drug records, staff curriculum vitae and 
authorization forms and other appropriate documents/correspondence, etc. 
Patient clinical source documents (usually defined by the project in advance to record key 
efficacy/safety parameters independent of the CRFs) would include patient hospital/clinic 
records, physician’s and nurse’s notes, appointment book, original laboratory reports, ECG, 
X-ray, pathology and special assessment reports, signed informed consent forms and consultant 
letters.  The Investigator must keep these 2 categories of documents on file for at least 15 years 
after completion or discontinuation of the study.  After that period of time the documents may be 
destroyed, according to local regulations.  
Should the Investigator wish to assign the study records to another party or move the study 
records to another location, the Sponsor must be notified in advance. 
If the Investigator cannot guarantee this archiving requirement at the investigational site for any 
or all of the documents, special arrangements must be made between the Investigator and the 


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Sponsor to store these in a sealed container(s) outside of the site so that they can be returned 
sealed to the Investigator in case of a regulatory audit.  Where source documents are required for 
the continued care of the patient, appropriate copies should be made for storing outside of the 
site. 
15.9.2. 
Source Documents and Background Data 
The Investigator shall supply the Sponsor on request with any required background data from the 
study documentation or clinic records.  This is particularly important when CRFs are illegible or 
when errors in data transcription are suspected.  In case of special problems and/or governmental 
queries or requests for audit inspections, it is also necessary to have access to the complete study 
records, provided that patient confidentiality is protected. 
15.10. 
Provision of Study Results and Information to Investigators 
When the clinical study report is completed, the sponsor will provide the major findings of the 
study to the investigator.  
15.11. 
Information Disclosure and Inventions 
15.11.1. 
Access to Information for Monitoring 
It is understood that the responsible Sponsor’s Monitor (or designee) will contact and visit the 
Investigator regularly and will be allowed, on request, to inspect the various records of the study 
(CRFs and other pertinent source data) provided that patient confidentiality is maintained in 
accord with local requirements. 
It will be the Monitor’s responsibility to inspect the CRFs at regular intervals throughout the 
study, to verify the adherence to the Protocol and the completeness, consistency and accuracy of 
the data being entered on the CRFs.  The Monitor should have access to laboratory test reports 
and other patient records needed to verify the entries on the CRF.  The Investigator (or his/her 
deputy) agrees to cooperate with the Monitor to ensure that any problems detected in the course 
of these monitoring visits are resolved.  Refer to Monitoring Plan for further details. 
15.11.2. 
Access to Information for Auditing or Inspections 
The Investigator should understand that source documents for this study should be made 
available to appropriately qualified personnel from the Sponsor, or its designees, or to health 
authority inspectors after appropriate notification.  The verification of the CRF data must be by 
direct inspection of source documents. 


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16. 
REFERENCES 
1. Alexopoulous K, Kouroussis C, Androulakis N, et al. Docetaxel and granulocyte colony-
stimulating factor in patients with advanced non-small-cell lung cancer previously treated 
with platinum-based chemotherapy: a multicenter Phase II trial. Cancer Chemother 
Pharmacol 1999, 43: 257-262. 
2. Aarts M, Peters F, Mandigers C, et al. Primary granulocyte colony-stimulating factor 
prophylaxis during the first two cycles only or throughout all chemotherapy cycles in 
patients with breast cancer at risk for febrile neutropenia. J Clin Oncol. 2013 Dec 
1;31(34); 4290-4296.  
3. Asensi V, Valle E, Meana A, et al.  In Vivo Interleukin-6 Protects Neutrophils from 
Apoptosis in Osteomyelitis.  Infection and Immunity, July 2004, 72(7): p. 3823–3828 
4. Blackwell K, Semiglazov V, Krasnozhon D, et al. Comparison of EP2006, a ﬁlgrastim 
biosimilar, to the reference: a Phase III, randomized, double-blind clinical study in the 
prevention of severe neutropenia in patients with breast cancer receiving 
myelosuppressive chemotherapy. Annals of Oncology 26: 1948–1953, 2015. 
5. Blayney D, Bazhenova L, Lloyd K, et al. Plinabulin, a Novel Small Molecule That 
Ameliorates Chemotherapy-Induced Neutropenia, Is Administered on the Same Day of 
Chemotherapy and Has Anticancer Efficacy. Abstract. Jul 2016. 
6. Chow SC, Shao J, Wang H. 2003. Sample Size Calculations in Clinical Research. Marcel 
Dekker. New York. 
7. Crawford J, Dale DC, Lyman GH. Chemotherapy induced neutropenia.  Risks, 
consequences and new directions for its management. Cancer 2004; 100:228-237. 
8. Deming WE. (1943). Statistical adjustment of data. Wiley, NY (Dover Publications 
edition, 1985). 
9. Dinarello CA. A clinical perspective of IL-1β as the gatekeeper of inflammation. Eur J 
Immunol. 2011 May;41(5):1203-17. 
10. Gornstein E., Schwarz TL. The paradox of paclitaxel neurotoxicity: Mechanisms and 
unanswered questions. Neuropharmacology. 2014 Jan;76 Pt A:175-83. 
11. Green MD, Koelbl H, Baselga J, Galid A, Guillem V, Gascon P, Siena S, Lalisang RS, 
Samonigg H, Clemens MR, Zani1V, Liang BC, Renwick J, Piccart MJ.Hanna N, 
Shepherd F, Fossella F, et al. Randomized phase III trial of pemetrexed versus docetaxel 
in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin 
Oncol. 2004 May 1;22(9):1589-97. 
12. Hollander, M, Wolfe, DA, and Chicken, E. Nonparametric Statistical Methods, John 
Wiley & Sons, 2013.  
13. Holmes FA, O’Shaughnessy JA, Vukelja S, et al. Blinded, randomized, multicenter study 
to evaluate single administration pegfilgrastim once per cycle versus daily filgrastim as 
an adjunct to chemotherapy in high-risk stage II or stage III-IV breast cancer. J Clin. 
Oncol. 2002; 20:727-731. 


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14. Johnson, NL., Kotz, S. and Kemp, AW. (1992). Univariate Discrete Distributions (2nd 
ed.). Wiley. pp. 312–314 
15. Kaufman PA, Paroly W, Rinaldi D, et al. (2004). Randomized, double-blind, phase 2 
study evaluating the safety of same vs next day administration of pegfilgrastim with 
docetaxel, doxorubicin and cyclophosphamide (TAC) in women with breast cancer. 
Breast Canc Res Treat; 88:S59, Abstract 1054. 
16. Kennedy N, Sluss H, Jones, S, et al. Suppression of Ras-stimulated transformation by the 
JNK signal transduction pathway. Genes & Dev., 2003; 17: 629-637 
17. Kosaka Y, Rai Y, Masuda N, et al. Phase III placebo-controlled, double-blind, 
randomized trial of pegfilgrastim to reduce the risk of febrile neutropenia in breast cancer 
patients receiving docetaxel/cyclophosphamide chemotherapy Support Care Cancer 
(2015) 23:1137–1143 
18. Lan KKG. and DeMets DL. 1983. 'Discrete sequential boundaries for clinical trials.' 
Biometrika, 70, pages 659-663. 
19. Lloyd GK, Muller P, Kashyap A, et al. Plinabulin: Evidence for an immune-mediated 
mechanism of action, AACR Tumor Microenvironment Event 2016. 
20. Meza, L., Baselga, J., Holmes, F.A. et al, Incidence of febrile neutropenia (FN) is directly 
related to duration of severe neutropenia (DSN) after myelosuppressive chemotherapy. 
Proc Am Soc Clin Oncol. 2002; 21:255b (Abstr 2840). 
21. Nabholtz JM, Riva A., Taxane/Anthracycline Combinations: Setting A New Standard in 
Breast Cancer?, Oncologist. 2001; 6 Suppl 3:5-12 
22. Neulasta® Package Insert. Amgen. US 2002. 
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Pedia
tricAdvisoryCommittee/UCM235408.pdf2015. 
23. Nicholson B, Lloyd G, Miller B, et al. NPI-2358 is a tubulin-depolymerizing agent: in-
vitro evidence for activity as a tumor vascular-disrupting agent. Anti-Cancer Drugs 2006; 
17:25–31. 
24. O'Brien PC and Fleming TR. 1979. 'A multiple testing procedure for clinical trials.' 
Biometrics, 35, pages 549-556. 
25. Pizzo P. Management of fever in patients with cancer and treatment induced neutropenia. 
New Engl J Medicine 1993; 328:1323-1332. 
26. Plinabulin Investigator Brochure 2016. 
27. Singh AV, Bandi M, Raje N et al. A novel vascular disrupting agent plinabulin triggers 
JNK-mediated apoptosis and inhibits angiogenesis in multiple myeloma cells. Blood. 
2011;117(21):5692-5700. 
28. Study NPI-2358-100: A Phase I Study of the Vascular Disrupting Agent NPI-2358 
Administered via Intravenous Infusion in Patients with Advanced Solid Tumor 
Malignancies or Lymphoma. 


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29. Study NPI-2358-101: A Phase 1/2 study of the Vascular Disrupting Agent NPI-2358 in 
combination with Docetaxel in patients with Advanced Non-Small cell Lung Cancer. 
30. Study NPI-2358-103: A Randomized Single-Blinded Phase 3 Study of Second- or Third-
Line Chemotherapy with Docetaxel + Plinabulin Compared to Docetaxel + Placebo in 
Patients with Advanced Non-Small Cell Lung Cancer with at Least One Measurable 
Lung Lesion (DUBLIN-3) 
31. Taxotere® (Prescribing Information). Sanofi-aventis—US; Rev 12/2015 
(http://products.sanofi.us/Taxotere/taxotere.html). 
32. Vogel C, Wojtukiewicz M, Carroll R, et al. First and subsequent cycle use of 
pegfilgrastim prevents febrile neutropenia in patients with breast cancer: a multicenter, 
double-blind, placebo-controlled phase III study. J Clin Oncol. 2005 Feb 20;23(6):1178-
1184. 
33. Waller CF, Semiglazov VF, Tjulandin S, et al. A Phase III Randomized Equivalence 
Study of Biosimilar Filgrastim versus Amgen Filgrastim in Patients Receiving 
Myelosuppressive Chemotherapy for Breast Cancer Oncol.2010;33:504–511. 
34. Yoh K, Kasahara K, Yamada K, et al. A randomized, double-blind, phase II study of 
ramucirumab plus docetaxel vs placebo plus docetaxel in Japanese patients with stage IV 
non-small cell lung cancer after disease progression on platinum-based therapy. Lung 
Cancer. 2016 Sep;99:186-93. 
35. Zarixo® (filgrastim) FDA Oncologic Drugs Advisory Committee Meeting (FDA 
Advisory Committee Briefing Document). Jan 7, 2015. 


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17. 
APPENDICES 


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APPENDIX A. EORTC QLQ-C30 


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APPENDIX B. BONE PAIN INVENTORY (SHORT FORM) 


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APPENDIX C. NCCN GUIDELINES VERSION 2.2016 
NOTE: Persistent neutropenia, liver dysfunction (bilirubin > 2,0) and renal dysfunction 
(creatinine clearance < 50) intermediate risk factors are not applicable to this study.  
 
 


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APPENDIX D. EQ-5D-5L 
 


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APPENDIX E. CTCAE VERSION 4.03 
 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
 
 


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18. 
SIGNATURES 
Signature of Investigator 
PROTOCOL TITLE: 
A Phase 2/3, Multicenter, Randomized, Double Blind Study to 
Evaluate Duration of Severe Neutropenia with Plinabulin Versus 
Pegfilgrastim in Patients with Solid Tumors Receiving Docetaxel 
Myelosuppressive Chemotherapy 
PROTOCOL NO: 
 
BPI-2358-105 
This protocol is confidential  
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
Signature of Investigator: 
_______________________________   Date:  _____________ 
Printed Name: 
_______________________________ 
Investigator Title: 
_______________________________ 
Name/Address of Center: 
_______________________________ 
 
_______________________________ 
 
_______________________________ 
 
_______________________________ 
 
 


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Signature of Chief Medical Officer 
 
 

SAP_001.pdf: 
Document Cover Page 
Official Title: A Phase 2, Multicenter, Randomized Study to Evaluate Duration of Severe 
Neutropenia With Plinabulin Versus Pegfilgrastim in Patients With Solid Tumors Receiving 
Docetaxel Myelosuppressive Chemotherapy (Protective-1) 
NCT Number: NCT04345900 
Document Date: 07 December 2017 


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Version: 2.0 (Dated 07 December 2017) 
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Appendix 16.1.9 - Study BPI-2358-105 P2 
Confidential 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
PHASE 2 DATA 
 
Study Title: 
A Phase 2/3, Multicenter, Randomized, Double Blind, Study 
to Evaluate Duration of Severe Neutropenia with Plinabulin 
Versus Pegfilgrastim in Patients with Solid Tumors 
Receiving Docetaxel Myelosuppressive Chemotherapy 
Sponsor 
BeyondSpring Pharmaceuticals, Inc. 
48 Wall Street, 11th Floor 
New York, NY 10005 
Drug Product: 
Plinabulin (NPI-2358) 
Protocol Number: 
BPI-2358-105 
Phase: 
Phase 2/3 
Analysis Plan Version 
Version 2.0 
Analysis Plan Date 
07 December 2017 
Author 
Gary Stevens, Ph.D 
DynaStat Consulting, Inc. 
119 Fairway Ct. 
Bastrop, Texas 78602 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix 16.1.9 - Study BPI-2358-105 P2 
Confidential 
 
 
Signstur 
Date 
BeyoridSpring Pharmaceuticals, Inc. 
Protocol: BHI--2358-105 
Phase 2 Statistical Analysis Plan 
Vemion: 2.0 (Dated OT December 2017} 
 
 
 
 
STATISTICAL ANALYSIS PLAN APPROVAL SIGNATURE PAGE 
AUTOOR: 
Gary Stevens, Ph.D 
uynastat Consuiting, Inc. 
 
 
 
 
 
 
 
 
 
 
APPROVED BY: 
Signature 
 
 
 
Ramon Mohalilal, M.D, 
BeyondSpring Pharmaceuticals, Inc. 
Date 
 
 
 
 
 
 
 
Gary Stevens, Ph.D 
Dynastat Consulting, Inc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Conl'idential/Proprietary Property o/'BeyonrfSpring Pharmacenficals. me. 
Page 2 of 35 
ture 
Date 


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Appendix 16.1.9 - Study BPI-2358-105 P2 
Confidential 
 
 
 
 
 
TABLE OF CONTENTS 
Section 
Page 
1. INTRODUCTION .................................................................................................. 1 
1.1. Protocol Amendments ................................................................................... 2 
2. OVERVIEW OF STUDY DESIGN ........................................................................ 3 
2.1. Phase 2 Objectives ....................................................................................... 5 
2.1.1. Primary Objective .................................................................................. 5 
2.1.2. Secondary Objectives ............................................................................ 6 
2.1.3. Exploratory Objectives ........................................................................... 6 
2.1.4. Safety Objectives ................................................................................... 6 
3. SAMPLE SIZE JUSTIFICATION .......................................................................... 7 
4. RANDOMIZATION, STRATIFICATION, BLINDING, AND 
REPLACEMENT OF PATIENTS .......................................................................... 8 
Treatment Assignment .................................................................................... 8 
5. DEFINITIONS      OF      PATIENT      POPULATIONS       TO       BE 
ANALYZED........................................................................................................... 9 
5.1. Phase 2 Analysis Sets .................................................................................. 9 
5.1.1. Intent-to-Treat Analysis Set ................................................................... 9 
5.1.2. Safety Analysis Set ................................................................................ 9 
5.1.3. Pharmacokinetic Analysis Set ............................................................... 9 
5.1.4. Pharmacodynamic Analysis Set ............................................................ 9 
6. PHASE 2 STATISTICAL ANALYSIS CONSIDERATIONS ................................. 10 
6.1. General Principles ....................................................................................... 10 
6.2. Order of Analysis......................................................................................... 10 
6.3. Major Protocol Violations ............................................................................ 11 
6.4. Patient Enrollment and Disposition ............................................................. 11 
6.5. Description of Demographic and Baseline Characteristics .......................... 11 
6.6. Medical History............................................................................................ 12 
6.7. Cancer History ............................................................................................ 12 
6.8. Concomitant Medications ............................................................................ 12 
6.9. Physical Examination .................................................................................. 12 
6.10. 
Study Drug Exposure ........................................................................... 13 
6.11. 
Pharmacokinetic and Pharmacodynamic Analyses ............................. 13 
6.12. 
Efficacy Analysis .................................................................................. 13 
6.12.1. 
Primary Efficacy Pharmacodynamic Analysis .............................. 14 
6.12.2. 
Secondary Efficacy Pharmacodynamic Analysis ......................... 14 
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6.12.3. 
Primary Safety Pharmacodynamic Analyses ............................... 15 
6.12.4. 
Exploratory Efficacy Analyses ...................................................... 15 
6.13. 
Safety Analysis .................................................................................... 15 
6.13.1. 
Adverse Events ............................................................................ 15 
6.13.2. 
Serious Adverse Events .............................................................. 16 
6.13.3. 
Adverse Events Leading to Discontinuation from Study .............. 16 
6.13.4. 
Deaths ......................................................................................... 16 
6.13.5. 
Clinical Laboratory Tests ............................................................. 16 
6.13.6. 
Vital Signs .................................................................................... 17 
6.13.7. 
ECGs ........................................................................................... 17 
6.13.8. 
Other Safety Parameters ............................................................. 17 
6.13.9. 
Population Pharmacokinetic Analysis .......................................... 17 
7. INTERIM ANALYSIS .......................................................................................... 18 
8. STATISTICAL ANALYSIS CHANGES FROM THE 
PROTOCOL ....................................................................................................... 19 
9. CONVENTIONS ................................................................................................. 20 
10. STANDARD CALCULATIONS ........................................................................... 21 
12. REFERENCES ................................................................................................... 23 
13. SCHEDULE OF EVENTS FOR PHASE 2 .......................................................... 24 
14. APPENDICES .................................................................................................... 28 
14.1. 
List of Tables, Listings and Figures for Phase 2 Data .......................... 28 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Confidential 
 
 
 
LIST OF ABBREVIATIONS 
 
ABPM 
Ambulatory Blood Pressure Measurements 
AE 
Adverse Event 
ATC 
Anatomical Class (from WHODRUG dictionary) 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CTCAE 
Common Toxicity Criteria for Adverse Events 
DMN 
Duration of Moderate Neutropenia; the number of days with a 
neutrophil count of <1.0x109/L 
DSN 
Duration of Severe Neutropenia; the number of days with a 
neutrophil count of <0.5x109/L 
ECG 
Electrocardiogram 
FDA 
Foos and Drug Administration 
FN 
Febrile Neutropenia 
GCP 
Good Clinical Practices 
ICH 
International Committee for Harmonization 
ITT 
Intent to Treat 
MedDRA 
Medical Dictionary for Regulatory Affairs 
NSCLC 
Non-Small Cell Lung Cancer 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
QoL 
Quality of Life 
RP3D 
Recommended Phase 3 Dose of Docetaxel (75 mg/m2) + plinabulin 
(5, 10 or 20 mg/m2) 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
WHODRUG 
World Health Organization Drug Reference Listing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Confidential 
 
 
 
 
1. 
INTRODUCTION 
This document outlines the statistical methods to be implemented during the analyses of the 
Phase 2 data collected within the scope of BeyondSpring Pharmaceuticals, Inc. Protocol 
BPI-2358-105 titled “A Phase 2/3, Multicenter, Randomized, Double Blind, Study to 
Evaluate Duration of Severe Neutropenia with Plinabulin Versus Pegfilgrastim in Patients 
with Solid Tumors Receiving Docetaxel Myelosuppressive Chemotherapy”. 
Analysis of Phase 3 data will be described in a separate Statistical Analysis Plan (SAP). 
This SAP was prepared in accordance with BPI-2358-105 Protocol Amendment 3, dated 
30 May 2017 and Protocol Amendment 2, dated 10 February 2017. Key differences between 
the protocol versions are outlined in Section 1.1. 
The purpose of this SAP is to provide a framework in which answers to the protocol 
objectives related to the Phase 2 portion of the study, may be achieved in a statistically 
rigorous fashion, without bias or analytical deficiencies, following methods identified prior 
to database lock. 
This SAP governs: 
1. Tier 1 data from Phase 2, with all patients in Phase 2 having completed Cycle 1 
2. Tier 2 data from Phase 2, with all patients in Phase 2 having completed Cycle 1 
3. The Phase 2 Clinical Study Report (CSR) with all patients in Phase 2 having 
completed Cycles 1-4. 
The Phase 2 data will be analyzed at the end of the Phase 2 portion of the study as planned 
per protocol, and additionally at the point when the last patient in the Phase 2 portion has 
completed Cycle 1, in 2 tiers (Tier 1 and Tier 2), as described below. 
Once all patients have completed Cycle 1, the database will be locked and the available data 
(from all cycles) will be analyzed using a 2-tier approach. Pre-specified data (Tier 1) will be 
analyzed first, in order to inform dose selection for the Phase 3 portion of the study. This 
data set will be complete for Cycle 1 only; however, available data from Cycles 2-4 at the 
time of database lock will also be reported. The data will be summarized and submitted to 
the Food and Drug Administration (FDA) in the form of a Summary document (Summary of 
Pharmacokinetic [PK], Pharmacodynamic [PD], Safety and Exploratory Data to Establish 
RP3D for Phase 3). The focus will be on the PK/efficacy PD endpoints (duration of severe 
neutropenia [DSN] and duration of moderate neutropenia [DMN]) from Cycle 1 and the 


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PK/safety PD endpoint (semi-continuous blood pressure) from Cycle 1, as well as other 
relevant safety data. The remaining data (Tier 2) will be analyzed subsequently. 
The Phase 2 portion of the study will continue, and all data will be analyzed as planned per 
protocol at the end of this part of the study. This complete Phase 2 dataset will be reported in 
the Phase 2 BPI-2358-105 CSR. 
This SAP therefore has the following purposes: 
 To prospectively outline the specific types of analyses and presentations of Phase 2 
data that will form the basis for conclusions. 
 To clearly identify Tier 1 and Tier 2 data. 
xplTaoinein detail how all Phase 2 
data will be handled and analyzed, adhering to 
commonly accepted standards and practices of biostatistical analysis in the 
pharmaceutical industry. Any deviations from these guidelines must be substantiated 
by sound statistical reasoning and documented in the final CSR. 
1.1. 
Protocol Amendments 
This SAP is prepared in accordance with Protocol Amendment 3 (30 May 2017) and Protocol 
Amendment 2 (10 February 2017), as patients have been enrolled under both versions of the 
protocol. Minor differences in calculation of the primary PK/PD efficacy and safety 
endpoints are necessary, and are explained in detail in Section 2.1.1. 
The key differences between the protocol versions relating to statistical considerations are 
summarized below: 
 
Protocol Amendment 2 
10 February 2017 
Protocol Amendment 3 
30 May 2017 
Plinabulin infusion started 60 minutes after the 
end of the docetaxel infusion 
Plinabulin infusion started 30 minutes after the 
end of the docetaxel infusion 
Phase 2 portion randomized, double-blind with 
matching placebo 
Phase 2 portion changed to open-label, no 
matching placebo 
Assessments performed on Day 5 (including 
duration of severe neutropenia) 
All Day 5 assessments removed 
Semi-continuous blood pressure and ECG 
collection to last 6 hours after start of 
plinabulin/placebo infusion 
Semi-continuous blood pressure and ECG 
collection to last 4.5 hours after start of 
plinabulin/placebo infusion 
A Day 6 assessment added for CD34+ 
In the Phase 2 portion, bone pain assessment on 
Days 2 and 3 of Cycle 2 removed 


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2. 
OVERVIEW OF STUDY DESIGN 
This is a multicenter, randomized study with a Phase 2 portion and a Phase 3 portion. 
Approximately 190 patients will be enrolled in this study. Per Protocol Amendment 3, the 
Phase 2 portion will be open label with all patients receiving plinabulin or pegfilgrastim (no 
placebo will be administered). Prior to this amendment, the Phase 2 portion of the study was 
double-blind. 
All patients will receive docetaxel at a dose of 75 mg/m2. 
In Phase 2, patients only with advanced or metastatic non-small cell lung cancer (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 <5 prior lines of chemotherapy; advanced or metastatic NSCLC after 
failing platinum-based therapy; 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) 
Patients enrolled under Protocol Amendment 2 will receive matching placebo to blind for 
either pegfilgrastim or plinabulin. 
The study will be temporarily closed to enrollment when approximately 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 recommended Phase 3 dose (RP3D) of docetaxel (75 mg/m2) + 
plinabulin (5, 10 or 20 mg/m2). The PK/PD analysis will be performed by an independent 
party (Anoixis Corporation) and will be blinded to the study team. At this point, datasets will 


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be created for the Tier 1 and Tier 2 data, as further described in Section 6 and listed in 
Section 14.1. 
The Phase 2 portion of the study will continue as planned, and once completed, all data will 
be analyzed as planned per protocol. 
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. 
As previously noted, analysis of the Phase 3 portion of the study will be described in a 
separate SAP, and therefore this part of the study is not further described in this document. 
Phase 2 Study Design: 
Cycles 1 to 4 will consist of docetaxel 75 mg/m2 administered by IV infusion over 
60 minutes on Day 1 every 21 days. Administration of other study treatment is dependent on 
protocol version as follows: 
 Per Protocol Amendment 2, on Day 1 of each cycle, 2 hours (±10 minutes) after the 
start time of docetaxel infusion (i.e., approximately 60 minutes from the end of 
docetaxel infusion), patients will receive a single dose of plinabulin or placebo 
intravenously over 30 minutes (±5 minutes), in a double blinded manner. 
 Per Protocol Amendment 3, on Day 1 of each cycle, 1.5 hours (±10 minutes) after the 
start time of docetaxel infusion (i.e., approximately 30 minutes after the end of 
docetaxel infusion), patients assigned to a plinabulin arm (arms 2-4) will receive a 
single IV infusion of plinabulin at their assigned dose over 30 minutes (±5 minutes). 
On Day 2 of each cycle ≥24 hours after completing chemotherapy, all patients will receive a 
single dose of pegfilgrastim (6 mg), and if patients are enrolled under Protocol Amendment 2 
(but not Amendment 3), patients who will not receive pegfilgrastim on Day 2 will receive 
matching placebo (subcutaneous injection). 
If a chemotherapy cycle is delayed by more than 3 weeks, the patient will be withdrawn from 
the study. If a critical AE occurs during the cycle, the dosage of docetaxel may be reduced 
20% in the next cycle. Only 1 docetaxel dose reduction is allowed. No dose reductions are 
allowed with plinabulin or pegfilgrastim. 
All patients, including patients who withdraw from the study early, will complete a safety 
follow-up visit 30 days (± 7 days) after the last dose of study drug. Follow-up visits will be 
required to monitor for ongoing treatment-related adverse events (AEs). All patients 
experiencing drug-related toxicities of Grade  2 at the End of Treatment visit should be 
followed-up at least monthly until the AE(s) resolves to Grade  1, the event is considered to 
be chronic, or the patient receives other anti-cancer therapy. The method of follow-up 


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assessment will be at the Investigator’s discretion (for example, patient site visit or telephone 
call). All deaths which occur within 30 days of plinabulin administration regardless of 
relationship to the study drug must be reported to the Sponsor immediately and within 
24 hours of becoming aware of the event. 
Protocol-directed laboratory test results (hematology and serum chemistry) will be collected 
via a central laboratory. Safety laboratory tests are required prior to treatment on Day 1 of 
each cycle and can be collected by a local laboratory; however, all other scheduled blood 
samples as per the schedule assessments and procedure table must also be obtained for 
central laboratory assessment. Urinalysis will be performed at baseline only. CD34+ counts 
will be established through a fluorescence-activated cell sorting method. 
The schedule of events is provided in Section 13. 
Rescue Treatment: 
Patients who experience a febrile neutropenia (FN) event in Cycle 1 with plinabulin will 
receive pegfilgrastim in subsequent cycles. If the patient was orginally assigned to the 
pegfilgrastim arm, the patient should be treated at a lower dose of docetaxel or taken off 
study at the discretion of the investigator. 
If the patient develops an FN event on subsequent cycles, the patient should be discussed 
with the medical monitor and either treated with a lower dose of docetaxel, or taken off study 
at the discretion of the investigator.  Febrile neutropenia should be treated with antibiotics 
per institutional standard of care. If a patient is hospitalized, the procedure for reporting 
SAEs should be followed. 
 
2.1. 
Phase 2 Objectives 
Plinabulin PK and PD assessments will be made to enable PK/PD analysis. 
 
2.1.1. 
Primary Objective 
To establish the RP3D based on PK/PD analysis. 
 Primary efficacy PD objective: To assess DSN in treatment Cycle 1 in patients 
treated with docetaxel (75 mg/m2) + plinabulin (5, 10 or 20 mg/m2) or with docetaxel 
(75 mg/m2) + pegfilgrastim (6 mg). Neutrophil count will be assessed at baseline 
(prior to Cycle 1 docetaxel dose) and during Cycle 1 on Days 1, 2, 5*, 6, 7, 8, 9, 10, 
15 (pre-dose on dosing days; times equivalent to pre-dose on other days). 
* Day 5 is included per Protocol Amendment 2 but is omitted per Protocol 
Amendment 3. 
 Primary safety PD objective: To assess blood pressure semi-continuously with 
15-minute intervals, starting 15 minutes pre-plinabulin dose and lasting 4.5 hours 


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after start of infusion with plinabulin (Arms 2 to 4) or for 4.75 hours starting 
15 minutes after the end of docetaxel infusion (Arm 1). Under Protocol 
Amendment 2, blood pressure will be measured for 6 hours starting 15 minutes after 
the end of docetaxel infusion with a matching schedule in Arm 1. 
 
2.1.2. 
Secondary Objectives 
 Secondary efficacy PD objective: To assess duration of moderate neutropenia 
(DMN) in treatment Cycle 1 in patients treated with docetaxel (75 mg/m2) + 
plinabulin (5, 10 or 20 mg/m2) or with docetaxel (75 mg/m2) + pegfilgrastim (6 mg). 
Neutrophil count will be assessed at baseline (prior to Cycle 1 docetaxel dose) and 
during Cycle 1 on Days 1, 2, 5*, 6, 7, 8, 9, 10, 15 (pre-dose on dosing days; times 
equivalent to pre-dose on other days). 
* Day 5 is included per Protocol Amendment 2 but is omitted per Protocol 
Amendment 3. 
 To characterize the PK profile of plinabulin and docetaxel. 
 To characterize the exposure-response relationships between measures of plinabulin 
exposure and the PD endpoint DMN. 
 To characterize the exposure-response relationships between measures of plinabulin 
exposure and the PD endpoint DSN. 
 To characterize the exposure-safety relationships between measures of plinabulin 
exposure and safety events of interest. 
 
2.1.3. 
Exploratory Objectives 
 To assess CD34+ at screening, and on Days 2, 5, and 8 in Cycle 1 and Day 1 in 
Cycle 2. 
 Health-related quality of life (QoL) questionnaire evaluated with EORTC QLQ-C30 
and EQ-5D-5L. 
 To collect data on disease progression. 
2.1.4. 
Safety Objectives 
 Incidence, occurrence, and severity of AEs/serious adverse events (SAEs). 
 nciIdence, occurrence and severity of bone pain 
. 
 Systemic tolerance (physical examination and safety laboratory assessments). 


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3. 
SAMPLE SIZE JUSTIFICATION 
In the Phase 2 portion, approximately 40 patients with advanced or metastatic NSCLC will 
be enrolled, with approximately 10 patients per arm. 


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4. 
RANDOMIZATION, STRATIFICATION, BLINDING, AND 
REPLACEMENT OF PATIENTS 
Patients will be identified by a patient number. 
 
Treatment Assignment: 
Patients will be randomly assigned by Interactive Response Technology to 1 of the following 
treatment groups (10 patients per arm): 
 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) 
(Note, patients enrolled under Protocol Amendment 2 will receive matching placebo in a 
double-blind manner.) 


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5. 
DEFINITIONS OF PATIENT POPULATIONS TO BE 
ANALYZED 
5.1. 
Phase 2 Analysis Sets 
5.1.1. 
Intent-to-Treat Analysis Set 
The intent-to-treat (ITT) analysis set for Phase 2 includes all Phase 2 patients that have been 
randomized in the study and have received at least 1 dose of study medication. 
The analysis of all endpoints, unless noted otherwise, will be conducted on the intent-to-treat 
analysis set. 
 
5.1.2. 
Safety Analysis Set 
The safety analysis set will be the same as the intent-to-treat analysis set. 
 
5.1.3. 
Pharmacokinetic Analysis Set 
All patients who received at least 1 dose of plinabulin or docetaxel and had at least 1 PK 
sample collected will be included in the PK analysis set. These patients will be evaluated for 
PK unless significant protocol deviations affect the data analysis or if key dosing, dosing 
interruption, or sampling information is missing. Population PK modeling will be utilized to 
analyze the PK data, and informative sampling approaches will be used to determine the PK 
time points for Phase 3. 
 
5.1.4. 
Pharmacodynamic Analysis Set 
All patients who had blood pressure and DSN and/or DMN collected at any time during the 
study will be included in the PD analysis set. Exploratory PK/PD and exposure-response 
analyses will be conducted to evaluate the effects of plinabulin on safety and efficacy 
endpoints. Details of these analyses will be summarized in the pharmacometrics analysis 
plan. 


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6. 
PHASE 2 STATISTICAL ANALYSIS CONSIDERATIONS 
6.1. 
General Principles 
Statistical analyses will be reported using summary tables, figures, and data listings. 
Continuous variables will be summarized with counts, means, standard deviations, medians, 
confidence intervals, minimums, and maximums. Categorical variables will be summarized 
by counts and by percentage of patients. 
Formal inferential statistical analyses techniques will be discussed in subsequent sections of 
this SAP. 
Individual patient data obtained from the case report forms (CRFs), electrocardiogram 
(ECG), core laboratory, PK data and any derived data will be presented in by-patient listings 
sorted by study center and patient number. 
All analyses and tabulations will be performed using SAS Version 9.4 or higher on a PC 
platform. Table, listings, and figures will be presented in RTF format. Upon completion, all 
SAS programs will be validated by an independent programmer. In addition, all program 
output will undergo a senior level statistical review. The validation process will be used to 
confirm that statistically valid methods have been implemented and that all data 
manipulations and calculations are accurate. Checks will be made to ensure accuracy, 
consistency with this plan, consistency within tables, and consistency between tables and 
corresponding data listings. Upon completion of validation and quality review procedures, 
all documentation will be collected and filed by the project statistician or designee. 
Missing or invalid data will be generally treated as missing, not imputed, unless otherwise 
stated. 
 
6.2. 
Order of Analysis 
As previously described, Phase 2 data will initially be analyzed using a 2-tier approach, after 
all patients have completed Cycle 1. Appendix 14.1 provides a detailed listing of which data 
will be included in Tier 1 and Tier 2. Datasets will be created for Tier 1 data, encompassing: 
 Demographics 
 aseBline characteristics 
 Drug exposure (including summarization of the number of patients per cycle (1, 2, 3, 
and 4) in each treatment arm) 
 PK/efficacy PD: DMN (described in pharmacometrics analysis plan) 
 PK/efficacy PD: DSN (described in pharmacometrics analysis plan) 
 PK/safety PD: Blood pressure (semi continuous) (described in pharmacometrics 
analysis plan) 


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 Safety: AEs and SAEs. 
These data will be analyzed immediately, in order to inform dose selection for the Phase 3 
portion of the study. Other study data (Tier 2) will be analyzed as planned per protocol and 
all study data will be reported in the Phase 2 CSR. 
 
6.3. 
Major Protocol Violations 
Major protocol violations will be identified by the clinical study team, documented, signed 
and provided to the Sponsor prior to database lock. A protocol deviation is any 
noncompliance with the clinical trial protocol or Good Clinical Practice (GCP). The 
noncompliance may be either on the part of the patient, the investigator, or the study site 
staff. Reportable protocol violations will be listed by study center and patient numbers. 
6.4. 
Patient Enrollment and Disposition 
Patient enrollment by site will be tabulated by treatment arm and overall and per cycle for 
each treatment arm. 
Patient disposition will be summarized by treatment arm and overall. The summary will 
include the number and percentage of patients in each of the defined analysis populations in 
Section 5. In addition, frequency counts and percentages of patients’ reported reasons for 
ending the study will be summarized. 
A listing will be presented to describe patient study arm, date of first and last dose, date of 
last visit or contact, total number of completed cycles, and the reason for ending the study for 
each patient. 
Listings of inclusion/exclusion criteria responses will also be provided. 
 
6.5. 
Description of Demographic and Baseline Characteristics 
A summary of age, gender, race, ethnicity, vital signs, ECOG status, tumor staging, and 
prior: cancer-specific surgery, radiotherapy, and prior chemotherapy (Yes/No); along with 
the number of prior chemotherapy regimens will be presented using appropriate descriptive 
statistics by each treatment arm and overall total. The categorical (discrete) variables will be 
summarized using counts and percentages. The continuous variables will be summarized 
using mean, median, standard deviation, and range (maximum, minimum). These summaries 
will include patients in the ITT population. 
All demographic and baseline characteristics will be listed by study center, and subject 
number. 


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6.6. 
Medical History 
Medical history data will be coded by system organ class and preferred term, using the 
MedDRA dictionary (2008). 
Medical history will be summarized by body system for each study arm in the safety analysis 
set. The table will be sorted in alphabetic order by system organ class, as well as by 
incidence and preferred term, and the statistics n and % will be presented by study arm 
where: n is the number of patients who present at least 1 occurrence of the medical history 
and % is the percentage of patients. The denominator used for calculating the percentages 
will be the total number of patients included in the ITT analysis set on each study arm. 
6.7. 
Cancer History 
Histology of NSCLC, disease status, cancer-specific surgery, prior chemotherapy regimen, 
and best response will be summarized using frequency counts and percentage. 
6.8. 
Concomitant Medications 
All medication data will be coded by drug class and indication, using the WHO Drug 
dictionary (2008). All medication taken prior to the first dose of study drug will be classified 
as prior medication. All medication taken on or after the first dose of study drug will be 
classified as concomitant medication. Medications with start and stop date that bracket the 
date of first dose will be summarized as both prior and concomitant medication. 
For the purpose of inclusion concomitant medication tables, incomplete medication start and 
stop date will be imputed as detailed in Section 11. Based on imputed start and stop dates, 
medications that started on or after date of first dose will be included in the concomitant 
medications table. 
Concomitant medications will be summarized in the safety population by giving the number 
and percentage of patients by preferred term within each therapeutic class, with therapeutic 
class and medications in each class sorted in alphabetical order. The total number of drugs in 
each selected therapeutic class will also be presented, where, for example 2 drugs each 
belonging to the same class will only contribute once to the presented count. 
All prior and concomitant medications, as well as medical procedures will be listed by study 
center, and patient number. 
6.9. 
Physical Examination 
All physical examination findings will be listed by study center and patient number. 


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6.10. 
Study Drug Exposure 
Study treatment exposure will be summarized in the safety population. 
For each treatment arm for each product (doxetaxel, pegfilgrastim, and plinabulin), the 
following will be summarized using descriptive statistics by study arm and overall: 
 Duration of exposure, calculated as (date of last dose – date of first dose+1). 
 Number of cycles received per patient. 
 Number of cycles with dose modification and (or) dose delay. 
 Reasons for dose deviations from planned therapy. 
All study drug administration data will be listed by study center and patient number. 
 
6.11. 
Pharmacokinetic and Pharmacodynamic Analyses 
Plasma plinabulin and docetaxel concentrations will be measured using validated methods 
and PK parameters will be summarized using descriptive statistics. Individual and mean 
serum plinabulin and docetaxel concentration versus time profiles will be plotted on both 
linear and logarithmic scales. 
Exploratory graphical and statistical techniques, including linear, nonlinear, and logistic 
regression, etc., will be used to explore potential relationships between pharmacokinetic 
parameters of interest and efficacy endpoints, pharmacodynamic variables, and safety events 
of interest. These exposure-response analyses will support the RP3D of plinabulin which 
will be used during the Phase 3 of study treatment. 
The PK/PD analyses are described in Section 6.12 and include: 
 PK/Efficacy PD (DMN) from Cycle 1 
 K/EPfficacy PD (DSN) from Cycle 1 
 PK/Safety PD (semi-continous blood pressure) from Cycle 1 
Full methodology will be described in the pharmacometrics analysis plan. 
 
6.12. 
Efficacy Analysis 
The PK and PD efficacy and safety endpoints will be analyzed according to the 
pharmacometrics analysis plan. 


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6.12.1. 
Primary Efficacy Pharmacodynamic Analysis 
Phase 2 data from Cycle 1 will be subjected to PK/PD analysis to determine the RP3D of 
plinabulin which will be used during the Phase 3 portion of the study. The primary efficacy 
pharmacodynamic marker is DSN, defined as the number of days with a neutrophil count 
of < 0.5 x 109 neutrophils/L. 
In addition, an exploratory analysis to assess DSN in Treatment Cycle 1 in patients treated 
with docetaxel (75 mg/m2) + plinabulin (5, 10 or 20 mg/ m2) will be performed, using the 
Jonckheere-Terpstra Test for Ordered Alternatives (Hollander, Wolfe and Chicken, 2013). 
With this statistical procedure, the null hypothesis of equality among treatment group means 
will be tested (μj's, j = 2, 3, 4) 
H0: μ2 = μ3 = μ4 
against the alternative in which order is specified 
H1: μ2 ≥ μ3 ≥ μ4, 
where at least 1 of the inequalities is strict. The mean indices have the following 
interpretation: 2 = docetaxel (75 mg/m2) + plinabulin (5 mg/m2), 3 = docetaxel (75 mg/m2) + 
plinabulin (10 mg/m2), and 4 = docetaxel (75 mg/m2) + plinabulin (20 mg/m2). The 
statistically significant rejection of the null hypothesis will be interpreted, that there is an 
ordered alternative of responses as indicated by the alternative hypothesis H1. If the null 
hypothesis is rejected, then pair wise Wilcoxon tests will be performed to aid in the 
assessment of which treatment(s) contributed to the rejection of the null hypothesis. 
Since the Jonckheere-Terpstra Test for Ordered Alternatives is a non-parametric test, this 
will be performed in SAS using PROC FREQ with JT option. The DSN for this analysis is 
calculated as in Section 6.10, and since this is an exploratory, non-parametric analysis, no 
adjustment will be made for the potential number of 0 values of the DSN. The 
non-parametric nature of the test factors these into consideration. Missing ANC values will 
not be imputed. 
 
6.12.2. 
Secondary Efficacy Pharmacodynamic Analysis 
The secondary efficacy pharmacodynamic marker is DMN, defined as the number of days 
with a neutrophil count of < 1.0 x 109 neutrophils/L. 
In addition, an exploratory analysis to assess DMN in Treatment Cycle 1 in patients treated 
with docetaxel (75 mg/m2) + plinabulin (5, 10 or 20 mg/ m2) will be performed as described 
in Section 6.12.1. 


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6.12.3. 
Primary Safety Pharmacodynamic Analyses 
A PK/ambulatory blood pressure measurements (ABPM) model will be developed to 
characterize the exposure-ABPM relationship. Circadian rhythm will be accounted for in the 
PK/ABPM model, as appropriate. The details of the PK/ABPM are described in the 
pharmacometrics analysis plan. 
 
6.12.4. 
Exploratory Efficacy Analyses 
An exploratory analysis is to assess CD34+ at screening, and on Days 2, 5, and 8 in Cycle 1 
and Day 1 in Cycle 2. These data will be summarized by Cycle and Day and the differences 
between the treatment arms will be assessed by day using an Analysis of Variance with a 
term for ARM. Pairwise differences will be assessed using pre-defined contrasts. 
DSN and DMN data will be summarized via confidence intervals for the 30 minute and 
60 minute wait times, in order to investigate possible effect of changing the timing of dosing 
in Protocol Amendment 3. 
 
6.13. 
Safety Analysis 
All patients will be evaluable for safety analysis if they receive at least 1 dose of study drug. 
All patients receiving a dose of study drug will be included in all safety summaries. The 
safety data will be presented by study arm in individual listings and summary tables, 
including frequency tables for adverse events and frequency and shift tables for laboratory 
variables. All AEs and abnormal laboratory variables will be assessed according to the NCI 
CTCAE (v 4.0) grading system. Descriptive statistics will be used to summarize ECOG 
performance status. Vital signs will be reported in listings. AEs and SAEs will be reported 
in combined tables and SAEs will also be in tabulated in a separate table. 
All safety information will be listed by study center and subject number. 
 
6.13.1. 
Adverse Events 
Incidences (overall and treatment-emergent) of adverse events will be summarized by system 
organ class and by preferred terms (MedDRA). AEs will be considered as 
treatment-emergent adverse events (TEAEs) if onset is on or after the initiation of study 
treatment. AEs with missing onset dates will be summarized as TEAEs regardless of 
severity and relationship to study medication. 
The incidence of AEs by severity and/or CTCAE adverse events grade (mild, moderate, 
severe, life threatening or death) and by relationship to study drug will be tabulated similarly. 
Each AE will be reported by greatest known severity and by strongest relationship to the 
study drug. 


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Each patient will be counted only once within a system organ class or a preferred term by 
using the AEs with the highest severity grade. 
All information pertaining to AEs noted during the study will be listed per patient, detailing 
verbatim, preferred term, system organ class, start date, stop date, severity and relationship to 
study treatment. AE onset will be shown relative (in number of days) to the day of the first 
study treatment. 
6.13.2. 
Serious Adverse Events 
All SAEs will be listed by study arm and summarized in tabular and graphical form (using 
TTE methods if data warrant) 
6.13.3. 
Adverse Events Leading to Discontinuation from Study 
All AEs leading to discontinuation from study will be listed by study arm and summarized in 
tabular and graphical form (using time-to-event methods). 
6.13.4. 
Deaths 
All deaths within 30 days of last study treatment will be listed by study arm. Treatment 
emergent deaths are those deaths within 30 days of last dose of any study therapy. Early 
deaths are those deaths within 60 days of the first dose of study therapy. 
Treatment emergent and/or early deaths will be tabulated and summarized by treatment 
groups using tabular and graphical methods (Time-to-event methods). 
 
6.13.5. 
Clinical Laboratory Tests 
Safety laboratory data will include clinical chemistries, hematology and urinalysis. Safety 
summaries in the form of shift tables for key laboratory parameters showing the number and 
percentage of patients who experience changes in laboratory parameters during the course of 
the study (e.g. change from normal to high, based on the laboratory reference ranges) will be 
displayed. Also shift tables for changes in CTCAE grades will be summarized by counts and 
percents. 
Descriptive summary statistics (mean, standard deviation, median, minimum, maximum, 
frequencies, and percentages, as appropriate) for laboratory values will be presented at 
baseline, the follow-up time points, and change from baseline for each study treatment arm 
All laboratory data, values, units, normal reference range, and out-of-range flags collected in 
the clinical database will be included in by-patient listings for further medical review. 
Graphs of key parametric clinical lab tests should be presented by group (mean ± standard 
deviation). 


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6.13.6. 
Vital Signs 
Vital signs (including temperature, respiratory rate, blood pressure, heart rate, and weight) 
will be presented descriptively at baseline and for each follow-up time point for each study 
treatment arm. The number (n), mean, standard deviation, median, range will be presented. 
Changes from baseline to each time point will also be summarized as well as shifts from 
normal to abnormal results. Missing blood pressure values will not be imputed. 
All vital sign parameters will be included in by-patient listings for further medical review. 
 
6.13.7. 
ECGs 
Patients will be analyzed for QTc prolongation by Fridericia’s adjustment to QTc. The 
average of the 3 replicates will be used and compared to the average of the 3 replicates done 
just prior to the start of the infusion. The incidence of QTc prolongation by either calculation 
of >30 and >60 ms will be presented. The incidence of QTc prolongation by either 
calculation of >480 ms post-infusion will be presented. 
All ECGs will be summarized descriptively using N, mean, standard deviation, median, and 
range for each treatment arm at each visit ECGs are collected (see Section 13). Missing ECG 
values will not be imputed. 
All ECG parameters will be included in by-patient listings for further medical review. 
 
6.13.8. 
Other Safety Parameters 
The health related QOL EORTC QLQ-C30 and the EQ-5D-dL questionnaires will be 
summarized for each visit performance status was assessed and as changes from the baseline 
assessment. Differences between treatment arms will be tested using a t-test for each time 
point where the data is collected. 
 
6.13.9. 
Population Pharmacokinetic Analysis 
Population pharmacokinetic analyses will be conducted to evaluate the effect of intrinsic and 
extrinsic factors on the PK of plinabulin and its active metabolite(s), if identified, in humans. 
Intrinsic factors such as gender, age, hepatic or renal impairment, and race and/or ethnicity 
and extrinsic factors such as concomitant drugs, herbal products will be assessed in 
relationship to drug exposure according to FDA Guidance for Industry: Population 
Pharmacokinetics. 
Further details of PK analysis will be presented in the pharmacometrics analysis plan. 


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7. 
INTERIM ANALYSIS 
Interim analysis is not planned for Phase 2 of the study. 


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8. 
STATISTICAL ANALYSIS CHANGES FROM THE 
PROTOCOL 
 
None. 


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9. 
CONVENTIONS 
The precision of original measurements will be maintained in summaries, when possible. 
Means, medians and standard deviations will be presented with an increased level of 
precision; means and medians will be presented to 1 more decimal place than the raw data, 
and the standard deviations will be presented to 2 more decimal places than the raw data. 
Summaries of continuous variables that have some values recorded using approximate values 
(e.g., < or >) will use imputed values. The approximate values will be imputed using the 
closest exact value for that measurement. For tables where rounding is required, rounding 
will be done to the nearest round-off unit. For example, if the round-off unit is the ones place 
(i.e., integers), values ≥XX.5 will be rounded up to XX+1 while values <XX.5 will be 
rounded down to XX. 
Percentages will be based on available data and denominators will generally exclude missing 
values. For frequency counts of categorical variables, categories whose counts are zero will 
be displayed for the sake of completeness. For example, if none of the patients discontinue 
due to “lost to follow-up,” this reason will be included in the table with a count of 0. 
Categories with zero counts will not have zero percentages displayed. 
For AE incidence tables: 
 The order of SOCs presented in tables will be according to the internationally agreed 
order of SOCs according to MedDRA. Within each SOC, the preferred terms will be 
shown in alphabetic order. 
 Patients who have multiple events in the same SOC and/or preferred term will be 
counted only once at each level of summation (overall, by SOC, and by preferred 
term) in the tables. For summaries of AEs by severity, only the highest severity of 
AE will be counted at each level of summation (overall, by SOC, and by preferred 
term) in the tables. For summaries of related AEs, patients with more than 1 related 
AE will be counted only once at each level of summation (overall, by SOC, and by 
preferred term) in the tables. 


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10. 
STANDARD CALCULATIONS 
Variables requiring calculation will be derived using the following formulas: 
Study day – For a given date (date), study day is calculated as days since the date of first 
dose of study drug (firstdose): 
 Study day = date – firstdose + 1, where date ≥ firstdose 
 Study day = date – firstdose, where date < firstdose 
Days – Durations, expressed in days between 1 date (date1) and another later date (date2), 
are calculated using the following formula: duration in days = (date2-date1). 
Weeks – Durations, expressed in weeks between 1 date (date1) and another later date (date2), 
are calculated using the following formula: duration in weeks = (date2-date1)/7. 
Months – Durations, expressed in months between 1 date (date1) and another later date 
(date2), are calculated using the following formula: duration in months = (date2-date1)/30.4. 
Years – Durations, expressed in years between 1 date (date1) and another later date (date2), 
are calculated using the following formula: duration in years = (date2-date1)/365.25. 
Minutes – Durations, expressed in minutes between 1 timepoint (time1) and another later 
timepoint (time2), are calculated using the following formula: duration in minutes = 
(time2-time1)/60. 
Age – The patient’s age is calculated as the number of years from the patient’s date of birth 
to the date of randomization into the study: 
Age = ([Randomization Date - Date of Birth] / 365.25). 
11. 
IMPUTATION OF DATES 
Incomplete Cancer Diagnosis 
If day is missing, day will be set to 15th of the month, or date of first dose, whichever is 
earlier. If month and day are missing, month and day will be set to July 1st, or date of first 
dose, whichever is earlier. 
AE 
If onset date is completely missing, onset date is set to date of first dose unless end date is 
before date of first dose, in which case the onset date is set to 28 days prior to end date. 
If (year is present and month and day are missing) or (year and day are present and month is 
missing): 


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 If year = year of first dose, then set month and day to month and day of first dose 
unless end date is before date of first dose, in which case the onset date is set to 
28 days prior to end date. 
 If year < year of first dose, then set month and day to December 31st. 
 If year > year of first dose, then set month and day to January 1st. 
If month and year are present and day is missing: 
 If year=year of first dose and if month = month of first dose then set day to day of 
first dose date unless end date is before date of first dose, in which case the onset date 
is set to 28 days prior to end date. 
 If month < month of first dose then set day to last day of month 
 If month > month of first dose then set day to 1st day of month 
 If year < year of first dose then set day to last day of month 
 If year > year of first dose then set day to 1st day of month 
For all other cases, set onset date to date of first dose unless end date is before date of first 
dose, in which case the onset date is set to 28 days prior to end date. 
Concomitant Medications 
If start date is completely missing: start date will not be imputed. 
If (year is present and month and day are missing) or (year and day are present and month is 
missing): set month and day to January 1. 
If year and month are present and day is missing: set day to 1st day of month. 
If end date is completely missing: end date will not be imputed. 
If (year is present and month and day are missing) or (year and day are present and month is 
missing): set month and day to December 31. 
If year and month are present and day is missing: set day to last day of the month. 
Any partial dates will be displayed in data listings without imputation of missing days and/or 
months (e.g., MAR2011, 2009). No other imputation of missing data will be performed. 


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12. 
REFERENCES 
Hollander, M, Wolfe, DA, and Chicken, E. Nonparametric Statistical Methods, John Wiley 
& Sons, 2013. 
International Federation of Pharmaceutical Manufacturers and Associations. Medical 
Dictionary for Regulatory Activities (MedDRA). Version 14.0 Reston, Virginia, USA; 2008. 
SAS Institute Inc. SAS Version 9.4. Cary, NC, USA; 2013 or later versions. 
Taxotere® (Prescribing Information). Sanofi-aventis—US; Rev 12/2015 
(http://products.sanofi.us/Taxotere/taxotere.html). 
WHO Collaborating Center for International Drug Monitoring. WHO Drug Dictionary. June 
2012 B Format edition. Uppsala, Sweden; 2008. 


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13. 
SCHEDULE OF EVENTS FOR PHASE 2 
Study Assessments and Procedures Schedule for Phase 2/Cycles 1 through 4, End of Treatment, Safety Follow-up, and Early 
Termination Visits 
 
Period 
Screening 
Period 
Treatment Period for Phase 2/Cycle 1 
Treatment Period for Phase 
2 Cycle 2, 3 and 4 
EOTa 
Early 
Discontin- 
uationb 
30 Day 
Safety 
Follow-upc 
Cycle Day 
-28 to -1 
-1 
1 
2 
3 
6 
7 
8 
9 
10 
15 
-1 
1 
2 
3 
8 
Post Cycle 4 
on Day 22 
(+7 days) 
(± 21 days) 
± 7 days 
Cycle Week 
1 
2 
3 
1 
2 
Informed consent 
X 
Inclusion/Exclusion 
X 
Demographicsd 
X 
Medical History/ 
Baseline 
Characteristicse 
X 
Vital Signsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance 
Status 
X 
Temperatureg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examinationh 
X 
X 
X 
Body weight 
X 
X 
X 
X 
X 
X 
12-lead ECGi 
X 
X 
X 
X 
X 
X 
Hematologyj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Chemistryj 
X 
X 
X 
X 
X 
PT, INR, PTTk 
X 
Exploratory Biomarker 
analysis CD34+l 
X 
X 
X 
X 
Xm 


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Urinalysisk 
X 
Hepatitis B/C testingn 
X 
HIVk 
X 
Pregnancy testo 
X 
Randomization 
X 
PK sample collectionp 
X 
X 
Disease progression 
evaluationq 
Assessments of disease progression will be performed in accordance with standard 
medical practice per institution standard 
X 
Docetaxel 
Pre-Medication 
Xr 
X 
r 
X 
r 
Xr 
Xr 
Xr 
Docetaxel treatment 
X 
X 
Plinabulin s 
X 
X 
Pegfilgrastim s 
X 
X 
Bone Pain Inventory 
Short Formt 
X 
X 
u 
X 
u 
X 
X 
X 
Xv 
X 
Health-related QoL 
EORTC QLQ-C30 and 
EQ-5D-5L 
questionnairew 
X 
X 
X 
Concomitant 
medicationsx 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse eventsy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: ECG = electrocardiogram, EORTC = European Organization for Research and Treatment of Cancer, HIV = human immunodeficiency virus, QoL = Quality of Life. 
a. 
EOT is defined as the last assessment for the protocol-specified treatment post cycle 4 (Day 22 [+ 7 days]) of the study for an individual patient. 
b. If a patient discontinues the study, procedures should be performed within 21 days of the last dose of study drug. 
c. 
All patients, (including patients who withdraw from the study early), will complete a safety follow-up visit 30 (+7) days after the last dose. Follow-up visits will be required to 
monitor for ongoing treatment-related adverse events.  All patients experiencing drug-related toxicities of Grade  2 at the End of Treatment visit should be followed-up at 
least monthly until the adverse event(s) resolves to Grade  1, the event is considered to be chronic or the patient receives other anti-cancer therapy. The method of follow-up 
assessment will be at the Investigator’s discretion (for example, patient site visit or telephone call). All deaths which occur within 30 days of study drug administration 
regardless of relationship to the study drug must be reported the Sponsor immediately and within 24 hours of becoming aware of the event. 
d. Demographic data will include gender, date of birth (or age), and race/ethnicity. 
e. 
Background characteristics will include a history of disease and current disease status, bone marrow involvement, sites of disease, prior anticancer therapies, and prior 
medications/significant non-drug therapies. 


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f. 
Patients must be in a supine position in a rested and calm state for at least 5 minutes before blood pressure is assessed. If the patient is unable to be in the supine position, the 
patient should be in the most recumbent position possible. The position selected for a patient, the same arm, and same blood pressure cuff should be kept the same throughout 
the study. 
Two methods will be used to collect blood pressure. 
Method 1 in Phase 2, Cycle 1 Day 1 ONLY, using blood pressure devices provided by the sponsor (SpaceLabs 90217 ambulatory blood pressure monitor): 
 
Day 1 (Arm 1): Blood pressure and heart rate will be measured semi-continuously starting at 15 minutes after completion of docetaxel infusion, and at every 15 minutes 
thereafter for 4.5 hours. 
 
Day 1 (Arms 2 to 4): Blood pressure and heart rate will be measured semi-continuously starting at 15 minutes before plinabulin infusion (15 minutes after completion of 
docetaxel infusion), and at every 15 minutes thereafter for 4.5 hours after start of infusion with plinabulin. 
Method 2 in Phase 2 in Cycles 1, 2, 3, and 4 as follows: 
A standard cuff will be used to measure blood pressure (heart rate will also be measured): 
 
Cycle 1 (Arms 1 to 4): At screening, Day 1 (pre-docetaxel), Days 2, 6, 7, 8, 9, 10, and 15 (once, prior to blood draw). 
 
Cycles 2 to 4 (Arm 1): Day 1 pre-docetaxel dose, and on Day 8 prior to blood draw 
 
Cycles 2 to 4 (Arms 2 to 4): On Day 1 at pre-dose, 30 min, 1 hour, 2 hours post-infusion with plinabulin, and on Day 8 
g. Temperature is to be taken every time a blood draw is taken for neutrophil count and can be taken orally or in the ear; however, the same method (ear or oral) should be used 
throughout the study for each patient; thus if the ear method was used the first time for a given patient, the ear method should be used throughout the study for that patient. 
h. Height (cm) will be measured at screening. 
i. 
A single 12-lead ECG will be performed at screening, EOT, Early Discontinuation and 30 Day Safety Follow-Up. All other ECGs will be performed in triplicate. In Cycle 1 
Day 1, ECG will be collected before docetaxel infusion, immediately before plinabulin infusion, 5-minutes before end of plinabulin infusion, 30 minutes and 4.5 hours after 
start of infusion with plinabulin. In Cycle 1 Day 2, ECG will be performed in triplicate prior to the blood draws on Day 2 in Arms 2 to 4. For Arm 1, the triplicate ECGs will 
not be performed. 
j. 
Laboratory test samples (hematology and serum chemistry) will be collected and sent to the protocol central laboratory. Safety laboratory tests are required prior to treatment 
on Day 1 of each cycle and can be collected by a local laboratory and will be used to determine docetaxel dosing; however, all other safety (e.g. protocol specified) blood 
samples as per the schedule assessments and procedure table must also be obtained for central laboratory assessment. In addition a central laboratory blood draw needs to be 
taken on the day of dosing on Day 1 of each cycle, prior to the docetaxel dosing. Neutrophils are to be collected on time points as indicated in this schedule; neutrophils must 
be collected at pre-dose on day 1 of each cycle. During Cycle 1, neutrophils count will be assessed at baseline (prior to Cycle 1 docetaxel dose), pre-dose on Day 1 and on 
Days 2, 6, 7, 8, 9, 10, and 15. 
k. Analyzed at a central laboratory. 
l. 
CD34+ will be analyzed using FACS via a central laboratory. 
m. Samples for CD34+ analysis to be collected at Day 1 Cycle 2 only. Do not collect at cycle 3 and 4 visits. 
n. Hepatitis B surface antigen reactive, hepatitis B core antibody, hepatitis B surface antibody, and hepatitis C antibodies 
o. Pregnancy tests will be done using urine samples in women of childbearing potential. Subject must have a negative urine pregnancy test documented within the 24-hour period 
prior to the first infusion. Confirm with serum testing (central laboratory) if urine sample is positive. 
p. Plasma samples (5 mL each) for plinabulin and docetaxel PK. All patients will be sampled for PK via a central laboratory. For PK collection schedule refer to Tables 13 and 
14 of the Protocol. During the Phase 2 open label portion of the study patients randomized to pegfilgrastim will not have samples collected for plinabulin PK analysis. 
q. Investigator opinion of progression (yes/no) at End of Treatment (EOT) recorded in CRF. For example if the patient completes 2 cycles of docetaxel and study drug, and in the 
opinion of the investigator per institutional practice the cancer is growing and a new treatment is required, then the EOT evaluation will be performed as specified, and the 
“disease progression” will be scored as “yes.” As an another example, if after four cycles of docetaxel and study drug, the cancer is stable or responding, and the patient 
receives further docetaxel, then the EOT evaluation will be completed as specified, and the “disease progression” will be scored as “no.”. 
r. 
Docetaxel infusion: 75 mg/m2 docetaxel will be administered via IV infusion over 1 hour on Day 1 of each cycle. All patients should be premedicated with oral corticosteroids 
such as dexamethasone 16 mg per day (e.g., 8 mg bid) for 3 days starting 1 day prior to docetaxel administration in order to reduce the incidence and severity of fluid retention 
as well as the severity of hypersensitivity reactions (refer to Taxotere® Package Insert). 


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s. 
Cycles 1 to 4 will consist of docetaxel 75 mg/m2 administered by IV on Day 1 over 60 minutes (±5 minutes) each 21 day cycle. Patients will get a single dose of plinabulin 
intravenously over 30 minutes (± 5 minutes) 30 minutes after the end of the docetaxel infusion if in arms 2-4. On Day 2 of each cycle ≥ 24 hours after completing 
chemotherapy, patients will receive a single dose of pegfilgrastim (6 mg) if in arm 1. 
t. 
The bone pain questionnaire should be completed prior to docetaxel infusion and at the site if possible, if not the questionnaire needs to be returned to the site at the next 
scheduled visit. 
u. Bone pain questionnaire to be completed prior to pegfilgrastim and plinabulin pre dose, Cycle 1 
v. Bone pain questionnaire to be collected at Cycle 2: Pre-dose Day 1, only. Do not collect at Cycle 3 and 4 visits. 
w. Health-related QoL questionnaire evaluated with EORTC QLQ-C30 and EQ 5D-5L will be collected prior to docetaxel infusion on Day 1 of each cycle (Protocol, Appendices 
A and D). 
x. All concomitant medicines (dose, schedule, and duration of treatment) and in particular analgesics as well as antibiotics should be entered in the eCRF. 
y. All hospitalizations should be entered in the eCRF. 


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14. 
APPENDICES 
14.1. 
List of Tables, Listings and Figures for Phase 2 Data 
Index 
Listings 
Tables 
Tier 1 
1 
Listing of Demographic 
Characteristics 
Summary of Demographic Characteristics 
2 
Listing of Exposure Information 
Summary of Exposure by Treatment Group 
3 
Listing of ECOG 
Summary of ECOG by Treatment Group 
4 
Listing of Pregnancy Information 
5 
Listing of Medical History 
Summary of Significant Medical History by 
Treatment Group 
6 
Listing of Concomitant 
Medications 
7 
Listing of Adverse Events 
High Level Summary of Adverse Events by 
Treatment Group 
Summary of AE by SOC and PT – by 
Treatment Group – Number of Patients and 
Number of AE 
Summary of AE by SOC and PT – AE 
Grade – By Treatment Group– Number of 
Patients and Number of AE 
Summary of AE by SOC and PT – Serious – 
By Treatment Group– Number of Patients 
and Number of AE 
8 
Listing of Deaths 
9a 
Listing of DSN data 
Table of the Analysis of DSN 
9b 
Listing of DMN data 
Table of the Analysis of DMN 
10 
Listing of Vital Signs 
Summary and Analysis of Blood Pressure 
Data 
11 
Listing of Patient Excluded from 
any Efficacy Analysis 
PK/PD Tables, Figures and Listings are included in the pharmacometrics analysis plan. 


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Index 
Listings 
Tables 
Tier 2 
1 
Listing of Disposition Data and 
Discontinued Patients 
Summary of Disposition by Treatment 
Group 
2 
Listing of Protocol Deviations 
3 
Listing of Demographic 
Characteristics 
Summary of Demographic Characteristics 
4 
Listing of Exposure Information 
Summary of Exposure by Treatment Group 
5 
Listing of ECOG 
Summary of ECOG by Treatment Group 
6 
Listing of Pregnancy Information 
7 
Listing of HIV Information 
8 
Listing of Hepatitis B/C 
Information 
9 
Listing of Medical History 
Summary of Significant Medical History by 
Treatment Group 
10 
Listing of PT, INR, PTT 
Summary Statistics for PT, INR, PTT by 
Treatment Group 
11 
Listing of Urinalysis Results 
12 
Listing of Concomitant 
Medications 
13 
Listing of Adverse Events 
High Level Summary of Adverse Events by 
Treatment Group 
Summary of AE by SOC and PT – by 
Treatment Group – Number of Patients and 
Number of AE 
Summary of AE by SOC and PT – AE 
Grade – By Treatment Group– Number of 
Patients and Number of AE 
Summary of AE by SOC and PT – Serious – 
By Treatment Group– Number of Patients 
and Number of AE 
14 
Listing of Deaths 
15 
Listing of Patients with Serious and 
Significant Adverse Events 
16a 
Listing of DSN data 
Table of the Analysis of DSN 
16b 
Listing of DMN data 
Table of the Analysis of DMN 
17 
Listing of Vital Signs 
Summary and Analysis of Blood Pressure 
Data 
18 
Listing of Physical Examination 
Results 
Summary of Changes in Physical 
Examinations by Visit and Treatment Group 
19 
Listing of Laboratory Results 
Summary of Laboratory Results by Visit and 
Treatment Group 
Summary of Changes from Baseline in 
Laboratory Results by Visit and Treatment 
Group 


BeyondSpring Pharmaceuticals, Inc. 
Protocol: BPI-2358-105Version: 
Phase 2 Statistical Analysis Plan 
2.0 (Dated 07 December 2017) 
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continued 
 
Index 
Listings 
Tables 
Tier 2 
20 
Listing of Abnormal Laboratory 
Values 
21 
Listing of Laboratory Results for 
Patients with Grades 3 and 4 
Summary of Change in Grades from 
Baseline by Visit and Treatment Group 
22 
Listing of CD34 Results 
Summary of CD34 Results by Treatment 
Group 
Summary of CD34 Results changes from 
Baseline by Treatment Group 
23 
Listing of Bone Pain Data 
Summary of Bone Pain Data – Categorical 
Yes/No by Treatment Group 
Summary of Bone Pain Data – Individual 
Questions for Yes by Treatment Group 
24 
Listing of EORTC-QLQ-C30 
Summary of Scored EORTC-QLQ-C30 
results by Treatment Group 
Summary of Scored EORTC-QLQ-C30 
Changes from Baseline Results by 
Treatment Group 
25 
Listing of EQ-5D-5L 
Summary of Scored EQ-5D-5L results by 
Treatment Group 
Summary of Scored EQ-5D-5L Changes 
from Baseline results by Treatment Group 
PK/PD Tables, Figures and Listings are included in the pharmacometrics analysis plan. 


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Protocol: BPI-2358-105 
Statistical Analysis Plan Supplement 
Version: 1.0 (Dated January 6, 2019) 
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Confidential 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
Supplement 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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BeyondSpring Pharmaceuticals, Inc. 
Protocol: BPI-2358-105 
Statistical Analysis Plan Supplement 
Version: 1.0 (Dated January 6, 2019) 
Page 74 of 79 
Appendix 16.1.9 - Study BPI-2358-105 P2 
Confidential 
 
 
Study Title: 
A Phase 2/3, Multicenter, Randomized, Double Blind, Study to 
Evaluate Duration of Severe Neutropenia with Plinabulin 
Versus Pegfilgrastim in Patients with Solid Tumors Receiving 
Docetaxel Myelosuppressive Chemotherapy 
 
 
Sponsor 
BeyondSpring Pharmaceuticals, Inc. 
28 Liberty Street, 39th Floor 
New York, NY 10005 
 
Drug Product: 
Plinabulin (BPI-2358) 
Protocol Number: 
BPI-2358-105 
Phase: 
Phase 2 
 
 
 
Analysis Plan Version 
Supplement Version 1.0 
Analysis Plan Date 
January 6, 2019 
Author 
Shuxin Yin, Ph.D 
BeyondSpring Pharmaceuticals, Inc. 
28 Liberty Street, 39th Floor 
New York, NY 10005 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidential/Proprietary Property of BeyondSpring Pharmaceuticals, Inc. 
Page 2 of 7 


Page 75 of 79 
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BeyondSpririg Pharmaceuticals, Inc. 
Protocof: BPI-23$8-105 
Statistical Analysis Plan Supp/emenf 
V’ers/on: 1.0 (Dated January 6, 2019) 
 
 
STATISTICAL ANALYSIS PLAN APPROVAL SIGNATURE PAGE 
AUTHOR: 
Shuxin Yin, Princinpal Statistician 
BeyondSpring Pharmaceuticals, Inc. 
 
 
 
 
 
 
APPROVED BY: 
Signature 
 
 
Ramon Mohanlal, Chief Medical Officer 
BeyondSpring Pharmaceuticals, Inc. 
 
 
 
 
Signatiire 
Date 
 
 
 
 
 
 
 
 
 
 
”Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Con fidential/Proprietary Properly of BeyondSpring Pharmaceuticals, Inc. 
 
Page 3 of 7 


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Protocol: BPI-2358-105 
Statistical Analysis Plan Supplement 
Version: 1.0 (Dated January 6, 2019) 
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Confidential 
 
 
 
TABLE OF CONTENTS 
Section 
Page 
1. INTRODUCTION .................................................................................................. 6 
2. DESCRIPTION OF DISCREPANCIES ................................................................. 6 
3. GENERAL CONSIDERTION ................................................................................ 7 
4. EFFICACY ENDPOINTS ...................................................................................... 7 
DSN ...................................................................................................................... 7 
CD34+ .................................................................................................................. 7 
QoL related endpoints .......................................................................................... 7 
Time to disease progression ................................................................................ 7 
Incidence of bone pain ......................................................................................... 7 
5. SAFETY ENDPOINTS .......................................................................................... 7 
Laboratory parameters ......................................................................................... 7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol: BPI-2358-105 
Statistical Analysis Plan Supplement 
Version: 1.0 (Dated January 6, 2019) 
Page 77 of 79 
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Confidential 
 
 
LIST OF ABBREVIATIONS 
DSN 
Duration of Severe Neutropenia 
TEAE 
TreatmentEmergent Adverse Event 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol: BPI-2358-105 
Statistical Analysis Plan Supplement 
Version: 1.0 (Dated January 6, 2019) 
Page 78 of 79 
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Confidential 
 
 
 
1. 
INTRODUCTION 
This document outlines the discrepancies of analysis methods between Statisitcal Analysis 
Plan 2.0 dated on 27 December 2017 and protocol BPI-2358-105, amendment 4 dated on 21 
March 2018 and add the analyses which are indicated in protocol amendment 4 but are 
missing or different from SAP 2.0. 
 
2. 
DESCRIPTION OF DISCREPANCIES 
 
SAP 2.0 
Protocol Amendment 4.0 
The primary efficacy endpoint DSN will be 
analyzed by using Jonckleere-Terpstra test 
The primary efficacy endpoint DSN will be 
analyzed by using Negative Binomial 
Regression (NBR) model. 
Secondary efficacy endpoint is DMN and 
Jonckleere-Terpstra test will be used. 
Secondary efficacy endpoints are PK, 
exposure-response and exposure-safety and 
they will be discussed in PAP 
CD34+ will be analyzed by using analysis 
of variance 
CD34+ will be analyzed by using repeated 
measures mixed linear model. 
QoL related endpoints will be analyzed by 
using t-test 
QoL related endpoints will be analyzed by 
using Wilcoxon rank sum test 
Time to disease progression is not indicated 
Time to disease progression will be 
analyzed by using log-rank test 
Bone pain information will be displayed in 
listing 
Incidence of bone pain will be analyzed by 
using NBR model 
Lab parameters will be summarized in 
descriptive and/or shift tables 
For lab parameters, continuous variables and 
proportions will be analyzed using exact t- 
tests. Other categorical data will be analyzed 
using non-parametric statistical methods. 
 
 
 
 
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Protocol: BPI-2358-105 
Statistical Analysis Plan Supplement 
Version: 1.0 (Dated January 6, 2019) 
Page 79 of 79 
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Confidential 
 
 
3. 
GENERAL CONSIDERTION 
All analysis in ITT and SP will be based on actual treatment regardless of assigned treatment. 
Durations, expressed in days between 1 date (date1) and another later date (date2), are calculated 
using the following formula: duration in days = (date2-date1+1). 
4. 
EFFICACY ENDPOINTS 
DSN 
In addition to J-T test, the NBR model will also be used to analyze the DSN endpoint with 
the treatment arm as the only covariate. The method will also be used to construct point 
estimates and confidence intervals. The NBREG, GLM and TABSTAT procedures in Stata 
v11.0 or later will be used. 
CD34+ 
CD34+ will be analyzed by using repeated measures mixed linear model. Analysis of 
variance is not applicable. 
QoL related endpoints 
Wilcoxon rank sum test or t-test is not applicable for QoL related endpoints. A repeated 
measure mixed linear model with the baseline value and treatment arm as covariates will be 
used to analyze this type of endpoints. The method will also be used to construct point 
estimates and confidence intervals. The MIXED procedure in SAS version 9.4 or later will 
be used for the analysis. 
Time to disease progression 
Due to the limit of data, time to disease progression will be only listed. 
Incidence of bone pain 
Due to the limit of data, incidence of bone pain will be listed and plotted. 
 
5. 
SAFETY ENDPOINTS 
Laboratory parameters 
The t-test and non-parametric statistical tests are specified in protocol amendment 4 but they 
are not applicable to laboratory parameters so they will not be performed. 
 
 
 
 
 
 
 
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