A Phase 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)
Phase: PHASE3
Conditions: Chemotherapy-induced Neutropenia
Sponsor: BeyondSpring Pharmaceuticals Inc.

 
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: NCT03102606  
Document Date: 13 December 2019 

Protocol BPI-2358-105 
IND 131490-0127 
BeyondSpring Pharmaceuticals, Inc. 
Protocol Amendment 7  
Date: 11 December 2019 
CONFIDENTIAL 
Page:1 of 138 
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 
Date of Protocol Amendment 4: 
21 March 2018 
Date of Protocol Amendment 5: 
04 December 2018 
Date of Protocol Amendment 6: 
05 August 2019 
Date of Protocol Amendment 7:      13 December 2019 
IND No: 
131490-0127 
EudraCT No: 
2017-000834-80 
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 
parties not associated with the study or used for any purpose without the prior written consent of 
BeyondSpring Pharmaceuticals Inc. 

Protocol BPI-2358-105 
 
IND 131490-0127 
BeyondSpring Pharmaceuticals, Inc. 
 
 
 
Protocol Amendment 7  
Date: 13 December 2019 
CONFIDENTIAL 
Page: 2 of 138 
SUMMARY OF CHANGES TO PROTOCOL BPI-2358-105 
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”. 
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: 
 

Protocol BPI-2358-105 
 
IND 131490-0127 
BeyondSpring Pharmaceuticals, Inc. 
 
 
 
Protocol Amendment 7  
Date: 13 December 2019 
CONFIDENTIAL 
Page: 3 of 138 
• 
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. 
• 
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’. 
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. 

Protocol BPI-2358-105 
 
IND 131490-0127 
BeyondSpring Pharmaceuticals, Inc. 
 
 
 
Protocol Amendment 7  
Date: 13 December 2019 
CONFIDENTIAL 
Page: 4 of 138 
 
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  
• 
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 

Protocol BPI-2358-105 
 
IND 131490-0127 
BeyondSpring Pharmaceuticals, Inc. 
 
 
 
Protocol Amendment 7  
Date: 13 December 2019 
CONFIDENTIAL 
Page: 5 of 138 
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. 
• 
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. 
SUMMARY OF AMENDMENT 4 
At the time of implementation of Amendment 4.0, all patients recruited into the Phase 2 
portion had completed the study under a previous version of the protocol. Therefore changes 
found in Amendment 4.0 that relate to the operation of the study primarily apply to the 
Phase 3 portion. 
Changes to the protocol are as follows: 
• EudraCT number added to the title page. 
• IND serial number updated. 
• Footers were changed to reflect the amendment number and date. 
• 
Latin America and Australia removed and South America and Central America added to the list 
of investigational sites. 
• 
Part of inclusion criterion 3 revised for Phase 3 from “[patients with] advanced or metastatic 
NSCLC after failing platinum-based therapy” to “[patients with] advanced or metastatic NSCLC 
who have previously received platinum based therapy and have either disease progression, are 
intolerant of platinum-based therapy, or in the opinion of the investigator, would benefit from 
docetaxel chemotherapy”. 
• 
For Phase 3 only, pain inventory (short version) removed and patient bone pain scale and pain 
medication assessment added at Days 1 to 8 for Cycle 1. 
• 
For Phase 3, secondary objectives/endpoints separated into those to be assessed in Cycle 1 and 

Protocol BPI-2358-105 
 
IND 131490-0127 
BeyondSpring Pharmaceuticals, Inc. 
 
 
 
Protocol Amendment 7  
Date: 13 December 2019 
CONFIDENTIAL 
Page: 6 of 138 
those to be assessed in Cycles 1 to 4. 
• 
Mean bone pain score and change in bone pain score added as secondary objectives/endpoints for 
Phase 3; statistical methodology updated accordingly. 
• 
Incidence of Grade 4 neutropenia in Cycle 1 added as a Cycle 1 secondary objective/endpoint for 
Phase 3; statistical methodology updated accordingly. 
• 
Incidences of use of pegfilgrastim or filgrastim as treatment for neutropenia removed from the 
Phase 3 secondary objectives/endpoints .  
• 
Area under the curve using the trapezoidal quadrature method for bone pain, from Day 1 through 
Day 8 in Cycle 1, proportion of patients who needed bone pain medication, and time to first use 
of bone pain medication added as exploratory objectives/endpoints for Phase 3; statistical 
methodology updated accordingly. 
• 
Incidence of Grade 4 neutropenia on any of the Days 8 and 15 in Cycle 1 and on Day 8 in Cycles 
2 to 4 moved from a secondary objective/endpoint to an exploratory objective/endpoint for Phase 
3. 
• 
For Phase 2, safety objective/endpoint to assess the “incidence, occurrence and severity of bone 
pain” updated to “incidences of bone pain”. 
• 
For Phase 3, safety objective/endpoint to assess the incidence, occurrence and severity of bone 
pain removed. 
• 
“Systemic tolerance” amended to “safety and tolerability” in the Phase 2 and Phase 3 safety 
objectives/endpoints.  
• 
Section added detailing the rationale for the assessment of bone pain. 
• 
Updated to specify a fixed 40 mg dose as the Recommended Phase 3 Dose (RP3D) following the 
Phase 2 pharmacokinetic/pharmacodynamic analysis and rationale for the selection of the RP3D 
added. 
• 
Definition of febrile neutropenia (FN) updated in line with CTCAE version 4.03 
• 
A non-interventional post-treatment assessment has been added, to collect data on time to next 
treatment. 
• 
Neutrophil(s) count replaced with absolute neutrophil count at first use and ANC thereafter. 
• 
Window for the safety follow-up amended from ±7 days to ±2 days after the last dose of study 
drug and text added to clarify that “If, in the opinion of the investigator, the patient will benefit 
from more than 4 cycles of docetaxel and open label pegfilgrastim, then the fifth cycle will not 
start until completion of the safety follow-up visit (in this instance, the safety follow-up visit will 
be Cycle 4 Day 21)”. 
• 
Exclusion Criterion 17 updated to include specific serology testing. Serology tests updated to 
include hepatitis C antibody, hepatitis B surface antigen (HBsAg), and hepatitis B surface 
antibody (anti-HBs). 
• 
Clarified that hepatitis serology can be performed by local laboratory or by the central laboratory 
if local testing is not available.  
• 
“Should” replaced with “must” in the following statement: “If a patient was originally assigned to 
the pegfilgrastim arm, patients should be treated at a lower dose of docetaxel, or taken off study 
at the discretion of the investigator”. 

Protocol BPI-2358-105 
 
IND 131490-0127 
BeyondSpring Pharmaceuticals, Inc. 
 
 
 
Protocol Amendment 7  
Date: 13 December 2019 
CONFIDENTIAL 
Page: 7 of 138 
• 
Table 3 updated to add ±5 minute window for the timing of plinabulin/placebo matching 
plinabulin in relation to the end of the docetaxel infusion  
• 
Removal of the requirement for vital signs to be checked every 15 minutes during docetaxel 
infusion. 
• 
Updated to state that all patients must be pre-medicated with oral corticosteroids (previously 
should be pre-medicated) 
• 
Aprepitant added as an acceptable prophylactic anti-emetic. 
• 
Tropisetron added as an acceptable substitute 5HT3 receptor agonist. 
• 
Text relating to hematopoietic growth factors or transfusion and the initiation of hematological 
support updated for clarity.  
• 
Text to state that “Milk and milk products should be avoided, and other appropriate dietary 
interventions should be advised to patients” removed. 
• 
Table 4 (Dose Modifications for Docetaxel): Action for AST, ALT and AP abnormalities updated 
from “reduce docetaxel by 20%” to “withhold docetaxel until the abnormality returns toward 
normal and then resume at 55 mg/m2” . 
• 
“X” added to Day 1 for pregnancy text row in Table 7. 
• 
“X” added to Screening for disease status evaluation row in Table 7. 
• 
In Phase 3, all patients who discontinue will complete the End of Treatment assessments; Early 
Discontinuation visit removed from Table 7 and any references to an early discontinuation visit 
for Phase 3 removed from text. 
• 
Definition of End of Treatment revised to “the last assessment for the protocol-specified 
treatment post Cycle X (Day 22 [+ 7 days]) of the study for an individual patient, regardless at 
what time the patient discontinues the study (changes shown in bold). 
• 
Updated to state that confirmatory serum pregnancy testing can be performed by a local or central 
laboratory and that additional testing may be performed at the discretion of the investigator. 
• 
Added that HIV testing is at the discretion of the investigator and if performed the test will be 
conducted at the local site.  
• 
Added that “assessments for UDP glucuronosyltransferase (UGT) 1A1 genotyping and total 
bilirubin, conjugated bilirubin, and unconjugated bilirubin may be performed at the discretion of 
the investigator”. 
• 
Added that “Disease progression or deterioration of the malignancy under study (including new 
sites of metastasis due to disease progression) will be recorded as part of the subject’s disease 
status and should not be reported as an AE/SAE”. 
• 
Added that “The sponsor will collect all deaths on study regardless of its potential relationship to 
disease progression and up to 30 days after the last dose of plinabulin on an SAE form”. 
• 
Country specific fax numbers for the reporting of serious adverse events (SAEs) removed. 
• 
Additional clinical laboratory test parameters added (MCV, MCH, MCHC, glucose, creatine 
phosphokinase). 
• 
ECG assessment changed from 30 (+ 15) minutes  after the start of the infusion to 60 
(± 5) minutes after the start of the infusion for Phase 3. 

Protocol BPI-2358-105 
 
IND 131490-0127 
BeyondSpring Pharmaceuticals, Inc. 
 
 
 
Protocol Amendment 7  
Date: 13 December 2019 
CONFIDENTIAL 
Page: 8 of 138 
• 
Updated Section 11.8 (Pharmacokinetics) to present docetaxel sampling before plinabulin 
sampling; numbering for Tables 13 and 14 switched. 
• 
Possible temperature reading locations updated to include axillary. 
• 
Clarification regarding when to report an elevated temperature as an adverse event added. 
• 
Removed specific details of the vendor to be used for PK/PD analyses. 
• 
Sections of text providing an overview of the analyses removed and full details of statistical 
analyses added after each of the study endpoints. 
• 
Clarified that the PK analysis set will include all patients who had pre-dose sample collection and 
at least 1 PK sample collected postdose. 
• 
Confirmed that the plinabulin and docetaxel PK sampling schedules for Phase 2 will be followed 
for Phase 3. 
• 
Pharmacokinetic and pharmacodynamic analyses updated. 
• 
Appendix A (EORTC QLQ-C30), Appendix B (Patient Bone Inventory [Short Form]) and Appendix 
D (EQ-5D-5L) removed. 
• 
Other minor edits were made to correct typographical errors, enhance the readability of the text, 
to provide further clarity, to update minor inconsistencies, and to update formatting.  
SUMMARY OF AMENDMENT 5 
At the time of Amendment 5.0, a total of 105 patients had been enrolled in the Phase 3 
portion under Amendment 4.0 and 55 patients had completed the Phase 2 portion, under 
Amendments 1.0, 2.0 and 3.0. 
All changes to objectives are reflected throughout the protocol in the appropriate 
sections, including the statistical endpoints sections. 
Changes to the protocol are as follows. In addition, minor edits have been made for internal 
consistency and clarity. 
• The Phase 2 exploratory objectives were updated to include: 
− For selected countries only: to investigate the following cytokine panel: IL-1beta, 
IL-6, IL-12p70, IL-12p40, IL-17A, IL-23, G-CSF, GM-CSF, IFN-alpha, IFN-
gamma, TNF-alpha, IL-2, FLT-3 ligand, and IL-8. 
• The Phase 3 primary objective was amended from “[patients with]… advanced or 
metastatic non-small cell lung cancer (NSCLC) who have previously received 
platinum based therapy and have either disease progression, are intolerant of 
platinum-based therapy, or in the opinion of the investigator, would benefit from 
docetaxel chemotherapy…” to “[patients with] …locally advanced or metastatic non 
small cell lung cancer (NSCLC) after platinum therapy failure…” 
• The Phase 3 secondary and exploratory objectives were amended following 
preliminary results from the Phase 2 portion of the study, to include new objectives 
regarding healthcare utilization and to re-order for hierarchical analysis.  

Protocol BPI-2358-105 
 
IND 131490-0127 
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Protocol Amendment 7  
Date: 13 December 2019 
CONFIDENTIAL 
Page: 9 of 138 
− Secondary efficacy objectives were amended to evaluate: 
1. 
Change in platelet count from baseline in Cycle 1 
2. 
The proportion of patients with neutrophil-to-lymphocyte ratio > 5 during 
Cycle 1 
3. 
Area under the concentration-time curve using the trapezoidal quadrature 
method for bone pain, from Day 1 through Day 8 (pegfilgrastim will be 
administered on Day 2) in Cycle 1, based on the pain score from the 
patient bone pain scale 
4. 
Change in estimated mean bone pain in Cycle 1 
5. 
The proportion of patients with thrombocytopenia (all grade) in Cycles 1 
to 4 
− Exploratory efficacy objectives (Cycle 1) were amended to evaluate: 
o The proportion of patients in Cycle 1 with: 
 Thrombocytopenia (all grade) 
 Grade 4 neutropenia (absolute neutrophil count [ANC] < 0.5 × 
109/L) 
 Grade 3 neutropenia (ANC < 1 × 109/L) 
 Grade 3 (ANC < 1 × 109/L) and Grade 4 neutropenia (ANC < 0.5 
× 109/L) 
 Bands > 0 after Day 7 through Day 15 
 Promyelocytes plus myelocytes > 0 after Day 7 through Day 15 
 Lymphocyte-to-monocyte ratio < 3.2 after Day 7 through Day 15 
 Platelet-to-lymphocyte ratio > 200 after Day 7 through Day 15 
 At least 1 day of bone pain 
 At least 2 days of bone pain 
 At least 3 days of bone pain 
 At least 4 days of bone pain 
 At least 5 days of bone pain 
 At least 6 days of bone pain 
 At least 7 days of bone pain 
 At least 8 days of bone pain 
o The proportion of patients who needed bone pain medication in Cycle 1  
o The time (in days) to first use of bone pain medication between the 
treatment groups  

Protocol BPI-2358-105 
 
IND 131490-0127 
BeyondSpring Pharmaceuticals, Inc. 
 
 
 
Protocol Amendment 7  
Date: 13 December 2019 
CONFIDENTIAL 
Page: 10 of 138 
o Duration of severe neutropenia (DSN) in Cycle 1 in patients with locally 
advanced or metastatic NSCLC after platinum therapy failure 
o To assess DSN in Cycle 1 in patients with hormone refractory prostate 
cancer (HRPC) 
o To assess DSN in Cycle 1 in patients with advanced or metastatic breast 
cancer who have failed < 5 prior lines of chemotherapy 
o DSN in Cycle 1 in patients with locally advanced or metastatic NSCLC 
after platinum therapy failure or HRPC 
o Platelet count at least 30% change from baseline at any time during 
Cycle 1 
o ANC nadir during Cycle 1 
o For selected countries only: to investigate the following cytokine panel: 
IL-1beta, IL-6, IL-12p70, IL-12p40, IL-17A, IL-23, G-CSF, GM-CSF, 
IFN-alpha, IFN-gamma, TNF alpha, IL-2, FLT-3 ligand, and IL-8. 
− Exploratory efficacy objectives (Cycles 1 to 4) were amended to evaluate: 
o The proportion of patients in Cycles 1 to 4 with: 
 Febrile neutropenia (FN) (ANC <1.0 × 109/L AND a single 
temperature of >38.3°C or a sustained temperature of ≥38°C for 
more than 1 hour). 
 Grade 4 neutropenia (ANC < 0.5 × 109/L). 
o The following healthcare utilization objectives: 
 Incidence of 30-day rehospitalizations - all cause.  
 Incidence of all cause hospitalizations 
 Duration of all cause hospitalizations 
 Incidence of all cause emergency room (ER) visits 
 Incidence of all cause intensive care unit (ICU) stays 
 Duration of all cause ICU stays 
 Incidence of all cause docetaxel dose delay (≥7 days), dose 
reduction (≤85%), or dose discontinuation 
 Incidence of platelet transfusions 
 Incidence of antibiotics use 
o Data on disease progression 
o Health-related quality of life questionnaire evaluated with European 
Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 
and EQ-5D-5L 

Protocol BPI-2358-105 
 
IND 131490-0127 
BeyondSpring Pharmaceuticals, Inc. 
 
 
 
Protocol Amendment 7  
Date: 13 December 2019 
CONFIDENTIAL 
Page: 11 of 138 
• It was clarified that cytokine panel testing will be done using plasma samples 
collected at the pharmacokinetic (PK) time points and that reconsenting of the 
patients will be required before analysis is performed. 
• It was specified that unused samples (urine/serum plasma) will also be saved for 
future potential biomarker research, with patient consent. 
• Timings were included for the new endpoints associated with new objectives (eg 
healthcare utilization). 
• The following statement was added: “In order to facilitate balanced treatment arms 
with respect to cancer type, once either arm reaches at least 1/3 (of total) of patients 
with that cancer type, it will be closed to that cancer type and enrollment will 
continue for patients with the other cancer types, up to the planned maximum number 
of patients. ”  
• It was clarified throughout the protocol that patients who withdraw for progressive 
disease and who will continue to another chemotherapy regimen will complete the 
end of treatment (EOT) visit at Cycle X Day 21. They then continue to another 
chemotherapy regimen and do not need to have the safety follow-up visit (where X is 
the last cycle prior to progression, and is 4 or less). Additionally, if, in the opinion of 
the investigator, the patient will benefit from more than 4 cycles of docetaxel and 
open label pegfilgrastim, then the fifth cycle will not start until completion of the 
EOT visit (in this instance, the EOT visit will be Cycle 4 Day 21). 
• It was clarified throughout the protocol that patients without progressive disease at 
the EOT visit will undergo a follow-up visit every 2 months until the occurrence of 
either disease progression or death. The visits may be conducted per telephone or 
other means. 
• Inclusion Criterion 7 was amended to include a footnote as follows “Results are from 
the central laboratory. Local laboratory results may be accepted on a case by case 
basis after discussion with the Medical Monitor, however in this case central 
laboratories must also be taken within the screening time window” 
• Exclusion Criterion 17 was revised from “Active Hepatitis B virus (HBV) infection 
which requires antiviral treatment or the patient has detectable Hepatitis B surface 
Antigen (HBsAg) ”…to “Active Hepatitis B virus (HBV) infection which requires 
antiviral treatment. Patients with detectable Hepatitis B surface Antigen (HBsAg) 
may be eligible provided the patient has a negative viral load. Patients with a positive 
HBsAg must have a negative viral load before each chemotherapy administration... ” 
• It was clarified throughout the protocol that new NSAIDs are prohibited but patients 
already receiving NSAIDs are allowed to continue taking treatment as long as the 
dose remains stable. 
• It was clarified that if a patient develops a positive viral load during the study, 
chemotherapy should be held for a maximum of 21 days.  If the viral load returns to 
zero treatment can be restarted, otherwise the patient should be withdrawn from the 
study. 

Protocol BPI-2358-105 
 
IND 131490-0127 
BeyondSpring Pharmaceuticals, Inc. 
 
 
 
Protocol Amendment 7  
Date: 13 December 2019 
CONFIDENTIAL 
Page: 12 of 138 
• Throughout the protocol, the following text was added to clarify the PK analysis for 
plinabulin “Plinabulin PK will be characterized using the population PK approach. 
Population PK parameter estimates, and individual PK parameters, including AUC 
and Cmax will be summarized.” 
• It was clarified that the interim analysis will be performed by an independent 
statistician. 
• The requirement to document vital signs (position selected, arm, and blood pressure 
cuff used) and temperature location on the vital signs CRF was removed. 
• A ± 15 minute window was included for the standard cuff vital sign measurements. 
• The use of hospitalization or prolongation of hospitalization as an indicator of the 
seriousness of the AE was clarified. 
• Additional references were included to support the information provided. 
SUMMARY OF AMENDMENT 6 
• The formula for calculating the propotion of relative dose intensity =< 85% was clarified 
•  Calculation method for EORTC QLQ C30 was clarified 
• Additional anyalysis for EORTC QLQ C30 using EORTC QLQ C30 method was added 
• Calculation method for EQ 5D-5L ‘Your Health Today’ was clarified 
• Calculation of EQ 5D-5L utitility measures was added 
• Statistical method for bone pain measurements was updated 
• Statistical method for QoL endpoints was updated 
• DSN definition is updated 
• Statistical method for tesing difference of proportions is changed to be Barnard’s test 
• Definition of Grade 3 Neutrpenia is updated 
• Imputation rule of missing data of primary and key secondary efficacy endpoints is 
changed 
• Definition of intent-to-treat analysis set and safety analysis set is changed 
•  Statistical method of laboratory parameters is updated 
• Shift table for vital signs parameters is removed 
 

Protocol BPI-2358-105 
 
IND 131490-0127 
BeyondSpring Pharmaceuticals, Inc. 
 
 
 
Protocol Amendment 7  
Date: 13 December 2019 
CONFIDENTIAL 
Page: 13 of 138 
SUMMARY OF AMENDMENT 7 
Changes found in Protocol BPI-2358-105 Amendment 7.0 have been made based on the 
EOP2 Meeting recommendations, the Agency recommended that the Sponsor capture safety 
data for a minimum of year one and ideally up to five years from Study 105. The Agency 
recommended that the Sponsor consider follow-up telephone calls and queries of treating 
physicians or designee health care provider to ascertain safety information on secondary 
malignancies or tumor progression as well as other potential safety findings/concerns. 
Subjects who receive at least one dose of plinabulin or pegfilgrastim will be followed up. 
In addition, headers and footers were changed to reflect the amendment number and dates. 
• Changes to the protocol are as follows:Section 11.8.1 Long-term Safety Follow-up (up to 5 
years) 
• Safety endpoints to be collected include; 
o Disease progression  
o Disease relapse (local, regional or distant) 
o Second primary tumors 
o Health status check, including autoimmune and hematological disorders 
o Any further anti-cancer treatment information 
o Reporting of medical problems, including information on unexpected hospitalizations 
and medications (including SAEs) 
o Death (including autopsy report, if available) 
• Table 7 (Phase 3) updated to include a column for the Post-study Long-term Safety Follow-
up and Exploratory Biomarker Analysis CD34+  and Haptoglobin Assessments 
• Secondary Efficacy Objectives (Cycle 1 and Cycles 1 to 4) Updated as follows: 
o To assess DSN in Cycle 1 with only mature neutrophils 
o To assess the incidence of infections in Cycles 1 to 4 
• Secondary Efficacy Endpoints (Cycle 1 and Cycles 1 to 4) Updated as follows: 
o DSN in Cycle 1 with only mature neutrophils. The NBR model, on the integer number of 
days of severe neutropenia, will be used to analyze the DSN endpoint during the fixed 
time window outlined above, with the treatment arm as the only covariate. The method 
will also be used to construct point estimates and confidence intervals. The GENMOD 
procedure in SAS version 9.4 or later will be used. 
o Incidence of infections in Cycles 1 to 4. The NBR model will be used to analyze the endpoint, 
with the treatment arm as the only covariate. An offset variable will be used to account for 
exposure time. The method will also be used to construct point estimates and confidence 
intervals. The GENMOD procedure in SAS version 9.4 or later will be used.Synopsis and 
Section 7.2 Phase 3 Objectives (Exploratory Efficacy Objectives, Cycle 1) 
 
• The following Objectives were added to assess the proportion of patients in Cycle 1 with 

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the following: 
 Grade 4 neutropenia (ANC<0.5 x109/L) for mature neutrophils only  
 Promyelocytes, myelocytes, metamyelocytes and bands >0 after Day 7 through Day 
15  
 To assess DSN in Cycle 1 in patients with locally advanced or metastatic NSCLC 
after platinum therapy failure for mature neutrophils only  
 To assess DSN in Cycle 1 in patients with locally advanced or metastatic NSCLC 
after platinum therapy failure for mature neutrophils only 
 To assess DSN in Cycle 1 in patients with advanced or metastatic breast cancer who 
have failed < 5 prior lines of chemotherapy for mature neutrophils only 
 To assess DSN in Cycle 1 in patients with locally advanced or metastatic NSCLC 
after platinum therapy failure or HRPC for mature neutrophils only 
 To assess CD34+ at Day 1 pre-dose, Day 2 pre-dose, Day 6, 7, 8, 9, 10, and 15, Day 
1 Cycle 2 pre-dose 
• Synopsis and Section 14.1.2 Phase 3 Endpoints  
• Exploratory Efficacy Endpopints (Cycle 1) updated to align to addition of Phase 3 
Objectives above: 
 Grade 4 neutropenia (ANC<0.5 x109/L) for mature neutrophils only. The method 
will also be used to construct point estimates and 2-sided confidence intervals. The 
FREQ procedure in SAS version 9.4 or later will be used for the analysis. 
 Promyelocytes, myelocytes, metamyelocytes and bands >0  after Day 7 through 
Day 15. The method will also be used to construct point estimates and 2-sided 
confidence intervals. The FREQ procedure in SAS version 9.4 or later will be used 
for the analysis. 
 DSN in Cycle 1 with only mature neutrophils in patients with locally advanced or 
metastatic NSCLC after platinum failure. The analysis will be done as per the 
primary endpoint.  
 DSN in Cycle 1 with only mature neutrophils in patients with with HRPC. The 
analysis will be done as per the primary endpoint.  
 DSN in Cycle 1 with only mature neutrophils in patients with advanced or metastatic 
breast cancer who have failed <5 prior lines of chemotherapy. The analysis will be 
done as per the primary endpoint.  
 DSN in Cycle 1 with only mature neutrophils in patients with locally advanced or 
metastatic NSCLC after platinum failure or HRPC. The analysis will be done as per 
the primary endpoint.  
 CD34+ at pre-dose on Day 1, pre-dose on Day 2, Days 6, 7, 8, 9, 10, and 15 in Cycle 
1, and pre-dose on Day 1 in Cycle 2. A repeated measure mixed linear model with 
the pre-dose on day 1 cycle 1 value and treatment arm as covariates will be used to 
analyze this endpoint. 
 
 
 

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• Synopsis and Section 7.2 Phase 3 Objectives (Exploratory Objectives, Cycles 1-4) 
• The following Objectives were added to assess maximum change and difference from 
baseline for CD34+ and haptoglobin: 
 To assess the maximum change from baseline in CD34 + counts in each treatment 
arm 
 To assess the maximum difference between treatment arms in CD34+ counts 
 To assess the maximum change from baseline in haptoglobin levels in each 
treatment arm 
 To assess the maximum difference between treatment arms in haptoglobin levels 
• Synopsis and Section 14.1.2 Phase 3 Endpoints  
o Exploratory Efficacy Endpopints (Cycles 1-4) updated to align to addition of Phase 3 
Objectives above: 
 Maximum change from baseline in CD34+ counts in each arm. A Wilcoxon signed-
rank test will be used to analyze this endpoint. The UNIVARIATE procedure in SAS 
version 9.4 or later will be used for the analysis. 
 Maximum difference between treatment arms in CD34+ counts. The Wilcoxon Rank 
Sum test will be used to analyze this endpoint. The method will also be used to 
construct point estimates and confidence intervals. The NPAR1WAY procedure in 
SAS version 9.4 or later will be used for the analysis. 
 Maximum change from baseline in haptoglobin level in each arm. A Wilcoxon 
signed-rank test will be used to analyze this endpoint. The UNIVARIATE procedure 
in SAS version 9.4 or later will be used for the analysis. 
 Maximum difference between treatment arms in haptoglobin level. The Wilcoxon 
Rank Sum test will be used to analyze this endpoint. The method will also be used to 
construct point estimates and confidence intervals. The NPAR1WAY procedure in 
SAS version 9.4 or later will be used for the analysis. 
• Table 12 Clinical Laboratory Tests 
• Under Hematology, reticulocyte count added 
• Synopsis (Pharmacokinetics) Updated language as follows: 
o Phase 2 and Phase 3: Pharmacokinetic parameters (e.g., Cmax, time to reach Cmax 
[Tmax], AUC0-t, AUC0-∞, terminal half-life [t1/2], volume of distribution in the 
terminal elimination phase [Vz], and clearance [CL]) will be derived, where 
calculable, from plasma concentration-time data of plinabulin and docetaxel. 
Plinabulin concentration-time data will be pooled with data from other studies in a 
population PK analysis. Details of this analyses will be summarized in the 
Pharmacometrics Analysis Plan and may be reported outside of the main clinical 
study report. 
• Pharmacokinetic Analysis Set Updated as follows: 
o All patients who received at least 1 dose of plinabulin or docetaxel and had at least 1 

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PK sample collected postdose 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. 
• Synopsis: South America and Central America deleted from Number of Sites 
• Section 6.2.2 Rationale Updated as follows: 
o Total ANC is comprised of mature and immature neutrophils. Immature neutrophils 
have reduced functional capacity compared to mature neutrophils to enable optimal 
innate immunity. Compared to mature neutrophils, immature neutrophils exert 
reduced ROS production leading to reduced microbicidal activity, reduced 
phagocytic activity, reduced granularity, reduced ability to create NETs (Mackay G 
et al, Frontiers in Immunology 2019; Mortaz E et al Frontiers in Immunology 2018). 
Therefore an additional analysis will be made with mature neutrophils only. 
• Section 10.5 Dose Interruptions and Modifications updated to reflect Long Term Safety 
Follow up as follows: 
o Patients included after November 2019 will have a long term FU approximately 
every 6 months up to 5 years to monitor long term safety of plinabulin. These visits 
may be conducted per telephone or other means. Updated References added 
• Updated References added 
 
 

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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 North America, , Europe, or Asia Pacific. 
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). Severe (Grade 4) neutropenia is an absolute neutrophil count (ANC) <0.5 × 
109/L. ANC will 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) 
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 Quality of Life (QoL) questionnaire evaluated with EORTC QLQ-C30 and 
EQ-5D-5L 
• 
To collect data on disease progression 
• 
For selected countries only: to investigate the following cytokine panel: IL-1beta, IL-6, IL-12p70, 
IL-12p40, IL-17A, IL-23, G-CSF, GM-CSF, IFN-alpha, IFN-gamma, TNF-alpha, IL-2, FLT-3 
ligand, and IL-8 

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Safety Objectives 
• 
Incidence, occurrence, and severity of adverse events (AEs)/serious adverse events (SAEs)  
• 
Incidences of bone pain  
• 
Safety and tolerability (physical examination and safety laboratory assessments) 
Phase 3 (Double Blind) Objectives 
Primary Efficacy Objective (Cycle 1): 
• 
To assess DSN in treatment Cycle 1 in patients with advanced or metastatic breast cancer, who 
have failed < 5 prior lines of chemotherapy; locally advanced or metastatic non small cell lung 
cancer (NSCLC) after platinum therapy failure; or hormone refractory (androgen independent) 
metastatic prostate cancer (HRPC) treated with docetaxel (75 mg/m2) + plinabulin (40 mg) 
(Arm 2) versus docetaxel (75 mg/m2) + pegfilgrastim (6 mg) (Arm 1). ANC will 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. 
Blood draws for ANC will be taken approximately the same time as the time of the pre-dose 
sample on Day 1, and will be taken by preference in the morning. DSN should be calculated as the 
number of consecutive days from the first day when a patient's ANC is below 0.5 x l09/L until the 
patient reaches an ANC> 0.5 x 109/L, in Cycle 1. For patients who do not experience any severe 
neutropenia in Cycle 1, the DSN is set to 0. For patient’s experiencing several episodes, the 
number of days of DSN will be summed up.  
Secondary Efficacy Objectives (Cycle 1 and Cycles 1 to 4): 
• 
 To assess DSN in Cycle 1 with only mature neutrophils.  
• 
Platelet count in Cycle 1: maximum decrease from baseline (prior to Cycle 1 docetaxel dose) 
• 
Proportion of patients with neutrophil-to-lymphocyte ratio (NLR) > 5 after Day 7 through Day 15 
in Cycle 1 
• 
Area under the concentration-time curve (AUC) using the trapezoidal quadrature method for bone 
pain, from Day 1 through Day 8 (pegfilgrastim will be administered on Day 2) in Cycle 1, based 
on the pain score from the patient bone pain scale 
• 
Change in estimated mean bone pain score from pre-dose Day 1 through Day 8 in Cycle 1 
• 
Proportion of patients with thrombocytopenia (all grade) in Cycles 1 to 4 
• 
To assess the incidence of infections in Cycles 1 to 4 
Exploratory Efficacy Objectives (Cycle 1): 
• 
To evaluate the proportion of patients in Cycle 1 with: 
o 
Thrombocytopenia (all grade) 
o 
Grade 4 neutropenia (ANC < 0.5 × 109/L) 
o 
Grade 4 neutropenia (ANC<0.5 x109/L) for mature neutrophils  
o 
Grade 3 neutropenia (ANC < 1 × 109/L) 
o 
Grade 3 (ANC < 1 × 109/L) and Grade 4 neutropenia (ANC < 0.5 × 109/L) 
o 
Bands > 0 after Day 7 through Day 15 
o 
Promyelocytes plus myelocytes > 0 after Day 7 through Day 15 
o 
Promyelocytes, myelocytes, metamyelocytes and bands >0 after Day 7 through Day 
15Lymphocyte-to-monocyte ratio (LMR) < 3.2 after Day 7 through Day 15 
o 
Platelet-to-lymphocyte ratio (PLR) > 200 after Day 7 through Day 15 
o 
At least 1 day of bone pain 
o 
At least 2 days of bone pain 
o 
At least 3 days of bone pain 
o 
At least 4 days of bone pain 
o 
At least 5 days of bone pain 

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o 
At least 6 days of bone pain 
o 
At least 7 days of bone pain 
o 
At least 8 days of bone pain 
• 
To compare the proportion of patients who needed bone pain medication (defined as any 
medication reported on pain medication assessment from Day 1 through Day 8) in Cycle 1  
• 
To compare the time (in days) to first use of bone pain medication between the treatment groups  
• 
To assess DSN in Cycle 1 in patients with locally advanced or metastatic NSCLC after platinum 
therapy failure 
• 
To assess DSN in Cycle 1 in patients with locally advanced or metastatic NSCLC after platinum 
therapy failure for mature neutrophils only 
• 
To assess DSN in Cycle 1 in patients with HRPC 
• 
To assess DSN in Cycle 1 in patients with locally advanced or metastatic NSCLC after platinum 
therapy failure for mature neutrophils only 
• 
To assess DSN in Cycle 1 in patients with advanced or metastatic breast cancer who have failed 
< 5 prior lines of chemotherapy 
• 
To assess DSN in Cycle 1 in patients with advanced or metastatic breast cancer who have failed 
< 5 prior lines of chemotherapy for mature neutrophils only 
• 
To assess DSN in Cycle 1 in patients with locally advanced or metastatic NSCLC after platinum 
therapy failure or HRPC 
• 
To assess DSN in Cycle 1 in patients with locally advanced or metastatic NSCLC after platinum 
therapy failure or HRPC for mature neutrophils only 
• 
Platelet count at least 30% change from baseline at any time during Cycle 1 
• 
ANC nadir during Cycle 1 
• 
To assess CD34+ at Day 1 pre-dose, Day 2 pre-dose, Day 6, 7, 8, 9, 10, and 15, Day 1 Cycle 2 
pre-dose 
• 
For selected countries only: to investigate the following cytokine panel: IL-1beta, IL-6, IL-12p70, 
IL-12p40, IL-17A, IL-23, G-CSF, GM-CSF, IFN-alpha, IFN-gamma, TNF-alpha, IL-2, FLT-3 
ligand, and IL-8. 
Exploratory Efficacy Objectives (Cycles 1 to 4): 
• 
To evaluate the proportion of patients in Cycles 1 to 4 with: 
• 
Febrile neutropenia (FN) (ANC <1.0 × 109/L AND a single temperature of >38.3°C or a sustained 
temperature of ≥38°C for more than 1 hour). 
• 
Grade 4 neutropenia (ANC < 0.5 × 109/L). 
• 
To assess the maximum change from baseline in CD34 + counts in each treatment arm 
• 
To assess the maximum difference between treatment arms in CD34+ counts 
• 
To assess the maximum change from baseline in haptoglobin levels in each treatment arm 
• 
To assess the maximum difference between treatment arms in haptoglobin levels 
• 
To evaluate the following healthcare utilization objectives: 
o 
Incidence of 30-day rehospitalizations - all cause 
o 
Incidence of all cause hospitalizations 
o 
Duration of all cause hospitalizations 
o 
Incidence of all cause emergency room (ER) visits 
o 
Incidence of all cause intensive care unit (ICU) stays 
o 
Duration of all cause ICU stays 

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o 
Incidence of all cause docetaxel dose delay (≥7 days), dose reduction (≤85%), or dose 
discontinuation 
o 
Incidence of platelet transfusions 
o 
Incidence of antibiotics use 
• 
To collect data on disease progression 
• 
To evaluate the following QoL objective: 
o 
Health-related QoL questionnaire evaluated with European Organization for Research and 
Treatment of Cancer (EORTC) QLQ-C30 and EQ-5D-5L 
Safety Objectives: 
• 
Incidence, occurrence, and severity of adverse events (AEs)/serious adverse events (SAEs)  
• 
Safety and tolerability (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; locally advanced or metastatic NSCLC after platinum therapy 
failure; or HRPC.  
The eligibility of all patients will be determined during a 28-day screening period.   
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 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.  
A fixed dose of 40 mg has been selected as the RP3D following the Phase 2 PK/PD analysis (details of dose 
selection are provided in Section 6.2.3). 
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; locally advanced or 
metastatic NSCLC after platinum therapy failure; or HRPC. Each eligible patient will be stratified according to 
his or her tumor type (breast cancer, NSCLC or HRPC) and region (Asia, non-Asia). 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 

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Arm 2: Docetaxel (75 mg/m2) + plinabulin (40 mg) + placebo matching pegfilgrastim 
In order to facilitate balanced treatment arms with respect to cancer type, once either arm reaches at least 1/3 (of 
total) of patients with that cancer type, it will be closed to that cancer type and enrollment will continue for 
patients with the other cancer types, up to the planned maximum number of patients.  
Data from all patients receiving the RP3D plinabulin dose in Phase 2 and Phase 3 will not be pooled for assessing 
the primary and secondary study endpoints, but analyzed separately. 
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 one 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 
(± 2 days) after the last dose of study drug.  Patients who withdraw for progressive disease and who will continue 
to another chemotherapy regimen will complete the End of Treatment (EOT) visit at Cycle X Day 21. They then 
continue to another chemotherapy regimen and do not need to have the safety follow-up visit (where X is the last 
cycle prior to progression, and is 4 or less). If, in the opinion of the investigator, the patient will benefit from 
more than 4 cycles of docetaxel and open label pegfilgrastim, then the fifth cycle will not start until completion of 
the EOT visit (in this instance, the EOT visit will be Cycle 4 Day 21). Follow-up visits will be required to 
monitor for ongoing treatment-related AEs.  All patients experiencing drug-related toxicities of ≥ Grade 2 at the 
EOT 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. 
Patients without progressive disease at the EOT visit will undergo a follow-up visit every 2 months until the 
occurrence of either disease progression or death. These visits may be conducted per telephone or other means.  
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. 

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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. 
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 or 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) 
• 
Locally advanced or metastatic NSCLC after platinum therapy failure  
• 
HRPC (Note that study treatment may be the first chemotherapy treatment).  
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 A): 
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 assessed within 14 days prior to study drug administration:1 
• 
Hemoglobin ≥ 9 g/dL independent of transfusion or growth factor support 
• 
ANC ≥ 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.1  
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 
 
1 Results are from the central laboratory. Local laboratory results may be accepted on a case by case basis after 
discussion with the Medical Monitor; however in this case central laboratories must also be taken within the 
screening time window. 

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any evidence of menses in the past 12 months. However, women who have been amenorrhoeic for 12 or 
more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior 
chemotherapy, anti-estrogens, or ovarian suppression. 
• 
Women of childbearing potential (i.e., menstruating women) must have a negative urine 
pregnancy test (positive urine tests are to be confirmed by serum test) documented within the 24-
hour period prior to the first dose of study drug.  
• 
Sexually active women of childbearing potential enrolled in the study must agree to use two 
forms of accepted methods of contraception during the course of the study and for 3 months after 
their last dose of study drug. Effective birth control includes (a) intrauterine device (IUD) plus 
one barrier method; (b) on stable doses of hormonal contraception for at least 3 months (e.g., 
oral, injectable, implant, transdermal) plus one barrier method; (c) 2 barrier methods. Effective 
barrier methods are male or female condoms, diaphragms, and spermicides (creams or gels that 
contain a chemical to kill sperm); or (d) a vasectomized partner. 
• 
For male patients who are sexually active and who are partners of premenopausal women: 
agreement to use two forms of contraception during the treatment period and for at least 3 
months after the last dose of study drug. 
Exclusion Criteria 
1. History of myelogenous leukemia, myelodysplastic syndrome or concomitant sickle cell disease. 
2. Received chemotherapy within 4 weeks prior to the first dose of study drug. 
3. Received prior docetaxel, 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. 

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14. History of hemorrhagic diarrhea, inflammatory bowel disease, or active uncontrolled peptic ulcer disease.  
(Concomitant therapy with ranitidine or its equivalent and/or omeprazole or its equivalent is acceptable).  
History of ileus or other significant gastrointestinal disorder known to predispose to ileus or chronic bowel 
hypomotility. 
15. Any other malignancy requiring active therapy.  
16. Known human immunodeficiency virus (HIV) seropositivity. 
17. Active Hepatitis B virus (HBV) infection which requires antiviral treatment. Patients with detectable 
Hepatitis B surface Antigen (HBsAg) may be eligible provided the patient has a negative viral load. Patients 
with a positive HBsAg must have a negative viral load before each chemotherapy administration. Hepatitis 
B surface antibody (anti HBs) without detectable HBsAg does NOT exclude patients from the study. 
Hepatitis C infection (Hepatitis C antibody reactive) which requires treatment also excludes patients from 
the study. 
18. Female subject who is pregnant or lactating. 
19. Unwilling or unable to comply with procedures required in this protocol 
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)  
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; locally advanced or metastatic NSCLC after platinum therapy failure; or 
HRPC): 
Arm 1: Docetaxel (75 mg/m2) + pegfilgrastim (6 mg) + placebo matching plinabulin 
Arm 2: Docetaxel (75 mg/m2) + plinabulin (40 mg) + placebo matching pegfilgrastim 
All patients must 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 must 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 (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 (± 2 days) after the last dose of 
study drug (see Table 6 and Table 7 Study Assessments and Procedures Schedule). If, in the opinion of the 
investigator, the patient will benefit from more than 4 cycles of docetaxel and open label pegfilgrastim, then the 
fifth cycle will not start until completion of the EOT visit (in this instance, the EOT visit will be Cycle 4 Day 21). 
Patients with progressive disease requiring another treatment will also complete the EOT visit at Cycle X Day 21 

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and can then continue on another chemotherapy regimen (where X is the last treatment cycle prior to progression, 
and is 4 or less). 
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 must 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 
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). 
Corticosteroids (except as described for premedication) and new non-steroidal anti-inflammatory drugs 
(NSAIDs) are prohibited except for the treatment of AEs and as premedication. Patients already receiving 
NSAIDs are allowed to continue taking treatment as long as the dose remains stable. 
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. Tropisetron is an acceptable substitute 5HT3 receptor agonist (Yavas et al, 2008).  
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 antipsychotic 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. Aprepitant is an 
acceptable prophylactic anti-emetic in this situation [Marbury et al, 2009]). 
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. 

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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 ANC < 1.0 × 109/L AND a single temperature of 
>38.3°C or a sustained temperature of ≥38°C for more than 1 hour (as per CTCAE v4.03).   
Pharmacokinetics 
Phase 2 and Phase 3: Pharmacokinetic parameters (e.g., Cmax, time to reach Cmax [Tmax], AUC0-t, AUC0-∞, 
terminal half-life [t1/2], volume of distribution in the terminal elimination phase [Vz], and clearance [CL]) will 
be derived, where calculable, from plasma concentration-time data of plinabulin and docetaxel. Plinabulin 
concentration-time data will be pooled with data from other studies in a population PK analysis. Details of this 
analyses will be summarized in the Pharmacometrics Analysis Plan and may be reported outside of the main 
clinical study report. 
Patients in Phase 3 will follow the plinabulin and docetaxel PK sampling schedules from Phase 2. 
Pharmacodynamics 
Patients in phase 2 will participate in the PD assessments.  The PD assessments include blood pressure, DSN, and 
area over the neutropenia curve (AOC) in cycle 1 of the phase 2 portion of the study.  
Exploratory Markers 
Phase 2 only: 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. 
Phase 2 and Phase 3: Plasma cytokine panel: IL-1beta, IL-6, IL-12p70, IL-12p40, IL-17A, IL-23, GCSF, 
GMCSF, IFN alpha, IFN-gamma, TNF-alpha, IL-2, FLT-3 ligand, and IL-8 analysis. This test will be performed 
in selected countries participating in the study, using unused plasma samples collected at PK time points.  
Statistical Methods 
Note: Patients in Phase 3 will be stratified based on his or her tumor type (breast cancer, NSCLC, HRPC) and 
region (Asia, non-Asia).  
Study Endpoints and Analyses 
Phase 2 (Open Label) 
Plinabulin pharmacokinetic (PK) and pharmacodynamic (PD) assessments will be made to enable a PK/PD 
analysis.  
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). ANC will 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). The Negative Binomial Regression 
(NBR) model, on the integer number of days of severe neutropenia, will be used to analyze the DSN 
endpoint during the fixed time window outlined above, with the treatment arm as the only covariate. 
The method will also be used to construct point estimates and confidence intervals. The GENMOD 
procedure in SAS version 9.4 or later will be used. Contrasts for pairwise comparisons between 

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Arm 1 and the plinabulin arms will be used for the evaluation. A closed testing procedure by 
Hommel (Hommel 1988, Hommel and Bernhard 1999) will be used for the multiple comparisons. 
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).  See the 
Pharmacometrics Analysis Plan for the analysis methods. 
Secondary Endpoints: 
 To characterize the pharmacokinetic profile of plinabulin and docetaxel.  See the Pharmacometrics 
Analysis Plan for the analysis methods. 
 To characterize the exposure-response relationships between measures of plinabulin exposure and 
the pharmacodynamic endpoint DSN. Robust linear regression (Bablok et al, 1988) with DSN as the 
dependent variable and plinabulin exposure as the independent variable. The method will also be 
used to construct point estimates and confidence intervals. The NCSS version 12 statistical software 
will be used. 
 To characterize the exposure-safety relationships between measures of plinabulin exposure and 
safety events of interest. Robust linear regression (Bablok et al, 1988) with the number of safety 
events as the dependent variable and plinabulin exposure as the independent variable. The method 
will also be used to construct point estimates and confidence intervals. The NCSS version 12 
statistical software will be used. 
Exploratory Endpoints 
 To assess CD34+ at screening, and on Days 2, 6 and 8 in Cycle 1 and Day 1 in Cycle 2. A repeated 
measures mixed linear model with the Day 1 value and treatment arm as covariates will be used to 
analyze this endpoint. 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. Contrasts 
for pairwise comparisons between Arm 1 and the plinabulin arms will be used for the evaluation. A 
closed testing procedure by Hommel (Hommel 1988, Hommel and Bernhard 1999) will be used for 
the multiple comparisons. 
 Health-related QoL questionnaire evaluated with EORTC QLQ-C30 and EQ-5D-5L. The Wilcoxon 
Rank Sum test will be used to analyze the responses to the individual questions. The method will 
also be used to construct point estimates and confidence intervals. The NPAR1WAY procedure in 
SAS version 9.4 or later will be used for the analysis. Contrasts for pairwise comparisons between 
Arm 1 and the plinabulin arms will be used for the evaluation. A closed testing procedure by 
Hommel (Hommel 1988, Hommel and Bernhard 1999) will be used for the multiple comparisons. 
 Data collection on disease progression. The log-rank test (LIFETEST procedure in SAS) will be 
used to compare time to disease progression between the treatment groups. The method will also be 
used to construct point estimates and confidence intervals. Contrasts for pairwise comparisons 
between Arm 1 and the plinabulin arms will be used for the evaluation. A closed testing procedure 
by Hommel (Hommel 1988, Hommel and Bernhard 1999) will be used for the multiple 
comparisons. 
 CD34+ at pre-dose on Day 1, pre-dose on Day 2, Days 6, 7, 8, 9, 10, and 15 in Cycle 1, and pre-
dose on Day 1 in Cycle 2. A repeated measure mixed linear model with the pre-dose on day 1 cycle 
1 value and treatment arm as covariates will be used to analyze this endpoint. 
 For selected countries only: to investigate the following cytokine panel: IL-1beta, IL-6, IL-12p70, 
IL-12p40, IL-17A, IL-23, G-CSF, GM-CSF, IFN-alpha, IFN-gamma, TNF-alpha, IL-2, FLT-3 
ligand, and IL-8.  
Safety Endpoints 
 Incidence, occurrence, and severity of AEs/SAEs. These endpoints will be presented descriptively 
in tables and listings. 

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 Incidences of bone pain. The NBR model will be used to analyze the endpoint during the fixed time 
window from pre-dose Day 1 through Day 8 in Cycle 1, with the treatment arm as the only 
covariate. The method will also be used to construct point estimates and confidence intervals. The 
GENMOD procedure in SAS version 9.4 or later will be used. Contrasts for pairwise comparisons 
between Arm 1 and the plinabulin arms will be used for the evaluation. A closed testing procedure 
by Hommel (Hommel 1988, Hommel and Bernhard 1999) will be used for the multiple 
comparisons. 
 Safety and tolerability (physical examination and safety laboratory assessments). These endpoints 
will be presented descriptively in tables and listings. 
 
Phase 3 (Double Blind) 
Primary Efficacy Endpoint (Cycle 1): 
 DSN in Cycle 1 in patients treated with docetaxel (75 mg/m2) + plinabulin (40 mg) (Arm 2) 
compared with patients treated with docetaxel (75 mg/m2) + pegfilgrastim (6 mg) (Arm 1). ANC 
will 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.  Blood draws for ANC will be taken approximately the same time as the time of the 
pre-dose sample on Day 1, and will be taken by preference in the morning. The NBR model, on the 
integer number of days of severe neutropenia, will be used to analyze the DSN endpoint during the 
fixed time window outlined above, with the treatment arm as the only covariate. The method will 
also be used to construct point estimates and confidence intervals. The GENMOD procedure in SAS 
version 9.4 or later will be used.  
Secondary Efficacy Endpoints (Cycle 1 and Cycles 1 to 4): 
 DSN in Cycle 1 with only mature neutrophils.The NBR model, on the integer number of days of 
severe neutropenia, will be used to analyze the DSN endpoint during the fixed time window 
outlined above, with the treatment arm as the only covariate. The method will also be used to 
construct point estimates and confidence intervals. The GENMOD procedure in SAS version 9.4 or 
later will be used.  
 Maximum decrease from baseline (prior to docetaxel dose) in platelet count for each patient in 
Cycle 1. The Wilcoxon Rank Sum test will be used. The method will also be used to construct point 
estimates and confidence intervals. The NPAR1WAY procedure in SAS version 9.4 or later will be 
used for the analysis. 
 Proportion of patients with NLR > 5 after Day 7 through Day 15 in Cycle 1. The Barnard’s test 
will be used to evaluate the difference in proportions between the treatment arms. The method 
will also be used to construct point estimates and 2-sided confidence intervals. The FREQ 
procedure in SAS version 9.4 or later will be used for the analysis. 
 AUC using the trapezoidal quadrature method for bone pain, from Day 1 through Day 8 in Cycle 1, 
based on the bone pain score from the patient bone pain scale. The Wilcoxon Rank Sum test will be 
used. The method will also be used to construct point estimates and confidence intervals. The 
NPAR1WAY procedure in SAS version 9.4 or later will be used for the analysis. 
 Estimated mean pain score from the patient bone pain scale from pre-dose Day 1 through Day 8 in 
Cycle 1. A repeated measures mixed linear model with the pre-dose Day 1 value and treatment arm 
as covariates will be used to analyze this endpoint. 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. 
 Proportion of patients with thrombocytopenia (all grade) in Cycles 1 to 4. The Barnard’s test will 
be used to evaluate the difference in proportions between the treatment arms. The method will 
also be used to construct point estimates and 2-sided confidence intervals. The FREQ procedure 
in SAS version 9.4 or later will be used for the analysis. 
 Incidence of infections in Cycles 1 to 4. The NBR model will be used to analyze the endpoint, 
with the treatment arm as the only covariate. An offset variable will be used to account for 
exposure time. The method will also be used to construct point estimates and confidence 
intervals. The GENMOD procedure in SAS version 9.4 or later will be used. 

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Exploratory Efficacy Endpoints (Cycle 1): 
 Proportion of patients in Cycle 1 with: 
o 
Thrombocytopenia (all grade). The Barnard’s test will be used to evaluate the difference in 
proportions between the treatment arms. The method will also be used to construct point 
estimates and 2-sided confidence intervals. The FREQ procedure in SAS version 9.4 or later 
will be used for the analysis. 
o 
Grade 3 (ANC < 1 × 109/L) and ANC >= 0.5 × 109/L) and Grade 4 neutropenia (ANC < 
0.5 × 109/L). The Barnard’s test will be used to evaluate the difference in proportions between 
the treatment arms. The method will also be used to construct point estimates and 2-sided 
confidence intervals. The FREQ procedure in SAS version 9.4 or later will be used for the 
analysis. 
o 
Grade 4 neutropenia (ANC < 0.5 × 109/L). The Barnard’s test will be used to evaluate the 
difference in proportions between the treatment arms. The method will also be used to construct 
point estimates and 2-sided confidence intervals. The FREQ procedure in SAS version 9.4 or 
later will be used for the analysis. 
o 
Grade 4 neutropenia (ANC<0.5 x109/L) for mature neutrophils only. The method will also be 
used to construct point estimates and 2-sided confidence intervals. The FREQ procedure in SAS 
version 9.4 or later will be used for the analysis. 
o 
Grade 3 neutropenia (ANC < 1 × 109/L) and ANC >= 0.5 × 109/L). The Barnard’s test will be 
used to evaluate the difference in proportions between the treatment arms. The method will 
also be used to construct point estimates and 2-sided confidence intervals. The FREQ 
procedure in SAS version 9.4 or later will be used for the analysis. 
o 
Bands > 0 after Day 7 through Day 15. The Barnard’s test will be used to evaluate the 
difference in proportions between the treatment arms. The method will also be used to 
construct point estimates and 2-sided confidence intervals. The FREQ procedure in SAS 
version 9.4 or later will be used for the analysis. 
o 
Promyelocytes plus myelocytes >0 after Day 7 through Day 15. The Barnard’s test will be used 
to evaluate the difference in proportions between the treatment arms. The method will also be 
used to construct point estimates and 2-sided confidence intervals. The FREQ procedure in 
SAS version 9.4 or later will be used for the analysis. 
o 
Promyelocytes, myelocytes, metamyelocytes and bands >0  after Day 7 through Day 15. The 
method will also be used to construct point estimates and 2-sided confidence intervals. The 
FREQ procedure in SAS version 9.4 or later will be used for the analysis. 
o 
LMR < 3.2 after Day 7 through Day 15; time course of percentage of patients with LMR < 3.2 
over time in Cycle 1. The Barnard’s test will be used to evaluate the difference in proportions 
between the treatment arms. The method will also be used to construct point estimates and 2-
sided confidence intervals. The FREQ procedure in SAS version 9.4 or later will be used for 
the analysis. 
o 
PLR > 200 after Day 7 through Day 15; time course of percentage of patients with PLR > 200 
over time in Cycle 1. The Barnard’s test will be used to evaluate the difference in proportions 
between the treatment arms. The method will also be used to construct point estimates and 2-
sided confidence intervals. The FREQ procedure in SAS version 9.4 or later will be used for the 
analysis. 
o 
For the below bone pain measurements The Barnard’s test will be used to evaluate the difference 
in proportions between the treatment arms. The method will also be used to construct point 
estimates and 2-sided confidence intervals. The FREQ procedure in SAS version 9.4 or later will 
be used for the analysis. 
o 
At least 1 day of bone pain 
o 
At least 2 days of bone pain 
o 
At least 3 days of bone pain 
o 
At least 4 days of bone pain 

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o 
At least 5 days of bone pain 
o 
At least 6 days of bone pain 
o 
At least 7 days of bone pain 
o 
At least 8 days of bone pain 
 Proportion of patients in Cycle 1 who needed bone pain medication (defined as any medication 
reported on the pain medication assessment from Day 1 through Day 8). The Barnard’s test will be 
used to evaluate the difference in proportions between the treatment arms. The method will also be 
used to construct point estimates and 2-sided confidence intervals. The FREQ procedure in SAS 
version 9.4 or later will be used for the analysis. 
 Time (in days) to first use of bone pain medication. The log-rank test (LIFETEST procedure in SAS) 
will be used to compare time to first use of bone pain medication between the treatment groups. 
Separate analyses will be made with respect to narcotic and non-narcotic analgesics. 
 DSN in Cycle 1 in patients with locally advanced or metastatic NSCLC after platinum failure. The 
analysis will be done as per the primary endpoint.  
 DSN in Cycle 1 with only mature neutrophils in patients with locally advanced or metastatic NSCLC 
after platinum failure. The analysis will be done as per the primary endpoint.  
 DSN in Cycle 1 in patients with HRPC. The analysis will be done as per the primary endpoint.  
 DSN in Cycle 1 with only mature neutrophils in patients with with HRPC. The analysis will be done as 
per the primary endpoint.  
 DSN in Cycle 1 in patients with advanced or metastatic breast cancer who have failed < 5 prior lines of 
chemotherapy. The analysis will be done as per the primary endpoint.  
 DSN in Cycle 1 with only mature neutrophils in patients with advanced or metastatic breast cancer 
who have failed <5 prior lines of chemotherapy. The analysis will be done as per the primary endpoint.  
 DSN in Cycle 1 in patients with locally advanced or metastatic NSCLC after platinum failure or 
HRPC. The analysis will be done as per the primary endpoint. 
 DSN in Cycle 1 with only mature neutrophils in patients with locally advanced or metastatic NSCLC 
after platinum failure or HRPC. The analysis will be done as per the primary endpoint.  
 Platelet count at least 30% change from baseline at any time during Cycle 1. The Barnard’s test will 
be used to evaluate the difference in proportions between the treatment arms. The method will also 
be used to construct point estimates and 2-sided confidence intervals. The FREQ procedure in SAS 
version 9.4 or later will be used for the analysis. 
 ANC nadir during Cycle 1. The Wilcoxon Rank Sum test will be used to analyze the endpoint. The 
method will also be used to construct point estimates and confidence intervals. The NPAR1WAY 
procedure in SAS version 9.4 or later will be used for the analysis. 
 For selected countries only: maximum change from baseline in the following cytokine panel: IL-1beta, 
IL-6, IL-12p70, IL-12p40, IL-17A, IL-23, G-CSF, GM-CSF, IFN-alpha, IFN-gamma, TNF-alpha, IL-
2, FLT-3 ligand, and IL-8. The Wilcoxon Rank Sum test will be used to analyze the endpoint. The 
method will also be used to construct point estimates and confidence intervals. The NPAR1WAY 
procedure in SAS version 9.4 or later will be used for the analysis. 
Exploratory Efficacy Endpoints (Cycles 1 to 4): 
 Proportion of patients in Cycles 1 to 4 with: 
o 
FN (ANC <1.0 × 109/L AND a single temperature of >38.3°C or a sustained temperature of 
≥38°C for more than 1 hour). The Barnard’s test will be used to evaluate the difference in 
proportions between the treatment arms. The method will also be used to construct point estimates 
and 2-sided confidence intervals. The FREQ procedure in SAS version 9.4 or later will be used 
for the analysis. 
o 
Grade 4 neutropenia (ANC < 0.5 × 109/L). The Barnard’s test will be used to evaluate the 
difference in proportions between the treatment arms. The method will also be used to construct 
point estimates and 2-sided confidence intervals. The FREQ procedure in SAS version 9.4 or later 
will be used for the analysis. 

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 Maximum change from baseline in CD34+ counts in each arm. A Wilcoxon signed-rank test will be 
used to analyze this endpoint. The UNIVARIATE procedure in SAS version 9.4 or later will be 
used for the analysis. 
 Maximum difference between treatment arms in CD34+ counts. The Wilcoxon Rank Sum test will 
be used to analyze this endpoint. The method will also be used to construct point estimates and 
confidence intervals. The NPAR1WAY procedure in SAS version 9.4 or later will be used for the 
analysis. 
 Maximum change from baseline in haptoglobin level in each arm. A Wilcoxon signed-rank test will 
be used to analyze this endpoint. The UNIVARIATE procedure in SAS version 9.4 or later will be 
used for the analysis. 
 Maximum difference between treatment arms in haptoglobin level. The Wilcoxon Rank Sum test 
will be used to analyze this endpoint. The method will also be used to construct point estimates and 
confidence intervals. The NPAR1WAY procedure in SAS version 9.4 or later will be used for the 
analysis. 
 Healthcare utilization endpoints: 
o 
Incidence of 30-day rehospitalizations - all cause. The NBR model will be used to analyze 
the endpoint, with the treatment arm as the only covariate. An offset variable will be used 
to account for exposure time. The method will also be used to construct point estimates and 
confidence intervals. The GENMOD procedure in SAS version 9.4 or later will be used. 
o 
Incidence of all cause hospitalizations. The NBR model will be used to analyze the 
endpoint, with the treatment arm as the only covariate. An offset variable will be used to 
account for exposure time. The method will also be used to construct point estimates and 
confidence intervals. The GENMOD procedure in SAS version 9.4 or later will be used. 
o 
Duration of all cause hospitalizations. The Wilcoxon Rank Sum test will be used. The 
method will also be used to construct point estimates and confidence intervals. The 
NPAR1WAY procedure in SAS version 9.4 or later will be used for the analysis. 
o 
Incidence of all cause ER visits. The NBR model will be used to analyze the endpoint, with 
the treatment arm as the only covariate. An offset variable will be used to account for 
exposure time. The method will also be used to construct point estimates and confidence 
intervals. The GENMOD procedure in SAS version 9.4 or later will be used. 
o 
Incidence of all cause ICU stays. The NBR model will be used to analyze the endpoint, 
with the treatment arm as the only covariate. An offset variable will be used to account for 
exposure time. The method will also be used to construct point estimates and confidence 
intervals. The GENMOD procedure in SAS version 9.4 or later will be used. 
o 
Duration of all cause ICU stays. The Wilcoxon Rank Sum test will be used. The method 
will also be used to construct point estimates and confidence intervals. The NPAR1WAY 
procedure in SAS version 9.4 or later will be used for the analysis. 
o 
Incidence of all cause docetaxel dose delay, dose reduction, or dose discontinuation. The 
NBR model will be used to analyze the endpoints, with the treatment arm as the only 
covariate. An offset variable will be used to account for exposure time. The method will 
also be used to construct point estimates and confidence intervals. The GENMOD 
procedure in SAS version 9.4 or later will be used: 
o 
Docetaxel dose delays > 7 days 
o 
Regimen switching 
o 
Treatment discontinuation 
o 
Proportion of Relative dose intensity (RDI) ≤ 85% where the RDI is defined as 
RDI = 
Cumulative dose of administered docetaxel (mg/m2)/ Number of weeks 
from Day1 Cycle 1 to Day 1 Cycle 4 plus 3 weeks 

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Total calculated doses/12 weeks 
The Barnard’s test will be used to evaluate the difference in proportions between 
the treatment arms. The method will also be used to construct point estimates and 
confidence intervals. The FREQ procedure in SAS version 9.4 or later will be used 
for the analysis 
o 
Incidence of transfusions due to thrombocytopenia. The NBR model will be used to 
analyze the endpoint, with the treatment arm as the only covariate. An offset variable will 
be used to account for exposure time. The method will also be used to construct point 
estimates and confidence intervals. The GENMOD procedure in SAS version 9.4 or later 
will be used. 
o 
Incidence of antibiotics use. The NBR model will be used to analyze the endpoint, with the 
treatment arm as the only covariate. An offset variable will be used to account for exposure 
time. The method will also be used to construct point estimates and confidence intervals. 
The GENMOD procedure in SAS version 9.4 or later will be used. 
 Data collection on disease progression. The log-rank test (LIFETEST procedure in SAS version 9.4 
or later) will be used to compare time to disease progression between the treatment groups. The 
method will also be used to construct point estimates and confidence intervals. 
  QoL endpoints will be analyzed in safety analysis set: 
o 
Health-related QoL questionnaire evaluated with EORTC QLQ-C30 Item 30 (response 
to question “How do you rate your overall quality of life during the past week”) in Cycle 
1 to 4 will be analyzed using linear mixed model for repeated measures (MMRM) with 
the Cycle 1 Day 1 value and treatment arm as covariates. The method will also be used 
to construct point estimates and confidence intervals. The MIXED procedure in SAS 
v9.4 or later will be used for the analysis. The summary statistics in terms of counts, 
means, standard deviations, medians, minimums, and maximums for individual 
questions will be summarized in a tabular format. 
o 
Health-related QoL questionnaire evaluated with EORTC QLQ-C30 will also be 
analyzed with the summary scores. The EORTC QLQ-C30 scoring method combines the 
30 questions from the questionnaire into 15 scores: global health state/QoL, functional 
scale (5 items), and symptoms scale (9 items) (Fayers et al, 2001). Three summary 
measures will be constructed: the QLQ-C30 Summary Score, which combined the 
symptom and functional scales (excluding the financial difficulties item), the symptom 
summary score (excluding the financial difficulties item), and the functional summary 
score (Hinz et al, 2012). The symptom summary score will be analyzed using linear 
mixed model for repeated measures (MMRM) with the Cycle 1 Day 1 value and 
treatment arm as covariates. The method will also be used to construct point estimates 
and confidence intervals. The MIXED procedure in SAS v9.4 or later will be used for the 
analysis. The summary statistics in terms of counts, means, standard deviations, medians, 
minimums, and maximums for the 15 scores, the QLQ-C30 summary score, symptom 
score and the functional summary score will be summarized in a tabular format. 
o 
The response to the question “Your Health Today” from EQ-5D-5L in Cycle 1 to 4 will 
be analyzed using linear mixed for model repeated measures (MMRM) with the Cycle 1 
Day 1 value and treatment arm as covariates. The method will also be used to construct 
point estimates and confidence intervals. The MIXED procedure in SAS v9.4 or later 
will be used for the analysis. The summary statistics in terms of counts, means, standard 
deviations, medians, minimums, and maximums for the question “Your Health Today” 
will be summarized in a tabular format. 
o 
The EQ-5D-5L data will be converted into a health utility score using the interim EQ-
5D-5L crosswalk value set for the United States (van Hout et al, 2012) unless a validated 
EQ-5D-5L value set for the United States becomes available. The EQ-5D-5L health 
utility score in Cycle 1 to 4 will be analyzed using linear mixed model for repeated 

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measures (MMRM) with the Cycle 1 Day 1 value and treatment arm as covariates. The 
method will also be used to construct point estimates and confidence intervals. The 
MIXED procedure in SAS v9.4 or later will be used for the analysis. The summary 
statistics in terms of counts, means, standard deviations, medians, minimums, and 
maximums for the health utility score will be summarized in a tabular format. 
Safety Endpoints 
 Incidence, occurrence, and severity of AEs/SAEs. These endpoints will be presented descriptively 
in tables and listings. 
 Safety and tolerability (physical examination and safety laboratory assessments). These endpoints 
will be presented descriptively in tables and listings. 
Primary efficacy endpoint will be imputed by multiple imputation method as sensitivity analysis. 
 
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.  
 
Pharmacokinetic Analysis Set 
All patients who received at least 1 dose of plinabulin or docetaxel and had at least 1 PK sample collected 
postdose 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. 
 
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. 
 
Analysis Sets Phase 3  
Intent-to-Treat Analysis Sets 
The intent-to-treat (ITT) analysis set for Phase 3 is comprised of all Phase 3 patients that have been randomized 
in the study. 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 is comprised of all Phase 3 patients that have been randomized in the study and have 
received at least one dose of study medication.  
Efficacy Analyses Considerations 
Primary efficacy analysis considerations 
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 ANC 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 

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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, ANCs 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 
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.  
Pharmacokinetic and Pharmacodynamic Analyses Considerations  
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. 
Exposure-Neutropenia Relationship 
A sequential population PK/PD modeling approach will be used to characterize the exposure neutropenia 
relationship.  The semi-physiological model described by Friberg (2003) will be used to characterize the time 
course of neutropenia in the exposure-neutropenia model.   
The developed exposure-response models will be used to simulate ANC profiles for the computation of key PD 
endpoints such as DSN, DMSN, and area over the ANC curve (AOC). The latter will be calculated as the area 
below the threshold of <0.5 x 109 cells/L and above ANC-time response curve in a chemotherapy cycle.   

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Exposure-Blood Pressure Analysis 
A sequential PK-PD model analysis will be performed.  Since the ambulatory blood pressure measurements 
(ABPM) are subject to circadian variations, ABPM will be modeled to describe the circadian rhythm in blood 
pressure over the 4.5-hour observation period.  The diurnal rhythm in the AMBP data will be described with the 
cosine function (Hempel 1998) in the exposure ABPM models.   
Exposure-QTc Analysis 
Either a direct or sequential PK-PD model analysis will be performed.  The choice of the modeling approach will 
be informed by the matching or non-matching of PK sampling times with ECG observation times. QT 
measurements corrected with the Fridericia formula will be used in the exposure-QTc analysis.  
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 (40 mg) 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 by an independent statistician and will be reviewed by the Data Safety 
Monitoring Board at the interim analysis.  
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 (40 mg) 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 (40 mg) 
50 
75 
 
Interim Analysis 
Final Analysis 

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2. 
TABLE OF CONTENTS 
SUMMARY OF CHANGES TO PROTOCOL BPI-2358-105 ......................................................2 
SUMMARY OF AMENDMENT 1 .................................................................................................2 
SUMMARY OF AMENDMENT 2 .................................................................................................2 
SUMMARY OF AMENDMENT 3 .................................................................................................3 
SUMMARY OF AMENDMENT 4 .................................................................................................5 
SUMMARY OF AMENDMENT 5 .................................................................................................8 
SUMMARY OF AMENDMENT 6 ...............................................................................................12 
SUMMARY OF AMENDMENT 7 ...............................................................................................13 
1. 
PROTOCOL SYNOPSIS ...........................................................................................17 
2. 
TABLE OF CONTENTS ...........................................................................................36 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................42 
4. 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE 
PROCEDURES ..........................................................................................................45 
4.1. 
Regulatory Authority Approval ..................................................................................45 
4.2. 
Investigator Responsibilities .......................................................................................45 
4.2.1. 
Good Clinical Practice ................................................................................................45 
4.2.2. 
Ethical Conduct of the Study and Ethics Approval ....................................................45 
4.2.3. 
Informed Consent .......................................................................................................46 
5. 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE .................47 
6. 
INTRODUCTION ......................................................................................................48 
6.1. 
Overview .....................................................................................................................48 
6.1.1. 
Pharmacokinetics and Drug Disposition in Humans ..................................................55 
6.2. 
Study Rationale ...........................................................................................................55 
6.2.1. 
Rationale for the Assessment of Bone Pain ................................................................55 
6.2.2. 
Rationale for the use of Plinabulin in the Prevention of Chemotherapy 
Induced Neutropenia ...................................................................................................56 
6.2.3. 
Rationale for the Selection of the Recommended Phase 3 Dose ................................57 
7. 
STUDY OBJECTIVES ..............................................................................................58 
7.1. 
Phase 2 (Open Label) Objectives ...............................................................................58 
7.2. 
Phase 3 (Double Blind) Objectives.............................................................................59 
8. 
STUDY DESIGN .......................................................................................................63 
8.1. 
Summary of Study Design ..........................................................................................63 

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9. 
STUDY POPULATION .............................................................................................66 
9.1. 
Inclusion Criteria ........................................................................................................66 
9.2. 
Exclusion Criteria .......................................................................................................67 
9.3. 
Removal of Patients from Therapy or Assessments ...................................................69 
10. 
STUDY TREATMENTS............................................................................................70 
10.1. 
Study Treatment ..........................................................................................................70 
10.1.1. 
Treatments Administered ............................................................................................70 
10.1.2. 
Identity of Study Drugs ..............................................................................................72 
10.2. 
Study Drug Preparation and Dispensation ..................................................................73 
10.2.1. 
Packaging and Labeling ..............................................................................................73 
10.2.2. 
Handling and Storage .................................................................................................73 
10.2.3. 
Compliance and Accountability .................................................................................74 
10.2.4. 
Disposal and Destruction ............................................................................................74 
10.3. 
Patient Numbering and Treatment Assignment ..........................................................74 
10.3.1. 
Patient Numbering ......................................................................................................74 
10.3.2. 
Treatment Assignment ................................................................................................75 
10.3.3. 
Treatment Allocation ..................................................................................................75 
10.4. 
Dosage and Administration ........................................................................................75 
10.4.1. 
Plinabulin or Matching Placebo ..................................................................................75 
10.4.2. 
Pegfilgrastim or Matching Placebo ............................................................................76 
10.4.3. 
Docetaxel ....................................................................................................................76 
10.5. 
Dose Interruptions and Modifications ........................................................................77 
10.5.1. 
Criteria for Premature Withdrawal .............................................................................78 
10.6. 
Concomitant Medications and Non-drug Therapies ...................................................79 
10.6.1. 
Permitted Medications ................................................................................................79 
10.6.2. 
Prohibited Medications ...............................................................................................80 
10.6.3. 
Anti-emetics, Antidiarrheals, and Bowel Maintenance Regimens .............................80 
10.6.4. 
Other Concomitant Medications .................................................................................81 
11. 
STUDY ASSESSMENTS ..........................................................................................83 
11.1. 
Study Flow and Visit Schedule...................................................................................83 
11.2. 
General Study Procedures ...........................................................................................93 
11.2.1. 
Demographics .............................................................................................................93 
11.2.2. 
Medical History ..........................................................................................................93 

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11.2.3. 
Baseline Characteristics ..............................................................................................93 
11.2.4. 
Vital Signs ..................................................................................................................93 
11.2.5. 
Temperature ................................................................................................................95 
11.2.6. 
Physical Examinations, Height, and Weight ..............................................................95 
11.2.7. 
Performance Status .....................................................................................................95 
11.2.8. 
Electrocardiogram .......................................................................................................96 
11.2.9. 
Health-Related Quality of Life Questionnaire Evaluated with EORTC QLQ-
C30 and EQ-5D-5L .....................................................................................................97 
11.2.10. 
Bone Pain Inventory (Short Form) (Phase 2 Only) ....................................................97 
11.2.11. 
Patient Bone Pain Scale and Pain Medication Assessment (Phase 3 only) ................97 
11.3. 
Efficacy .......................................................................................................................98 
11.3.1. 
Disease Progression ....................................................................................................98 
11.4. 
Safety ..........................................................................................................................99 
11.4.1. 
Adverse Events ...........................................................................................................99 
11.4.2. 
Concomitant Medications ...........................................................................................99 
11.5. 
Healthcare Resource Utilization .................................................................................99 
11.6. 
Laboratory Evaluations ...............................................................................................99 
11.6.1. 
Pregnancy Testing ....................................................................................................101 
11.6.2. 
Hepatitis B/C Testing ...............................................................................................101 
11.7. 
End of Treatment Assessment ..................................................................................101 
11.7.1. 
Exploratory Markers .................................................................................................101 
11.7.2. 
HIV Testing ..............................................................................................................101 
11.8. 
Safety Follow-up/End of Study Assessment ............................................................101 
11.8.1  
Long-term Safety Follow-up (up to 5 years) ............................................................102 
11.9. 
Pharmacokinetics ......................................................................................................102 
11.10. 
Appropriateness of Measurements ...........................................................................103 
12. 
DATA HANDLING AND QUALITY ASSURANCE ............................................104 
12.1. 
Data Collection .........................................................................................................104 
12.2. 
Data Management/Coding ........................................................................................104 
12.3. 
Quality Assurance .....................................................................................................104 
13. 
SAFETY MONITORING AND REPORTING .......................................................105 
13.1. 
Adverse Events .........................................................................................................105 
13.1.1. 
Definitions and Reporting .........................................................................................105 

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13.1.1.1. 
Assessment of Severity .............................................................................................105 
13.1.1.2. 
Relationship to Study Drug ......................................................................................105 
13.1.1.3. 
Follow-Up of Adverse Events and Serious Adverse Events ....................................106 
13.1.2. 
Laboratory Test Abnormalities .................................................................................107 
13.2. 
Serious Adverse Events ............................................................................................107 
13.2.1. 
Definitions ................................................................................................................107 
13.2.2. 
Reporting ..................................................................................................................108 
13.2.2.1. 
Timeframes for Submitting Serious Adverse Events ...............................................108 
13.3. 
Pregnancies ...............................................................................................................108 
13.4. 
Independent Data Safety Monitoring Board .............................................................109 
14. 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN .....................110 
14.1. 
Study Endpoints ........................................................................................................110 
14.1.1. 
Phase 2 Endpoints .....................................................................................................110 
14.1.2. 
Phase 3 Endpoints .....................................................................................................112 
14.2. 
Statistical Analysis Considerations ...........................................................................119 
14.2.1. 
Analysis Sets of Phase 2 ...........................................................................................119 
14.2.1.1. 
Intent-to-Treat Analysis Set ......................................................................................119 
14.2.1.2. 
Safety Analysis Set ...................................................................................................119 
14.2.1.3. 
Pharmacokinetic Analysis Set ..................................................................................119 
14.2.1.4. 
Pharmacodynamic Analysis Set ...............................................................................119 
14.2.2. 
Analysis Sets of Phase 3 ...........................................................................................120 
14.2.2.1. 
Intent-to-Treat Analysis Set ......................................................................................120 
14.2.2.2. 
Safety Analysis Set ...................................................................................................120 
14.2.2.3. 
Health Economic and Patient Reported Outcomes ...................................................120 
14.2.3. 
Patient Disposition ....................................................................................................120 
14.2.4. 
Demographics and Other Baseline Characteristics ...................................................120 
14.2.5. 
Prior and Concomitant Therapy ................................................................................120 
14.2.6. 
General Efficacy Analyses Considerations ..............................................................120 
14.2.6.1. 
Phase 3 Efficacy Analyses Considerations ...............................................................121 
14.2.7. 
Pharmacokinetic and Pharmacodynamic Analyses Considerations .........................122 
14.3. 
Safety Analyses Considerations ...............................................................................123 
14.3.1. 
Deaths .......................................................................................................................123 
14.3.2. 
Extent of Exposure ...................................................................................................123 

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14.3.3. 
Adverse Events .........................................................................................................123 
14.3.4. 
Laboratory Analyses .................................................................................................123 
14.3.5. 
Vital Signs ................................................................................................................124 
14.3.6. 
Electrocardiogram .....................................................................................................124 
14.4. 
Sample Size Considerations .....................................................................................124 
14.4.1. 
Phase 2 ......................................................................................................................124 
14.4.2. 
Phase 3 ......................................................................................................................124 
14.5. 
Interim Analysis ........................................................................................................124 
14.6. 
Withdrawal ...............................................................................................................125 
14.7. 
Independent Data Safety Monitoring Board Interim Safety Review........................125 
15. 
ADMINISTRATIVE PROCEDURES .....................................................................126 
15.1. 
Investigator Reporting Requirements .......................................................................126 
15.2. 
Confidentiality ..........................................................................................................126 
15.3. 
Case Report Forms ...................................................................................................126 
15.4. 
Drug Accountability .................................................................................................126 
15.5. 
Protocol Compliance ................................................................................................126 
15.6. 
Protocol Modifications .............................................................................................126 
15.7. 
Study Report and Publications..................................................................................127 
15.8. 
Study Discontinuation ..............................................................................................127 
15.9. 
Records Retention and Study Files ...........................................................................127 
15.9.1. 
Study Files and Retention of Records ......................................................................127 
15.9.2. 
Source Documents and Background Data ................................................................128 
15.10. 
Provision of Study Results and Information to Investigators ...................................128 
15.11. 
Information Disclosure and Inventions ....................................................................128 
15.11.1. 
Access to Information for Monitoring ......................................................................128 
15.11.2. 
Access to Information for Auditing or Inspections ..................................................128 
16. 
REFERENCES .........................................................................................................129 
17. 
APPENDICES ..........................................................................................................134 
APPENDIX A. NCCN GUIDELINES VERSION 2.2016 .......................................................135 
APPENDIX B. CTCAE VERSION 4.03 ..................................................................................136 
18. 
SIGNATURES .........................................................................................................137 
Signature of Investigator ..............................................................................................................137 
Signature of Chief Medical Officer .............................................................................................138 

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LIST OF TABLES 
Table 1: 
Summary of Docetaxel Dose Reductions and G-CSF Use (NPI-2358-101, 
Phase 2 ........................................................................................................................54 
Table 2: 
Treatments Administered for Phase 2 .........................................................................71 
Table 3: 
Treatments Administered for Phase 3 .........................................................................72 
Table 4: 
Dose Modifications for Docetaxel ..............................................................................78 
Table 5: 
Strong Inhibitors of CYP3A4, as Docetaxel Exposure Increases by 
Approximately 2-fold .................................................................................................80 
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 .............................................................................................84 
Table 7: 
Study Assessments and Procedures Schedule for Phase 3 (Double 
Blind)/Cycles 1 through 4, End of Treatment, 30 Day Safety Follow-up, 
Post-study Long-term Safety Follow-up, and Early Termination Visits ....................88 
Table 8: 
Vital Signs Assessments .............................................................................................94 
Table 9: 
ECOG Performance Status .........................................................................................95 
Table 10: Schedule for ECG Collection (Phase 2) .....................................................................96 
Table 11: Schedule for ECG Collection (Phase 3) .....................................................................97 
Table 12: Clinical Laboratory Tests (Central Laboratory) .......................................................100 
Table 13: Docetaxel Pharmacokinetic Sampling Schedule (Cycle 1, Day 1) ...........................103 
Table 14: Plinabulin Pharmacokinetic Sampling Schedule  (Cycle 1) .....................................103 
Table 15: Timing of Statistical Analyses ..................................................................................125 
 
LIST OF FIGURES 
 
Figure 1: 
Grade 4 Neutropenia for Docetaxel Plus Plinabulin and Docetaxel Alone by 
21-day Cycles (NPI-2358, Phase 2)............................................................................51 
Figure 2: 
Grade 4 Neutropenia on Cycle 1 Day 8 ......................................................................52 
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 ...........................................................................................................................53 
 

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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ABPM 
Ambulatory blood pressure measurement  
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
Anti-HBs 
Hepatitis B surface antibody 
AOC 
Area over the curve 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BSA 
Body surface area 
BOCF 
Baseline observation carried forward 
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 
DMSN 
Duration of moderate and severe neutropenia 
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 
ER 
Emergency Room 
FACS 
Fluorescence-activated cell sorting 
FDA 
Food and Drug Administration 
FN 
Febrile neutropenia 
G-CSF 
Granulocyte colony-stimulating factor 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HIV 
Human immunodeficiency virus 

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Abbreviation 
Definition 
HRPC 
Hormone refractory prostate cancer 
ICH 
International Council on Harmonisation 
ICU 
Intensive Care Unit 
IEC 
Institutional Ethical Committee 
IND 
Investigational New Drug Application 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IV 
Intravenous 
IWRS 
Interactive web response system 
JSCO 
Japanese Society of Clinical Oncology 
LMR 
Lymphocyte-to-monocyte ratio 
LOCF 
Last observation carried forward 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCCN 
National Comprehensive Cancer Network 
NBR 
Negative Binomial Regression  
NCI 
National Cancer Institute  
NLR 
Neutrophil-to-lymphocyte ratio 
NSAID 
Non-steroidal anti-inflammatory drug 
NSAIDs 
Non-steroidal anti-inflammatory drugs 
NSCLC 
Non-small cell lung cancer 
PAP 
Pharmacometrics Analysis Plan  
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PLR 
Platelet-to-lymphocyte ratio 
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 

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Abbreviation 
Definition 
SOC 
System organ class 
SOP 
Standard Operating Procedure 
TAC 
Taxotere/Adriamycin/cyclophosphamide 
TEAE 
Treatment emergent adverse event 
UGT 
UDP glucuronosyltransferase 
ULN 
Upper limit of normal 
US 
United States 
WHO 
World Health Organization 
WOCF 
Worst observation carried forward 

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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 
operate in accordance with the current Federal Regulations.  A letter or certificate of approval 

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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 (to be determined) in North America, Europe, or Asia 
Pacific. 
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; Aarts et al, 2013; 
Dinan et al, 2015). 
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 (Kawatkar et al, 2017).  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 (a single temperature of >38.3°C or a sustained temperature of ≥38°C for 
more than 1 hour) in addition to chemotherapy-induced Grade 3 or 4 neutropenia (absolute 
neutrophil count [ANC] < 1.0 × 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 (Zhang et al, 2018). 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.  

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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 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 

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target existing tumor vasculature, including inhibition of angiogenesis, induction of tumor cell 
apoptosis, sustained suppression of tumor growth after treatment, inhibition of tubulin 
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 

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included safety assessments, such as complete blood count measurements, on Days 1, 8, and 15 
of each cycle. 
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 (ANC < 0.5 x 109/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 (see current Investigator Brochure). 
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 (are under the curve [AUC]tot) 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 Assessment of Bone Pain 
Generalized bone pain is a risk associated with the use of G-CSF and is correlated with the 
mechanism of action (Lambertini et al, 2014).  A meta-analysis of 5 controlled trials indicates 
that the overall incidence of bone pain with G-CSF can range from 20% to 50% (Lambertini et 
al, 2014; Kubista et al, 2003).  The overall incidence of mild-to-moderate bone pain attributed to 
G-CSF is approximately 24%, and overall incidence of severe bone pain can range from 1% to 
5% of patients (Lambertini et al, 2014; Kubista et al, 2003).  The G-CSF-induced bone pain can 
lead to the discontinuation of this growth factor, which in turn can reduce the chemotherapy dose 
intensity (Kirshner et al, 2012). 
Generally, bone pain with pegfilgrastim reached its peak at Day 3 after dosing with pegfilgrastim 
on a scale of 1 to 10 (Kirshner et al, 2012).  An AUV analysis of bone pain over at least 5 days 
after dosing with pegfilgrastim was previously employed to evaluate bone pain with 
pegfilgrastim (Kirshner et al, 2012). 
G-CSFs mobilize hematopoietic progenitor cells from the bone marrow into the systemic 
circulation (Lambertini et al, 2014).  This progenitor-cell-mobilizing effect is an important 
reason why G-CSFs should wait 24 hours after the chemotherapy, and if administered sooner (ie, 
on the same day of chemotherapy), G-CSFs are known to lead to a paradoxical worsening of the 

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neutropenia (Burris et al, 2010).  The possible biologic explanation for the increase in FN 
observed with same-day pegfilgrastim dosing, relates to G-CSFs release of bone marrow-derived 
hematopoietic progenitor cells, and that the stimulation of these myeloid progenitor cells by 
G-CSFs makes these progenitor cells more sensitive to the effects of cytotoxic chemotherapy 
(Burris et al, 2010).  Therefore, pegfilgrastim is not recommended to be administered on the 
same day but on the next day of chemotherapy (Burris et al, 2010). 
A therapeutic intervention that is effective though a mechanism that is independent from 
mobilization of progenitor cells from the bone marrow has the potential to have superior efficacy 
over G-CSFs, as this therapeutic intervention can be administered on the same day, shortly after 
the chemotherapy.  Since no bone marrow effects are involved, this agent should therefore also 
not cause bone pain. 
The absence of an effect on neutrophil counts with plinabulin monotherapy (in the absence of 
chemotherapy), and the relative absence of bone pain with plinabulin, is indicative of differential 
mechanisms of action between plinabulin and G-CSF in the prevention of chemotherapy induced 
neutropenia. In addition, in contrast to G-CSFs, plinabulin has anti-cancer effect, which 
potentially represents an important advantage over G-CSFs, which do not have anti-cancer 
effects, or may even promote cancer growth, being a growth factor. 
Based on the bone pain data from the completed Phase 2 study NPI-2358-101 in 90 patients on 
plinabulin (at the dose of 30 or 20 mg/m2), a significant bone pain benefit is expected with 
plinabulin compared to G-CSF, while having an at least comparable benefit on 
chemotherapy-induced neutropenia. 
The patient reported outcome bone pain is included as a secondary endpoint in the Phase 3 
portion of the present study. 
6.2.2. 
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 (ANC < 0.5 x 
109/L) on Day 8, the approximate day after docetaxel administration corresponding to the largest 
reduction in ANC (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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Total ANC is comprised of mature and immature neutrophils. Immature neutrophils have 
reduced functional capacity compared to mature neutrophils to enable optimal innate immunity. 
Compared to mature neutrophils, immature neutrophils exert reduced ROS production leading to 
reduced microbicidal activity, reduced phagocytic activity, reduced granularity, reduced ability 
to create NETs (Mackay G et al, Frontiers in Immunology 2019; Mortaz E et al Frontiers in 
Immunology 2018). Therefore an additional analysis will be made with mature neutrophils only. 
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 (Kuderer et al, 2006). 
6.2.3. 
Rationale for the Selection of the Recommended Phase 3 Dose  
A model-based approach was used to characterize the effect of plinabulin on docetaxel-induced 
neutropenia.  The population pharmacokinetic/pharmacodynamic model developed was used to 
perform simulations.  Daily sampling for neutrophils was implemented to enable accurate 
delineation of the efficacy metrics, duration of severe neutropenia (DSN; number of days with an 
ANC of < 0.5 x 109/L), duration of moderate and severe neutropenia (DMSN; number of days 
with an ANC of < 1.0 x 109/L ), and area over the curve (AOC), which measure the duration and 
severity of neutropenia. The results were summarized by dose groups 5, 10, and 20 mg/m2 
studied in the Phase 2 portion of the present study. 
Based on AOC, DMSN, and DSN, 20 mg/m2 of plinabulin performed better than the 5 and 
10 mg/m2 doses, and was therefore the recommended dose for the Phase 3 study.  In 
recommending the dose, the minimal dose-independent effect of plinabulin on ambulatory blood 
pressure monitoring, and negligible effect on QT interval are taken into account. 
Simulations were also performed to determine the fixed dose of plinabulin that is similar to the 
body surface area (BSA)-based dose of 20 mg/m2.  Simulations were performed with plinabulin 
fixed doses of 20, 40, 60, and 80 mg and compared with the selected BSA-based dose of 
20 mg/m2 as the reference, assuming a similar population as that studied in the Phase 2 portion of 
the study and used in the BSA-based dosing simulations.  The  40 mg fixed dose yielded similar 
peak concentration and AUC as the body surface area-based dose of  20 mg/m2, indicating that 
subjects are not predicted to be at any risk of over or under exposure to plinabulin at this dose.  
The efficacy performance of the 40 mg fixed dose is predicted to be similar to that of the 
BSA-based dose of 20 mg/m2.  The 60 and 80 mg fixed doses yielded results similar to the 
40 mg fixed dose.  Thus, a fixed plinabulin dose of 40 mg is predicted to yield a similar efficacy 
as a BSA-based dose of 20 mg/m2.     
 

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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). 
Severe (Grade 4) neutropenia is an absolute neutrophil count (ANC) <0.5 × 109/L 
ANC will 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). 
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 Quality of Life (QoL) questionnaire evaluated with EORTC QLQ-C30 
and EQ-5D-5L  
• To collect data on disease progression 
• For selected countries only: to investigate the following cytokine panel: IL-1beta, 
IL-6, IL-12p70, IL-12p40, IL-17A, IL-23, G-CSF, GM-CSF, IFN-alpha, IFN-gamma, 
TNF-alpha, IL-2, FLT-3 ligand, and IL-8. 
Safety objectives: 
• Incidence, occurrence, and severity of AEs/SAEs 
• Incidences of bone pain  

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• Safety and tolerability (physical examination and safety laboratory assessments) 
7.2. 
Phase 3 (Double Blind) Objectives 
Primary Efficacy Objective (Cycle 1): 
To assess DSN in treatment Cycle 1 in patients with advanced or metastatic breast cancer, who 
have failed < 5 prior lines of chemotherapy; locally advanced or metastatic non small cell lung 
cancer (NSCLC) after platinum therapy failure; or hormone refractory (androgen independent) 
metastatic prostate cancer (HRPC) treated with docetaxel (75 mg/m2) + plinabulin (40 mg) 
(Arm 2) versus docetaxel (75 mg/m2) + pegfilgrastim (6 mg) (Arm 1). ANC will 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. 
Blood draws for ANC will be taken approximately the same time as the time of the pre-dose 
sample on Day 1, and will be taken by preference in the morning. DSN should be calculated as 
the number of consecutive days from the first day when a patient's ANC is below 0.5 x l09/L 
until the patient reaches an ANC> 0.5 x 109/L, in Cycle 1. For patients who do not experience 
any severe neutropenia in Cycle 1, the DSN is set to 0. For patient’s experiencing several 
episodes, the number of days of DSN will be summed up.  
Secondary Efficacy Objectives (Cycle 1 and Cycles 1 to 4): 
• To assess DSN in Cycle 1 with only mature neutrophils 
• Platelet count in Cycle 1: maximum decrease from baseline (prior to Cycle 1 
docetaxel dose) 
• Proportion of patients with neutrophil-to-lymphocyte ratio (NLR) > 5 after Day 7 
through Day 15 in Cycle 1 
• AUC using the trapezoidal quadrature method for bone pain, from Day 1 through 
Day 8 (pegfilgrastim will be administered on Day 2) in Cycle 1, based on the pain 
score from the patient bone pain scale 
• Change in estimated mean bone pain score from pre-dose Day 1 through Day 8 in 
Cycle 1 
• Proportion of patients with thrombocytopenia (all grade) in Cycles 1 to 4 
• To assess the incidence of infections in Cycles 1 to 4 
Exploratory Efficacy Objectives (Cycle 1): 
• To evaluate the proportion of patients in Cycle 1 with: 
o Thrombocytopenia (all grade) 
o Grade 4 neutropenia (ANC < 0.5 × 109/L) 
o Grade 4 neutropenia (ANC<0.5 x109/L) for mature neutrophils  
o Grade 3 neutropenia (ANC < 1 × 109/L) 
o Grade 3 (ANC < 1 × 109/L) and Grade 4 neutropenia (ANC < 0.5 × 109/L) 
o Bands > 0 after Day 7 through Day 15 

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o Promyelocytes plus myelocytes > 0 after Day 7 through Day 15 
o Promyelocytes, myelocytes, metamyelocytes and bands >0 after Day 7 
through Day 15 
o Lymphocyte-to-monocyte ratio (LMR) < 3.2 after Day 7 through Day 15 
o Platelet-to-lymphocyte ratio (PLR) > 200 after Day 7 through Day 15 
o At least 1 day of bone pain 
o At least 2 days of bone pain 
o At least 3 days of bone pain 
o At least 4 days of bone pain 
o At least 5 days of bone pain 
o At least 6 days of bone pain 
o At least 7 days of bone pain 
o At least 8 days of bone pain 
• To compare the proportion of patients who needed bone pain medication (defined as 
any medication reported on pain medication assessment from Day 1 through Day 8) 
in Cycle 1  
• To compare the time (in days) to first use of bone pain medication between the 
treatment groups  
• To assess DSN in treatment Cycle 1 in patients with locally advanced or metastatic 
NSCLC after platinum therapy failure 
• To assess DSN in Cycle 1 in patients with locally advanced or metastatic NSCLC 
after platinum therapy failure for mature neutrophils only 
• To assess DSN in treatment Cycle 1 in patients with HRPC 
• To assess DSN in Cycle 1 in patients with locally advanced or metastatic NSCLC 
after platinum therapy failure for mature neutrophils only 
• To assess DSN in treatment Cycle 1 in patients with advanced or metastatic breast 
cancer who have failed < 5 prior lines of chemotherapy 
• To assess DSN in Cycle 1 in patients with advanced or metastatic breast cancer who 
have failed < 5 prior lines of chemotherapy for mature neutrophils only 
• To assess DSN in treatment Cycle 1 in patients with locally advanced or metastatic 
NSCLC after platinum therapy failure or HRPC 
• To assess DSN in Cycle 1 in patients with locally advanced or metastatic NSCLC 
after platinum therapy failure or HRPC for mature neutrophils only 
• Platelet count at least 30% change from baseline at any time during Cycle 1. 
• ANC nadir during Cycle 1 

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• To assess CD34+ at Day 1 pre-dose, Day 2 pre-dose, Day 6, 7, 8, 9, 10, and 15, Day 
1 Cycle 2 pre-dose 
• For selected countries only: to investigate the following cytokine panel: IL-1beta, 
IL-6, IL-12p70, IL-12p40, IL-17A, IL-23, G-CSF, GM-CSF, IFN-alpha, IFN-
gamma, TNF-alpha, IL-2, FLT-3 ligand, and IL-8. 
Exploratory Efficacy Objectives (Cycles 1 to 4): 
• To evaluate the proportion of patients in Cycles 1 to 4 with: 
o Febrile neutropenia (FN) (ANC <1.0 × 109/L AND a single temperature of 
>38.3°C or a sustained temperature of ≥38°C for more than 1 hour). 
o Grade 4 neutropenia (ANC < 0.5 × 109/L). 
• To assess the maximum change from baseline in CD34 + counts in each 
treatment arm 
• To assess the maximum difference between treatment arms in CD34+ counts 
• To assess the maximum change from baseline in haptoglobin levels in each 
treatment arm 
• To assess the maximum difference between treatment arms in haptoglobin levels 
• To evaluate the following healthcare utilization objectives: 
o Incidence of 30-day rehospitalizations - all cause 
o Incidence of all cause hospitalizations 
o Duration of all cause hospitalizations 
o Incidence of all cause emergency room (ER) visits 
o Incidence of all cause intensive care unit (ICU) stays 
o Duration of all cause ICU stays 
o Incidence of all cause docetaxel dose delay (≥7 days), dose reduction (≤85%), 
or dose discontinuation 
o Incidence of platelet transfusions 
o Incidence of antibiotics use 
• To collect data on disease progression 
• To evaluate the following QoL objective: 
o Health-related QoL questionnaire evaluated with European Organization for 
Research and Treatment of Cancer (EORTC) QLQ-C30 and EQ-5D-5L 
Safety Objectives: 
• Incidence, occurrence, and severity of adverse events (AEs)/serious adverse events 
(SAEs)  

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• Safety and tolerability (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; locally advanced or metastatic NSCLC 
after platinum therapy failure; or hormone refractory (androgen independent) metastatic prostate 
cancer. 
The eligibility of all patients will be determined during a 28-day screening period.   
Phase 2 (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 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.  
A fixed dose of 40 mg has been selected as the RP3D following the Phase 2 PK/PD analysis 
(details of dose selection are provided in Section 6.2.3). 
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; locally advanced or metastatic NSCLC after platinum therapy failure; or hormone 
refractory (androgen independent) metastatic prostate cancer.  Each eligible patient will be 

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stratified according to his or her tumor type (breast cancer, NSCLC, or HRPC) and region (Asia, 
non-Asia).  Patients will be randomly assigned with equal probability (1:1 ratio) or 75:75, with 
the arm designation and planned intervention as follows: 
Arm 1: Docetaxel (75 mg/m2) + pegfilgrastim (6 mg) + placebo matching plinabulin 
Arm 2: Docetaxel (75 mg/m2) + plinabulin (40 mg) + placebo matching pegfilgrastim 
In order to facilitate balanced treatment arms with respect to cancer type, once either arm reaches 
at least 1/3 (of total) of patients with that cancer type, it will be closed to that cancer type and 
enrollment will continue for patients with the other cancer types, up to the planned maximum 
number of patients.  
Data from all patients receiving the RP3D plinabulin dose  in Phase 2 and Phase 3 will not be 
pooled for assessing the primary and secondary study endpoints, but analyzed separately.  
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 one 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 (± 2 days) after the last dose of study drug. Patients who withdraw for 
progressive disease and who will continue to another chemotherapy regimen will complete the 
EOT visit at Cycle X Day 21. They then continue to another chemotherapy regimen and do not 
need to have the safety follow-up visit (where X is the last cycle prior to progression, and is 4 or 
less).  
If, in the opinion of the investigator, the patient will benefit from more than 4 cycles of docetaxel 
and open label pegfilgrastim, then the fifth cycle will not start until completion of the EOT visit 
(in this instance, the EOT visit will be Cycle 4 Day 21). Follow-up visits will be required to 
monitor for ongoing treatment-related AEs.  All patients experiencing drug-related toxicities of ≥ 
Grade 2 at the EOT visit should be followed-up at least monthly until the AE(s) resolves to ≤ 

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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 
schedule assessments and procedure table must also be obtained for central laboratory 
assessment.  Urinalysis will be performed at screening only.   
Post-Treatment Assessment 
For both Phase 2 and Phase 3, once a patient has completed all cycles of study treatment they 
will enter a post-treatment (non-interventional) assessment phase. On a monthly basis, the 
patients will be contacted to assess whether they have started to receive another anti-cancer 
therapy, which could be cytotoxic chemotherapy, a programmed death-ligand 1 (PD-L1) 
inhibitor, radiation therapy, or other therapy. This assessment will continue until the patient starts 
another anti-cancer therapy, the patient chooses to have no further therapy, the patient dies, or 
the patient becomes lost to follow-up. This information will be used to analyze the time to next 
treatment. 
This will be performed in addition to any follow up for monitoring of ongoing treatment-related 
AEs, as described above. 
Patients without progressive disease at the EOT visit will undergo a follow-up visit every 
2 months until the occurrence of either disease progression or death. These visits may be 
conducted per telephone or other means.  
 
For patients included into the Phase 3 part of the study after November 2019, there will be a  
long-term safety follow-up through patient contacts by phone calls, letters or electronic 
means; or medical records reviews will be conducted to all subjects approximately every 6 
months up to 5 years to monitor long term safety of plinabulin. Follow-up telephone calls 
and queries of treating physicians or designee health care provider to ascertain safety 
information on secondary malignancies or tumor progression as well as other potential 
safety findings/concerns. Subjects who receive at least one dose of plinabulin or 
pegfilgrastim will be followed up. 
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 or 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) 
− locally advanced or metastatic NSCLC after platinum therapy failure 
− HRPC (Note that study treatment may be the first chemotherapy treatment) 
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 A): 
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 assessed within 14 days prior to study drug 
administration2: 
− Hemoglobin ≥ 9 g/dL independent of transfusion or growth factor support 
− ANC ≥ 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) 
 
2 Results are from the central laboratory. Local laboratory results may be accepted on a case by case basis after 
discussion with the Medical Monitor, however in this case central laboratories must also be taken within the 
screening time window. 

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− Serum creatinine ≤ 1.5 x ULN  
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. 2 
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) 

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

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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 (± 2 days) after the last dose of study drug. If, in the 
opinion of the investigator, the patient will benefit from more than 4 cycles of docetaxel and 
open label pegfilgrastim, then the fifth cycle will not start until completion of the EOT visit (in 
this instance, the EOT visit will be Cycle 4 Day 21). The safety follow-up visit does not need to 
be performed in this case. The same situation applies for patients with progressive disease who 
need another chemotherapy treatment, they also will perform the EOT visit at Cycle X Day 21 
and continue to the next chemotherapy regimen (where X is the last cycle prior to progression, 
and is 4 or less). The safety follow-up visit is not applicable in these cases.  
If a patient develops a positive viral load during the study, chemotherapy should be held for a 
maximum of 21 days.  If the viral load returns to zero treatment can be restarted, otherwise the 
patient should be withdrawn from the study. 
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 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 an 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; locally advanced or metastatic 
NSCLC after platinum therapy failure; 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 (40 mg) + 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).   
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, 

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patients must 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 (refer to Section 10.6.1). If a patient is hospitalized, as a result of a 
Serious Adverse Event, 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 (±5) minutes after the end of 
the docetaxel infusion 
 
Plinabulin or Placebo 
Cycles 1 to 4, Day 2 of 
each 
21 Day Cycle 
≥ 24 hours after the end 
of the docetaxel 
infusion 
 
Pegfilgrastim or 
Placebo 
Arm 1 
docetaxel (75 mg/m2) 
60-minute (±5 minutes) IV infusion 
placebo matching plinabulin 
30-minute (±5 minutes) IV infusion 
pegfilgrastim (6 mg) 
SC single dose 
Arm 2 
docetaxel (75 mg/m2) 
60-minute (±5 minutes) IV infusion 
plinabulin (40 mg) 
30-minute (±5 minutes) 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 

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severe neutropenia in patients with non-myeloid malignancies receiving docetaxel monotherapy.  
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. 

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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 
the drug administration process.  
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.   

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10.3.2. 
Treatment Assignment 
Patients in Phase 3 will be stratified based on his or her tumor type (breast cancer, NSCLC, 
HRPC) and region (Asia, non-Asia).  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)   
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 (40 mg) + 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 
In the Phase 2 portion, 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, plinabulin will be administered at a fixed dose of 
40 mg and the study matching placebo of plinabulin will be administered in an equal volume. 

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10.4.2. 
Pegfilgrastim or Matching Placebo 
In the Phase 2 portion, pegfilgrastim will be administered at a dose of 6 mg as a single dose 
syringe.  In the Phase 3 portion,  pegfilgrastim will be administered at a dose of 6 mg as a single 
dose syringe and the study matching placebo of pegfilgrastim 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.  
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 (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 (but do not mandate) 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, the 
patient should continue on study, and have dose adjustments as specified in Sections 10.5 and 
10.6.1. 

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Patient risk factors for developing febrile neutropenia when receiving docetaxel at the dose 
and schedule used in the protocol are per NCCN guidelines (Version 2.2016, refer to 
Appendix A). 
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 (± 2 days) after the last dose of study drug. Patients who withdraw for 
progressive disease and who will continue to another chemotherapy regimen will complete the 
EOT visit at Cycle X Day 21. They then continue to another chemotherapy regimen and do not 
need to have the safety follow-up visit (where X is the last cycle prior to progression, and is 4 or 
less). 
If, in the opinion of the investigator, the patient will benefit from more than 4 cycles of docetaxel 
and open label pegfilgrastim, then the fifth cycle will not start until completion of the EOT visit 
(in this instance, the EOT visit will be Cycle 4 Day 21). Follow-up visits will be required to 
monitor for ongoing treatment-related AEs.  All patients experiencing drug-related toxicities of 
≥ Grade 2 at the EOT 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. 
Patients without progressive disease at the EOT visit will undergo a follow-up visit every 
2 months until the occurrence of either disease progression or death. Patients included after 
November 2019 will have a long term FU approximately every 6 months up to 5 years to 
monitor long term safety of plinabulin. These visits may be conducted per telephone or other 
means.  
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 one 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.   
Hematologic support, such as erythropoietin, darbopoetin, granulocyte colony-stimulating factor 
(Neupogen® or Neulasta®), or red blood cell or platelet transfusions prior to 4 weeks of the first 
dose of study drug in order to meet entry criteria is not permitted. 

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Patients may receive hemopoietic support or transfusions during the study as clinically indicated.  
Please note the special instructions regarding Neupogen® or Neulasta® use during study 
treatment in Section 10.6.1. 
Any delay of docetaxel dosing will result in the delay of plinabulin administration.  For each 
cycle, the dose of plinabulin is always administered 30 minutes after the docetaxel infusion.  If 
docetaxel is discontinued, plinabulin will also be discontinued.   
Table 4: 
Dose Modifications for Docetaxel 
Condition 
Action 
Febrile neutropenia or 
ANC < 0.5 x 109/L for > 1 week or 
Grade 4 thrombocytopenia 
withhold docetaxel until ANC > 1.5 x 109/L and 
platelets > 100 x 109/L, 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 
withhold docetaxel until the abnormality returns 
toward normal and then resume at 55 mg/m2 
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.  

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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 11.7.  
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. 
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 must 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 Table 5 for prohibited medications). 
Corticosteroids (except as described for premedication) and new non-steroidal anti-inflammatory 
drugs (NSAIDs) are prohibited except for the treatment of AEs and as premedication as 
described above.  Patients already receiving NSAIDs are allowed to continue taking treatment as 
long as the dose remains stable. 
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 

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Investigator should contact the Medical Monitor prior to its use.  FN is defined as ANC <1.0 × 
109/L AND a single temperature of >38.3°C or a sustained temperature of ≥38°C for more than 
1 hour (as per CTCAE v4.03).  
10.6.2. 
Prohibited Medications 
Corticosteroids (except as described in Section 10.6.1) and new NSAIDs are prohibited except 
for the treatment of AEs.  Patients already receiving NSAIDs are allowed to continue taking 
treatment as long as the dose remains stable.   
Table 5: 
Strong Inhibitors of CYP3A4, as Docetaxel Exposure Increases by 
Approximately 2-fold 
Class/Therapeutic Area 
Drugs/Agents 
Antibiotics 
clarithromycin, telithromycin 
Antidepressant 
nefazodone 
Antifungals 
itraconazole, ketoconazole, posaconazole, 
voriconazole 
Antiretroviral 
ritonavir/lopinavir, ritonavir, saquinavir, ,  
Antiviral 
boceprevir, telaprevir 
Miscellaneous,  
conivaptan, grapefruit juice, mibefradil 
 Topical formulations of prohibited medication(s) are permitted. 
 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). 
 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 

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(which is not known to prolong QT/QTc intervals) is safest and must be chosen over other 5HT3 
receptor agonists. Tropisetron is an acceptable substitute 5HT3 receptor agonist (Yavas et al, 
2008). 
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 
antipsychotic 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. Aprepitant is an acceptable prophylactic anti-emetic in this situation 
[Marbury et al, 2009]). 
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. 
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. 
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 

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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 
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 
Discontinuationb 
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 
Discontinuationb 
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 
Xr 
Xr 
 
 
 
 
 
 
 
Xr 
Xr 
Xr 
 
 
 
 
 
Docetaxel treatment 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Plinabulin s 
 
X 
 
 
X 
 
 
 
 
 
 
Pegfilgrastim s 
 
X 
 
 
 
X 
 
 
 
 
 
Bone Pain Inventory 
Short Formt 
X 
 
Xu  
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 11.9).  During the phase 2 open label portion of the study patients randomized to pegfilgrastim will not have samples collected for plinabulin 
PK analysis. Cytokine panel testing will be done using unused plasma samples collected at the PK time points; reconsenting of the patients will be required before 
analysis is performed. 
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”. 
Patients without progressive disease at the EOT visit will undergo a follow-up visit every 2 months until the occurrence of either disease progression or death. These 
visits may be conducted per telephone or other means. 

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r. 
Docetaxel infusion: 75 mg/m2 docetaxel will be administered via IV infusion over 1 hour on Day 1 of each cycle.  All patients must 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). 
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. 
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, 
30 Day Safety Follow-up, Post-study Long-term 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 
30 Day  
Safety 
Follow-
upb 
Post-
study 
Long 
term 
safety 
follow-
up 
Cycle Day 
-28 to -1 
1 
 2 
3, 
4, 
5 
6 
7 
8 
9 
10 
15 
-1 
1 
2 
3 
8 
Post 
Cycle 
X on  
Day 
22 
(+ 7 
days) 
± 2 
days 
Once 
every 6 
months 
for up to 
5 years 
after 
EOT 
Cycle Week 
 
1 
2 
3 
1 
2 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographicsc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/ Baseline Characteristicsd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signse 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
X 
X 
 
ECOG Performance Status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Temperaturef 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
X 
X 
 
Physical examinationg 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Body weight 
X 
X 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
12-lead ECGh 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Hematologyi 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
X 
X 
 
Serum Chemistryi 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
 
 
PT, INR, PTTj 
X 
 
 
 
 
 
 
 
 
 
 
 
Urinalysisj 
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 
30 Day  
Safety 
Follow-
upb 
Post-
study 
Long 
term 
safety 
follow-
up 
Cycle Day 
-28 to -1 
1 
 2 
3, 
4, 
5 
6 
7 
8 
9 
10 
15 
-1 
1 
2 
3 
8 
Post 
Cycle 
X on  
Day 
22 
(+ 7 
days) 
± 2 
days 
Once 
every 6 
months 
for up to 
5 years 
after 
EOT 
Hepatitis B/C testingk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIVl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testm 
X 
X 
 
 
 
 
 
 
 
 
 
 
Randomizationn 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK sample collectiono 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Haptoglobin 
 
Xy 
Xy 
 
X 
X 
X 
X 
X 
X 
 
Xz 
 
 
Xaa 
 
 
 
Exploratory Biomarker Analysis CD34+ 
 
Xy 
Xy 
 
X 
X 
X 
X 
X 
X 
 
Xz 
 
 
Xaa 
 
 
 
Disease status evaluationp 
X 
 
Assessments of disease progression will be performed in 
accordance with standard medical practice per institution standard 
X 
 
 
Docetaxel  
Pre-Medication 
 
Xq 
Xq 
 
 
 
 
 
 
 
Xq 
Xq 
Xq 
 
 
 
 
 
Docetaxel treatmentr 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Plinabulin or placebor 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Pegfilgrastim or placebor 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Patient bone pain scale & pain medication assessments 
 
Xt 
Xt,u X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Health-related QoL EORTC QLQ-C30 and EQ 5D-5L questionnairev 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
X 
 
 
Concomitant medicationsw 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse eventsx 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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 
30 Day  
Safety 
Follow-
upb 
Post-
study 
Long 
term 
safety 
follow-
up 
Cycle Day 
-28 to -1 
1 
 2 
3, 
4, 
5 
6 
7 
8 
9 
10 
15 
-1 
1 
2 
3 
8 
Post 
Cycle 
X on  
Day 
22 
(+ 7 
days) 
± 2 
days 
Once 
every 6 
months 
for up to 
5 years 
after 
EOT 
Post-study contact patients or access to patient’s medical records 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Abbreviations: ANC = absolute neutrophil count; 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 X (Day 22 [+ 7 days]) of the study for an individual patient, regardless at what time 
the patient discontinues the study. 
b. 
All patients, (including those who discontinued from the study) will complete a safety follow-up visit 30 (±2) days after the last dose. Patients who withdraw for 
progressive disease and who will continue to another chemotherapy regimen will complete the EOT visit at Cycle X Day 21 (where X is the last cycle prior to 
progression, and is 4 or less). They then continue to another chemotherapy regimen and do not need to have the safety follow-up visit. If, in the opinion of the 
investigator, the patient will benefit from more than 4 cycles of docetaxel and open label pegfilgrastim, then the fifth cycle will not start until completion of the EOT visit 
(in this instance, the EOT visit will be Cycle 4 Day 21). 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. 
c. 
Demographic data will include gender, date of birth (or age), and race/ethnicity 
d. 
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 
e. 
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), with a ±15 minute window: 
• 
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 
f. 
Temperature is to be taken every time a blood draw is taken for ANC. The same temperature location selected for a patient (ear, oral, or axillary) should be used 
throughout the study for each patient. 
g. 
Physical examination will include height (cm) at screening. 

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h. 
A single 12-lead ECG will be performed at screening, EOT, 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, 60 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.  
i. 
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, ANC will be assessed at baseline (prior to Cycle 1 docetaxel dose), on 
Days 1, 2, 6, 7, 8, 9, 10, and 15.  Blood draws for ANC will be taken approximately the same time as the time of the pre-dose sample on Day 1, and will be taken by 
preference in the morning.  If Grade 4 neutropenia is observed in a patient, absolute neutrophil count will be evaluated daily (central and local laboratories) during the 
first cycle, until Grade 4 neutropenia is resolved. 
j. 
Analyzed at a central laboratory. 
k. 
Hepatitis C antibody, hepatitis B surface antigen (HBsAg), viral load at local laboratory if HBsAg is positive, hepatitis B surface antibody (anti-HBs). Hepatitis serology 
can be performed using laboratory standard methodology, by local laboratory or by the central laboratory if local testing is not available. 
l. 
If HIV testing is done (at the discretion of the investigator), the test will be conducted at the local site. 
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 (either on Day -1 or prior to infusion on Day 1). Confirm with serum testing (local or central laboratory) if urine sample is positive. 
Additional testing may be performed at the discretion of the investigator. 
n. 
Patients can be randomized on Cycle 1 Day -1 or Cycle 1 Day 1, to allow site flexibility to dispense pre-medication treatment. 
o. 
Plasma samples (5 mL each) for plinabulin and docetaxel PK. All patients will be sampled for PK via a central laboratory. Patients in Phase 3 will follow the plinabulin 
and docetaxel PK sampling schedules from Phase 2. For PK collection schedule refer to Table 13 and Table 14 (see Section 11.9).  Cytokine panel testing will be done 
using unused plasma samples collected at the PK time points;   
p. 
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.” 
Patients without progressive disease at the EOT visit will undergo a follow-up visit every 2 months until the occurrence of either disease progression or death. These 
visits may be conducted per telephone or other means. 
q. 
Docetaxel infusion: 75 mg/m2 docetaxel will be administered via IV infusion over 1 hour on Day 1 of each cycle.  All patients must 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).  
r. 
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). 
s. 
The bone pain scale and pain medication assessment should be completed on Day 1 prior to docetaxel infusion and on each remaining day through Day 8 at 
approximately the same time (Moore et al, 2017).  On  Days 2, 6, 7, and 8 the patient will complete the bone pain scale and pain medication assessment at the 
investigational site  
t. 
Bone pain assessment to be completed pre-dose. 
u. 
On Day 2 the patient will be provided with a further copy of the assessment to be completed at home on Day 3, Day 4, and Day 5 and returned to the study center at the 
next visit (Day 6). 

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v. 
Health-related QoL questionnaire evaluated with EORTC QLQ-C30 and EQ 5D-5L will be collected on Day 1 (prior to the infusion) and on Day 8 of each cycle 
(Giesinger et al, 2014). 
w. All concomitant medicines (dose, schedule, and duration of treatment) and in particular analgesics as well as antibiotics should be entered in the eCRF. 
x. 
All hospitalizations should be entered in the eCRF. Adverse events 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 and up to 30 days following the last dose of the study drug. 
y. 
Collected at pre-dose only. 
z. 
Pre-dose Cycle 2 only 
aa. All Cycles, Day 8 
 

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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.   
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, with a ± 15 minute window for the 
standard cuff measurements. 

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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 after end of 
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 after end of 
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 
All cycles 
End of Treatment, Early 
Discontinuation, and 
30-Day Safety Follow-up 
- 
2 (standard cuff) 

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Cycle 
Day 
Time Point(s) 
Method 
Phase 3 
All cycles 
End of Treatment, and 
30-Day Safety Follow-up 
- 
2 (standard cuff) 
11.2.5. 
Temperature 
The temperature location (ear,oral, or axillary) selected for a patient should be the same 
throughout the study.   
If abnormalities are found and they are considered an AE, record on the AE summary page. If an 
isolated elevated temperature is not clinically significant, it should not be reported as an AE. If 
an elevated temperature is part of an AE that is reported elsewhere, elevated temperature (fever) 
should not be reported as an AE. 
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 

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ECOG Scale 
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 
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 (Phase 2 only), 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, 60 minutes (30 minutes in 
Phase 2) 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 
after 
start of 
infusion* 
(+ 15 
minutes 
window) 
(Arms 
2 to 4) 
4.5 
hours 
after start 
of 
infusion** 
(+ 15 
minutes 
window) 
(Arms 
2 to 4) 
Single 
Triplet# 
Triplet# 
Triplet# 
Triplet# 
Triplet# 
Triplet# 
Single 
* ECG measurement 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 and 
30 Day Safety 
Follow-up 
60 minutes 
after start 
of 
infusion* 
(± 5 
minutes 
window) 
4.5 hours 
after start 
of 
infusion** 
(± 15 
minutes 
window) 
Single  
Triplet  
Triplet  
Triplet  
Triplet 
Triplet  
Triplet 
Single 
* ECG measurement 30 minutes (± 5 minutes window) after the end of the 30-minute infusion with 
plinabulin/placebo. 
** ECG measurement 4 hours (± 15 minutes window) after the end of the 30-minute 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. 
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) (Phase 2 Only) 
The incidences of bone pain will be recorded through a validated questionnaire. 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 
11.2.11. 
Patient Bone Pain Scale and Pain Medication Assessment (Phase 3 only) 
The incidences, occurrences, and severity of bone pain will be recorded through a patient bone 
pain scale during Cycle 1, at the times presented in Table 7.  
The bone pain scale will be based upon the validated Wong Baker Faces® Pain Rating Scale 
(http://wongbakerfaces.org). 
The bone pain scale and pain medication assessment should be completed on Day 1 prior to 
docetaxel infusion and on each remaining day through Day 8 at approximately the same time. On  
Days 2, 6, 7, and 8 the patient will complete the bone pain scale and pain medication assessment 
at the investigational site.  If the patient is discharged from hospital prior to Day 8, the bone pain 
scale and pain medication assessment pages for the remaining days will be handed to the patient 

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with the date field completed by the site personnel for each of the remaining days.  The patient 
will be instructed to fill in the documents at home, approximately at the same time as on Day 1. 
On each day following the patient’s discharge from the hospital when the patient returns to the 
site for study procedures, they will return any available completed assessments.  
Increases of bone pain severity are assessed as an objective during Phase 3 of the study, using the 
bone pain scale (“Please rate your bone pain by circling the one number below the faces that 
best describes your pain at its worst in the last 24 hours”). The severity of pain is marked on a 
scale from 0 (‘no hurt’) to 10 (‘hurt worst’). 
Concomitant pain medication use will be recorded via a pain medication assessment. Information 
recorded for concomitant pain medication use will include date, name of medication, route of 
administration, dosage, total taken in one day, and reason medication was taken. 
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.  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. 
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 reviewed, but images (such 
as CT scan, MRI etc.) or other documents will not be collected for central review. The disease 
progression will be judged by the investigator. 
The assessment of disease progression during the follow-up period for patients assessed as 
non-progressive at the EOT visit does not need to be reported, only the determination of disease 
progression will be collected.  

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(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 and up 
to 30 days following the last dose of the study drug. 
All AEs, SAEs, treatment emergent AEs, treatment emergent SAEs, and treatment emergent 
deaths regardless of the relationship to the study drug, will be collected. 
Disease progression or deterioration of the malignancy under study (including new sites of 
metastasis due to disease progression) will be recorded as part of the subject's disease status and 
should not be reported as an AE/SAE. If death is determined to be due to disease progression, the 
SAE form will attribute the death to disease progression and document that disease progression 
was determined to have caused the event(s). These events will not be included in the safety 
analysis. 
The Sponsor will collect all deaths on study regardless of its potential relationship to disease 
progression and up to 30 days after the last dose of plinabulin on an SAE form. 
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. 
Healthcare Resource Utilization 
Information on all cause hospitalizations (including ICU) and ER visits will be collected at all 
visits to the study center and throughout the study, at end of study and during any follow-up post 
study (except for FU visits for patients without disease progression at the EOT visit).  
11.6. 
Laboratory Evaluations 
Chemistry, coagulation tests, hematology, and urinalysis will be performed using a central 
laboratory and serum pregnancy testing and hepatitis serology will be performed using a local or 
central laboratory; results 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 obtained for central laboratory 

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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, MCV, MCH, 
MCHC, RBC count, WBC count with differential (bands, basophils, 
eosinophils, lymphocytes, monocytes, neutrophils), ANC and 
reticulocyte count 
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, Creatinine Clearance 
 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 (local or central laboratory) if urine sample is positive. 
Additional testing may be performed at the discretion of the 
investigator. 
 Coagulation 
PT, INR, PTT 
 Other 
Albumin, amylase, calcium, lactate dehydrogenase, lipase, 
phosphorus, total protein, uric acid, glucose, creatine phosphokinase, 
hepatitis B/C testing (local or central laboratory): hepatitis C 
antibody, HBsAg, anti-HBs 
Urinalysis 
glucose, ketones, pH, protein, RBCs, specific gravity 
Exploratory Biomarker 
 
 
CD34+ (Phase 2 and Phase 3, in selected countries) 
cytokine panel (in selected countries) 
Abbreviations: ANC= absolute neutrophil count, anti-HBs = hepatitis B surface antibody, β hCG = beta-human 
chorionic gonadotropin, HBsAg = hepatitis B surface antigen, INR = International Normalized Ratio, MCV = mean 
corpuscular volume, MCH = mean corpuscular hemoglobin, MCHC = mean corpuscular hemoglobin concentration, 
PT = prothrombin time, PTT = partial thromboplastin time, RBC = red blood cells, WBC = white blood cells 
 
Assessments for UDP glucuronosyltransferase (UGT) 1A1 genotyping and total bilirubin, 
conjugated bilirubin, and unconjugated bilirubin may be performed at the discretion of the 
investigator. 

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11.6.1. 
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 (local or central laboratory) if urine sample is positive. 
Additional testing may be performed at the discretion of the investigator. 
11.6.2. 
Hepatitis B/C Testing 
Hepatitis B/C serologic markers (hepatitis C antibody, HBsAg, viral load in case HBsAG is 
positive and anti-HBs) will be tested. If HBsAg is positive but viral load is negative, the patient 
should be tested prior to each treatment cycle to ensure that viral load remains negative. 
Hepatitis (hepatitis C antibody, HBsAg, viral load and anti-HBs) serology can be performed 
using laboratory standard methodology, by local laboratory or by the central laboratory if local 
testing is not available (not for viral load). 
11.7. 
End of Treatment Assessment 
EOT is defined as the last assessment for the protocol-specified treatment post Cycle X (Day 22 
[+ 7 days]) of the study for an individual patient, regardless at what time the patient discontinues 
the study. 
11.7.1. 
Exploratory Markers 
Phase 2 only: 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.  
Phase 2 and Phase 3: Plasma cytokine panel: IL-1beta, IL-6, IL-12p70, IL-12p40, IL-17A, IL-23, 
GCSF, GMCSF, IFN alpha, IFN-gamma, TNF-alpha, IL-2, FLT-3 ligand, and IL-8 analysis. 
This test will be performed in selected countries participating in the study, using unused plasma 
samples collected at PK time points. 
Unused samples (urine/serum plasma) will also be saved for future potential biomarker research, 
with patient consent. 
11.7.2. 
HIV Testing 
If HIV testing is done (at the discretion of the investigator), the test will be conducted at the local 
site using standard methodology. 
11.8. 
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 (± 2) days after the last dose (refer to Table 6 and Table 7). Patients who 
withdraw for progressive disease and who will continue to another chemotherapy regimen will 
complete the EOT visit at Cycle X Day 21. They then continue to another chemotherapy regimen 
and do not need to have the safety follow-up visit (where X is the last cycle prior to progression, 
and is 4 or less). If, in the opinion of the investigator, the patient will benefit from more than 
4 cycles of docetaxel and open label pegfilgrastim, then the fifth cycle will not start until 

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completion of the EOT visit (in this instance, the EOT visit will be Cycle 4 Day 21). Follow-up 
visits will be required to monitor for ongoing treatment-related AEs. All patients experiencing 
drug-related toxicities of ≥ Grade 2 at the EOT 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. 
Patients without progressive disease at the EOT visit will undergo a follow-up visit every 
2 months until the occurrence of either disease progression or death. These visits may be 
conducted per telephone or other means.  
The assessment of disease progression during the follow-up period for patients assessed as 
non-progressive at the EOT visit does not need to be reported, only the determination of disease 
progression will be collected. 
11.8.1  Long-term Safety Follow-up (up to 5 years) 
The long-term safety follow-up through patient contacts by phone calls, letters or electronic 
means; or medical records reviews will be conducted to all subjects approximately every 6 
months up to 5 years to monitor long term safety of plinabulin. Follow-up telephone calls and 
queries of treating physicians or designee healthcare provider to ascertain safety information on 
secondary malignancies or tumor progression as well as other potential safety findings/concerns. 
Subjects from each treatment arm will be followed up. Subjects who receive at least one dose of 
plinabulin or pegfilgrastim will be followed up. 
 
Safety endpoints to be collected include; 
• 
Disease progression  
• 
Disease relapse (local, regional or distant) 
• 
Second primary tumors 
• 
Health status check, including autoimmune and hematological disorders 
• 
Any further anti-cancer treatment information 
• 
Reporting of medical problems, including information on unexpected hospitalizations and 
medications (including SAEs) 
• 
Death (including autopsy report, if available) 
11.9. 
Pharmacokinetics 
All patients in Phase 2 and Phase 3 will participate in the PK assessments.  
Docetaxel Sampling 
All patients in Phase 2 and Phase 3 will have samples taken for docetaxel PK on Cycle 1 Day 1 
for up to 24 hours after the start of the docetaxel infusion. 

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Table 13: 
Docetaxel Pharmacokinetic Sampling Schedule (Cycle 1, Day 1) 
Day 
Day 1 
Day 2 
Time  
End-of infusion  
(+/- 5 min) 
1.5 hours after 
start of 
infusion*  
(+/- 5 min) 
6.0 hours after 
start of 
infusion**  
(+/- 15 min) 
24 hours after 
start of infusion 
on Day 1 
(+/- 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. Sample can be taken at the same 
time as the plinabulin 4.5 hour sample. 
 
Plinabulin Sampling 
All patients randomized to a plinabulin treatment arm in Phase 2 and Phase 3 will have samples 
taken for plinabulin PK on Cycle 1 for up to 24 hours after the start of the plinabulin infusion.  
Patients in Phase 2 randomized to pegfilgrastim during open label treatment will not have 
samples collected for plinabulin PK. Cytokine panel testing will be done using unused plasma 
samples collected at the PK time points.  
Table 14: 
Plinabulin Pharmacokinetic Sampling Schedule  (Cycle 1) 
Day 
Day 1 
Day 2 
Time 
Immediately 
before 
infusion 
starts 
 
End-of 
infusion  
(+/- 5 min) 
60 minutes 
after start of 
infusion*  
(+/- 5 min) 
4.5 hours after 
start of 
infusion**  
(+/- 15 min ) 
24 hours after 
start of infusion 
on Day 1 
(+/- 6 hr) 
* 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. 
11.10. 
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.  
Health-related QoL questionnaire evaluated with EORTC QLQ-C30 and EQ-5D-5L is validated 
for use in this population.   
The patient bone pain scale will be based upon a validated pain rating scale (the Wong-Baker 
Faces® Pain Rating Scale (http://wongbakerfaces.org). 

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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 AEs encountered during the clinical study, irrespective of the likelihood that the event is 
related to disease progression, 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 causality 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. 
Hospitalization or prolongation of hospitalization is used as an indicator of the seriousness of the 
AE and should ONLY be submitted as an SAE where the event truly fits this definition (see 
regulatory definition above) and NOT for hospitalizations associated with non serious reasons 
for hospitalization or prolongation of hospitalization. If a patient is hospitalized or 
hospitalization is prolonged due to planned procedures such as administration of scheduled IV 
therapy or minor treatment such as hydration; administration of growth factors; elective surgery; 
social reasons and respite care; or economic reasons in the absence of any deterioration in the 
patient’s general condition, these hospitalizations do not meet the criteria of seriousness from a 
medical perspective and do not need to be reported as SAEs. Hospitalizations or prolonged 
hospitalizations that are required for an SAE but also include a portion of hospitalization for 

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nonmedical reasons should be reported as an SAE. However, AEs that do not meet criteria for 
serious should be entered into the EDC and all hospitalizations should be entered into EDC with 
the reason for hospitalization identified. 
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. 
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 number: 
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 

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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 
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 data safety monitoring board (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 in Phase 3 will be stratified according to his or her by tumor type (breast cancer, 
NSCLC, HRPC) and region (Asia, non-Asia). 
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). ANC will 
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).  The Negative Binomial Regression (NBR) model, on the integer number 
of days of severe neutropenia, will be used to analyze the DSN endpoint during the 
fixed time window outlined above, with the treatment arm as the only covariate.  
The method will also be used to construct point estimates and confidence intervals. 
The GENMOD procedure in SAS version 9.4 or later will be used. Contrasts for 
pairwise comparisons between Arm 1 and the plinabulin arms will be used for the 
evaluation. A closed testing procedure by Hommel (Hommel 1988, Hommel and 
Bernhard 1999) will be used for the multiple comparisons. 
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).  See the Pharmacometrics Analysis Plan for the analysis 
methods. 
Secondary Endpoints:   
• To characterize the pharmacokinetic profile of plinabulin and docetaxel.  See the 
Pharmacometrics Analysis Plan for the analysis methods. 
• To characterize the exposure-response relationships between measures of plinabulin 
exposure and the pharmacodynamic endpoint DSN. Robust linear regression (Bablok 

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et al, 1988) with DSN as the dependent variable and plinabulin exposure as the 
independent variable. The method will also be used to construct point estimates and 
confidence intervals. The NCSS version 12 statistical software will be used. 
• To characterize the exposure-safety relationships between measures of plinabulin 
exposure and safety events of interest. Robust linear regression (Bablok et al, 1988) 
with the number of safety events as the dependent variable and plinabulin exposure as 
the independent variable. The method will also be used to construct point estimates 
and confidence intervals. The NCSS version 12 statistical software will be used. 
Exploratory Endpoints: 
• To assess CD34+ at screening, and on Days 2, 6, and 8 in Cycle 1 and Day 1 in 
Cycle 2. A repeated measures mixed linear model with the Day 1 value and treatment 
arm as covariates will be used to analyze this endpoint. 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. Contrasts for pairwise comparisons 
between Arm 1 and the plinabulin arms will be used for the evaluation. A closed 
testing procedure by Hommel (Hommel 1988, Hommel and Bernhard 1999) will be 
used for the multiple comparisons. 
• Health-related QoL questionnaire evaluated with EORTC QLQ-C30 and EQ-5D-5L. 
The Wilcoxon Rank Sum test will be used to analyze the responses to the individual 
questions. The method will also be used to construct point estimates and confidence 
intervals. The NPAR1WAY procedure in SAS version 9.4 or later will be used for the 
analysis. Contrasts for pairwise comparisons between Arm 1 and the plinabulin arms 
will be used for the evaluation. A closed testing procedure by Hommel (Hommel 
1988, Hommel and Bernhard 1999) will be used for the multiple comparisons. 
• Data collection on disease progression. The log-rank test (LIFETEST procedure in 
SAS) will be used to compare time to disease progression between the treatment 
groups. The method will also be used to construct point estimates and confidence 
intervals. Contrasts for pairwise comparisons between Arm 1 and the plinabulin arms 
will be used for the evaluation. A closed testing procedure by Hommel (Hommel 
1988, Hommel and Bernhard 1999) will be used for the multiple comparisons.     
• For selected countries only: to investigate the following cytokine panel: IL-1beta, IL-
6, IL-12p70, IL-12p40, IL-17A, IL-23, G-CSF, GM-CSF, IFN-alpha, IFN-gamma, 
TNF-alpha, IL-2, FLT-3 ligand, and IL-8. 
Safety Endpoints 
• 
Incidence, occurrence, and severity of AEs/SAEs. These endpoints will be presented 
descriptively in tables and listings. 
• 
Incidences of bone pain. The NBR model will be used to analyze the endpoint during the 
fixed time window from pre-dose Day 1 through Day 8 in Cycle 1, with the treatment arm as 
the only covariate. The method will also be used to construct point estimates and confidence 
intervals. The GENMOD procedure in SAS version 9.4 or later will be used. Contrasts for 
pairwise comparisons between Arm 1 and the plinabulin arms will be used for the 
evaluation. A closed testing procedure by Hommel (Hommel 1988, Hommel and Bernhard 

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1999) will be used for the multiple comparisons. 
• 
Safety and tolerability (physical examination and safety laboratory assessments). These 
endpoints will be presented descriptively in tables and listings. 
14.1.2. 
Phase 3 Endpoints  
Primary Efficacy Endpoint (Cycle 1): 
DSN in Cycle 1 in patients treated with docetaxel (75 mg/m2) + plinabulin (40 mg) (Arm 2) 
compared with patients treated with docetaxel (75 mg/m2) + pegfilgrastim (6 mg) (Arm 1). ANC 
will 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.  Blood draws for ANC will be taken approximately the same time as the time 
of the pre-dose sample on Day 1, and will be taken by preference in the morning. DSN should be 
calculated as the number of consecutive days from the first day when a patient's ANC is below 
0.5 x l09/L until the patient reaches an ANC> 0.5 x 109/L, in Cycle 1. For patients who do not 
experience any severe neutropenia in Cycle 1, the DSN is set to 0. For patient’s experiencing 
several episodes, the number of days of DSN will be summed up. The NBR model, on the 
integer number of days of severe neutropenia, will be used to analyze the DSN endpoint during 
the fixed time window outlined above, with the treatment arm as the only covariate. The method 
will also be used to construct point estimates and confidence intervals. The GENMOD procedure 
in SAS version 9.4 or later will be used.  
Secondary Efficacy Endpoints (Cycle 1 and Cycles 1 to 4): 
 DSN in Cycle 1 with only mature neutrophils. The NBR model, on the integer 
number of days of severe neutropenia, will be used to analyze the DSN endpoint 
during the fixed time window outlined above, with the treatment arm as the only 
covariate. The method will also be used to construct point estimates and confidence 
intervals. The GENMOD procedure in SAS version 9.4 or later will be used.  
Maximum decrease from baseline (prior to docetaxel dose) in platelet count for each 
patient in Cycle 1. The Wilcoxon Rank Sum test will be used. The method will also 
be used to construct point estimates and confidence intervals. The NPAR1WAY 
procedure in SAS version 9.4 or later will be used for the analysis. 
 Proportion of patients with NLR > 5 after Day 7 through Day 15 in Cycle 1. The 
Barnard’s test will be used to evaluate the difference in proportions between the 
treatment arms. The method will also be used to construct point estimates and 2-sided 
confidence intervals. The FREQ procedure in SAS version 9.4 or later will be used 
for the analysis. 
 AUC using the trapezoidal quadrature method for bone pain, from Day 1 through 
Day 8 in Cycle 1, based on the bone pain score from the patient bone pain scale. The 
Wilcoxon Rank Sum test will be used. The method will also be used to construct 
point estimates and confidence intervals. The NPAR1WAY procedure in SAS version 
9.4 or later will be used for the analysis. 
 Estimated mean pain score from the patient bone pain scale from pre-dose Day 1 
through Day 8 in Cycle 1. A repeated measures mixed linear model with the pre-dose 
Day 1 value and treatment arm as covariates will be used to analyze this endpoint. 

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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. 
 Proportion of patients with thrombocytopenia (all grade) in Cycles 1 to 4. The 
Barnard’s test will be used to evaluate the difference in proportions between the 
treatment arms. The method will also be used to construct point estimates and 2-sided 
confidence intervals. The FREQ procedure in SAS version 9.4 or later will be used 
for the analysis. 
 Incidence of infections in Cycles 1 to 4. The NBR model will be used to analyze the 
endpoint, with the treatment arm as the only covariate. An offset variable will be used 
to account for exposure time. The method will also be used to construct point 
estimates and confidence intervals. The GENMOD procedure in SAS version 9.4 or 
later will be used. 
Exploratory Efficacy Endpoints (Cycle 1): 
 Proportion of patients in Cycle 1 with: 
o Thrombocytopenia (all grade). The Barnard’s test will be used to evaluate the 
difference in proportions between the treatment arms. The method will also be 
used to construct point estimates and 2-sided confidence intervals. The FREQ 
procedure in SAS version 9.4 or later will be used for the analysis. 
o Grade 3 (ANC >= 0.5 and < 1 × 109/L)  and Grade 4 neutropenia (ANC < 0.5 
× 109/L). The Barnard’s test will be used to evaluate the difference in 
proportions between the treatment arms. The method will also be used to 
construct point estimates and 2-sided confidence intervals. The FREQ 
procedure in SAS version 9.4 or later will be used for the analysis. 
o Grade 4 neutropenia (ANC < 0.5 × 109/L). The Barnard’s test will be used to 
evaluate the difference in proportions between the treatment arms. The 
method will also be used to construct point estimates and 2-sided confidence 
intervals. The FREQ procedure in SAS version 9.4 or later will be used for the 
analysis. 
o Grade 4 neutropenia (ANC<0.5 x10E9/L) for mature neutrophils only. The 
method will also be used to construct point estimates and 2-sided confidence 
intervals. The FREQ procedure in SAS version 9.4 or later will be used for the 
analysis. 
o Grade 3 neutropenia (ANC < 1 × 109/L) and ANC >= 0.5 × 109/L). The 
Barnard’s test will be used to evaluate the difference in proportions between 
the treatment arms. The method will also be used to construct point estimates 
and 2-sided confidence intervals. The FREQ procedure in SAS version 9.4 or 
later will be used for the analysis. 
o Bands > 0 after Day 7 through Day 15. The Barnard’s test will be used to 
evaluate the difference in proportions between the treatment arms. The 
method will also be used to construct point estimates and 2-sided confidence 

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intervals. The FREQ procedure in SAS version 9.4 or later will be used for the 
analysis. 
o Promyelocytes plus myelocytes >0 after Day 7 through Day 15. The 
Barnard’s test will be used to evaluate the difference in proportions between 
the treatment arms. The method will also be used to construct point estimates 
and 2-sided confidence intervals. The FREQ procedure in SAS version 9.4 or 
later will be used for the analysis. 
o Promyelocytes, myelocytes, metamyelocytes and bands > 0 after Day 7 
through Day 15. The method will also be used to construct point estimates and 
2-sided confidence intervals. The FREQ procedure in SAS version 9.4 or later 
will be used for the analysis. 
o LMR < 3.2 after Day 7 through Day 15; time course of percentage of patients 
with LMR < 3.2 over time in Cycle 1. The Barnard’s test will be used to 
evaluate the difference in proportions between the treatment arms. The 
method will also be used to construct point estimates and 2-sided confidence 
intervals. The FREQ procedure in SAS version 9.4 or later will be used for the 
analysis. 
o PLR > 200 after Day 7 through Day 15; time course of percentage of patients 
with PLR > 200 over time in Cycle 1. The Barnard’s test will be used to 
evaluate the difference in proportions between the treatment arms. The 
method will also be used to construct point estimates and 2-sided confidence 
intervals. The FREQ procedure in SAS version 9.4 or later will be used for the 
analysis. 
o For the below bone pain measurements, The Barnard’s test will be used to 
evaluate the difference in proportions between the treatment arms. The 
method will also be used to construct point estimates and 2-sided confidence 
intervals. The FREQ procedure in SAS version 9.4 or later will be used for the 
analysis: 
o At least 1 day of bone pain 
o At least 2 days of bone pain 
o At least 3 days of bone pain 
o At least 4 days of bone pain 
o At least 5 days of bone pain 
o At least 6 days of bone pain 
o At least 7 days of bone pain 
o At least 8 days of bone pain 
 Proportion of patients in Cycle 1 who needed bone pain medication (defined as any 
medication reported on the pain medication assessment from Day 1 through Day 8). 
The Barnard’s test will be used to evaluate the difference in proportions between the 
treatment arms. The method will also be used to construct point estimates and 2-sided 

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confidence intervals. The FREQ procedure in SAS version 9.4 or later will be used 
for the analysis.  
 Time (in days) to first use of bone pain medication. The log-rank test (LIFETEST 
procedure in SAS) will be used to compare time to first use of bone pain medication 
between the treatment groups. Separate analyses will be made with respect to narcotic 
and non-narcotic analgesics.  
 DSN in Cycle 1 in patients with locally advanced or metastatic NSCLC after 
platinum failure. The analysis will be done as per the primary endpoint. 
 DSN in Cycle 1 with only mature ANC, thus excluding bands in patients with locally 
advanced or metastatic NSCLC after platinum failure. The analysis will be done as 
per the primary endpoint.  
 DSN in Cycle 1 in patients with HRPC. The analysis will be done as per the primary 
endpoint. 
 DSN in Cycle 1 with only mature ANC, thus excluding bands in patients with with 
HRPC. The analysis will be done as per the primary endpoint.  
 DSN in Cycle 1 in patients with advanced or metastatic breast cancer who have failed 
< 5 prior lines of chemotherapy. The analysis will be done as per the primary 
endpoint. 
 DSN in Cycle 1 with only mature ANC, thus excluding bands in patients with 
advanced or metastatic breast cancer who have failed <5 prior lines of chemotherapy. 
The analysis will be done as per the primary endpoint.  
 DSN in Cycle 1 in patients with locally advanced or metastatic NSCLC after 
platinum failure or HRPC. The analysis will be done as per the primary endpoint. 
 DSN in Cycle 1 with only mature ANC, thus excluding bands in patients with locally 
advanced or metastatic NSCLC after platinum failure or HRPC. The analysis will be 
done as per the primary endpoint. 
 Platelet count at least 30% change from baseline at any time during Cycle 1. The 
Barnard’s test will be used to evaluate the difference in proportions between the 
treatment arms. The method will also be used to construct point estimates and 2-sided 
confidence intervals. The FREQ procedure in SAS version 9.4 or later will be used 
for the analysis. 
 ANC nadir during Cycle 1. The Wilcoxon Rank Sum test will be used to analyze the 
endpoint. The method will also be used to construct point estimates and confidence 
intervals. The NPAR1WAY procedure in SAS version 9.4 or later will be used for the 
analysis. 
 CD34+ at pre-dose on Day 1, pre-dose on Day 2, Days 6, 7, 8, 9, 10, and 15 in Cycle 
1, and pre-dose on Day 1 in Cycle 2. A repeated measure mixed linear model with the 
pre-dose on day 1 cycle 1 value and treatment arm as covariates will be used to 
analyze this endpoint. 

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 For selected countries only: maximum change from baseline in the following 
cytokine panel: IL-1beta, IL-6, IL-12p70, IL-12p40, IL-17A, IL-23, G-CSF, 
GM-CSF, IFN-alpha, IFN-gamma, TNF-alpha, IL-2, FLT-3 ligand, and IL-8. The 
Wilcoxon Rank Sum test will be used to analyze the endpoint. The method will also 
be used to construct point estimates and confidence intervals. The NPAR1WAY 
procedure in SAS version 9.4 or later will be used for the analysis. 
Exploratory Efficacy Endpoints (Cycles 1 to 4): 
 Proportion of patients in Cycles 1 to 4 with: 
o FN (ANC <1.0 × 109/L AND a single temperature of >38.3°C or a sustained 
temperature of ≥38°C for more than 1 hour). The Barnard’s test will be used 
to evaluate the difference in proportions between the treatment arms. The 
method will also be used to construct point estimates and 2-sided confidence 
intervals. The FREQ procedure in SAS version 9.4 or later will be used for the 
analysis. 
o Grade 4 neutropenia (ANC < 0.5 × 109/L). The Barnard’s test will be used to 
evaluate the difference in proportions between the treatment arms. The 
method will also be used to construct point estimates and 2-sided confidence 
intervals. The FREQ procedure in SAS version 9.4 or later will be used for the 
analysis 
 Maximum change from baseline in CD34+ counts in each arm. A Wilcoxon signed-
rank test will be used to analyze this endpoint. The UNIVARIATE procedure in SAS 
version 9.4 or later will be used for the analysis. 
 Maximum difference between treatment arms in CD34+ counts. The Wilcoxon Rank 
Sum test will be used to analyze this endpoint. The method will also be used to 
construct point estimates and confidence intervals. The NPAR1WAY procedure in 
SAS version 9.4 or later will be used for the analysis. 
 Maximum change from baseline in haptoglobin level in each arm. A Wilcoxon 
signed-rank test will be used to analyze this endpoint. The UNIVARIATE procedure 
in SAS version 9.4 or later will be used for the analysis. 
 Maximum difference between treatment arms in haptoglobin level. The Wilcoxon 
Rank Sum test will be used to analyze this endpoint. The method will also be used to 
construct point estimates and confidence intervals. The NPAR1WAY procedure in 
SAS version 9.4 or later will be used for the analysis. 
 Healthcare utilization endpoints: 
o Incidence of 30-day rehospitalizations - all cause. The NBR model will be 
used to analyze the endpoint, with the treatment arm as the only covariate. An 
offset variable will be used to account for exposure time. The method will also 
be used to construct point estimates and confidence intervals. The GENMOD 
procedure in SAS version 9.4 or later will be used. 
o Incidence of all cause hospitalizations. The NBR model will be used to 
analyze the endpoint, with the treatment arm as the only covariate. An offset 

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variable will be used to account for exposure time. The method will also be 
used to construct point estimates and confidence intervals. The GENMOD 
procedure in SAS version 9.4 or later will be used. 
o Duration of all cause hospitalizations. The Wilcoxon Rank Sum test will be 
used. The method will also be used to construct point estimates and 
confidence intervals. The NPAR1WAY procedure in SAS version 9.4 or later 
will be used for the analysis. 
o Incidence of all cause ER visits. The NBR model will be used to analyze the 
endpoint, with the treatment arm as the only covariate. An offset variable will 
be used to account for exposure time. The method will also be used to 
construct point estimates and confidence intervals. The GENMOD procedure 
in SAS version 9.4 or later will be used. 
o Incidence of all cause ICU stays. The NBR model will be used to analyze the 
endpoint, with the treatment arm as the only covariate. An offset variable will 
be used to account for exposure time. The method will also be used to 
construct point estimates and confidence intervals. The GENMOD procedure 
in SAS version 9.4 or later will be used. 
o Duration of all cause ICU stays. The Wilcoxon Rank Sum test will be used. 
The method will also be used to construct point estimates and confidence 
intervals. The NPAR1WAY procedure in SAS version 9.4 or later will be 
used for the analysis. 
o Incidence of all cause docetaxel dose delay, dose reduction, or dose 
discontinuation. The NBR model will be used to analyze the endpoints, with 
the treatment arm as the only covariate. An offset variable will be used to 
account for exposure time. The method will also be used to construct point 
estimates and confidence intervals. The GENMOD procedure in SAS version 
9.4 or later will be used: 
o Docetaxel dose delays > 7 days 
o Regimen switching 
o Treatment discontinuation 
o 
Proportion of Relative dose intensity (RDI) ≤ 85% where the RDI is defined as 
RDI = 
Cumulative dose of administered docetaxel (mg/m2)/ Number 
of weeks from Day1 Cycle 1 to Day 1 Cycle 4 plus 3 weeks 
Total calculated doses/12 weeks 
The Barnard’s test will be used to evaluate the difference in 
proportions between the treatment arms. The method will also be used 
to construct point estimates and confidence intervals. The FREQ 
procedure in SAS version 9.4 or later will be used for the analysis 
 

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o Incidence of transfusions due to thrombocytopenia. The NBR model will be 
used to analyze the endpoint, with the treatment arm as the only covariate. An 
offset variable will be used to account for exposure time. The method will also 
be used to construct point estimates and confidence intervals. The GENMOD 
procedure in SAS version 9.4 or later will be used. 
o Incidence of antibiotics use. The NBR model will be used to analyze the 
endpoint, with the treatment arm as the only covariate. An offset variable will 
be used to account for exposure time. The method will also be used to 
construct point estimates and confidence intervals. The GENMOD procedure 
in SAS version 9.4 or later will be used. 
 Data collection on disease progression. The log-rank test (LIFETEST procedure in 
SAS version 9.4 or later) will be used to compare time to disease progression between 
the treatment groups. The method will also be used to construct point estimates and 
confidence intervals. 
 QoL endpoints will be analyzed in safety analysis set: 
o Health-related QoL questionnaire evaluated with EORTC QLQ-C30 Item 30 
(response to question “How do you rate your overall quality of life during the past 
week”) in Cycle 1 to 4 will be analyzed using linear mixed model for repeated 
measures (MMRM) with the Cycle 1 Day 1 value and treatment arm as covariates. 
The method will also be used to construct point estimates and confidence intervals. 
The MIXED procedure in SAS v9.4 or later will be used for the analysis. The 
summary statistics in terms of counts, means, standard deviations, medians, 
minimums, and maximums for individual questions will be summarized in a tabular 
format. 
o Health-related QoL questionnaire evaluated with EORTC QLQ-C30 will also be 
analyzed with the summary scores. The EORTC QLQ-C30 scoring method 
combines the 30 questions from the questionnaire into 15 scores: global health 
state/QoL, functional scale (5 items), and symptoms scale (9 items) (Fayers et al, 
2001). Three summary measures will be constructed: the QLQ-C30 Summary 
Score, which combined the symptom and functional scales (excluding the financial 
difficulties item), the symptom summary score (excluding the financial difficulties 
item), and the functional summary score (Hinz et al, 2012). The symptom summary 
score will be analyzed using linear mixed model for repeated measures (MMRM) 
with the Cycle 1 Day 1 value and treatment arm as covariates. The method will also 
be used to construct point estimates and confidence intervals. The MIXED 
procedure in SAS v9.4 or later will be used for the analysis. The summary statistics 
in terms of counts, means, standard deviations, medians, minimums, and 
maximums for the 15 scores, the QLQ-C30 summary score, symptom score and the 
functional summary score will be summarized in a tabular format. 
o The response to the question “Your Health Today” from EQ-5D-5L in Cycle 1 to 4 
will be analyzed using linear mixed for model repeated measures (MMRM) with 
the Cycle 1 Day 1 value and treatment arm as covariates. The method will also be 
used to construct point estimates and confidence intervals. The MIXED procedure 
in SAS v9.4 or later will be used for the analysis. The summary statistics in terms 
of counts, means, standard deviations, medians, minimums, and maximums for the 
question “Your Health Today” will be summarized in a tabular format. 
o The EQ-5D-5L data will be converted into a health utility score using the interim 

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EQ-5D-5L crosswalk value set for the United States (van Hout et al, 2012) unless a 
validated EQ-5D-5L value set for the United States becomes available. The EQ-
5D-5L health utility score in Cycle 1 to 4 will be analyzed using linear mixed 
model for repeated measures (MMRM) with the Cycle 1 Day 1 value and treatment 
arm as covariates. The method will also be used to construct point estimates and 
confidence intervals. The MIXED procedure in SAS v9.4 or later will be used for 
the analysis. The summary statistics in terms of counts, means, standard deviations, 
medians, minimums, and maximums for the health utility score will be summarized 
in a tabular format. 
Safety Endpoints 
 Incidence, occurrence, and severity of AEs/SAEs. These endpoints will be presented 
descriptively in tables and listings. 
 Safety and tolerability (physical examination and safety laboratory assessments). 
These endpoints will be presented descriptively in tables and listings. 
14.2. 
Statistical Analysis Considerations 
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 patients who received at least 1 dose of plinabulin or docetaxel and collection and at least 1 
PK sample collected postdose 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.  Patients in Phase 3 will follow the 
plinabulin and docetaxel PK sampling schedules from Phase 2. 
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. 

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14.2.2. 
Analysis Sets of Phase 3 
14.2.2.1. Intent-to-Treat Analysis Set 
The intent-to-treat (ITT) analysis set for Phase 3 is comprised of all Phase 3 patients that have 
been randomized in the study.  
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 is comprised of all Phase 3 patients that have been randomized in the 
study and have received at least one dose of study medication.  
14.2.2.3. Health Economic and Patient Reported Outcomes 
Health economic and patient reported outcomes will be conducted on the safety analysis set, 
which is 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. 
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. 
General Efficacy Analyses Considerations  
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.  
Primary efficacy endpoint will be imputed by multiple imputation method as sensitivity analysis. 
Missing pain score data: In the case in which analgesic medication was taken during the 
treatment period, as sensitivity analyses, the pain scores will be imputed using the last 

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observation carried forward (LOCF) method, Worst Observation Carried Forward (WOCF), and 
Baseline Observation Carried Forward (BOCF).  
14.2.6.1. Phase 3 Efficacy Analyses Considerations 
14.2.6.1.1. Primary Efficacy Analysis Considerations 
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 ANC 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, 
ANCs 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 
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 

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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. 
14.2.7. 
Pharmacokinetic and Pharmacodynamic Analyses Considerations 
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. 
Plinabulin PK will be characterized using the population PK approach. Population PK parameter 
estimates, and individual PK parameters, including AUC and Cmax will be summarized. 
Exposure-Neutropenia Relationship 
A sequential population PK/PD modeling approach will be used to characterize the 
exposure-neutropenia relationship.  The semi-physiological model described by Friberg (2003)  
will be used to characterize the time course of neutropenia in the exposure-neutropenia model.   
The developed exposure-response models will be used to simulate ANC profiles for the 
computation of key PD endpoints such as DSN, DMSN, and area over the ANC curve (AOC). 
The latter will be calculated as the area below the threshold of <0.5 x 109 cells/L and above 
ANC-time response curve in a chemotherapy cycle.  Details will be included in the 
Pharmacometrics Analysis Plan (PAP). 
Exposure-Blood Pressure Analysis 
A sequential PK-PD model analysis will be performed.  Since the ambulatory blood pressure 
measurements (ABPM) are subject to circadian variations, ABPM will be modeled to describe 
the circadian rhythm in blood pressure over the 4.5-hour observation period.  The diurnal rhythm 

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in the AMBP data will be described with the cosine function (Hempel 1998) in the 
exposure-ABPM models.  Details will be included in the PAP. 
Exposure-QTc Analysis 
Either a direct or sequential PK-PD model analysis will be performed.  The choice of the 
modeling approach will be informed by the matching or non-matching of PK sampling times 
with ECG observation times. QT measurements corrected with the Fridericia formula will be 
used in the exposure-QTc analysis. Details will be included in the PAP. 
14.3. 
Safety Analyses Considerations 
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. 
14.3.4. 
Laboratory Analyses 
Descriptive summary statistics for laboratory values will be provide as well as the shift table..  

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14.3.5. 
Vital Signs 
Descriptive statistics 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 (40 mg) 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 [40 mg] 
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 (40 mg) 
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 
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). 

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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 
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 

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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 
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. 
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. 
Andersen, PK, Borgan O, Gill RD, Keiding N. (1992), Statistical Models Based on Counting 
Processes, New York: Springer-Verlag. 
Andersen PK and Gill RD. Cox’s Regression Model Counting Process: A Large Sample Study. 
Annals of Statistics. 1982;10:1100-1120.  
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 
Bablok W, Passing H, Bender R, Schneider B. A general regression procedure for method 
transformation. Application of linear regression procedures for method comparison studies in 
clinical chemistry, Part III. J Clin Chem Clin Biochem. 1988;26(11):783-90. 
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. 
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. Blood 2016 128:2508. 
Burris HA, Belani CP, Kaufman PA, Gordon AN, Schwartzberg LS, Paroly WS, Shahin S, 
Dreiling L, Saven A. Pegfilgrastim on the Same Day Versus Next Day of Chemotherapy in 
Patients With Breast Cancer, Non-Small-Cell Lung Cancer, Ovarian Cancer, and Non-Hodgkin's 
Lymphoma: Results of Four Multicenter, Double-Blind, Randomized Phase II Studies. J Oncol 
Pract. 2010;6(3):133-40. 
Chow SC, Shao J, Wang H. 2003. Sample Size Calculations in Clinical Research. Marcel 
Dekker. New York. 
Crawford J, Dale DC, Lyman GH. Chemotherapy induced neutropenia.  Risks, consequences and 
new directions for its management. Cancer 2004; 100:228-237. 
Deming WE. (1943). Statistical adjustment of data. Wiley, NY (Dover Publications edition, 
1985).  
Dinan MA, Hirsch BR, Lyman GH. Management of chemotherapy-induced neutropenia: 
measuring quality, cost, and value. J. Natl Compr Canc Netw. 2015 Jan;13(1):e1-7.  
Dinarello CA. A clinical perspective of IL-1β as the gatekeeper of inflammation. Eur J 
Immunol. 2011 May;41(5):1203-17. 

Protocol BPI-2358-105 
  
 
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Fayers, PM. Interpreting Quality of Life Data: Population-based reference data for the EORTC 
QLQ-C30. Eur J cancer. 2001 Jul;37(11):1331-4. 
Friberg LE, Karlsson MO. Mechanistic models for myelosuppression. Invest New Drugs. 2003; 
21:183-194.  
Gornstein E., Schwarz TL. The paradox of paclitaxel neurotoxicity: Mechanisms and 
unanswered questions. Neuropharmacology. 2014 Jan;76 Pt A:175-83. 
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. 
Hempel G, Karlsson MO, de Alwis DP, Toublanc N, McNay J and Schaefer HG. Population 
pharmacokinetic-pharmacodynamic modeling of moxonidine using 24-hour ambulatory blood 
pressure measurements. Clin Pharmacol Ther. 1998; 64:622-635. 
Hinz, A, Einenkel, J,and Briest, S, et al. Is it useful to calculate sum scores of the quality of life 
questionnaire EORTC QLQ-C30? Eur J Cancer Care. 2012 Sep;21(5):667-83 
Hochberg, Y.; Benjamini, Y. More powerful procedures for multiple significance testing. 
Statistics in Medicine. 1990, 9 (7): 811–818. 
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. 
Hommel G. A stagewise rejective multiple test procedure based on a modified Bonferroni test. 
Biometrika. 1988;75:383-386. 
Hommel G and Bernhard G. (1999). Bonferroni procedures for logically related hypotheses. 
Journal of Statistical Planning and Inference. 1999;82:119-128. 
Giesinger JM, Wintner LM, Zabernigg A, Gamper EM, Oberguggenberger AS, Sztankay MJ, et 
al. Assessing quality of life on the day of chemotherapy administration underestimates patients' 
true symptom burden. BMC Cancer. 2014 Oct 10;14:758. 
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. 
Kawatkar AA, Farias AJ, Chao C, Chen W, Barron R, Vogl FD, Chandler DB. Hospitalizations, 
outcomes, and management costs of febrile neutropenia in patients from a managed care 
population. Support Care Cancer. 2017 Sep;25(9):2787-2795. 
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 
Kirshner JJ, Heckler CE, Janelsins MC, Dakhil SR, Hopkins JO, Coles C, Morrow GR. 
Prevention of pegfilgrastim-induced bone pain: a phase III double-blind placebo-controlled 

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randomized clinical trial of the university of rochester cancer center clinical community 
oncology program research base. J Clin Oncol. 2012;30(16):1974-9. 
Kubista E, Glaspy J, Holmes FA, Green MD, Hackett J, Neumann T; Pegfilgrastim Study Group. 
Bone pain associated with once-per-cycle pegfilgrastim is similar to daily filgrastim in patients 
with breast cancer. Clin Breast Cancer. 2003;3(6):391-8. 
Kuderer NM, Dale DC, Crawford J, Cosler LE, Lyman GH. Mortality, morbidity, and cost 
associated with febrile neutropenia in adult cancer patients. Cancer. 2006 May 
15;106(10):2258-66. 
Lambertini M, Del Mastro L, Bellodi A, Pronzato P. The five "Ws" for bone pain due to the 
administration of granulocyte-colony stimulating factors (G-CSFs). Crit Rev Oncol Hematol. 
2014;89(1):112-28. 
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 
Lan KKG. and DeMets DL. 1983. 'Discrete sequential boundaries for clinical trials.' Biometrika, 
70, pages 659-663. 
Lloyd GK, Muller P, Kashyap A, et al. Plinabulin: Evidence for an immune-mediated 
mechanism of action, AACR Tumor Microenvironment Event 2016. 
Mackey, JBG, Coffelt, SB and Carlin, LM. Neutrophil Maturity in Camcer. Frontiers in 
Immunology. Aug (2014) Vol 10:1-11. 
Marbury TC, Jin B, Panebianco D et al. Lack of effect of aprepitant or its prodrug fosaprepitant 
on QTc intervals in healthy subjects. Anesth Analg. 2009;109(2):418-25. 
Mehrotra DV, Liu F, Permutt T. Missing data in clinical trials: control‐based mean imputation 
and sensitivity analysis. Pharmaceutical Statistics. 2017;16:378–392. 
Meza L, Baselga J, Holmes FA. 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). 
Moore DC, Pellegrino AE. Pegfilgrastim-Induced Bone Pain: A Review on Incidence, Risk 
Factors, and Evidence-Based Management. Ann Pharmacother. 2017 Sep;51(9):797-803. 
Mortaz, E, Alipoor, SD, Adcock, IM, Mumby, S and Koenderman, L. Update on Neutrophil 
Function in Severe Inflammation. Frontiers in Immunology. Oct (2018) Vol 9:1-14. 
Nabholtz JM, Riva A., Taxane/Anthracycline Combinations: Setting A New Standard in Breast 
Cancer?, Oncologist. 2001; 6 Suppl 3:5-12 
Neulasta® Package Insert. Amgen. US 2002. 
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/PediatricAd
visoryCommittee/UCM235408.pdf2015. 
Newcombe RG. Two-sided confidence intervals for the single proportion: comparison of seven 
methods. Stat Med. 1998a;17(8):857-72. 

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BeyondSpring Pharmaceuticals, Inc. 
 
 
 
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Newcombe RG. Interval estimation for the difference between independent proportions: 
comparison of eleven methods. Stat Med. 1998b;17(8):873-90. 
Newcombe RG. Improved confidence intervals for the difference between binomial proportions 
based on paired data. Stat Med. 1998c;17(22):2635-50. 
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. 
O'Brien PC and Fleming TR. 1979. 'A multiple testing procedure for clinical trials.' Biometrics, 
35, pages 549-556. 
Pizzo P. Management of fever in patients with cancer and treatment induced neutropenia. New 
Engl J Medicine 1993; 328:1323-1332. 
Plinabulin Investigator Brochure. 14 September 2017. 
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. 
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. 
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. 
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). 
Taxotere® (Prescribing Information). Sanofi-aventis—US; Rev 12/2015 
(http://products.sanofi.us/Taxotere/taxotere.html). 
Therneau TM and Grambsch PM. (2000), Modeling Survival Data: Extending the Cox Model, 
New York: Springer-Verlag. 
Van Hout, B, Jansssen, MF, and Feng, MF, et al. Interim scoring for the EQ-5D-5L: mapping the 
EQ-5D-5L to EQ-5D-3L value sets. Value Health. 2012. Jul-Aug;15(5):708-15. 
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. 
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. 
Yavas O, Yazici M, Eren O et al. Support Care Cancer. 2008;16: 1011. 
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. 

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Zarixo® (filgrastim) FDA Oncologic Drugs Advisory Committee Meeting (FDA Advisory 
Committee Briefing Document). Jan 7, 2015. 
Zhang L, Yu Q, Wu XC, Hsieh MC, Loch M, Chen VW, et al. Impact of chemotherapy relative 
dose intensity on cause-specific and overall survival for stage I-III breast cancer: ER+/PR+, 
HER2- vs. triple-negative. Breast Cancer Res Treat. 2018 May;169(1):175-187. 

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17. 
APPENDICES 

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APPENDIX A. 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 B. 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 Amendment 7 
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: 
_______________________________ 
 
_______________________________ 
 
_______________________________ 
 
_______________________________