An Open-label, Single-Center, Phase 1b/2 Study to Evaluate the Safety of Plinabulin in Combination With Radiation/Immunotherapy in Patients With Select Advanced Malignancies After Progression on PD-1 or PD-L1 Targeted Antibodies
Phase: PHASE1
Conditions: Advanced Bladder Carcinoma, Advanced Lung Non-Small Cell Carcinoma, Advanced Malignant Solid Neoplasm, Advanced Melanoma, Advanced Merkel Cell Carcinoma, Advanced Renal Cell Carcinoma, Clinical Stage III Cutaneous Melanoma AJCC v8, Clinical Stage III Merkel Cell Carcinoma AJCC v8, Clinical Stage IV Cutaneous Melanoma AJCC v8, Clinical Stage IV Merkel Cell Carcinoma AJCC v8, Pathologic Stage III Cutaneous Melanoma AJCC v8, Pathologic Stage III Merkel Cell Carcinoma AJCC v8, Pathologic Stage IIIA Cutaneous Melanoma AJCC v8, Pathologic Stage IIIA Merkel Cell Carcinoma AJCC v8, Pathologic Stage IIIB Cutaneous Melanoma AJCC v8, Pathologic Stage IIIB Merkel Cell Carcinoma AJCC v8, Pathologic Stage IIIC Cutaneous Melanoma AJCC v8, Pathologic Stage IIID Cutaneous Melanoma AJCC v8, Pathologic Stage IV Cutaneous Melanoma AJCC v8, Pathologic Stage IV Merkel Cell Carcinoma AJCC v8, Stage III Bladder Cancer AJCC v8, Stage III Lung Cancer AJCC v8, Stage III Renal Cell Cancer AJCC v8, Stage IIIA Bladder Cancer AJCC v8, Stage IIIA Lung Cancer AJCC v8, Stage IIIB Bladder Cancer AJCC v8, Stage IIIB Lung Cancer AJCC v8, Stage IIIC Lung Cancer AJCC v8, Stage IV Bladder Cancer AJCC v8, Stage IV Lung Cancer AJCC v8, Stage IV Renal Cell Cancer AJCC v8, Stage IVA Bladder Cancer AJCC v8, Stage IVA Lung Cancer AJCC v8, Stage IVB Bladder Cancer AJCC v8, Stage IVB Lung Cancer AJCC v8
Sponsor: M.D. Anderson Cancer Center

MD Anderson IND Sponsor Cover Sheet 
Protocol ID 
2020-0296 
Protocol Title 
An Open-label, Single-center, Phase 1b/2 Study to Evaluate the Safety 
of Plinabulin in Combination with Radiation/Immunotherapy in Patients 
with Select Advanced Malignancies after progression on PD-1 or PD-L1 
Targeted Antibodies 
Protocol Phase 
Phase 1b/2 
Protocol Version 
6.0 
Version Date 
10 May 2023 
Protocol PI 
Dr. Siqing Fu 
Department 
Investigational Cancer Therapeutics 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
154404 
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CLINICAL STUDY PROTOCOL 
 
An Open-label, Single-center, Phase1b/2 Study to Evaluate the Safety of 
Plinabulin in Combination with Radiation/Immunotherapy in Patients with Select 
Advanced Malignancies after progression on PD-1 or PD-L1 Targeted Antibodies 
 
Study Number: 2020-0296 
 
Study Phase: 1b/2 
 
IND Number: 154404 
 
MD Anderson Cancer Center 
1515 Holcombe Boulevard 
Houston, Texas 77030 
 
 
 
Version Number 
Amendment  
Date 
Original Protocol 
 
4.0 
 
 
 
08 June 2021 
 
5.0 
 
16 November 2021 
 
6.0 
 
10 May 2023 
 
 
 
 
 
 
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PROTOCOL SYNOPSIS 
Name of Study Institute: MD Anderson Cancer Center 
Protocol Number: 2020-0296 
Name of Investigational Product: Plinabulin 
Name of Active Ingredient: Plinabulin+ Anti-PD-1/PD-L1 Antibodies + Radiation Therapy 
Study Title: A Single-Center, Phase1b/2 Study to Evaluate the Safety and Efficacy of Plinabulin in 
Combination with Radiation/Immunotherapy in Subjects with Select Advanced Solid Malignancies after 
progression on PD-1 or PD-L1 Targeted Antibodies   
Study Phase:  1b/2 
Indication Under Investigation: Advanced Solid Malignancies 
Study Objectives: 
Primary Objective:  
• 
To assess the safety and tolerability of plinabulin when administered in combination with a 
radiation/immunotherapy regimen in subjects with select advanced solid malignancies after 
progression on anti-PD-1/PD-L1 mAb 
• 
To assess the objective tumor response rate (ORR) (complete response + partial response) 
Secondary Objectives: 
• 
To assess disease control rate (complete response, partial response + stable disease)  
• 
To determine progression-free survival (PFS)  
• 
To assess overall survival (OS) 
Exploratory Objectives:  
• 
To determine the gene mutation density for the evaluable samples 
• 
To assess TCR immune repertoire by sequencing in peripheral blood, pre- and post- treatment.  
• 
To perform Imaging CyTOF and/or single cell RNAseq analysis on tumor tissue: Immune 
Phenotyping, including DC, T cells, TAMs, pre and post treatment 
• 
To conduct phenotyping analysis of immune cells from peripheral blood using multicolor flow 
cytometry 
• 
To evaluate dendritic cell activation from whole blood upon the treatment  
• 
To utilize collected blood and tumor biopsy samples to discover novel response biomarkers 
Study Design: 
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This is a single center study with a Phase 1b and a Phase 2 component. 
Phase 1b: 
This is an open label, single-center study to assess the safety and tolerability of plinabulin when 
administered in combination with radiation/immunotherapy regimens in subjects with one of several 
metastatic or locally advanced cancers who had disease progression on anti-PD-1/PD-L1 mAb treatment 
as standard of care, and to assess objective response rate of the study regimen.  
The targeted cancer types for this study are as follows: 
1. Bladder Cancer 
2. Melanoma 
3. Merkel Cell Cancer 
4. MSI-H Cancers (of any histology) 
5. Non-small Cell Lung Cancer 
6. Renal Cell Cancer 
7. Small Cell Lung Cancer 
8. Any tumor type that has a checkpoint inhibitor approval 
The study cohort is tumor type specific. There are 8 study cohorts as mentioned above for this study. 
Anti-PD-1/PD-L1 mAb treatment cycle will define subject’s treatment cycle for the study.  
All subjects in Phase 1b will receive a triple combo treatment of Radiation Therapy (RT) + Plinabulin + 
anti-PD-1/PD-L1 mAb in Cycle 1, followed by anti-PD-1/PD-L1 mAb and plinabulin combo regimen in 
Cycle 2 and beyond until disease progression or development of unacceptable toxicity, withdrawal from 
study treatment, or discontinuation of this study (see table below). A short course of local consolidative 
RT will be administered in Cycle 1 starting from Day 1. Optional sequential RT may be administered to 
target other untreated lesions at discretion of the treating doctor in Cycle 2 of any regimens. Plinabulin 
will be dosed on Day 1 and Day 4 of Cycle 1 of any anti-PD-1/PD-L1 regimen, and if optional RT is 
given in Cycle 2, Plinabulin will also be given on Day 4 of Cycle 2. Plinabulin will be given on Day 1 of 
Cycle 3 and thereafter. Anti-PD-1/PD-L1 mAb will be dosed on Day 1 of every treatment cycle (also on 
Day 15 [Q4W] in case of regimen containing Avelumab or Durvalumab or Nivolumab as Anti-PD-1/PD-
L1 mAb). Subjects must receive the same anti-PD-1/PD-L1 mAb they failed in the prior treatment.  
Phase 1b/Phase 2: Study Drugs/Regimen 
Phase 1b/Phase 2: 
Study  
Drugs/Regimen 
Cycle 
Length 
Radiation 
Therapy 
(RT) 
Plinabulin 
 
30 mg/m2 
(Starting 
dose) 
or 
20 mg/m2 
Anti-PD-1/PD-L1 
mAb 
DLT Window 
After 2 doses of Anti-
PD-1/PD-L1 mAb 
RTX + Plinabulin + 
Avelumab 
1 Cycle = 
4 weeks 
C1D1-3 (8 
Gy x 3 
fractions) 
or C1D1-4 
(12.5 Gy x 
4 fractions) 
C1D1, 4  
C2D1 
C2D4 
(optional if 
RT on 
C2D1)  
Avelumab (800 
mg): D1, 15 of 
every cycle 
C1 = 4 weeks 
RTX + Plinabulin + 
Durvalumab 
1 Cycle = 
4 weeks 
Durvalumab (10 
mg/kg): D1, 15 of 
every cycle 
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RTX + Plinabulin + 
Nivolumab 
1 Cycle = 
4 weeks 
or C1D1-5 
(4 Gy x 5 
fractions) 
 
C2D1 
(optional) 
C3 onward 
D1 
Nivolumab (240 
mg): D1, 15 of 
every cycle 
RTX + Plinabulin + 
Atezolizumab 
1 Cycle = 
3 weeks 
Atezolizumab 
(1200 mg): D1 of 
every cycle 
C1-2 = 6 weeks 
RTX + Plinabulin + 
Pembrolizumab 
1 Cycle = 
3 weeks 
Pembrolizumab 
(200 mg): D1 of 
every cycle 
C = cycle, D = day, DLT = dose limiting toxicity, mAb = monoclonal antibody, PD = progression disease, RT = radiation 
therapy. 
The determination of maximum tolerated dose (MTD) 
The study will begin with 30 mg/m2 plinabulin in combination with a full dose of anti-PD-1/PD-L1 mAb 
and RT. Lower dose level at 20 mg/m2 of plinabulin will be explored as necessary depending on observed 
toxicity. Anti-PD-1 or PD-L1 antibody dose according to FDA drug inserts will not change in Phase 1b.  
The dose-limiting toxicity (DLT) is calculated after two doses of PD1/PDL1. Due to variability of the 
frequency of dosing, there is a range when the DLT is assessed. When PD1/PDL1 is Q2weeks, DLT 
period is 4 weeks. When PD1/PDL1 is Q3weeks, the DLT period is 6 weeks.  
A DLT is defined as any of the following plinabulin-related adverse events (AEs) or laboratory 
abnormalities, graded according to NCI CTCAE version 5.0: 
• 
Febrile neutropenia 
• 
Grade 4 hypertension 
• 
Grade 4 anemia unrelated to underlying disease 
• 
Grade 3 thrombocytopenia with clinically significant bleeding or grade 4 thrombocytopenia 
lasting more than 7 days and/or requiring a platelet transfusion 
• 
Grade 4 neutropenia lasting more than 7 days 
• 
≥Grade 3 nausea, vomiting, diarrhea, or electrolyte imbalances lasting >48 hours despite optimal 
prophylactic and curative treatment 
• 
≥Grade 3 hypersensitivity reaction (unless first occurrence and resolves within 6 hours with 
appropriate clinical management) 
• 
Treatment delay >21 days secondary to recovery from study drugs-related AEs.  
• 
≥Grade 3 non-hematologic AEs, except for the exclusions listed below. 
The following events will be excluded from the DLT definition: 
• 
Any AE ≥grade 3 clearly determined to be unrelated to study drug(s) (e.g., disease progression) 
• 
≥Grade 3 isolated alkaline phosphatase laboratory abnormality of any duration 
• 
≥Grade 3 isolated, asymptomatic amylase or lipase laboratory abnormality of any duration 
• 
≥Grade 3 endocrinopathies controlled by corticosteroids or hormone replacement 
• 
Vitiligo or Alopecia of any grade 
• 
Grade 3 fatigue. 
We will employ the Bayesian optimal interval (BOIN) design (Liu and Yuan, 2015; Yuan et al., 2016) to 
find the MTD based on all comers, including the targeted cancer types. The BOIN design is implemented 
in a simple way similar to the traditional 3+3 design, but is more flexible and possesses superior operating 
characteristics that are comparable to those of the more complex model-based designs, such as the 
continual reassessment method (CRM) (Zhou, Yuan and Nie, 2018). The two dose levels are 20 mg/m2 
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and 30 mg/m2 and the starting dose is 30 mg/m2. The target DLT rate for the MTD is ɸ = 0.25 and the 
maximum sample size is 12. We will enroll and treat patients in cohorts of size 3. 
Once we determine the MTD, an additional 10 patients will be enrolled for additional experience with 
safety and efficacy in each of the eight cancer cohorts and to determine the recommended Phase 2 dose 
(RP2D). The RP2D will be selected based on both safety and totality of clinical evidence (e.g., PK/PD 
data), and is not necessarily the MTD. Patients treated at the MTD/RP2D in the dose finding will roll over 
into the cohort expansion. Anti-PD-1/PD-L1 mAb dose will follow FDA recommendations to each 
indication and will not change in the expansion. 
Selection of cohort that will advance into Phase 2 will be based on the following consideration: 
1. The cohort with the best response rate, within a 9-week window after RT plus plinabulin with 2 
cycles (3 weeks Anti-PD-1/PD-L1 mAb dosing) of Anti-PD-1/PD-L1 mAb, will advance into 
Phase 2, if deemed well-tolerated. Upon sponsor’s discretion and totality of clinical evidence, 
other cohort(s) instead may be selected to advance into Phase 2. The final selection of the group 
to go into Phase 2 will be determined by a Safety Monitoring Committee. Please see charter for 
details. 
2. The response evaluation will be based on a minimum of 5 subjects and up to 10 subjects per 
cohort, unless enrollment of a given cohort is very slow and incomplete at the time sufficient 
response data is available on other cohorts, in which case that given cohort could be closed for 
further patient accrual.  
Phase 2: 
Subjects with the selected tumor type will be accrued to receive the plinabulin MTD/RP2D in 
combination with RT and anti-PD-1/PD-L1 mAb. Anti-PD-1/PD-L1 mAb dose will follow FDA 
recommendations to each indication and will not change in the study. They will be randomized to one of 
two treatment arms in a 1:1 ratio. The randomization will be stratified by the number of mets (oligo (<=3 
vs > 3) and ECOG 0-1 vs 2. 
Arm A: Radiation Therapy + Plinabulin + anti-PD-1/PD-L1 mAb (experimental) 
Arm B: Radiation Therapy + anti-PD-1/PD-L1 mAb (control) 
Subjects in Arm A will receive triple combo in Cycle 1, followed by plinabulin and anti-PD-1/PD-L1 
mAb double combo for Cycle 2 and beyond (see table below). 
Subjects in arm B will receive combo regimen of RT and anti-PD-1/PD-L1 mAb in Cycle 1, followed by 
anti-PD-1/PD-L1 mAb alone for Cycle 2 and beyond (see table below).  
Treatment will continue until disease progression, development of unacceptable toxicity, withdrawal from 
study treatment, or discontinuation of this study. Because the experimental combination arm is not 
expected to be worse than the control arm, no futility monitoring is planned.   
A short course of local consolidative RT will be administered in Cycle 1 starting from Day 1. An optional 
sequential RT to other untreated lesions at discretion of the treating doctor is allowed (Cycle 2 Q4W; 
Cycle 2 Q3W). Plinabulin will be dosed on Day 1 of every treatment cycle and/ or anti-PD-1/PD-L1 mAb 
will be dosed on Day 1 of every treatment cycle ((also on Day 15 [Q4W] in case of regimen containing 
Avelumab or Durvalumab or Nivolumab as Anti-PD-1/PD-L1 mAb) to subjects based on their treatment 
assignment.  
Assuming the ORR is 5% in control arm and 15% in experimental arm, based on Chi-squared test, a 
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sample size of 51 evaluable patients in each group is required to detect the difference with one sided type 
I error 0.2 and power 80% (nQuery 4.0). The BOIN elimination rule will be used to monitor toxicity in 
both arms independently. The monitoring will start from the 11thpatient and carried out every 10 patients.  
For subjects in Phase 1b and Phase 2, toxicity will be managed by treatment interruption, dose reduction 
and/or treatment discontinuation in accordance with prespecified dose modification instructions.  
Phase 2 Only: Study Drugs/Regimen 
Phase 2 only: Study 
Drugs/Regimen 
Cycle Length Radiation Therapy 
(RT) 
Plinabulin 
30 mg/m2 
(Starting dose) 
or 
20 mg/m2 
Anti-PD-1/PD-L1 
mAb 
DLT Window 
RTX + Avelumab 
1 Cycle = 4 
weeks 
C1D1-3 (8 Gy x 3 
fractions) or 
C1D1-4 (12.5 Gy x 
4 fractions) or 
C1D1-5 (4 Gy x 
5fractions) 
 
C2D1 (optional) 
N/Aa 
Avelumab (800 mg): 
D1, 15 of every cycle 
N/A 
RTX + Durvalumab 1 Cycle = 4 
weeks 
Durvalumab (10 
mg/kg): D1, 15 of 
every cycle 
RTX + Nivolumab 
1 Cycle = 4 
weeks 
Nivolumab (240 mg): 
D1, 15 of every cycle 
RTX + Atezolizumab 1 Cycle = 3 
weeks 
Atezolizumab (1200 
mg): D1 of every 
cycle 
RTX + 
Pembrolizumab 
1 Cycle = 3 
weeks 
Pembrolizumab (200 
mg): D1 of every 
cycle 
C = cycle, D = day, DLT = dose limiting toxicity, mAb = monoclonal antibody, N/A = not applicable, PD = progression disease, 
RT = radiation therapy. 
a. Plinabulin marked N/A only applies to Arm B for Phase 2, not Arm A. Plinabulin will be administered to subjects in Arm A on 
days listed in Phase 1b/Phase 2: Study Drugs/Regimen table above. 
The Study Treatments:  
Radiation Therapy (RT) Administration 
Radiation therapy will be delivered using external beam radiation, with either 2D/conventional 
techniques, three-dimensional conformal therapy, intensity modulated radiation therapy (IMRT), 
stereotactic radiosurgery (SRS) or proton beam therapy (PBT), at the discretion of the treating radiation 
oncologist. 
Radiation Therapy (RT) will be administered with one of three regimens: 8 Gy x 3 fractions, 12.5 Gy x 
4 fractions, and/or 4 Gy x 5 fractions from Days 1 to 3 (3 fractions), Days 1 to 4 (4 fractions), or Days 1 
to 5 (5 fractions) in Cycle 1. The choice of RT regimens for tumors and lesions is at the discretion of the 
treating radiation oncologist. RT will target up to a maximum of 5 tumor lesions, and any of the radiation 
regimens could be use simultaneously or sequentially. Optional sequential RT is at the discretion of the 
treating radiation oncologist is warranted to target other untreated lesions with same regimens described 
above (Cycle 2 Q4W; Cycle 2 Q3W). Treatment could be for any lesions in nodes and organs including 
brain and bone. Please always leave at least one measurable lesion untreated for disease assessment 
during the study. Assessment of responses however should not be reliant on RT treated tumor lesions and 
bony lesions. Brain metastasis should be treated and not be used for irRECIST response assessment.  
If patients develop toxicity attributable to radiation after receiving at least one dose of radiation, the rest 
of the radiation treatment may be discontinued if deemed by treating radiation oncologist to be in the best 
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interest of the patient, and the AEs will be documented. Since the number of fractions are between 3-5 
fractions, patients could receive at least 1 fraction up to 5 fractions. The initially prescribed dose per 
fraction will not change, but it is possible to simply reduce the total dose delivered. The patient will have 
a visit with the treating radiation oncologist at the end of every cycle of radiation treatment. 
PD-1 or PD-L1 Administration: 
Subjects must be given the same anti-PD-1/PD-L1 mAb on which they have failed in prior treatment. 
Anti-PD-1/PD-L1 mAb will be dosed according to FDA recommendations as specified under Phase 1b 
and Phase 2 above. Anti-PD-1/PD-L1 mAb treatment cycle will define subject’s treatment cycle for the 
study. The list of anti-PD-1/PD-L1 mAb approved to date for the following indications is provided here: 
1) Merkel cell cancer: Avelumab, Pembrolizumab  
2) Renal cell cancer: Pembrolizumab, Nivolumab  
3) Bladder cancer: Durvalumab 
4) MSI-H cancers (of any histology): Pembrolizumab, Nivolumab 
5) Non-small cell lung cancer: Pembrolizumab, Nivolumab, Atezolizumab, Durvalumab 
6) Small cell lung cancer: Pembrolizumab, Nivolumab, Atezolizumab 
7) Melanoma: Nivolumab or Pembrolizumab single agent 
8) Any tumor type that has any approved immune checkpoint inhibitors  
 
Please note any approved anti-PD-1/PD-L1 mAb can be used for the study.  
Anti-PD-1/PD-L1 mAb dose and administration route: 
1. Avelumab 800 mg IV over 1 hr on Day 1 and Day 15 in Q4W 
2. Atezolizumab 1200 mg Q3W IV 1 hr in 1st dose, may infuse over 30 min in subsequent doses if 
tolerated well  
3. Durvalumab 10 mg/kg IV over 1 hr on Day 1 and Day 15 in Q4W 
4. Nivolumab 240 mg IV over 30-60 min on Day 1 and Day 15 in Q4W 
5. Pembrolizumab 200 mg Q3W IV over 30 min 
Anti-PD-1/PD-L1 mAb will be administered after the rest period (at least 3 hours, but no later than 
12 hours) of RT, if applicable, and before plinabulin infusion. Please follow FDA product insert for the 
instructions of treatment dosing and toxicity management of each approved anti-PD-1 or PD-L1 mAb.  
Plinabulin Administration. Plinabulin will be administered on Day 1 and Day 4 in Cycle 1 
intravenously, and if optional RT is given in Cycle 2, Plinabulin will also be given on Day 1 and Day 4 of 
Cycle 2. Optional RT will always be given in Cycle 2 on Day 1. Plinabulin will always be given on Day 1 
of Cycle 3 and after. 
Two plinabulin dose levels may be explored in Phase 1b trial. Plinabulin dose level at 30 mg/m2 will be 
first tested in Phase 1b trial. If it is not deemed tolerable during the DLT observation, then the dose at 
20 mg/m2 will be explored.  
For plinabulin at 30 mg/m2 dose level a 60-minute infusion through IV with ± 10 min window is 
recommended. For plinabulin at 20 mg/m2 dose level a 30-minute infusion through IV with ± 5 min 
window is recommended. For patients with a body surface area (BSA) greater than 2.4 m2, dosing should 
be calculated using the maximum BSA of 2.4 m2 for Plinabulin. 
Plinabulin should always be administered at 1-2 hours after completion of anti-PD-1 or PD-L1 mAb 
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infusion when applicable, or at least 3 hours (but not longer than 12 hours) after the radiotherapy.  
Schedule of Assessments 
The Schedule of Assessments for the study is shown in Table 7. 
Safety & Efficacy Assessments 
Safety and tolerability are assessed throughout the study according to NCI-CTCAE version 5.0 
Vital signs, physical examination, and safety lab test result review (hematology, chemistry & urinalysis) 
will have to be performed prior to the study treatment to make sure the study treatment is safe to be 
administered. 
Tumor assessments will be performed by the investigators based on both immune-related Response 
Evaluation Criteria In Solid Tumors (irRECIST) and modified Response Evaluation Criteria In Solid 
Tumors (RECIST) 1.1. Treatment decisions by the investigator will be based on irRECIST. 
Tumor assessments will be carried out during the Screening, and every 9 weeks (± 1 week) for 27 weeks 
(during Q3W dosing) or every 8 weeks (± 1 week) for 24 weeks (during Q4W dosing), then every 
12 weeks during treatment cycles in the Treatment Phase regardless of treatment cycles and follow up 
period. Computed tomography (CT)/magnetic resonance imaging (MRI) scans of chest, abdomen, and 
pelvis and of other known sites of disease will be obtained at Screening (within 28 days prior to Cycle 1/ 
Day 1), at all tumor assessment time points, and as indicated clinically. RT treated lesions will not be 
used for response assessment. Please keep at least one measurable tumor lesion untreated by RT for 
disease response assessment across the treatment.  
The tumor assessment schedule should not be affected by interruptions in study treatment. The same 
method of assessment used at screening must be used at all time points. 
Subjects going off treatment without disease progression will also undergo tumor assessments per the 
Schedule of Procedures/Assessments until disease progression is documented or another anticancer 
therapy is initiated. 
If the time point tumor assessment is progressive disease (PD), treatment should continue, and tumor 
assessments repeated at least 4 weeks later in order to confirm immune-related progressive disease (irPD). 
Study Population: Advanced staged cancer subjects who are either unresponsive or relapsed following 
prior standard PD-1 or PD-L1 regimen +/- chemotherapy or anti-CTLA4, for one of the following 
cancers: non-small cell lung cancer, small cell lung cancer, renal cell cancer, bladder cancer, Merkle cell 
cancer, MSI-H cancer (any history), melanoma, and any other tumor type that has a checkpoint inhibitor 
approval.  
Treatment Duration: Treatment will continue until disease progression, development of 
unacceptable toxicity (i.e., DLTs), withdrawal from study treatment, or discontinuation of this study. 
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Duration of Study:  
Screen period: up to 28 days 
Treatment period: Study treatment continues until disease progression (estimate 2-6 months), 
development of unacceptable toxicity, withdrawal from study treatment, or discontinuation of this study. 
Follow-up period: Study Follow-up consists of the End of Treatment Visit and the Follow-up Visits. The 
End of Treatment Visit will occur within 30 days following the last dose of study treatment, then transit to 
the Follow-up visit period. The Follow-up Visit at every 12 weeks (±1 week) continue as long as the 
study subject is alive unless the subject withdraws consent or until the sponsor terminates the study. In the 
Follow-up Period, Subjects who discontinued for reasons other than progression of disease (and 
withdrawal from study treatment) will continue to visit the clinic for study assessments and evaluation of 
their disease by CT, MRI, or positron emission tomography (PET)/CT scan approximately every 
12 weeks until progression of disease is determined, the patient receives additional anti-neoplastic 
medication, or for a maximum of 5 years. Subjects who stopped treatment due to disease progression will 
be followed up for survival status. 
Subject Eligibility Criteria: 
Inclusion Criteria: 
1. Subjects must have one of several histologically or cytologically confirmed malignant 
neoplasms (non-small cell lung cancer, small cell lung cancer, renal cell cancer, bladder 
cancer, Merkle cell cancer, MSI-H cancer (any history), melanoma, and any other tumor 
type with checkpoint inhibitor approval that may or may not have progressed on previous 
anti-PD-1/PD-L1 mAb treatment +/- chemotherapy or anti-CTLA4 requiring further 
treatment. 
2. At least one lesion is amenable to radiation 
3. At least one additional non-contiguous lesion that has not been irradiated amenable to 
radiographic evaluation 
4. Have measurable disease based on irRECIST. 
5. Tissue must be newly obtained as a core needle biopsy (not FNA) of the lesion being 
evaluated  
6. Age ≥ 18 years. 
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. 
8. Subjects must be recovered from any prior major surgery. The major surgery must be 
performed at least 4weeks prior to consent date. 
9. Adequate hematologic function defined as: 
i. 
platelets≥100×109/L, 
ii. 
hemoglobin ≥ 9 g/dL  
iii. 
absolute neutrophil count (ANC) ≥1.5×109/L, 
iv. 
white blood cell (WBC) ≥ 3×109/L. 
Transfusions and growth factors are allowed. 
10. Adequate liver function defined as: 
i. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
≤2.5×upper limit of normal (ULN) (≤1.5×ULN if alkaline phosphatase is 
>2.5×ULN) (In the expansion cohort, subjects with known liver 
involvement may have ALT ≤5×ULN), 
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ii. Alkaline phosphatase < 4×ULN, 
iii. Total Bilirubin ≤1×ULN (In the expansion cohort, subjects with Gilbert’s 
syndrome [hereditary indirect hyperbilirubinemia] who must have a total 
bilirubin of ≤ 3×ULN), 
iv. Albumin ≥ 3g/dL. 
11. Renal function defined as a calculated or measured glomerular filtration rate (GFR) 
≥30 mL/min and Cockcroft-Gault equation. 
12. The patient has recovered to Grade ≤ 1 by the National Cancer Institute Common 
Terminology Criteria for Adverse Events, Version 5.0 (NCI-CTCAE v5.0) from the effects 
of recent surgery, radiotherapy, chemotherapy, hormonal therapy, or other targeted 
therapies, with the exception of alopecia. The exceptions for such effects are allowed lab 
values of ≤ Grade 2 specified elsewhere in these inclusion criteria. 
13. Subjects must give informed consent according to the rules and regulations of the 
individual participating sites. 
14. Negative urine pregnancy test in women of childbearing potential within 7 days of first 
dose of treatment and subjects of child-bearing potential must agree to use effective 
contraception during and for 5 months following the last dose of atezolizumab or 
nivolumab, for 4 months after the last dose of pembrolizumab, and for 3 months after last 
dose of Durvalumab and Avelumab, and for 3 months after your last dose of plinabulin. A 
woman of childbearing potential is defined as a premenopausal female capable of becoming 
pregnant. This includes women on oral, injectable or mechanical contraception; women 
who are single and women whose male sexual partners have been vasectomized or whose 
male sexual partners have received or are utilizing mechanical contraceptive devices. 
Exclusion Criteria: 
1. Evidence of complete or partial bowel obstruction. 
2. Subjects with primary central nervous system (CNS) tumor or CNS tumor involvement. 
However, subjects with metastatic CNS tumors may participate in this study if the patient 
is: 
• 
>4 weeks from prior therapy completion 
• 
Clinically stable with respect to the CNS tumor at the time of study entry 
• 
Not receiving steroid therapy in treating CNS tumor or CNS tumor involvement 
• 
Not receiving anti-convulsive medications (that were started for brain metastases). 
3. Need of Total Parenteral Nutrition. 
4. Allergic to any of PD1/ PDL1 agents intended to receive. 
5. Prior exposure to plinabulin. 
6. Pregnancy or lactation. 
7. Radiation (except planned or ongoing palliative radiation to bone outside of the region of 
measurable disease) ≤3 weeks prior to study drug administration date. 
8. Chemotherapy, or immunotherapy or any other systemic anticancer therapy ≤ 3 weeks prior 
to study drug administration date except anti-PD-1/PD-L1 mAb mono or combination 
therapy. 
9. Diagnosis or recurrence of invasive cancer other than the present cancer within 3 years 
(except basal or squamous cell carcinoma of the skin that has been definitively treated). 
10. Major surgery within four weeks before consent date. 
11. Unstable cardiovascular function or active cardiac disease: 
• 
Symptomatic ischemia (chest pain of cardiac origin), or 
• 
Uncontrolled clinically significant conduction abnormalities (e.g. 
ventricular tachycardia on antiarrhythmics are excluded; 1st degree AV 
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block or asymptomatic left anterior fascicular block (LAFB)/ right bundle 
branch block (RBBB) will not be excluded), or 
• 
Congestive heart failure (CHF) of NYHA Class ≥3, or 
• 
Myocardial infarction (MI) within 3 months of consent date. 
12. Uncontrolled active infection requiring parenteral antibiotics, antivirals, or antifungals 
within one week prior to the first dose. Active infection with concurrent treatment is 
acceptable only if the patient is clinically stable. 
13. Subject is known to be positive for Human Immunodeficiency Virus (HIV), Hepatitis B or 
Hepatitis C. 
14. Significantly diseased (as determined by the Principal Investigator [PI] or treating 
physician) or obstructed gastrointestinal tract or uncontrolled vomiting or diarrhea. 
Presence of ileus or other significant gastrointestinal disorder known to predispose to ileus 
or chronic bowel hypomotility 
15. Treatment with an investigational anti-cancer study drug within 3 weeks prior to study drug 
administration date. 
16. Concurrent therapy with approved or investigational anticancer therapeutics except 
PD-1/PD-L1 associated treatments. 
17. Medical, psychological, or social conditions that may interfere with the patient's 
participation in the study or evaluation of the study results. 
18. Men whose partner is a woman of child-bearing potential, (i.e., biologically able to 
conceive), and who is not employing two forms of highly effective contraception. Highly 
effective contraception (e.g., male condom with spermicide, diaphragm with spermicide, 
intra-uterine device) must be used by both sexes during the study and must be continued 
for 5 months following the last dose of atezolizumab or nivolumab, and 4 months after the 
last dose of pembrolizumab, and for 3 months after last dose of Durvalumab and 
Avelumab, and for 3 months after your last dose of plinabulin. Women of child-bearing 
potential is defined as sexually mature women who are not surgically sterile or who have 
not been naturally postmenopausal for at least 12 consecutive months (e.g., who has had 
menses any time in the preceding 12 consecutive months). 
Study Endpoints: 
Primary Endpoint: 
1. Safety and Tolerability:  AEs will be evaluated according to NCI-CTCAE version 5.0 
2. The objective tumor response rate (complete response + partial response), assessed 
according to irRECIST criteria 
Secondary Endpoints: 
1. Disease control rate (complete response, partial response+ stable disease) assessed 
according to irRECIST criteria) 
2. Progression-free survival (PFS). 
3. Overall Survival (OS) 
Exploratory Endpoints: 
1. Gene mutation density 
2. Immune repertoire TCR sequencing change in peripheral blood 
3. Immune phenotypes in tumor tissue, including DC, T cells, TAMs, pre- and post-treatment 
4. Phenotypes of Immune cells in peripheral blood 
5. Dendritic cell activation in peripheral blood 
6. To explore predictive and response biomarkers for treatment response based on the 
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collected biomarkers 
Statistical Methods: 
Statistical Considerations: 
Pre-planned analysis population 
Safety Population: All subjects who received at least one dose of study medication. 
Modified Intent-to-Treat population (mITT Population): All safety subjects who provide post treatment 
tumor assessments or present clinical disease progression post treatment without any formal post 
treatment tumor assessments. The efficacy analysis will be based on the mITT population.  
Per Protocol Population (PP Population) will include all mITT population without major protocol 
deviation. The criteria for PP Population exclusion will be documented before data base is locked. 
PK Population: All the subjects who have received at least 1 dose of plinabulin and have evaluable 
concentration data. 
Sample Size  
In the initial Phase 1b portion of the study, 12 all-comers patients will be recruited for the dose 
determination and up to 80 subjects are expected to be recruited in 8 tumor specific cohorts. In the Phase 
2 portion, 102 will be recruited in two arms. A maximum number of 194 patients will be enrolled. Screen 
failures will be replaced with the next eligible patient. 
Safety Analysis 
All AEs occurring during the course of the study and for up to 30 Days after the last dose of study 
medication will be captured, documented and reported. Toxicity is graded according to NCI-CTCAE 
version 5.0. 
Vital signs and safety blood tests including complete blood count and clinical chemistry (including 
liver/renal function tests) will be checked at screening, every treatment Cycle and end of treatment. A 
physical examination will be performed at screening, Day 1 of each Cycle, end of study, and at follow-up; 
a symptom-directed examination will be performed at other visits. Urinalysis will be performed at 
screening, and the end of treatment. Coagulation and will be performed at the screening, Cycle 1 Day 1, 
and end of Treatment, and will be additionally monitored when clinically indicated. Electrocardiogram 
(EKG) will be performed at Screening, Cycle 1 Day 1, and as clinically indicated. 
Pregnancy test for childbearing potential subjects will be performed within 7 Days of the 1st study 
treatment, on Day 1 of each Cycle afterward.  
In Phase 1, BOIN study design is used to determine the MTD. In Phase 2, the BOIN elimination rule is 
used for toxicity monitoring. 
Efficacy Analysis 
ORR will be defined as percent of subjects achieved complete response (CR) or partial response (PR).  
Disease control rate defined as percent of subjects achieved CR, PR, and stable disease 
PFS is defined as the time from the first study dose date to the date of first documentation of confirmed 
disease progression or death (whichever occurs first). 
OS is measured from the start date of the treatment period until date of death from any cause. Subjects 
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who are lost to follow-up and the subjects who are alive at the date of data cutoff will be censored at the 
date the subject was last known alive. 
The mITT Subjects without any post treatment tumor assessments will be treated as non-responders. 
Chi-square or Fisher’s exact test is used to compare ORR and disease control rate between two arms in 
phase 2. ORR and disease control rate are estimated with 95% confidence interval. 
The time-to-event endpoints including overall survival, progression free survival will be analyzed using 
Kaplan-Meier method or Cox regression. 
Companion Translational Study 
Gene Mutation Evaluation:  
We expect most patients enrolled will have had hot spot mutation testing or targeted exome profiling 
performed prior to enrollment. If there is evidence of clinical activity, targeted exome sequencing on a 
200-400 gene platform or larger will be performed in those patients with objective responses and 
prolonged stable disease >6 months as well as any patients with rapid progression (this could be done as 
part of an Institute of Personalized Cancer Therapy Unusual Responder Program). In addition, patients 
who have a response with subsequent progression will be approached for optional biopsies for molecular 
characterization as well as generation of patient derived xenografts and conditionally reprogrammed cells. 
This evaluation will determine the evolution of mutations with treatment under this protocol. 
Biomarker Testing  
The following immune regulatory cells and markers will be studied to better understand the plinabulin’s 
mechanisms of action and to identify potential predictors of responsive subjects that can be utilized to 
enrich for responders in subsequent clinical studies.   
• 
The Imaging-guided core needle tumor biopsy samples (at least 2 to 4 research cores) will be 
collected at Pre-dose (<2 week prior to radiation therapy) and within 7 days prior to Cycle 3 
Day 1 of immunotherapy with Plinabulin. The biopsied lesion should not have been targeted by 
radiation. If there has been a complete response in the pre-treatment biopsied lesion, another non-
irradiated lesion could be biopsied with any response (partial, stable, or progressive), but should 
be documented clearly. Multiple lesions could be biopsied if it is safe to do and has clear biologic 
or clinical rationale to do so. 
• 
The whole blood samples will be collected at screening (<1 week prior to triple combo), and 
Cycle 1 Day 4, then pre-treatment Day 1 of every 2 cycles and End of treatment (EOT) (2 – 
10 mL EDTA/purple top (processed for peripheral blood mononuclear cell [PBMC], plasma, 
whole blood DNA), 1 – 10 mL Heparin/Green top (for flow cytometry and DC activation assay), 
1 – 10 mL Streck tube (for plasma and germline DNA).  
Minimum measurements on core needle tumor biopsies 
• 
Imaging CyTOF analysis and/or single cell RNAseq: Immune phenotypes of tumor phenotypes 
including DC, T cells, TAMs 
 
Minimum measurements on whole blood PBMC collected for biomarker evaluation 
• 
Phenotyping analysis of immune cells from peripheral blood using multicolor flow cytometry 
(Purple top tube) 
• 
Immune repertoire TCR sequencing on whole blood or PBMCs (Purple top tube) 
• 
Dendritic Cell activation assay from whole blood (Green cap tube) 
 
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Exploratory Biomarker Research including Pharmacogenomic Study 
Blood samples for the development of exploratory predictive biomarkers will be collected prior to the 
first dose of study drug, on Cycle 1 Day 4, then on Day 1 of every 2 cycles (C3, 5, etc.) for both Q4W and 
Q3W during Treatment Phase, and at the End-Of-Treatment assessment. Subjects will be required to 
provide a fresh biopsy of tumor before treatment, and within 7 days prior to Cycle 3 Day 1 of the study 
treatment for biomarker analyses. Biomarker discovery and/or validation will be performed to identify 
blood or tumor biomarkers which may be useful to predict subject response to the study treatment, as 
determined by evaluation of response-related and/or safety-related outcomes as well as for potential use in 
diagnostic development. Blood samples from subjects receiving study treatment may be analyzed using 
RNAseq, Flow cytometry, multiplex bead-based immunoassay, or other assays/methods or new 
technology. In addition, biomarkers identified in other plinabulin studies may also be assessed in the 
biomarker samples collected from subjects enrolled in this study.  
A blood sample for PBMCs and plasma isolation will be collected from enrolled subjects. Cell free 
nucleic acid isolated from plasma samples may be used to obtain circulating tumor DNA (ctDNA) and 
explore tumor genetic alterations such as mutations observed in archival tumor samples as well as those 
which develop during drug treatment. 
The PG samples may be used to identify genetic factors that may influence a subject’s exposure to the 
study drug, as well as genetic factors that may have an effect on clinical response or potential AEs related 
to study treatment, and to explore the role of genetic variability in response. Samples may be analyzed to 
determine a subject’s genotypes or sequence for a number of genes or non-coding regulatory 
regions. The research may include the investigation of polymorphisms in genes that are likely to 
influence the study drug pharmacokinetics or therapeutic response. 
The decision to perform exploratory biomarker analysis may be based on the clinical outcome of this 
study and/or the signals observed in other clinical studies or other information available at that time. 
Any leftover samples from the translational study will be stored for up to 15 years from the study closure 
for future research. The samples may be used to study the mechanism of the study treatment or to explore 
the predictive and response biomarkers for the diseases or the treatment. 
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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ..................................................................................................1 
PROTOCOL SYNOPSIS.................................................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................21 
1. 
INTRODUCTION AND BACKGROUND INFORMATION ..................................24 
1.1. 
Investigational Product(s) ...........................................................................................24 
1.1.1. 
Plinabulin ....................................................................................................................24 
1.2. 
Background Information .............................................................................................24 
1.2.1. 
Immune checkpoint inhibitors (ICI) as first line therapy for advanced 
cancers ........................................................................................................................24 
1.2.2. 
Plinabulin as an immune modulatory agent by stimulating dendritic cells ................24 
1.2.3. 
Radiation .....................................................................................................................25 
1.3. 
Study Rationale ...........................................................................................................25 
2. 
STUDY OBJECTIVES ..............................................................................................27 
2.1. 
Primary Objective .......................................................................................................27 
2.2. 
Secondary Objectives .................................................................................................27 
2.3. 
Exploratory Objectives ...............................................................................................27 
2.4. 
Overall Study Design and Plan ...................................................................................27 
2.5 
Study Endpoints ..........................................................................................................31 
2.5.1 
Primary Endpoint ........................................................................................................31 
2.5.2 
Secondary Endpoints ..................................................................................................31 
2.5.3 
Exploratory Endpoints ................................................................................................31 
2.5.4 
 Number of Patients ....................................................................................................31 
2.5.5 
 Study Duration ...........................................................................................................31 
2.5.6 
Study Discontinuation ................................................................................................32 
2.6 
Selection of Doses ......................................................................................................32 
2.6.1 
 Experimental Treatments ...........................................................................................32 
2.6.2 
Dose Delay or Dose Adjustment Criteria ...................................................................34 
3 
STUDY POPULATION .............................................................................................38 
3.1 
 Enrollment .................................................................................................................38 
3.1.1 
 Inclusion Criteria .......................................................................................................38 
3.1.2 
 Exclusion Criteria ......................................................................................................39 
3.2 
Removal of Subjects ...................................................................................................40 
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3.2.1 
Reasons for Withdrawal/Early Discontinuation .........................................................40 
4. 
STUDY TREATMENTS ............................................................................................42 
4.1 
 Investigational Products .............................................................................................42 
4.1.1  
 Investigational Product ..............................................................................................42 
4.1.2 
Anti-PD-1/PD-L1 mAbs .............................................................................................42 
4.1.3 
 Radiation Therapy .....................................................................................................43 
4.1.4 
 Study Drug Preparation .............................................................................................47 
4.1.5 
 Methods of Assigning Patients to Study Cohorts ......................................................48 
4.1.6 
 Study Drug Administration ........................................................................................48 
4.1.7 
 Method of Assessing Treatment Compliance ............................................................48 
4.1.8 
 Packaging and Labeling Information .........................................................................48 
4.1.9 
 Study Drug Storage ....................................................................................................49 
4.1.10 
 Study Drug Accountability ........................................................................................49 
4.1.11 
 Study Drug Handling and Disposal ...........................................................................49 
4.2  
Concomitant Medications ...........................................................................................49 
4.2.1 
 Permitted Medications ...............................................................................................49 
4.3 
 Prohibited Medications or Cancer Therapies ............................................................50 
5. 
STUDY PROCEDURES ............................................................................................51 
5.1 
 Screening Period (-28 to -1 Days) .............................................................................55 
5.2 
 Treatment Period .......................................................................................................56 
5.2.1 
Day 1 of all Treatment Cycles ....................................................................................56 
5.2.2 
Day 4 of Cycle 1& 2  for Immune Checkpoint Inhibitors with Q3W 
Regimens ....................................................................................................................56 
5.2.3 
Day  4 of Cycle 1 & Cycle 2 for Immune Checkpoint Inhibitors with Q4W 
Regimens ....................................................................................................................57 
5.2.4 
End of Study ...............................................................................................................57 
5.2.5 
Follow-up (Every 12 Weeks) ......................................................................................58 
6. 
STUDY VARIABLES AND METHODS OF ASSESSMENTS ...............................59 
6.1 
 Blood Sampling .........................................................................................................59 
6.2 
 Urine Sampling ..........................................................................................................59 
6.3 
 Tumor biopsy .............................................................................................................60 
6.4 
 Assessment of Efficacy ..............................................................................................60 
6.4.1 
Criteria for Disease Evaluation ...................................................................................60 
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7. 
ASSESSMENT OF SAFETY .....................................................................................63 
7.1 
 Safety Parameters ......................................................................................................63 
7.1.1 
Demographic/Medical History ...................................................................................63 
7.1.1 
Vital Signs ..................................................................................................................63 
7.1.2 
Weight and Height ......................................................................................................63 
7.1.3 
Physical Examination .................................................................................................64 
7.1.4 
Electrocardiogram (ECG) ...........................................................................................64 
7.1.5 
Laboratory Assessments .............................................................................................64 
7.1.5.1 
Clinical Laboratory Assessments ...............................................................................64 
7.1.5.2 
Pregnancy Testing ......................................................................................................65 
7.1.5.3 
Companion Translational Study .................................................................................65 
7.1.5.4 
Biomarker Testing ......................................................................................................65 
7.2 
Adverse and Serious Adverse Events .........................................................................66 
7.2.1 
Definition of Adverse Events .....................................................................................66 
7.2.1.1 
Adverse Event (AE) ....................................................................................................66 
7.2.1.2 
Serious Adverse Event (SAE) ....................................................................................67 
7.2.1.3 
Other Adverse Event (OAE) .......................................................................................68 
7.3 
Relationship to Study Drug ........................................................................................69 
7.4 
Recording Adverse Events .........................................................................................69 
7.5 
Reporting Serious Adverse Events .............................................................................70 
8 
STATISTICAL METHODS .......................................................................................72 
8.1 
Study Endpoints and Analysis ....................................................................................72 
8.1.1 
Primary Endpoint and Analysis ..................................................................................72 
8.1.2 
Secondary Endpoints and Analysis ............................................................................72 
8.1.3 
Exploratory Endpoints and Analysis ..........................................................................72 
8.2 
Statistical Analysis Sets and Considerations ..............................................................72 
8.2.1 
Analysis Sets ...............................................................................................................72 
8.2.2 
Patient Disposition ......................................................................................................73 
8.2.3 
Demographics and Other Baseline Characteristics .....................................................73 
8.2.4 
Prior and Concomitant Therapy .................................. Error! Bookmark not defined. 
8.2.5 
Study Treatment Exposure .........................................................................................73 
8.2.6 
Efficacy Analyses Displays ........................................................................................73 
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8.3 
Safety Analyses ..........................................................................................................74 
8.3.1 
Deaths .........................................................................................................................74 
8.3.2 
Extent of Exposure .....................................................................................................74 
8.3.3 
Adverse Events ...........................................................................................................74 
8.3.4 
Laboratory Analyses ...................................................................................................74 
8.3.5 
Vital Signs ..................................................................................................................74 
8.3.6 
Performance Status .....................................................................................................74 
8.4 
Sample Size Considerations .......................................................................................75 
8.5 
Withdrawal .................................................................................................................79 
9 
DATA INTEGRITY AND QUALITY ASSURANCE ..............................................80 
9.1 
Source Documents ......................................................................................................80 
9.2 
Data Collection and Case Report Form Monitoring ...................................................80 
9.3 
Study Records Retention ............................................................................................80 
9.4 
Audits and Inspections ................................................................................................80 
9.5 
Institutional Review Board (IRB) ...............................................................................81 
10 
ETHICAL CONSIDERATIONS, COMPLIANCE STATEMENT ND 
REGULATORY COMPLIANCE ..............................................................................82 
10.1 
Ethical Considerations ................................................................................................82 
10.2 
Good Clinical Practice ................................................................................................82 
10.3 
Delegation of Investigator Duties ...............................................................................83 
10.4 
Subject Confidentiality ...............................................................................................83 
10.5 
Written Informed Consent ..........................................................................................83 
10.6 
Regulatory Compliance ..............................................................................................84 
11 
STUDY ADMINISTRATIVE INFORMATION .......................................................85 
11.1 
Financial Disclosure ...................................................................................................85 
11.2 
Study Registration and Results Disclosure .................................................................85 
11.3 
Use of Stored Samples and Data ................................................................................85 
11.4 
Disposition of Stored Samples and Data ....................................................................85 
11.5 
Subject Identification and Confidentiality ..................................................................86 
11.6 
Protocol Amendments ................................................................................................86 
11.7 
Audits and Inspections ................................................................................................87 
12 
REFERENCES ...........................................................................................................88 
13 
APPENDICES ............................................................................................................90 
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APPENDIX A. CTCAE VERSION 5.0 ......................................................................................91 
APPENDIX B. IMMUNE-RELATED RESPONSE EVALUATION CRITERIA IN 
SOLID TUMORS .......................................................................................................92 
 
 
 
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LIST OF TABLES 
Table 1: 
Phase 1b/Phase 2: Study Drugs/Regimen ...................................................................28 
Table 2: 
Phase 2 Only: Study Drugs/Regimen .........................................................................30 
Table 3: 
Dose Modifications or Dose Discontinuation for Plinabulin .....................................35 
Table 4: 
Summary of Suggested OAR Dose Constraints for three-fraction regimens .............44 
Table 5: 
Summary of Suggested OAR Dose Constraints for four-fraction regimens ..............45 
Table 6: 
Summary of Suggested OAR Dose Constraints for five-fraction regimens ...............46 
Table 7: 
Schedule of Assessments for Anti-PD-1/PD-L1 mAb Treatment (1 Cycle = 3 
or 4 Weeks) .................................................................................................................52 
Table 8: 
Imaging and Treatment After First Radiologic Evidence of Progressive 
Disease ........................................................................................................................62 
Table 9: 
Recommended Adverse Event Reporting Guidelines ................................................70 
Table 10: ECOG Performance Status .........................................................................................75 
Table 11: Dose escalation/De-escalation Rule for the BOIN Design .........................................76 
Table 12: BOIN Operating Characteristics Table .......................................................................78 
Table 13: Toxicity Stopping Boundaries ....................................................................................78 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or Specialist Term 
Explanation 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
Anti-HBs 
Hepatitis B surface antibody 
AOC 
Area over the curve 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
BOIN 
Bayesian optimal interval 
BSA 
Body surface area 
CNS 
Central nervous system 
CR 
Complete response 
CRF 
Case report form 
CRM 
Continual reassessment method 
CSR 
Clinical Study Report 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
Cell free circulating tumor DNA 
CTV 
Clinical Target Volume 
D5W 
Dextrose 5% in distilled water 
DLT 
Dose-limiting toxicity 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EOT 
End of treatment 
FDA 
Food and Drug Administration 
G-CSF 
Granulocyte colony-stimulating factor 
GFR 
Glomerular filtration rate 
GI 
Gastrointestinal 
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Abbreviation or Specialist Term 
Explanation 
GTV 
Gross Tumor Volume 
HIV 
Human Immunodeficiency Virus 
HPF 
High power field 
ICF 
informed consent form 
ICH 
International Council on Harmonisation 
ICI 
Immune checkpoint inhibitor 
IEC 
Independent Ethics Committee 
iGTV 
Internal Gross Tumor Volume 
IL 
interleukin 
INR 
International normalized ratio 
IMRT 
Intensity modulated radiation therapy 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
irCR 
Immune-related complete response 
irPR 
Immune-related partial response 
irPD 
Immune-related progressive disease 
irRECIST 
immune-related Response Evaluation Criteria In Solid 
Tumors 
irSD 
Immune-related stable disease 
ITT 
intent-to-treat 
IV 
Intravenous 
LAFB 
Left anterior fascicular block 
mAb 
Monoclonal Antibody 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
mITT 
Modified Intent-to-Treat  
MRI 
Magnetic resonance imaging 
NCI 
National Cancer Institute 
NSCLC 
Non-small cell lung cancer 
OAE 
Other adverse event 
OAR 
Organ at Risk  
ORR 
Overall response rate 
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Abbreviation or Specialist Term 
Explanation 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cell 
PBT 
Proton beam therapy 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PG 
Pharmacogenomic 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
PP 
Per Protocol 
PR 
Partial response 
PT 
Prothrombin time 
PTV 
Planning Target Volume 
RBBB 
Right bundle branch block 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RT 
Radiation Therapy 
SAE 
Serious adverse events 
SAP 
Statistical Analysis Plan 
SOC 
System organ class 
SOP 
Standard Operating Procedure 
t½ 
Half-life 
ULN 
Upper limit of normal 
Vz 
Volume of distribution 
WHO 
World Health Organization 
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1. 
INTRODUCTION AND BACKGROUND INFORMATION 
1.1. Investigational Product(s) 
1.1.1. 
Plinabulin 
Plinabulin (BPI-2358) is a synthetic, low molecular weight, new chemical entity that 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, which inhibits the polymerization of tubulin monomers, is a differentiated tubulin 
binder, in binding pocket and binding kinetics, with other tubulin binders (La Sala et al., 2019). 
It 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, Kashyap et al., 2019). 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 potential safety advantage. 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). 
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 tissue level IL-6 is implicated in the prevention of neutrophil 
apoptosis (Asensi et al., 2004) and IL-1β with increased neutrophil count (Dinarello, 2011). 
1.2. 
Background Information 
1.2.1. 
Immune checkpoint inhibitors (ICI) as first line therapy for advanced 
cancers 
Immune checkpoint inhibitors (ICIs), most prominently are anti-PD-1 and PD-L1 agents, are first 
line indication for a number of tumor types, with responses that range from 15-60%. For cancers 
like lung cancer, ICI responses are augmented when combined with chemotherapy. These 
strategies have substantially enhanced survival of advanced cancer patients. However, many 
patients become refractory to ICI after which limited options are available. There is a significant 
need to identify strategies that could help reverse ICI resistance and prolong the utilization of 
ICI.  
1.2.2. 
Plinabulin as an immune modulatory agent by stimulating dendritic cells 
Plinabulin (BPI-2358) is derived from a molecule produced by a marine-fungus and is a unique 
molecular class of agents that reversibly bind to β-tubulin within the colchicine pocket, 
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preventing polymerization into microtubules. Following microtubule disruption, plinabulin 
causes diverse cellular effects include direct killing of cancer cells and increase dendritic cell 
maturation (Kashyap et al., 2019), leading to tumor antigen specific T cell activation, as well as 
reducing chemotherapy induced neutropenia in cancer patients. Plinabulin demonstrates a 
favorable safety profile and encouraging anti-tumor responses in two early phase clinical trials. 
Based on these results, plinabulin is currently in Phase 3clinical development in combination 
with docetaxel and in Phase 1/2 trials in combination with nivolumab in NSCLC as well as with 
nivolumab and ipilimumab combo in advanced Small Cell Lung Cancer.  
1.2.3. 
Radiation 
Radiation therapy has also been shown to promote a potent immunogenic release of tumor 
antigen and local cytokines, priming the adaptive immune system towards tumor control. Such 
immune education has been shown to promote distal disease control (also known as the abscopal 
effect) both in pre-clinical models, clinical cases, and early clinical trials. Clinical descriptions of 
this phenomenon have been predominately limited and most often in sporadic case reports where 
unexpected yet pronounced distal tumor regression are observed outside of radiation fields. The 
effect has become reproducible and robust when it is given concomitantly with immunotherapies 
(Kaminski et al., 2005). So far, most of the proof comes from preclinical studies showing 
synergy of radiation and immunotherapies, and some case reports or small clinical trials in 
metastatic melanoma showing that adding high dose ablative radiotherapy to a single site disease 
with either ipilimumab (Postow et al., 2012) or IL-2 (Seung et al., 2012) can generate systemic 
response rates that are much bigger than given drug alone. While trials in lung cancer are being 
planned, most of these trials are still being planned for the metastatic setting. 
1.3. 
Study Rationale 
Non-clinical studies demonstrated the efficacy of anti-PD-L1 combined with radiotherapy in 
preclinical models of lung cancer. One study (Deng et al., 2014), showed that combining anti-
PD-L1 enhanced the efficacy of radiation through a CD8+ T cell dependent mechanism. The 
anti-tumor effect was seen both locally in the primary tumor, but also in a contralateral, non-
irradiated tumor, supporting the role of radiation inducing a “distant”, or abscopal, anti-tumor 
effect, that is synergistic with anti-PD-L1. In a second study (Deng et al., 2014), the authors 
discovered that radiation induced PD-L1 expression, and by combining radiation with anti-PD-
L1 antibody therapy induces a T-cell mediated depletion of myeloid-derived suppressor cells 
(MDSC) via TNF-mediated signaling. A third study (Dovedi et al., 2014), also demonstrated that 
conventional fractionated radiotherapy led to upregulation of PD-L1 expression on a number of 
syngeneic mouse tumor models. By administering an anti-PD-L1 antibody along with 
conventional fractionated radiotherapy, the authors demonstrated significant improvement in 
CD8+ T cell infiltration into tumors, and generated significantly improved local tumor control, 
long term survival, and a protection against tumor rechallenge. It is however unknown in the 
setting of immunotherapy resistance, how radiation could resensitize tumor response when 
combined with ICI alone, or may require an additional pathway such as dendritic cell activation 
to help promote immunotherapy response in the context of resistance.  
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Hypothesis:  The central hypothesis of this study is that radiation with plinabulin could help 
reverse ICI resistance in ICI-refractory tumors and generate responses that are greater than 
radiation with ICI alone. 
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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
• To assess the safety and tolerability of plinabulin when administered in combination with 
radiation/immunotherapy regimen in subjects with select advanced solid malignancies after 
progression on anti-PD-1/PD-L1 monoclonal antibody (mAb) 
• To assess the objective tumor response rate (complete response + partial response)  
2.2. 
Secondary Objectives 
• To assess disease control rate (complete response, partial response + stable disease) 
• To determine progression-free survival (PFS)  
• To assess overall survival 
2.3. 
Exploratory Objectives 
• To analyze the gene mutation density within each sample 
• To assess TCR sequencing in tumor tissue and peripheral blood, pre- and post- treatment. 
• To perform Imaging CyTOF and/or single cell RNAseq analysis on tumor tissue: Immune 
phenotyping, including DC, T cells, TAMs, pre- and post-treatment. 
• To conduct phenotyping analysis of immune cells from peripheral blood using multicolor 
flow cytometry. 
• To evaluate dendritic cell activation from whole blood upon the treatment. 
• To explore general predictive and response biomarker measurements from the collected 
biomarkers  
2.4. 
Overall Study Design and Plan 
This is a single center study with a Phase 1b and a Phase 2 component. 
Phase 1b: 
This is an open label, single-center study to assess the safety and tolerability of plinabulin when 
administered in combination with Radiation/Immunotherapy regimens in subjects with one of 
several metastatic or locally advanced cancers who had disease progression on anti-PD-1/PD-L1 
mAb treatment as standard of care. The targeted cancer types for this study are as follows: 
1. Bladder Cancer 
2. Melanoma 
3. Merkel Cell Cancer 
4. MSI-H Cancers (of any histology) 
5. Non-small Cell Lung Cancer 
6. Renal Cell Cancer 
7. Small Cell Lung Cancer 
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8. Any other tumor type that has a checkpoint inhibitor approval  
Anti-PD-1/PD-L1 mAb treatment cycle will define subject’s treatment cycle for the study. 
All subjects in Phase 1b will receive a triple combo treatment of Radiation Therapy (RT) + 
plinabulin + anti-PD-1/PD-L1 mAb in Cycle 1, followed by anti-PD-1/PD-L1 mAb and 
plinabulin combo regimen in Cycle 2 and beyond until disease progression or development of 
unacceptable toxicity, withdrawal from study treatment, or discontinuation of this study (Table 
1). A short course of local consolidative RT will be administered in Cycle 1 starting from Day 1. 
Optional sequential RT to other untreated lesions at discretion of the treating doctor is allowed in 
Cycles 2 of any anti-PD-1/PD-L1 regimen. Plinabulin will be dosed on Day 1 and Day 4 of 
Cycle 1 of any anti-PD-1/PD-L1 regimen, and if optional RT is given in Cycle 2 Day 1, 
Plinabulin will also be given on Day 4 of Cycle 2. If optional RT is not given on Cycle 2 Day 1, 
then Plinabulin will be administered on Day 1 of Cycle 3 and after. Anti-PD-1/PD-L1 mAb will 
be dosed on Day 1 of every treatment cycle (also on Day 15 [Q4W] in case of regimen 
containing Avelumab or Durvalumab or Nivolumab as Anti-PD-1/PD-L1 mAb). Subjects must 
receive the same anti-PD-1/PD-L1 mAb they failed in the prior treatment.  
The two dose levels of plinabulin are 20 mg/m2 and 30 mg/m2 and the starting dose is 30 mg/m2. 
Lower dose level at 20 mg/m2 of plinabulin will be explored as necessary depending on observed 
toxicity. We will employ the Bayesian optimal interval (BOIN) design (Liu and Yuan, 2015; 
Yuan et al., 2016) to find the MTD. The BOIN design is implemented in a simple way similar to 
the traditional 3+3 design, but is more flexible and possesses superior operating characteristics 
that are comparable to those of the more complex model-based designs, such as the continual 
reassessment method (CRM) (Zhou et al., 2018). 
Once we determine the MTD, an additional 10 patients will be enrolled for additional experience 
with safety and efficacy in each of the eight cancer cohorts. Patients treated at the MTD in the 
dose finding will roll over into the cohort expansion. We will use the elimination boundaries for 
dose-limiting toxicity (DLT) monitoring. 
Anti-PD-1/PD-L1 mAb dose will follow FDA recommendations to each indication and will not 
change in the study. 
Table 1: 
Phase 1b/Phase 2: Study Drugs/Regimen 
Phase 1b/Phase 2: 
Study  
Drugs/Regimen 
Cycle 
Length 
Radiation 
Therapy 
(RT) 
Plinabulin 
30 mg/m2 
(Starting dose) 
Or 20 mg/m2 
Anti-PD-1/PD-L1 
mAb 
DLT Window 
After 2 doses of Anti-
PD-1/PD-L1 mAb 
RTX + Plinabulin 
+ Avelumab 
1 Cycle = 
4 weeks 
C1D1-3 (8 
Gy x 3 
fractions) 
or C1D1-4 
(12.5 Gy x 
4 
fractions) 
C1D1, 4  
C2D1 
C2D4 (optional if 
RT on C2D1)  
C3 onward D1 
Avelumab (800 mg): 
D1, 15 of every 
cycle 
C1 = 4 weeks 
RTX + Plinabulin 
+ Durvalumab 
1 Cycle = 
4 weeks 
Durvalumab (10 
mg/kg): D1, 15 of 
every cycle 
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Phase 1b/Phase 2: 
Study  
Drugs/Regimen 
Cycle 
Length 
Radiation 
Therapy 
(RT) 
Plinabulin 
30 mg/m2 
(Starting dose) 
Or 20 mg/m2 
Anti-PD-1/PD-L1 
mAb 
DLT Window 
After 2 doses of Anti-
PD-1/PD-L1 mAb 
RTX + Plinabulin 
+ Nivolumab 
1 Cycle = 
4 weeks 
or C1D1-5 
(4 Gy x 5 
fractions) 
 
C2D1 
(optional) 
Nivolumab (240 
mg): D1, 15 of 
every cycle 
RTX + Plinabulin 
+ Atezolizumab 
1 Cycle = 
3 weeks 
Atezolizumab (1200 
mg): D1 of every 
cycle 
C1-2 = 6 weeks 
RTX + Plinabulin 
+ Pembrolizumab 
1 Cycle = 
3 weeks 
Pembrolizumab 
(200 mg): D1 of 
every cycle 
C = cycle, D = day, DLT = dose-limiting toxicity, mAb = monoclonal antibody, PD = progression disease, RT = radiation 
therapy. 
Selection of cohort that will advance into Phase 2 will be based on the following consideration: 
1. The cohort with the best response rate, within a 9-week window after RT plus plinabulin 
with 2 cycles (3 weeks Anti-PD-1/PD-L1 mAb dosing) of Anti-PD-1/PD-L1 mAb, will 
advance into Phase 2, if deemed well-tolerated. 
2. The response evaluation will be based on a minimum of 5 subjects and up to 10 subjects 
per cohort, unless enrollment of a given cohort is very slow and incomplete at the time 
sufficient response data is available on other cohorts, in which case that given cohort 
could be closed for further patient accrual.  
3. The final selection of the group to go into Phase 2 will be determined by a Safety 
Monitoring Committee. 
Phase 2: 
The cohort which is selected by the Safety Monitoring Committee will be selected for the Phase 
2 portion of the study. Subjects with the selected tumor type will be accrued to receive the 
plinabulin MTD in combination with RT and anti-PD-1/PD-L1 mAb. Anti-PD-1/PD-L1 mAb 
dose will follow FDA recommendations to each indication and will not change in the study. 
They will be randomized to one of two treatment arms in a 1:1 ratio. The randomization will be 
stratified by the number of mets (oligo (<=3 vs > 3) and Eastern Cooperative Oncology Group 
(ECOG) 0-1 vs 2. 
Arm A: Radiation Therapy + Plinabulin + PD-1 or PD-L1 (experimental) 
Arm B: Radiation Therapy + PD-1 or PD-L1 (control) 
Subjects in Arm A will receive triple combo in Cycle 1, followed by plinabulin and anti-PD-
1/PD-L1 mAb double combo for Cycle 2 and beyond (Table 2). 
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Subjects in Arm B will receive combo regimen of RT and anti-PD-1/PD-L1 mAb in Cycle 1, 
followed by anti-PD-1/PD-L1 mAb alone for Cycle 2 and beyond (Table 2).  
Assuming the overall response rate (ORR) is 5% in control arm and 15% in experimental arm, 
based on Chi-squared test, a sample size of 51 evaluable patients in each group is required to 
detect the difference with one sided type I error 0.2 and power 80% (nQuery 4.0). The BOIN 
elimination rule will be used to monitor toxicity in both arms. The toxicity monitoring will start 
from the 11th patient and carried out every 10 patients.  
The study treatment continues until disease progression or development of unacceptable toxicity, 
withdrawal from study treatment, or discontinuation of this study. 
A short course of local consolidative RT will be administered in Cycle 1 starting from Day 1. An 
optional sequential RT to other untreated lesions at discretion of the treating doctor is allowed 
(Cycle 2 Q4W; Cycle 2 Q3W). Plinabulin and/or anti-PD-1/PD-L1 mAb will be dosed on Day 1 
of every treatment cycle to subjects based on their treatment assignment. 
Table 2: 
Phase 2 Only: Study Drugs/Regimen 
Phase 1b/Phase 
2: Study 
Drugs/Regimen 
Cycle Length 
Radiation Therapy 
(RT) 
Plinabulin 
30 mg/m2 
(Starting dose) 
Or  
20 mg/m2 
Anti-PD-1/PD-L1 
mAb 
DLT Window 
RTX + 
Avelumab 
1 Cycle = 4 
weeks 
C1D1-3 (8 Gy x 3 
fractions) or 
C1D1-4 (12.5 Gy x 4 
fractions) or 
C1D1-5 (4 Gy x 
5fractions) 
C2D1 (optional) 
N/A 
Avelumab (800 mg): 
D1, 15 of every cycle 
N/A 
RTX + 
Durvalumab 
1 Cycle = 4 
weeks 
Durvalumab (10 
mg/kg): D1, 15 of 
every cycle 
RTX + 
Nivolumab 
1 Cycle = 4 
weeks 
Nivolumab (240 mg): 
D1, 15 of every cycle 
RTX + 
Atezolizumab 
1 Cycle = 3 
weeks 
Atezolizumab (1200 
mg): D1 of every 
cycle 
RTX + 
Pembrolizumab 
1 Cycle = 3 
weeks 
Pembrolizumab (200 
mg): D1 of every 
cycle 
C = cycle, D = day, DLT = dose-limiting toxicity, mAb = monoclonal antibody, N/A = not applicable, PD = progression disease, 
RT = radiation therapy. 
a. Plinabulin marked N/A only applies to Arm B for phase 2, not Arm A. Plinabulin will be administered to subjects in Arm A on 
days listed in Table 1 above. 
For entire study all efficacy endpoints, other than overall survival (OS), will be based on the 
tumor assessments performed by the investigators using both immune-related Response 
Evaluation Criteria In Solid Tumors (irRECIST) and modified Response Evaluation Criteria In 
Solid Tumors (RECIST) 1.1. Treatment decisions by the Investigator will be based on irRECIST. 
Safety and tolerability are assessed according to National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE) version 5.0. 
Vital signs, physical examination, and safety lab test result review (hematology, chemistry & 
urinalysis) will have to be performed prior to the study treatment to make sure the study 
treatment is safe to be administered. 
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2.5. 
Study Endpoints 
2.5.1. 
Primary Endpoint 
1. Safety and tolerability, adverse events (AEs) according to NCI CTCAE version 5.0 
2. The objective tumor response rate (complete response + partial response), assessed 
according to irRECIST criteria 
 
2.5.2. 
Secondary Endpoints 
1. Disease control rate (complete response, partial response + stable disease) assessed 
according to irRECIST criteria 
2. Progression-free survival (PFS)  
3. Overall Survival (OS) 
 
2.5.3. 
Exploratory Endpoints 
1. Gene mutation density for each patient 
2. Immune repertoire TCR sequencing change in peripheral blood 
3. Immune phenotypes in tumor tissue, including DC, T cells, TAMs, pre and post treatment 
4. Phenotypes of immune cells in peripheral blood 
5. Dendritic cell activation in peripheral blood 
6. Additional exploratory measurements on Blood or Tumor Biopsy samples, with the goal 
of developing Predictive and Response Biomarkers 
 
2.5.4. 
Number of Patients 
In the initial Phase 1b portion of the study, 12 patients will be recruited for the dose 
determination and up to 80 subjects are expected to be recruited in 8 tumor specific cohorts. In 
the Phase 2 portion, 102 will be recruited in two arms. A maximum number of 194 patients will 
be enrolled. Screen failures will be replaced with the next eligible patient. 
2.5.5. 
Study Duration 
Screen period: up to 28 days. 
Treatment period: Study treatment continues until disease progression (estimate 2-6 months), 
development of unacceptable toxicity, withdrawal of consent, or discontinuation of this study. 
Follow-up period: Follow-up consists of the End of Treatment Visit and the Follow-up Visits. 
The End of Treatment Visit will occur within 30 days following the last dose of study treatment, 
then transit to the Follow-up visit period. The Follow-up Visit at every 12 weeks (±1 week) 
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continue as long as the study subject is alive unless the subject withdraws consent or until the 
study is terminated. In the Follow-up Period, Subjects who discontinued for reasons other than 
progression of disease (and withdrawal of consent for participation in the study) will continue to 
visit the clinic for study assessments and evaluation of their disease by computed tomography 
(CT), magnetic resonance imaging (MRI) scan approximately every 12 weeks until progression 
of disease is determined, the patient receives additional anti-neoplastic medication, or for a 
maximum of 5 years.  
2.5.6. 
Study Discontinuation 
MD Anderson 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, MD Anderson and the Investigator will assure 
that adequate consideration is given to the protection of the patient’s interests. Subjects will be 
followed up for survival status. 
The study treatment will continue until any one of the following occurs: 
• Drug related AEs which prevent further dosing  
• Initiation of a protocol-prohibited concomitant medication or non-protocol 
chemo/biological therapy for treatment of their disease. 
• Development of a serious adverse event (SAE)/AE, illness, or condition that may 
interfere with the patient’s participation or require treatment discontinuation. 
• Investigator opinion. 
• Voluntary withdrawal of consent. 
2.6. 
Selection of Doses 
2.6.1. 
Experimental Treatments 
The determination of maximum tolerated dose (MTD)  
Based on other plinabulin study data, the 30 mg/m2 plinabulin dose appeared to have more 
anti-cancer activity than the 20 mg/m2 plinabulin dose, when combined with Docetaxel, in 
NSCLC patients. The safety profile of the 30 mg/m2 dose was favorable as obtained from more 
than 250 patients exposed to the 30 mg/m2 plinabulin dose to-date. The most frequent safety 
events observed were nausea, vomiting and diarrhea, and transient hypertension around the time 
of infusion. 
The study will begin with 30 mg/m2 plinabulin in combination of full dose of anti-PD-1/PD-L1 
mAb according to FDA package inserts and RT. Lower dose level at 20 mg/m2 of plinabulin will 
be explored as necessary depending on observed toxicity. Anti-PD-1/PD-L1 mAb dose will not 
change in the study. For determination of MTD, only DLTs during the initial 4 or 6 weeks 
(dependent on study drug) of the treatment will be assessed. The DLT is calculated after two 
doses of PD1/PDL1. Due to variability of the frequency of dosing, there is a range when the 
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DLT is assessed. When PD1/PDL1 is Q2weeks, DLT period is 4 weeks. When PD1/PDL1 is 
Q3weeks, the DLT period is 6 weeks. 
A DLT is defined as any of the following plinabulin-related AEs or laboratory abnormalities, 
graded according to NCI CTCAE version 5.0: 
• Febrile neutropenia 
• Grade 4 hypertension 
• Grade 4 anemia unrelated to underlying disease 
• Grade 3 thrombocytopenia with clinically significant bleeding or Grade 4 
thrombocytopenia lasting more than 7 days and/or requiring a platelet transfusion 
• Grade 4 neutropenia lasting more than 7 days despite the use of granulocyte colony-
stimulating factor (G-CSF) 
• ≥Grade 3 nausea, vomiting, diarrhea, or electrolyte imbalances lasting >48 hours 
despite optimal prophylactic and curative treatment 
• ≥Grade 3 hypersensitivity reaction (unless first occurrence and resolves within 6 
hours with appropriate clinical management) 
• Treatment delay >21 days secondary to recovery from study drugs-related AEs 
• ≥Grade 3 non-hematologic AEs, except for the exclusions listed below. 
 
The following events will be excluded from the DLT definition: 
• Any AE ≥Grade 3 clearly determined to be unrelated to study drug(s) (e.g., disease 
progression) 
• ≥Grade 3 isolated alkaline phosphatase laboratory abnormality of any duration 
• ≥Grade 3 isolated, asymptomatic amylase or lipase laboratory abnormality of any 
duration 
• ≥Grade 3 endocrinopathies controlled by corticosteroids or hormone replacement 
• Vitiligo or Alopecia of any grade 
• Grade 3 fatigue. 
 
We will employ the BOIN design (Liu and Yuan, 2015, Yuan et al., 2016) to find the 
MTD/RP2D. The BOIN design is implemented in a simple way similar to the traditional 3+3 
design, but is more flexible and possesses superior operating characteristics that are comparable 
to those of the more complex model-based designs, such as CRM (Zhou et al., 2018).The target 
DLT rate for the MTD is ɸ = 0.25 and the maximum sample size is 12. We will enroll and treat 
patients in cohorts of size 3. 
In order to be evaluable for DLT assessment, subjects must complete first cycle treatment. 
Subjects who experience a DLT within the first 4 or 6 weeks (dependent on study drug) of 
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treatment and drop out of the study will be considered evaluable for DLT and will not be 
replaced. Patients who drop out of the study for reasons other than DLT during the first 4 or 6 
weeks (dependent on study drug) will be considered not evaluable and will be replaced.  
Once plinabulin MTD/RP2D is confirmed, it will be considered as the recommended dose for the 
Phase 1b expansion of the eight cancer cohorts and Phase 2.  
Anti-PD-1/PD-L1 mAb dose will follow FDA recommendations to each indication and will not 
change in the study. 
2.6.2. 
Dose Delay or Dose Adjustment Criteria 
The NCI CTCAE v5.0 will be used to grade AEs. Subjects enrolled in this study will be 
evaluated clinically and with standard laboratory tests before and at regular intervals during their 
participation in this study as specified in Study Calendar & Evaluations. Subjects will be 
evaluated for AEs (all grades), SAEs, and AEs requiring study drug interruption or 
discontinuation as specified in Study Calendar & Evaluations.   
In the event of multiple toxicities, dose delays and modifications should occur in accordance 
with the highest grade of AEs observed. All patients with dose interruptions for 28 consecutive 
days due to toxicity that does not resolve to grade 1 or less, with or without treatment, will be 
discontinued from study treatment. All patients with evidence of radiographically confirmed 
progressive disease or clinical evidence of disease progression or global deterioration of health 
unrelated to progressive disease, as defined by irRECIST, will be discontinued from study 
treatment. 
Plinabulin 
The general approach to dose delay and modification of plinabulin are shown below (Table 3). 
Two dose levels of plinabulin (30 mg/m2 and 20 mg/m2) are suggested for dose modification. 
Plinabulin dose reduction to below 20 mg/m2 is not recommended. In that case plinabulin should 
be discontinued. Plinabulin dosing must be withheld if the patient has evidence or signs of any 
medical conditions that would prevent dosing (such as an infection, grade 4 neutropenia or 
unacceptable medical condition). 
At the discretion of the Investigator, the dose may be delayed for up to 28 consecutive days for 
any toxicity possibly or probably related to plinabulin that does not meet DLT criteria. Dosage 
interruptions to assess or treat intercurrent illnesses are allowed and should be clearly described 
in the study eCRF. A delay greater than 28 consecutive days will require the patient to be 
removed from the study (except in case of potential patient benefit, which must be approved by 
the Investigator). 
If plinabulin is withheld, anti-PD-1/PD-L1 mAb will be withheld as well.  
As well as the adverse reactions described in Table 3, dose modifications and treatment 
discontinuation may also occur as a result of hematologic and other non-hematologic AEs and/or 
laboratory abnormalities ≥Grade 2. In the case of dose delay or modification, assigned treatment 
may be resumed once the relevant AE is classified as Grade 1. If a DLT would occur, a lower 
dose level at 20 mg/m2 of plinabulin will be explored as necessary depending on the observed 
toxicity.
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Table 3: 
Dose Modifications or Dose Discontinuation for Plinabulin 
Adverse 
Reaction 
Provide Supportive 
Care for: 
Withhold 
Plinabulin for: 
Permanently Discontinue 
Plinabulin for: 
Infusion 
related 
reaction 
Grade 2: Stop the infusion, begin an IV 
infusion of normal saline, and treat the 
subject with diphenhydramine 50 mg IV (or 
equivalent) and/or acetaminophen 325 to 
1000 mg; remain at bedside and monitor 
subject until resolution of symptoms. 
Corticosteroid or bronchodilator therapy may 
also be administered as appropriate. If the 
infusion is interrupted, restart the infusion at 
50% of the original infusion rate when 
symptoms resolve. Monitor subject closely. 
If symptoms recur, then no further plinabulin 
will be administered at that visit. Administer 
diphenhydramine 50 mg IV, remain at 
bedside and monitor the subject until 
resolution of symptoms. The amount of study 
drug infused must be recorded on the 
electronic case report form (eCRF). 
N/A 
Grade 3 or 4:  Immediately discontinue infusion of 
plinabulin Begin an IV infusion of normal saline 
and treat the subject as follows.  
• Recommend bronchodilators, epinephrine 0.2 to 
1 mg of a 1:1,000 solution for subcutaneous 
administration or 0.1 to 0.25 mg of a 1:10,000 
solution injected slowly for IV administration, 
and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), 
as needed. Subject should be monitored until the 
investigator is comfortable that the symptoms 
will not recur. Investigators should follow their 
institutional guidelines for the treatment of 
anaphylaxis. Remain at bedside and monitor 
subject until recovery from symptoms. In the case 
of late-occurring hypersensitivity symptoms (eg, 
appearance of a localized or generalized pruritis 
within 1 week after treatment), symptomatic 
treatment may be given (eg, oral antihistamine, or 
corticosteroids). 
Cytokine 
release 
syndrome 
Management of symptoms such as fever and 
muscle pain with acetaminophen or other 
analgesic. Consider oxygen therapy, fluids 
and antihypotensive agents (if hypotensive) 
for Grade 2 or higher. 
 
For Grade 2 symptoms that do not resolve or 
for Grade 3 or higher symptoms, high-dose 
steroids should be initiated, and patient 
should be admitted for management and 
observation. 
Grade 2: 
May restart plinabulin at 
one dose level lower once 
symptoms resolve. 
Grade 3 or 4 
Permanently discontinued  

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Adverse 
Reaction 
Provide Supportive 
Care for: 
Withhold 
Plinabulin for: 
Permanently Discontinue 
Plinabulin for: 
Hypertension For BP > 160: 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 
• First occurrence of BP 
>140 and <160 with the 
use of anti-hypertensives. 
• May restart plinabulin at 
one dose level lower with 
anti-hypertensive 
prophylaxis once BP 
returns to grade 1 or better  
• Second occurrence of BP >140 and <160 with 
use of antihypertensive and one dose reduction  
OR 
First occurrence of BP ≥ 160in spite of anti-
hypertensives. 
Diarrhea 
Grade 1 or 2 diarrhea. Institute symptomatic 
treatment including hydration, electrolyte 
replacement, dietary changes, and loperamide 
or other per institutional guidelines. 
• First occurrence of grade 
3 event. Withhold 
plinabulin and institute 
symptomatic treatment. 
Plinabulin may be 
restarted at the same dose 
level once toxicity 
resolved to grade 1 or 
better if SYMPTOMATIC 
treatment-controlled 
diarrhea. 
• Grade 3 event in patients 
on optimal symptomatic 
treatment: Withhold 
plinabulin and restart at 
one dose level lower once 
event resolves to Grade 1 
or better. 
• Any grade 4 event. 
• Recurrence of Grade 3 diarrhea after one dose 
reduction and optimal symptomatic treatment  
BP: Blood pressure; eCRF: Electronic case report form; IV: Intravenous 

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Anti-PD-1/PD-L1 mAb  
Please follow the instructions in FDA package inserts or institutional policies for dose 
modification and/or dose delay guidelines for anti-PD-1/PD-L1 mAbs. 
If anti-PD-1/PD-L1 mAb is withheld, plinabulin will be withheld too.  
Criteria for Re-Treatment  
In the absence of disease progression, laboratory tests are required prior to Day 1 of each cycle 
as per the schedule of assessments. The follow criteria must be met: 
a. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5×upper 
limit of normal (ULN) (≤1.5×ULN if alkaline phosphatase is >2.5×ULN) (In the 
expansion cohort, subjects with known liver involvement may have ALT 
≤5×ULN), 
b. Alkaline phosphatase <4×ULN, 
c. Total Bilirubin ≤1×ULN (In the expansion cohort, subjects with Gilbert’s 
syndrome [hereditary indirect hyperbilirubinemia] who must have a total bilirubin 
of ≤3×ULN), 
d. Albumin ≥ 3g/dL, 
e. Hematological parameters have returned to within grade 1 levels 
 
Radiation 
If patients develop toxicity attributable to radiation after receiving at least one dose of radiation, 
the rest of the radiation treatment may be discontinued if deemed by the treating radiation 
oncologist to be in the best interest of the patient, and the AEs will be documented. Since the 
number of fractions are between 3-5 fractions, patients could receive at least 1 fraction up to 5 
fractions. The initially prescribed dose per fraction will not change, but it is possible to simply 
reduce the total dose delivered. The patient will have a visit with the treating radiation oncologist 
at the end of every cycle of radiation treatment.  
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3. 
STUDY POPULATION 
3.1. 
Enrollment 
3.1.1. 
Inclusion Criteria 
1. Subjects must have one of several like histologically or cytologically confirmed 
malignant neoplasms (non-small cell lung cancer, small cell lung cancer, renal cell 
cancer, bladder cancer, Merkle cell cancer, MSI-H cancer (any histology),  
Melanoma and any other tumor type that has an approval for checkpoint inhibitor 
who may or may not have progressed on previous anti-PD-1/PD-L1 mAb treatment 
+/- chemotherapy or anti-CTLA4 requiring further treatment. 
2. At least one lesion is amenable to radiation 
3. At least one additional non-contiguous lesion that has not been irradiated amenable 
to radiographic evaluation 
4. Have measurable disease based on immune-related response criteria (irRECIST). 
5. Tissue must be newly obtained as a core needle biopsy (not FNA) of the lesion 
being evaluated  
6. Age ≥ 18 years. 
7. Eastern Cooperative Oncology Group (ECOG) performance status of0-2. 
8. Subjects must be recovered from any prior major surgery. The major surgery must 
be performed at least 4 weeks prior to consent date. 
9. Adequate hematologic function defined as: 
i. 
Platelets≥100×10
9/L, 
ii. 
Hemoglobin ≥ 9 g/dL  
iii. 
Absolute neutrophil count (ANC) ≥1.5×109/L, 
iv. 
White blood cell (WBC) ≥ 3×109/L. 
Transfusions and growth factors are allowed. 
10. Adequate liver function defined as: 
i. AST and ALT ≤2.5×ULN (≤1.5×ULN if alkaline phosphatase is 
>2.5×ULN) (In the expansion cohort, subjects with known liver 
involvement may have ALT ≤5×ULN), 
ii. Alkaline phosphatase <4×ULN, 
iii. Total Bilirubin≤1xULN (In the expansion cohort, subjects with 
Gilbert’s syndrome [hereditary indirect hyperbilirubinemia] who 
must have a total bilirubin of ≤3×ULN), 
iv. Albumin ≥3 g/dL. 
11. Renal function defined as a calculated or measured glomerular filtration rate (GFR) 
≥ 30mL/min and Cockcroft-Gault equation. 
12. The patient has recovered to Grade ≤ 1 by the National Cancer Institute Common 
Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0) from 
the effects of recent surgery, radiotherapy, chemotherapy, hormonal therapy, or 
other targeted therapies, with the exception of alopecia. The exceptions for such 
effects are allowed lab values of ≤ Grade 2 specified elsewhere in these inclusion 
criteria. 
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13. Subjects must give informed consent according to the rules and regulations of the 
individual participating sites. 
14. Negative urine pregnancy test in women of child bearing potential within 7 Days of 
first dose of treatment and subjects of child-bearing potential must agree to use 
effective contraception during and for 5 months following the last dose of 
atezolizumab or nivolumab, and for 4 months after the last dose of pembrolizumab, 
and for 3 months after last dose of Durvalumab and Avelumab, and for 3 months 
after your last dose of plinabulin. A woman of childbearing potential is defined as 
a premenopausal female capable of becoming pregnant. This includes women on 
oral, injectable or mechanical contraception; women who are single and women 
whose male sexual partners have been vasectomized or whose male sexual partners 
have received or are utilizing mechanical contraceptive devices. 
3.1.2. 
Exclusion Criteria 
1. Evidence of complete or partial bowel obstruction. 
2. Subjects with primary central nervous system (CNS) tumor or CNS tumor 
involvement. However, subjects with metastatic CNS tumors may participate in 
this study if the patient is: 
• >4 weeks from prior therapy completion 
• Clinically stable with respect to the CNS tumor at the time of study entry 
• Not receiving steroid therapy in treating CNS tumor or CNS tumor 
involvement 
• Not receiving anti-convulsive medications (that were started for brain 
metastases). 
3. Need of Total Parenteral Nutrition. 
4. Allergic to any of anti-PD-1/PD-L1 mAb intended to receive. 
5. Prior exposure to plinabulin. 
6. Pregnancy or lactation. 
7. Radiation (except planned or ongoing palliative radiation to bone outside of the 
region of measurable disease) ≤3weeks prior to study drug administration date. 
8. Chemotherapy, or immunotherapy or any other systemic anticancer therapy ≤ 3 
weeks prior to study drug administration date except anti-PD-1/PD-L1 mAb mono 
or combination therapy. 
9. Diagnosis or recurrence of invasive cancer other than the present cancer within 3 
years (except basal or squamous cell carcinoma of the skin that has been 
definitively treated). 
10. Major surgery within four weeks before consent date. 
11. Unstable cardiovascular function or active cardiac disease: 
• Symptomatic ischemia (chest pain of cardiac origin), or 
• Uncontrolled clinically significant conduction abnormalities (e.g., 
ventricular tachycardia on antiarrhythmics are excluded; 1st degree AV 
block or asymptomatic Left anterior fascicular block (LAFB)/ right 
bundle branch block (RBBB) will not be excluded), or 
• Congestive heart failure (CHF) of NYHA Class≥3, or 
• Myocardial infarction (MI) within 3 months of consent date. 
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12. Uncontrolled active infection requiring parenteral antibiotics, antivirals, or 
antifungals within one week prior to the first dose. Active infection with 
concurrent treatment is acceptable only if the patient is clinically stable. 
13. Subject is known to be positive for Human Immunodeficiency Virus (HIV), 
Hepatitis B or Hepatitis C 
14. Significantly diseased (as determined by the PI or treating physician) or obstructed 
gastrointestinal tract or uncontrolled vomiting or diarrhea. Presence of ileus or 
other significant gastrointestinal disorder known to predispose to ileus or chronic 
bowel hypomotility 
15. Treatment with an investigational anti-cancer study drug within 3 weeks prior to 
study drug administration date. 
16. Concurrent therapy with approved or investigational anticancer therapeutics. 
17. Medical, psychological, or social conditions that may interfere with the patient's 
participation in the study or evaluation of the study results. 
18. Men whose partner is a woman of child-bearing potential, (i.e., biologically able to 
conceive), and who is not employing two forms of highly effective contraception. 
Highly effective contraception (e.g., male condom with spermicide, diaphragm 
with spermicide, intra-uterine device) must be used by both sexes during the study 
and must be continued for 5 months following the last dose of atezolizumab or 
nivolumab, for 4 months after the last dose of pembrolizumab, and for 3 months 
after last dose of Durvalumab and Avelumab, and for 3 months after your last dose 
of plinabulin. Women of child-bearing potential is defined as sexually mature 
women who are not surgically sterile or who have not been naturally 
postmenopausal for at least 12 consecutive months (e.g., who has had menses any 
time in the preceding 12 consecutive months). 
3.2. 
Removal of Subjects 
3.2.1. 
Reasons for Withdrawal/Early Discontinuation 
A patient may decide to withdraw from the study at any time, for any reason, without prejudice 
to subsequent care or treatment by the Investigator. The Investigator also has the right to 
withdraw patients from the study if it is in the best interest of the patient. The MD Anderson 
Cancer Center may also decide to withdraw a patient. All efforts should be made to complete and 
report the observations as thoroughly as possible. Patients who discontinue the treatment due to 
AEs should remain under observation until the resolution or stabilization of the AEs. 
A patient may be discontinued from the study drug treatment before completion for any of the 
following reasons: 
• Patient death 
• Patient experiences an AE(s)/SAEs that warrants discontinuation, as judged by the 
Investigator and/or the MD Anderson Cancer Center 
• A major protocol deviation, which, in the opinion/discretion of the Investigator and/or the 
MD Anderson Cancer Center compromises the data integrity of the study. 
• Patient is noncompliant with the study drug treatment 
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• Drug related AEs as associated with the study treatment regimen which can prevent further 
dosing  
• Need for a dose reduction below protocol-defined recommendations or study drug delay 
greater than 28 consecutive days 
• Initiation of a protocol-prohibited concomitant medication or non-protocol 
chemo/biological therapy for treatment of their disease 
• Investigator discretion 
• MD Anderson Cancer Center terminates the study 
• Patient withdraws consent 
• Patient decision to discontinue treatment. 
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 AE or an abnormal laboratory test 
result, the principal specific event or test will also be recorded on the electronic case report form 
(eCRF). 
Patients with clearly confirmed progressive disease will be taken off the study treatment. 
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4. 
STUDY TREATMENTS 
4.1. 
Investigational Products 
4.1.1. 
Investigational Product 
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 an amber vial containing 80 mg in 
20 mL (4 mg/mL) or 40 mg in 10 mL (4 mg/mL). Each vial is designated for single use.  
Plinabulin is an investigational drug that will be supplied by BeyondSpring Pharmaceuticals or 
designee. 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. 
Plinabulin is given to all subjects in Phase 1b study and subjects on Arm A in Phase 2 study on 
Day 1 of every treatment cycle and day 4 of cycle 1 until disease progression. If an optional RT 
is administered on Cycle 2 Day 1, then plinabulin dose will be infused on Cycle 2 Day 4. 
Plinabulin will be given on Day 1 of Cycle 3 and after. 
4.1.2. 
Anti-PD-1/PD-L1 mAbs 
Subjects must be given the same anti-PD-1/PD-L1 mAb on which they have failed in prior 
treatment and keep the dose and treatment cycle unchanged. Anti-PD-1/PD-L1 mAb will be 
dosed according to recommendations until disease progression as specified in Table 1 and Table 
2 for Phase 1b and Phase 2, respectively. Anti-PD-1/PD-L1 mAb treatment cycle defines 
subject’s treatment cycle for this study. 
The list of anti-PD-1/PD-L1 mAbs approved to date for the following indications is provided 
here: Please note any approved anti-PD-1/PD-L1 mAbs can be used for the study.  
1. Merkel cell cancer: Avelumab, Pembrolizumab  
2. Renal cell Cancer: Pembrolizumab, Nivolumab  
3. Bladder cancer: Durvalumab 
4. MSI-H cancers (of any histology): Pembrolizumab, Nivolumab 
5. Non-small cell lung cancer: Pembrolizumab, Nivolumab, Atezolizumab, Durvalumab 
6. Small cell lung cancer: Pembrolizumab, Nivolumab, Atezolizumab 
7. Melanoma: Nivolumab or Pembrolizumab single agent 
8. Any other tumor type that has any approved immune checkpoint inhibitors  
 
Anti-PD-1/PD-L1 mAb dose and administration route: 
1. Avelumab 800 mg intravenous (IV) over 1 hr on Day 1 and Day 15 in Q4W 
2. Atezolizumab 1200 mg Q3W IV 1 hr in 1st dose, may infuse over 30 min in subsequent 
doses if tolerated well  
3. Durvalumab 10 mg/kg IV over 1 hr on Day 1 and Day 15 in Q4W 
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4. Nivolumab 240 mg IV over 30-60 min on Day 1 and Day 15 in Q4W  
5. Pembrolizumab 200 mg Q3W IV over 30min 
 
Anti-PD-1/PD-L1 mAbs will be covered under subject’s medical plan as part of standard of care. 
The site investigator shall take responsibility and all steps to maintain appropriate records and 
ensure appropriate supply, storage, handling, distribution, and usage of those medications in 
accordance with the protocol and any applicable laws and regulations. 
Anti-PD-1/PD-L1 mAb will be administered after the rest period (3-12 hours) of RT and before 
plinabulin dosing. Please follow the instructions from FDA package insert of each drug for drug 
storage, preparation, infusion, and treatment cycle etc. The anti-PD-1/PD-L1 mAb treatment 
cycle should maintain the same throughout the study.  
Please follow PD-1 or PD-L1 dose modification instructions per FDA package insert. If the PD-1 
or PD-L1 dose is withheld due to toxicity the plinabulin treatment should also be withheld. 
4.1.3. 
Radiation Therapy 
Radiation therapy will be delivered using external beam radiation, with either 2D/conventional 
techniques, three-dimensional conformal therapy, intensity modulated radiation therapy (IMRT), 
stereotactic radiosurgery (SRS) or proton beam therapy (PBT), at the discretion of the treating 
radiation oncologist. For implanted devices, such as pacemakers, MD Anderson Standard Operating 
Procedure (SOP) will be followed.   
Radiation Therapy (RT) will be administered with one of three regimens: 8 Gy x 3 fractions, or 
12.5 Gy x 4 fractions, and/or 4 Gy x 5 fractions from Days 1 to 3 (3 fractions), Days 1 to 4 
(4 fractions), or Days 1 to 5 (5 fractions). The choice of RT regimens for tumors and lesions is at 
the discretion of the treating radiation oncologist. RT will target up to a maximum of 5 tumor 
lesions, and any of the radiation regimens could be use simultaneously or sequentially. Optional 
sequential RT may be administered in Cycle 2 of any anti-PD-1/PD-L1 regimens at the 
discretion of the treating doctor to target the other untreated lesions with the regimens described 
in this protocol. Optional RT will always be given in Cycle 2 on Day 1.  
If patients develop toxicity attributable to radiation after receiving at least one dose of radiation, 
the rest of the radiation treatment may be discontinued, and the AEs will be documented. Since 
the number of fractions are between 3-5 fractions, patients could receive at least 1 fraction up to 
5 fractions. The initially prescribed dose per fraction will not change, but it is possible to simply 
reduce the total dose delivered. The patient will have a visit with the treating radiation oncologist 
at the end of every cycle of radiation treatment. 
Please always leave at least one measurable lesion untreated for disease assessment monitoring. 
There should be at least a 3-hour (but not longer than 12 hours) rest period after RT before any 
study drug infusion. Treatment could be for any lesions in organs including in nodes, brain, and 
bone. Assessment of responses however should not be reliant on bony lesions. Brain metastasis 
should be treated and not be used for irRECIST response assessment. 
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Radiation Simulation 
Patients will be simulated on a CT scanner and immobilized based on the site of disease. 
Immobilization devices will be at the discretion of the treating radiation oncologist. Typical 
immobilization devices include a head and neck mask for metastatic sites in this region, an upper 
body cradle for disease in the thorax, and a lower body cradle for disease in the abdomen, pelvis, 
or lower extremities. Four-dimensional CT scanning will be utilized at the treating radiation 
oncologist’s discretion, to assess for internal motion. 
Definition of Radiation Target Volumes 
Target volumes will be approved by the treating radiation oncologist, using the information 
obtained through clinical examination, radiologic images, the simulation planning study, and 
histologic specimens. When feasible and necessary, the patient’s diagnostic images (CT scan, 
MRI study, or positron emission tomography [PET]/CT imaging) will be fused with the 
simulation scan to delineate the suggested target volumes below. 
Gross Tumor Volume (GTV) – All known disease detected by the above methods, including 
nodal disease.   
Internal Gross Tumor Volume (iGTV) – GTV plus internal motion, if 4D scanning is obtained at 
the time of simulation. 
Clinical Target Volume (iCTV) – iGTV plus the region at risk for microscopic spread. This 
target volume will be added at the physician’s discretion, given that all patients in this study will 
have metastatic disease and thus the utility of accounting for microscopic spread is limited. 
Planning Target Volume (PTV) – iGTV or iCTV plus a margin to account for patient movement 
and daily setup error. 
Organ at Risk Volumes (OAR) – Delineation of the pertinent organs at risk, to include the lung, 
heart, esophagus, spinal cord, kidney, and liver.   
Contouring atlases are used standardly at MD Anderson contoured by the physicians and 
dosimetrists based on established atlases available through RTOG/NRG websites. These atlases 
are available for review at: https://www.nrgoncology.org/ciro-contouring-atlases-templates-and-
tools. All organs within a body site (thoracic site will include lung, great vessels, trachea, 
esophagus, heart, and spinal cord; for gastrointestinal (GI) sites, liver, small bowel, kidneys 
(right and left), and spinal cord) are contoured regardless of where the tumor being treated is 
situated. Due to dose scatter of radiation, if an OAR is within 5 cm from the PTV, that organ 
should be contoured. If outside superiorly or inferiorly by 5 cm, those OARs need not be 
contoured. 
The dose constraints for hypofractionated regimens will be adjusted based on the number of 
fractions. Normal tissue dose constraints will not vary between photons and protons. Suggested 
dose constraints for three, four, and five fraction regimens are shown in Table 4, Table 5, and 
Table 6. 
Table 4: 
Summary of Suggested OAR Dose Constraints for three-fraction regimens 
Serial Tissue 
Volume 
Volume Max (Gy) 
Max Point Dose 
(Gy)** 
Spinal Cord and medulla 
<0.35 cc 
15.9 Gy 
22.5 Gy 
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Serial Tissue 
Volume 
Volume Max (Gy) 
Max Point Dose 
(Gy)** 
<1.2 cc 
13 Gy 
Spinal Cord Subvolume (5-6 mm 
above and below level treated per 
Ryu) 
<10% of 
subvolume 
15.9 Gy (changed 
from 18Gy on 
original form) 
22.5 Gy 
Cauda Equina 
<5 cc 
21.9 Gy  
25.5 Gy 
Sacral Plexus 
<5 cc 
22.5 Gy 
24 Gy 
Esophagus* 
<5 cc 
17.7 Gy 
25.2 Gy 
Brachial Plexus 
<3 cc 
22 Gy 
26 Gy 
Heart/Pericardium 
<15 cc 
24 Gy 
30 Gy 
Great vessels 
<10 cc 
39 Gy 
45 Gy 
Trachea and Large Bronchus* 
<5 cc 
25.8 Gy 
30 Gy 
Bronchus- smaller airways 
<0.5 cc 
18.9 Gy 
23.1 Gy 
Rib 
<5 cc 
40 Gy 
50 Gy 
Skin 
<10 cc 
31 Gy 
33 Gy 
Stomach 
<5 cc 
22.5 Gy 
30 Gy 
Bile duct 
 
 
36 Gy 
Duodenum* 
<5 cc 
<10 cc 
15.6 Gy 
12.9 Gy 
22.2 Gy 
Jejunum/Ileum* 
<30 cc 
17.4 Gy 
27 Gy 
Colon* 
<20 cc 
24 Gy 
34.5 Gy 
Rectum* 
<3.5 cc 
<20 cc 
45 Gy 
27.5 Gy 
49.5 Gy 
Ureter 
 
 
40 Gy 
Bladder wall 
<15 cc 
17 Gy 
33 Gy 
Penile bulb 
<3 cc 
25 Gy 
 
Femoral Heads  
<10 cc 
24 Gy 
 
Renal hilum/vascular trunk 
15 cc 
19.5 Gy 
 
 
 
 
 
Parallel Tissue 
Critical Volume 
(cc) 
Critical Volume 
Dose Max (Gy) 
 
Lung (Right & Left) 
1500 cc 
10.5 Gy 
 
Lung (Right & Left) 
1000 cc 
11.4 Gy 
V-11Gy<37% 
Liver 
700 cc 
17.1 Gy 
 
Renal cortex (Right & Left) 
200 cc 
15 Gy 
 
OAR: Organ at Risk  
*Avoid circumferential irradiation 
** “point” defined as 0.035cc or less 
 
Table 5: 
Summary of Suggested OAR Dose Constraints for four-fraction regimens 
Serial Tissue 
Volume 
Volume Max (Gy) 
Max Point Dose 
(Gy)** 
Brainstem (not medulla) 
<0.5 cc 
20.8 Gy 
27.2 Gy 
Spinal Cord and medulla 
<0.35 cc 
<1.2 cc 
18 Gy 
14.6 Gy 
25.6 Gy 
Spinal Cord Subvolume (5-6 mm 
above and below level treated per 
<10% of 
subvolume 
18 Gy 
25.6 Gy 
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Serial Tissue 
Volume 
Volume Max (Gy) 
Max Point Dose 
(Gy)** 
Ryu) 
Cauda Equina 
<5 cc 
26 Gy 
28.8 Gy 
Sacral Plexus 
<5 cc 
26 Gy 
28 Gy 
Esophagus* 
<5 cc 
18.8 Gy 
30 Gy 
Brachial Plexus 
<3 cc 
24.8 Gy 
29.6 Gy 
Heart/Pericardium 
<15 cc 
28 Gy 
34 Gy 
Great vessels 
<10 cc 
43 Gy 
49 Gy 
Trachea and Large Bronchus* 
<5 cc 
28.8 Gy 
34.8 Gy 
Bronchus- smaller airways 
<0.5 cc 
20 Gy  
28 Gy 
Rib 
<5 cc 
43 Gy 
54 Gy 
Skin 
<10 cc 
33.6 Gy 
36 Gy 
Stomach 
<5 cc 
25 Gy 
33.2 Gy 
Bile duct 
 
 
38.4 Gy 
Duodenum* 
<5 cc 
<10 cc 
17.2 Gy 
14 Gy 
24.4 Gy 
Jejunum/Ileum* 
<30 cc 
18.8 Gy 
30 Gy 
Colon* 
<20 cc 
26 Gy 
37.2 Gy 
Rectum* 
<3.5 cc 
<20 cc 
47.2 Gy 
30 Gy 
52.4 Gy 
Ureter 
 
 
43 Gy 
Bladder wall 
<15 cc 
18.5 Gy 
35.6 Gy 
Penile Bulb 
<3 cc 
27 Gy 
 
Femoral Heads 
<10 cc 
27 Gy 
 
Renal hilum/vascular trunk 
15 cc 
21.5 Gy 
 
 
 
 
 
Parallel Tissue 
Critical Volume 
(cc) 
Critical Volume 
Dose Max (Gy) 
 
Lung (Right & Left) 
1500 cc 
11.6 Gy 
 
Lung (Right & Left) 
1000 cc 
12.4 Gy 
V-13Gy<37% 
Liver 
700 cc 
19.2 Gy 
 
Renal cortex (Right & Left) 
200 cc 
17 Gy 
 
OAR: Organ at Risk  
*Avoid circumferential irradiation 
** “point” defined as 0.035cc or less 
 
Table 6: 
Summary of Suggested OAR Dose Constraints for five-fraction regimens 
Serial Tissue 
Volume 
Volume Max (Gy) 
Max Point Dose 
(Gy)** 
Brainstem (not medulla) 
<0.5 cc 
23 Gy 
31 Gy 
Spinal Cord and medulla 
<0.35 cc 
<1.2 cc 
22 Gy 
15.6 Gy 
28 Gy 
Spinal Cord Subvolume (5-6 mm 
above and below level treated per 
Ryu) 
<10% of 
subvolume 
22 Gy 
28 Gy 
Cauda Equina 
<5 cc 
30 Gy 
31.5 Gy 
Sacral Plexus 
<5 cc 
30 Gy 
32 Gy 
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Serial Tissue 
Volume 
Volume Max (Gy) 
Max Point Dose 
(Gy)** 
Esophagus* 
<5 cc 
19.5 Gy 
35 Gy 
Brachial Plexus 
<3 cc 
27 Gy 
32.5 Gy 
Heart/Pericardium 
<15 cc 
32 Gy 
38 Gy 
Great vessels 
<10 cc 
47 Gy 
53 Gy 
Trachea and Large Bronchus* 
<5 cc 
32 Gy 
40 Gy 
Bronchus- smaller airways 
<0.5 cc 
21 Gy 
33 Gy 
Rib 
<5 cc 
45 Gy 
57 Gy 
Skin 
<10 cc 
36.5 Gy 
38.5 Gy 
Stomach 
<5cc 
26.5 Gy 
35 Gy 
Bile duct 
 
 
41 Gy 
Duodenum* 
<5 cc 
<10 cc 
18.5 Gy 
14.5 Gy 
26 Gy 
Jejunum/Ileum* 
<30 cc 
20 Gy 
32 Gy 
Colon* 
<20 cc 
28.5 Gy 
40 Gy 
Rectum* 
<3.5 cc 
<20 cc 
50 Gy 
32.5 Gy 
55 Gy 
Ureter 
 
 
45 Gy 
Bladder wall 
<15 cc 
20 Gy 
38 Gy 
Penile Bulb 
<3 cc 
30 Gy 
 
Femoral Heads  
<10 cc 
30 Gy 
 
Renal hilum/vascular trunk 
15 cc 
23 Gy  
 
 
 
 
 
Parallel Tissue 
Critical Volume 
(cc) 
Critical Volume 
Dose Max (Gy) 
 
Lung (Right & Left) 
1500 cc 
12.5 Gy 
 
Lung (Right & Left) 
1000 cc 
13.5 Gy 
V-13.5Gy<37% 
Liver 
700 cc 
21 Gy 
 
Renal cortex (Right & Left) 
200 cc 
18 Gy 
 
OAR: Organ at Risk  
*Avoid circumferential irradiation 
** “point” defined as 0.035cc or less 
 
4.1.4. 
Study Drug Preparation 
The plinabulin dose should be calculated based on the baseline body surface area (BSA). If BSA 
subsequently varies from baseline by more than ±10%, then the newer BSA value should be used 
for calculation of subsequent doses. For patients with a BSA greater than 2.4 m2, dosing should 
be calculated using a maximum BSA of 2.4 m2 for Plinabulin. Plinabulin will be diluted with 
dextrose 5% in water (D5W) for infusion. Please refer to plinabulin pharmacy manual for the 
Instructions of the drug preparation.   
Please refer to the instructions from FDA package inserts or local hospital guidance for the 
preparation of anti-PD-1/PD-L1 mAbs in the study. 
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4.1.5. 
Methods of Assigning Patients to Study Cohorts 
The Phase 1b trial is an open-label study. Subject in Phase 1b trial is assigned to the study cohort 
based on the type of cancers confirmed by pathology tests.  
The Phase 2 trial is an open-label study with two treatment cohorts. Subject in Phase 2 trial will 
be randomized 1:1 between two treatment arms.   
Arm A: Radiation Therapy + Plinabulin + anti-PD-1/PD-L1 mAb 
Arm B: Radiation Therapy + anti-PD-1/PD-L1 mAb 
The randomization will be stratified by (i) the number of mets (oligo (<=3 vs > 3) and (ii) ECOG 
0-1 vs 2. The block size of 6 will be used for randomization. Randomization will be carried out 
using the CTC website. 
4.1.6. 
Study Drug Administration 
Plinabulin 
Plinabulin is intended for intravenous (IV) infusion diluted with dextrose 5% in water (D5W) 
over 30 to 60 minutes. Plinabulin 30 mg/m2 will be administered intravenously over 60 minutes 
± 10 min. Plinabulin 20 mg/m2 will be infused through IV over 30 minutes ± 5 min. Plinabulin 
must be protected from light at all times (storage, prior to, during, and after dilution).  
Plinabulin should always be administered at 1-2 hour after completion of PD-1 or PD-L1 
inhibitor infusion on Day 1of treatment cycle. When required on Day 4, it will be given at least 
3 hours (but not longer than 12 hours) after the 4th fraction of radiotherapy if applicable.   
4.1.7. 
Method of Assessing Treatment Compliance 
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol. Patients will receive all study drug 
administrations under the supervision of the Investigator. 
Accountability for study drug administration during the study is the responsibility of the 
Investigators or designees.   
4.1.8. 
Packaging and Labeling Information 
Labels will be prepared in accordance with Good Manufacturing Practice Annex 13 requirements 
and local regulatory guidelines. The study drug label on the bottle specifies the appropriate 
storage. 
Plinabulin is supplied as a solution in 40% Kolliphor HS 15 (formerly known as 
Solutol HS-15®)/60% propylene glycol in amber vials containing 80 mg in 20 mL (4 mg/mL), or 
in amber vials containing 40 mg in 10 ml (4 mg/ml). Each vial is designated for single use. The 
labeled storage condition for the drug product is stored between 15°C and 25°C (59°F and 77°F). 
Vials are labeled with other information as per local regulatory requirements. The contents of the 
label will be in accordance with all applicable regulatory requirements. 
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4.1.9. 
Study Drug Storage 
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. Vials should be stored upright. Drug supplies must be kept in an 
appropriate secure area (e.g., locked cabinet) and drug storage temperature must be monitored 
and recorded. Refer to the Pharmacy Manual for further information. 
4.1.10. 
Study Drug Accountability 
Plinabulin will be provided by BeyondSpring Pharmaceuticals or its designee and shipped 
directly to the Investigator or the designated pharmacist.  
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 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. 
4.1.11. 
Study Drug Handling and Disposal 
Preparation should be performed by trained personnel in accordance with good practices rules, 
especially with respect to a sepsis. After final drug reconciliation, unused drug vials should be 
disposed at the site following procedures for the disposal of anticancer drugs.  
At the end of the study, all expired or unused medication will be returned to the BeyondSpring 
contract repository or destroyed on site according to site procedures. Refer to the Pharmacy 
Manual for further information. 
4.2. 
Concomitant Medications 
4.2.1. 
Permitted Medications 
All concomitant medications will be recorded from the time the subject signs the informed 
consent form. Concomitant medication will only be collected after end of treatment (EOT) if it is 
associated with an on ongoing AE. 
Prior medications of all cancer treatments will be collected for this study.  
Medications considered necessary for the patient’s welfare, which are not expected to interfere 
with the evaluation of the study drug, may be given at the discretion of the Investigator. 
Prophylactic anti-emetics and early symptomatic treatment to prevent GI AEs are encouraged. A 
5-HT3 blocker (palonosetron) is preferred, and if not available, ondansetron or granisetron could 
be considered as an alternative. Physicians should also provide patients with an antiemetic 
regimen (e.g., prochlorperazine) for subsequent use as needed. On cycle 1or 2 day 4, plinabulin is 
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administered without PD-1 or PD-L1 agents, and a 5-HT3 blocker must be given as an emesis 
prophylaxis. 
If diarrhea occurs, it must be treated. Anti-diarrheas such as loperamide must be prescribed for 
diarrhea. Suggested loperamide use: 4 mg orally after first loose stool or frequent bowel 
movement, then 2 mg every 2 hours (4 mg every 4 hours at night) until 12 hours have passed 
without a bowel movement. Do not exceed 16mg in 24 hours. The Prophylactic or therapeutic 
administration of atropine should be considered in patients experiencing cholinergic symptoms. 
Appropriate dietary interventions should be advised to patients. Patients should also be cautioned 
to avoid dehydration, and of the importance to drink water and electrolyte containing fluids 
throughout the day when diarrhea occurs. If IV fluids are needed, their administration must be 
recorded on the eCRF. 
Non-steroidal anti-inflammatory drugs are permitted for the treatment of AEs and as 
pre-medication. 
Corticosteroid use for nausea is to be avoided.  
Other pre-medications may be administered as appropriate and diphenhydramine with 
acetaminophen may be administered in the event of an infusion reaction. Institutional guidelines 
should be followed in the event of infusion/hypersensitivity reaction.  
Increases in systolic blood pressure above 200 mm Hg should be managed with nitroprusside or 
similar regimen per institutional practice. Blood pressure should be closely monitored. Please 
follow the plinabulin dose modification table (Table 3) for instructions. 
All medications will be recorded in an appropriate section of the CRF. 
4.3. 
Prohibited Medications or Cancer Therapies 
Subjects should not receive other antitumor therapies while on study. If a subject receives 
additional antitumor therapies, such as chemotherapy, hormone therapy, palliative radiotherapy, 
or immunotherapy, this will be judged to represent evidence of disease progression, and 
continuation of the study medication and further participation in the study must be discussed 
with the Investigator. 
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5. 
STUDY PROCEDURES 
A complete Schedule of Assessments for the Study can be seen in Table 7 for any 
Anti-PD-1/PD-L1 mAb regimen.
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Table 7: 
Schedule of Assessments for Anti-PD-1/PD-L1 mAb Treatment (1 Cycle = 3 
or 4 Weeks) 
 
Cycle 
Screen 
Cycle 1 & 2 
 
Cycle 3 & Onwards 
End of 
Treatment 
(EOT) 
Follow-Up 
Visits 
Day 
Days -28 to 
-1 
Day 1 Days 2 
& 3 
Day 4 Day 5 
Day 1 
 
 
30 Days after 
last dose of 
Plinabulin  
Every 12 
weeks 
Window 
 
±3d 
 
 
± 3 Days 
± 7 Days 
± 7 Days 
Informed consent1 
X 
 
 
 
 
 
 
 
Verify eligibility 
criteria2 
X 
X 
 
 
 
 
 
 
Medical history3 
X 
 
 
 
 
 
 
 
Urine beta- hCG4 
X 
X 
 
 
 
X 
 
 
Protocol/Safety Evaluation 
Physical Exam and 
ECOG5 
X 
X 
 
 
 
X 
X 
X 
Height6 
X 
 
 
 
 
 
 
 
Vital Signs6 
X 
X 
 
X 
 
X 
X 
X 
12-lead ECG7 
X 
X 
As Clinically Indicated 
 
 
AE/SAE Assessment 
X 
X 
 
X 
 
X 
X 
X 
Concomitant 
Medications 
X 
X 
 
X 
 
X 
X 
X 
Survival Status8 
 
 
 
 
 
 
X 
Safety Laboratory Evaluation 
Hematology9 
X 
X 
 
X 
 
X 
X 
X 
Serum Chemistry10 
X 
X 
 
X 
 
X 
X 
X 
Urine analysis11 
X 
 
 
 
 
 
X 
 
Coagulation test12 
X 
X 
As Clinically Indicated 
X 
 
 
 
 
 
 
 
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Footnote: 
1 Prior to the first study-specific measures. May include optional biobank study consent and pregnancy consent. 
2 Prior to Cycle 1 Day 1. 
3 Medical history includes baseline symptoms as well as a detailed history of prior cancer therapies including start and 
stop dates, disease progression during or after therapy, as well as discontinuations due to intolerability or any other serious 
illness. 
4 Applicable for women of childbearing potential. Urine B-HCG within 7 Days before the first dose of study treatment, 
and on Day 1 of every Cycle. Positive results to be confirmed by serum pregnancy testing. 
 
Screen 
Cycle1 & 2 
Cycle 
3&Onwards
End of 
Treat
Follow-Up 
Visits 
 
-28 to -1 
Day 
Day 1 Day 2, 3 Day 4 
Day 5 
Day 1 
30 Days after 
last dose of 
Plinabulin 
Every 12 
weeks 
Window 
 
±3d 
 
 
 
± 3 Days 
± 7 Days 
± 7 Days 
 Translational Study & Sample Collection 
Phenotyping analysis of immune 
cells from peripheral blood13 
X 
 
 
X 
X 
X 
Imaging guided core needle 
tumor biopsy14 
X 
 
 
 
 
 
X 
 
 
Cancer related Gene Mutation 
test15 
X 
 
 
 
 
 
 
TCR sequencing peripheral 
blood16 
X 
 
 
X 
 
X 
X 
TCR sequencing tumor tissue17   
X 
 
 
 
 
X 
 
Immune repertoire Imaging 
CyTOF analysis and/or single 
cell RNAseq18 
X 
 
 
 
 
X 
 
Dendritic cell activation assay19 
X 
 
 
X 
 
X 
X 
T cell activation assay20 
X 
 
 
X 
 
X 
X 
RNAseq including 
Phosphorylated GEF-H1-
dependent immune signature20 
X 
 
 
X 
 
X 
X 
Targeted cytokine panel assay20 
X 
 
 
X 
 
X 
X 
ctDNA20 
X 
 
 
X 
 
X 
X 
Study Treatment 
Radiation Therapy (RT)21 
X 
X 
X 
X 
 
Plinabulin Administration
22
 
X 
 
X 
 
X 
 Anti-PD-1/PD-L1 mAb 
Administration23 
X 
 
 
 
X 
 Tumor Measurement 
 CT, MRI or PET/CT
24
 
X 
 
 
 
 
X 
X 
X 
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5 ECOG performance status will be performed at screening, Day 1 of every cycle, end of study treatment (EOT) and 
follow-up visits. A full physical examination will be performed at screening, on Day 1of every cycle,EOT, and follow-up 
visits. Symptom-directed physical examinations will be performed at other visits.  
6 Vital signs including temperature, pulse, respiratory, blood pressure, body surface area (BSA) and body weight will be 
measure (body surface area (BSA) and body weight on D1 of each cycle). Subjects will have vital signs performed at screening, 
pre-dose on Days they receive infusion, EOT, and Follow-up. Additional vital signs should be measured on Day 1 of every 
cycle and when the optional RT in C2D4 is administered at immediately before and after Plinabulin infusions, and 30 (± 5 
min) and 60 (± 10 min) minutes following Plinabulin infusion. 
7 12-lead ECG(single) will be performed at screening, Cycle 1 Day 1 pre-dose, and as clinically indicated. 
8 Survival Status: Investigators will continue to collect survival data for subjects every 12 weeks after progression of 
disease or start of additional anti-neoplastic medication using information from a chart review, patient visit, or telephone 
call unless patient fully withdrew consent to participate in the study. The telephone call will be less than five minutes to 
obtain information regarding survival status. 
9 Hematology: White blood cell (WBC) count with differential, hhemoglobin, platelet count, red blood cell count, 
hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC). Subjects will have 
hematology lab performed on screening, pre-dose on Day 1 of every cycle, Day 4 of Cycle 1 or 2 prior to plinabulin dose when 
applicable, EOT, Follow-up Visits. Labs may be performed more frequently at the physician’s discretion. 
10 Chemistry: Sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, calcium, phosphate, magnesium, ALT, 
AST, alkaline phosphatase, total bilirubin, LDH, total protein, albumin, uric acid. Subjects will have labs at screening, Pre-
dose on Day 1 of every cycle, Day 4 of Cycle 1 or 2 prior to plinabulin dose when applicable, EOT, Follow-up Visits. 
Amylase, lipase, and creatine kinase will only be performed in Cycle1 and as clinically indicated. Labs may be performed 
more frequently at the physician’s discretion. 
11 Urine analysis will include Color, appearance, specific gravity, pH, protein, glucose, ketones, blood, bilirubin and 
microscopy including WBC/high powerfield (HPF), RBC/HPF if clinically indicated. Urine analysis will be at screening, 
and EOT. 
12 Coagulation tests include prothrombin time (PT), international normalization ratio (INR), and activated partial 
thromboplastin time (aPTT).Coagulation tests will be performed at screening, Cycle 1 Day 1, EOT, and as clinically 
indicated. 
13 Phenotyping analysis of immune cells from peripheral blood is performed on blood samples collected at baseline (<1 
week prior to triple combo treatment), Cycle 1 Day 4, then pre-dose for every 2 cycles (C3, 5, etc.), and EOT 
14 Imaging-guided core needle tumor biopsy samples (at least 2 to 4 research cores) will be collected at Pre-dose (<2 week 
prior to radiation therapy) and within 7 days prior to Cycle 3 Day 1of immunotherapy with Plinabulin. The biopsied lesion 
should not have been targeted by radiation. If there has been a complete response in the pre-treatment biopsied lesion, 
another non-irradiated lesion could be biopsied with any response (partial, stable, or progressive), but should be documented 
clearly. Multiple lesions could be biopsied if it is safe to do and has clear biologic or clinical rationale to do so. 
15 Cancer related gene mutation information will be collected from the patient medical records. If not available, the 
biopsied tumor samples will be used to test the gene mutations (<1 week prior to any study treatment). 
16 TCR sequencing peripheral blood is performed on blood samples collected at baseline (<1 week prior to triple combo 
treatment), Cycle 1 Day 4, then pre-dose for every 2 cycles (C3, 5, etc.) and EOT. 
17 TCR sequencing tumor tissue will be collected at Pre-dose (<2 week prior to radiation therapy) and within 7 days prior to 
Cycle 3 Day 1 of immunotherapy with Plinabulin. The decision to perform exploratory biomarker analysis may be based on 
the clinical outcome of this study and/or the signals observed in other clinical studies or other information available at that 
time.  
18 Immune repertoire Imaging CyTOF analysis and/or single cell RNAseq will be performed in tumor biopsies at Pre-dose 
(<2 week prior to radiation therapy) and within 7 days prior to Cycle 3 Day 1 of immunotherapy with Plinabulin. 
19 Dendritic cell activation assay is performed on blood samples collected at baseline (<1 week prior to triple combo 
treatment), Cycle 1 Day 4, then pre-dose for every 2 cycles (C3, 5, etc.) and EOT. 
20 These Assays are performed on blood samples collected at baseline (<1 week prior to triple combo treatment), Cycle 1 
Day 4, then pre-dose for every 2 cycles (C3, 5, etc.) and EOT. The decision to perform exploratory biomarker analysis may 
be based on the clinical outcome of this study and/or the signals observed in other clinical studies or other information 
available at that time. 
21 Radiation Therapy (RT), one of three regimens: 8 Gy x 3 fractions, 12.5 Gy x 4 fractions, and/or 4 Gy x 5 fractions from 
Days 1 to 3 (3 fractions), Days 1 to 4 (4 fractions), or Days 1 to 5 (5 fractions) in Cycle 1 should be prescribed. The choice 
of RT regimens for tumors and lesions is at the discretion of the treating radiation oncologist. RT will treat or target a 
maximum of 5 tumor lesions. Optional sequential RT in Cycle 2 is at the discretion of the treating doctor to `target other 
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untreated lesions with same regimens for the study. At least one measurable lesion untreated should be left for disease 
assessment monitoring. Each cycle, a radiation-related AE assessment will occur on the last day of the radiation treatment, 
and 1 week following (may be a telehealth visit). If acute RT-related toxicities of specified grades (i.e., Grade 3 or higher) 
develop, you should indicate that patients will be assessed at least weekly (may be a telehealth visit) until the AE(s) resolve 
to Grade ≤1 or baseline. 
22 Plinabulin will be administered intravenously on Cycle 1 Day 1 and Day 4. If optional RT is given in Cycle 2 Day 1, then 
Plinabulin will be dosed on Cycle 2 Day 1 and Day 4. Otherwise, Plinabulin will be administered only on Cycle 2 Day 1 if no 
RT is given, then Plinabulin will always be given on Day 1 of Cycle 3 and after. 
23 Atezolizumab or Pembrolizumab (Anti-PD-1/PD-L1 mAb) is infused on Day 1 of every cycle according to FDA approved 
indications and dosing instructions. The Anti-PD-1/PD-L1 mAb will always be administered at least 3 hours (but not longer 
than 12 hours) after the radiotherapy. The same PD-1 or PD-L1 which patient failed prior to the study must be administered 
in this study. Avelumab or Durvalumab or Novilumab (Anti-PD-1/PD-L1 mAb) is infused on Day 1 and 15 of every cycle 
according to FDA approved indications and dosing instructions. 
24 For Q3W regimens, CT, MRI or PET-CT Scans will be performed at screening, then every 9 weeks (3 Cycles) (± 7 days) for 
27 weeks (9 cycles), and then every 12 weeks (4 cycles) (± 7 days) during the treatment, at EOT and follow up period (Q12W). 
For Q4W regiments, CT, MRI, or PET-CT Scans will be performed at screening, then every 8 weeks (2 Cycles) (± 7 days) 
for 24 weeks (6 cycles), and then every 12 weeks (3 cycles) (± 7 days) during the treatment, at EOT and follow up period 
(Q12W). A repeat CT in 1 month should be conducted if there is evidence of progression but for confirmation that there is no 
“pseudoprogression”. Historical standard of care scans that are performed with scanning parameters consistent with the 
requirements for this protocol within 28 days prior to dosing are acceptable. Subjects who discontinued for reasons other than 
progression of disease or withdrawal from study treatment will continue to visit the clinic for study assessments and 
evaluation of their disease by CT, MRI, or PET/CT scan approximately every 12 (± 7 days) weeks until progression of 
disease is determined, the subject receives additional anti-neoplastic medication, or for a maximum of 5 years. A brain scan 
must be performed at screening to assess potential CNS disease and/or metastases. For subjects with previously treated 
eligible brain metastases, a brain scan must be performed at all tumor assessment timepoints. For all subjects, a follow-up 
brain scan must be performed to confirm irCR within 1 week of response confirmation, or if clinically indicated.  
 
5.1. 
Screening Period (-28 to -1 Days) 
At the screening visit, information will be collected, and patients will have clinical evaluations as 
follows: 
• Informed consent: main study and future research 
• Medical history: Present and past medical events, demographics; cancer gene 
mutation status, smoking history; prior cancer treatments) 
• Cancer diagnosis and staging 
• Tumor assessments and measurement by irRECIST (Historical standard of care scans 
that are performed with scanning parameters consistent with the requirements for this 
protocol within 28 days prior to dosing are acceptable) 
• Concomitant medications (starting from the time the patient signs the informed 
consent) 
• Complete physical examination, including height (screen only) and weight 
• Vital sign measurements 
• ECOG performance status. 
• Baseline electrocardiogram (ECG) 
• Hematology, serum chemistry and urinalysis, endocrine labs, and coagulation tests 
• Research blood and biopsy at screening will be as described in Section 6.1  
• Urine pregnancy test, if applicable (positive results to be confirmed by serum 
pregnancy testing). 
 
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5.2. 
Treatment Period 
5.2.1. 
Day 1 of all Treatment Cycles 
On Day 1 of treatment cycle, information will be collected, and patients will have clinical 
evaluations as follows: 
• Physical examination (within the past 48 working hours) 
• Vital sign measurements, Vital signs include temperature, blood pressure, heart rate, 
respiratory rate, weight, and BSA. Vital signs should be measured prior to the study 
treatment, immediately before and after plinabulin infusions, and 30 and 60 minutes 
following plinabulin infusion during Day 1 
• ECOG performance status 
• ECG (Cycle 1 mandatory, other cycles as clinically indicated) 
• Hematology and serum chemistry 
• Coagulation test (Cycle 1 only) 
• Urine pregnancy test, if applicable (positive results to be confirmed by serum 
pregnancy testing) 
• Tumor assessment and measurement: For Q3W regimens the assessment will be 
conducted every 9 weeks (3 cycles) (± 7 days) for 27 weeks (9 cycles), and then 
every 12 weeks (4 cycles) (± 7 days) during the treatment. For Q4W regimens the 
assessment will be conducted every 8 weeks (2 cycles) (±7 day) for the first 24 weeks 
(6 cycles), then every 12 weeks (±7 day) for post 24 weeks duration treatment, or as 
clinically indicated 
•  Imaging-guided core needle tumor biopsy samples (at least 2 to 4 research cores) will 
be collected at Pre-dose (<2 week prior to radiation therapy) and within 7 days prior 
to Cycle 3 Day 1of immunotherapy with Plinabulin. 
• Research laboratory tests collected before plinabulin administration, as described in 
Section 6.1 
• RT (Cycle 1 Day 1 out of 3 to 5 days, and also in Cycle 2 which is optional per 
treating physician’s discretion) 
• Anti-PD-1/PD-L1 mAb infusion 
• Plinabulin infusion (in Phase 2, only for patients in the RT+PD-1/PD-L1+Plinabulin 
arm) 
• Concomitant medications 
• Assessment of AEs on days of plinabulin administration. 
 
5.2.2. 
Day 4 of Cycle 1& 2 for Immune Checkpoint Inhibitors with Q3W 
Regimens 
On Days 4 of Cycle1 and Cycle 2, information will be collected, and patients will have the 
procedures performed as follows: 
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• Vital signs including weight, BSA, temperature, blood pressure, heart rate, and 
respiratory rate. Vital signs should be measured immediately before and after 
plinabulin infusions, and 30 and 60 minutes following plinabulin infusion during Day 
4 if optional RT is given in Cycle 2 Day 1. 
• Hematology, serum chemistry. (on cycle 1 Day 4 and only when Plinabulin is given 
on C2D4) 
• Research laboratory tests collected before plinabulin administration, as described in 
Section 6.1 
• Plinabulin infusion  
•  RT given to complete 3 to 5 fraction regimen (Cycle 1 mandatory, Cycle 2 optional 
per treating physician’s discretion). If given in Cycle 2, RT will be given on the same 
days as it was given in Cycle 1. 
• Assessment of AEs on days of plinabulin administration. 
• Concomitant medications (on Cycle 1 Day 4 and only when Plinabulin is given on 
C2D4) 
 
5.2.3. 
Day 4 of Cycle 1 & Cycle 2 for Immune Checkpoint Inhibitors with Q4W 
Regimens 
On Days 4, of Cycle 1& Cycle 2, information will be collected, and patients will have the 
procedures performed as follows: 
• Vital signs including weight, BSA, temperature, blood pressure, heart rate, and 
respiratory rate. Vital signs should be measured immediately before and after 
plinabulin/placebo infusions, and 30 and 60 minutes following plinabulin/ infusion 
during Day 4 if optional RT is given in Cycle 2 Day 1. 
• Hematology, serum chemistry (on Cycle 1 Day 4 and only when Plinabulin is given 
on C2D4) 
• Research laboratory tests collected before plinabulin administration, as described in 
Section 6.1 
• Plinabulin infusion  
• RT given to complete 3 to 5 fraction regimen (Cycle 1 mandatory, Cycle 2 optional 
per treating physician’s discretion). If given in Cycle 2, RT will be given on the same 
days as it was given in Cycle 1. 
• Assessment of AEs on days of plinabulin administration. 
• Concomitant medications (on Cycle 1 Day 4 and only when Plinabulin is given on 
C2D4) 
 
5.2.4. 
End of Study 
At the end of study, information will be collected, and patients will have clinical evaluations as 
follows: 
• Vital signs 
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• Physical examination 
• ECOG performance status 
• Hematology, serum chemistry, and urine analysis 
• Coagulation test 
• Tumor assessments and measurement 
• Research laboratory tests collected before plinabulin administration, as described in 
Section 6.1 
• Concomitant medications 
• 
Assessment of AEs 
 
5.2.5. 
Follow-up (Every 12 Weeks) 
At the Follow up visit, information will be collected, and patients will have clinical evaluations 
as follows: 
• Vital signs 
• Physical examination 
• ECOG performance status 
• Hematology, serum chemistry 
• Concomitant medications 
• Assessment of AEs 
• Tumor assessments and measurement (every 12 weeks until progression of disease is 
determined, the patient withdraws from study treatment, or the patient receives 
additional anti-neoplastic medication) 
• 
Survival follow-up (every 12 weeks after progression of disease, the subjects starts 
additional anti-neoplastic medication, or for a maximum of 5 years). 
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6. 
STUDY VARIABLES AND METHODS OF ASSESSMENTS 
6.1. 
Blood Sampling 
Subjects will only have hematology labs performed on Screening, pre study treatment on day 1 
of every cycle (RT or drug treatment) Day 4 of Cycle 1 or 2 prior to plinabulin dose when 
applicable, EOT, and Follow-up Visit. Labs may be performed more frequently at the 
physician’s discretion. 
Subjects will have chemistry labs at screening, Pre-dose on Day 1 of every cycle, Day 4 of Cycle 
1 or 2 prior to plinabulin dose when applicable, EOT, Follow-up Visits. Amylase, lipase, and 
creatine kinase will only be performed in Cycle 1 and as clinically indicated. Labs may be 
performed more frequently at the physician’s discretion.  
Coagulation tests include prothrombin time (PT), international normalization ratio (INR), and 
activated partial thromboplastin time (aPTT). Coagulation tests will be performed at screening, 
Cycle 1 Day 1, EOT, and as clinically indicated. 
Blood sampling for the following translational studies is performed on blood samples collected 
at baseline (<1 week prior to triple combo treatment), Cycle 1 Day 4, then pre-dose for every 
2 cycles (C3, 5, etc.) and EOT. 
• Immune repertoire TCR sequencing 
• Phenotyping analysis of immune cells from whole blood using multicolor flow 
cytometry  
• Dendritic Cell activation assay from whole blood 
The decision to perform additional exploratory biomarker analysis (including but not limited to 
the tests listed below) may be based on the clinical outcome of this study and/or the signals 
observed in other clinical studies or other information available at that time. 
• TCR sequencing for tumor tissue 
• T Cell activation assay from whole blood  
• RNAseq, including GEF-H1 immune signature evaluation  
• Cell free circulating tumor DNA (ctDNA) sequencing 
• Multiplex cytokine panel including, but not limited to: IL-2, IFNγ, IL-6, IL-12p70, 
IL-12p40, IL-13, IL-17A, IL-23, G-CSF, IL-8 and IFN-β 
Serum pregnancy test will be needed if urine pregnancy test is positive. 
6.2. 
Urine Sampling 
Urine analysis will include color, appearance, specific gravity, pH, protein, glucose, ketones, 
blood, bilirubin, and microscopy including WBC/high power field (HPF), RBC/HPF if clinically 
indicated. Urine analysis will be at screening, and EOT. 
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6.3. 
Tumor biopsy 
The Imaging-guided core needle tumor biopsy samples (at least 2 to 4 research cores) will be 
collected at Pre-dose (<2 week prior to radiation therapy) and within 7 days prior to Cycle 3 Day 
1 of immunotherapy with Plinabulin. The biopsied lesion should not have been targeted by 
radiation. If there has been a complete response in the pre-treatment biopsied lesion, another 
non-irradiated lesion could be biopsied with any response (partial, stable, or progressive), but 
should be documented clearly. Multiple lesions could be biopsied if it is safe to do and has clear 
biologic or clinical rationale to do so. If there has been a complete response without targetable 
lesions to biopsy, then the biopsy of this second time point will be optional and documented as 
such. 
6.4. 
Assessment of Efficacy 
6.4.1. 
Criteria for Disease Evaluation 
All efficacy endpoints, other than OS, will be based on the tumor assessments performed by the 
investigators using both irRECIST and modified RECIST 1.1. Treatment decisions by the 
Investigator will be based on irRECIST. All scans for tumor assessments performed during the 
study should be archived in accordance with the standard local practice. 
Tumor assessments will be carried out during the Screening, and then every 9 weeks (± 1 week) 
for 27 weeks (during Q3W dosing) or every 8 weeks (± 1 week) for 24 weeks (during Q4W 
dosing), then every 12 weeks during treatment cycles in the Treatment Phase regardless of 
treatment cycles and follow up period. CT/MRI scans of chest, abdomen, and pelvis and of other 
known sites of disease will be obtained at Screening (within 28 days prior to Cycle 1/ Day 1), at 
all tumor assessment time points, and as indicated clinically. RT treated lesions will not be used 
for response assessment. Please keep at least one measurable tumor lesion untreated by RT for 
disease response assessment across the treatment. Color photographs containing a millimeter 
scale must be taken of all skin lesions being used as target lesions. Historical standard of care 
scans that are performed with scanning parameters consistent with the requirements for this 
protocol within 28 days prior to dosing are acceptable.  
The CT scan should be a diagnostic quality spiral or multidetector CT with oral and iodinated IV 
contrast, and the MRI scan should be performed with IV gadolinium chelate. Scans of the neck, 
abdomen, pelvis, and other areas of the body may be done with MRI instead of CT, but 
evaluation of the chest must be done with CT. If iodinated IV contrast is contraindicated, the 
chest evaluation should be done with non-contrast CT, and the abdomen and pelvis evaluation 
should be performed using either CT with oral contrast (without IV contrast) or MRI with 
gadolinium chelate IV contrast (the latter is preferred). Spiral/multidetector CT should be 
performed with a 5-mm contiguous slice reconstruction algorithm. If body MRI scans are 
performed, contiguous slices of 5 mm are also recommended. 
Low-dose non-contrast CT transmission scans from a positron emission tomography-CT 
(PET-CT) combination scanner is not acceptable. Ultrasound should not be used for radiographic 
tumor assessment. Chest disease may not be followed using chest x-ray. 
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A brain scan (CT with contrast or MRI pre- and post-gadolinium) must be performed at 
screening to assess potential CNS disease and/or metastases. For subjects with previously treated 
eligible brain metastases, a brain scan must be performed at all tumor assessment timepoints. For 
all subjects, a follow-up brain scan must be performed to confirm irCR within 1 week of 
response confirmation, or if clinically indicated. Brain metastasis should be treated by RT and 
not be used for irRECIST response assessment.  
The tumor assessment schedule should not be affected by interruptions in study treatment. 
Subjects going off treatment without disease progression will also undergo tumor assessments 
per the Schedule of Procedures/Assessments until disease progression is documented or another 
anticancer therapy is initiated. 
The same method of assessment used at screening must be used at all time points. Throughout 
the study it is critical that the same imaging methodology be applied, and contrast be consistently 
provided unless IV contrast becomes medically contraindicated during the course of treatment or 
the dose of contrast needs to be adjusted based on the subject’s health status. 
In order for immune-related stable disease (irSD) to be considered the best overall response, it 
must occur ≥5 weeks following the first dose of study drug. 
The first radiological assessment of tumor response status will be performed at Week 8(±1 
week), unless there is clinical indication warranting earlier radiologic imaging. If imaging at 
Week 8 shows stable disease (irSD), treatment will be continued and tumor assessments will be 
conducted at the next regularly scheduled imaging time point, i.e., at Week 16 (±1 week). 
Responses (irPR [immune-related partial response] or irCR [immune-related complete response]) 
should be confirmed no less than 4 weeks after the initial response, but generally at the next 
scheduled tumor assessment time point. 
If the time point tumor assessment is PD, treatment should continue, and tumor assessments 
repeated at least 4 weeks later in order to confirm immune-related progressive disease (irPD). If 
repeat imaging shows a reduction in the tumor burden compared to the initial tumor assessment 
demonstrating PD, treatment may be continued as per treatment schedule. If repeat imaging 
confirms irPD, subjects will be discontinued from study treatment. In determining the tumor time 
point response, investigators should consider all target lesions as well as non-target lesions and 
new lesions. 
The decision to continue study treatment after the first evidence of PD is at the Investigator’s 
discretion based on the clinical status of the subject as described in Table 8 below. 
Subjects may continue receiving study treatment while waiting for confirmation of PD if they are 
clinically stable as defined by the following criteria: 
• Absence of signs and symptoms (including worsening of laboratory values) indicating 
disease progression 
• No decline in ECOG performance status 
• Absence of rapid progression of disease 
• Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention 
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If irPD is confirmed and the subject is experiencing extraordinary clinical benefit, site must 
discuss continuing treatment. 
Tumor assessments per modified RECIST 1.1 will follow Eisenhauer et al., 2009, however, 
instead of the maximum of 5 target lesions (up to 2 per organ), up to 10 target lesions, (up to 
5 per organ) may be selected. 
Table 8: 
Imaging and Treatment After First Radiologic Evidence of Progressive 
Disease 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
1st 
Repeat imaging at 
>4 
May continue study 
Repeat imaging at 
>4 
Discontinue 
radiologic 
weeks to confirm 
PD 
treatment at the 
weeks to confirm 
PD 
treatment 
evidence of 
PD 
Investigator’s discretion 
while 
awaiting 
confirmatory scans 
per physician 
discretion only  
Subsequent 
scan 
confirms 
PD 
No additional 
imaging required  
Discontinue treatment 
No additional 
imaging required 
N/A 
Subsequent 
scan shows 
SD, PR or 
CR  
Continue regularly 
scheduled imaging 
assessments 
Continue study treatment 
at the 
Investigator’s 
discretion 
Continue regularly 
scheduled imaging 
assessments 
May restart study 
treatment if condition has 
improved and/or 
clinically stable 
per investigator’s 
discretion 
CR = complete response, PR = partial response, SD = stable disease, PD = progression disease, N/A = not applicable. 
 
Assessment of responses however should not be reliant on bony lesions. A bone scan or PET/CT 
will only be performed in patients with known bone metastasis at study entry to monitor the 
status of metastatic disease in bone. If radiologic imaging shows progressive disease (PD), tumor 
assessment may be repeated approximately 4-6 weeks later in order to confirm continued PD (as 
compared to the initial scan). Treatment may continue at the discretion of the treating physician 
while awaiting radiologic confirmation of progression. If repeat imaging shows a reduction or 
stabilization in the tumor burden compared to the initial scan demonstrating PD, treatment may 
be continued as per treatment calendar. 
Brain metastasis should be treated and not be used for irRECIST response assessment. Irradiated 
lesion(s) should not be used in disease assessment. Please always keep one lesion untreated 
by RT for the clinical efficacy assessment. Please refer to irRECIST guidance in Section 13 
(Appendix B).  
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7. 
ASSESSMENT OF SAFETY 
Details are provided in Table 7. 
7.1. 
Safety Parameters 
Safety assessments should be performed at all visits to the study center and throughout the study.  
7.1.1. 
Demographic/Medical History 
Medical and surgical history and current medical conditions will be recorded at the Screening 
Visit. All clinically significant medical and surgical history must be noted in the Medical History 
and Current Medical Conditions CRF. 
Demographic data will include gender, date of birth (or age), and race/ethnicity. Medical history 
findings (i.e., previous diagnoses, diseases, or surgeries) started before signing the informed 
consent, information of all medications and cancer treatment used within 30 days of signing the 
informed consent, as well as the relevant information needed for checking study eligibility will 
be collected and captured in the eCRF. 
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 electrocardiogram 
[ECG]).  
7.1.2. 
Vital Signs 
The following measurements for vital signs must be performed: systolic/diastolic blood pressure, 
heart rate, and respiratory rate. Vital signs will be measured per standard of care and documented 
on the vital signs CRF. 
Subjects will have vital signs performed at screening, pre-dose on Days they receive infusion, 
EOT, and Follow-up. Additional vital signs should be measured immediately before and after 
plinabulin infusions, and 30 and 60 minutes following plinabulin infusion during Day 1 and Day 
4 when plinabulin is given.    
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. 
7.1.3. 
Weight and Height 
Height will be measured in centimeters once at screening. Weight will be measured at every drug 
dosing visit and BSA will be calculated.  
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7.1.4. 
Physical Examination 
Physical examinations will be performed. A comprehensive (including neurological) 
examination will be performed at screening, Day 1 of each cycle, end of treatment, and 
follow-up, as detailed in Table 7, and a symptom-directed examination will be performed at 
other visits. 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 eCRF. Changes from the screening physical examination findings that meet the 
definition of an AE will be recorded on the eCRF. 
7.1.5. 
Electrocardiogram (ECG) 
ECGs are to be performed using a standardized method within 1 hour before the start of 
chemotherapy administration. 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. 
Single safety ECGs will be obtained on screening visit and Day 1 of Cycle 1, and then as 
clinically indicated.  
7.1.6. 
Laboratory Assessments 
7.1.6.1. 
Clinical Laboratory Assessments 
Hematology: White blood cell (WBC) count with differential, hemoglobin, platelet count, red 
blood cell count, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin 
concentration (MCHC). Subjects will only have labs performed on Screening, pre study 
treatment on day 1 of every cycle (RT or drug treatment) Day 4 of Cycle 1 or 2 prior to 
plinabulin dose when applicable, EOT, and Follow-up Visit. Labs may be performed more 
frequently at the physician’s discretion. 
Chemistry: Sodium, potassium, chloride, bicarbonate, bun, creatinine, glucose, calcium, 
phosphate, magnesium, ALT, AST, alkaline phosphatase, total bilirubin, LDH, total protein, 
albumin, uric acid, amylase, lipase and creatine kinase. Subjects will have Chemistry labs at 
screening, Pre-dose on Day 1 of every cycle, Day 4 of Cycle 1 or 2 prior to plinabulin dose when 
applicable, EOT, Follow-up Visits. Amylase, Lipase, and Creatine Kinase will only be 
performed in Cycle 1 and as clinically indicated. Labs may be performed more frequently at the 
physician’s discretion. 
Coagulation tests include PT, INR, and aPTT. Coagulation tests will be performed at screening 
and Day 1 of Cycle 1, end of treatment, and as clinically indicated. 
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7.1.6.2. 
Pregnancy Testing 
Pregnancy tests will be done using urine samples in women of childbearing potential. Patients 
must have a negative urine pregnancy test documented within 7 days of the first dose of 
treatment. Urine pregnancy tests will also be performed on Day 1 of each cycle. Confirm with 
serum testing (local or central laboratory) if urine sample is positive. 
7.1.6.3. 
Companion Translational Study 
Gene Mutation Evaluation:  
We expect most patients enrolled will have had hot spot mutation testing or targeted exome 
profiling performed prior to enrollment. If there is evidence of clinical activity, targeted exome 
sequencing on a 200-400 gene platform or larger will be performed in those patients with 
objective responses and prolonged stable disease >6 months as well as any patients with rapid 
progression (this could be done as part of a Institute of Personalized Cancer Therapy Unusual 
Responder Program). In addition, patients who have a response with subsequent progression will 
be approached for optional biopsies for molecular characterization as well as generation of 
patient-derived xenografts and conditionally- reprogrammed cells. This evaluation will 
determine the evolution of the mutation. 
7.1.6.4. 
Biomarker Testing 
Biomarker testing will be performed during the study. Dr. James Reuben, Professor of 
Hematopathology at MD Anderson Cancer Center will perform the specific measurements for 
biomarker testing mentioned below.  
The following immune regulatory cells and markers will be studied to better understand the 
plinabulin’s mechanisms of action and to identify potential predictors of responsive subjects that 
can be utilized to enrich for responders in subsequent clinical studies.  
*Imaging-guided core needle tumor biopsy samples (at least 2 to 4 research cores) will be 
collected at Pre-dose (<2 week prior to radiation therapy) and within 7 days prior to Cycle 3 Day 
1 of immunotherapy with Plinabulin. The biopsied lesion should not have been targeted by 
radiation. If there has been a complete response in the pre-treatment biopsied lesion, another 
non-irradiated lesion could be biopsied with any response (partial, stable, or progressive), but 
should be documented clearly. Multiple lesions could be biopsied if it is safe to do and has clear 
biologic or clinical rationale to do so. 
*The whole blood samples will be collected at Pre-dose (<1 week prior to triple combo), and 
Cycle 1 Day 4, then pre-treatment Day 1 of every 2 cycles & EOT. (2 – 10 mL EDTA/purple top 
(processed for peripheral blood mononuclear cell [PBMC], plasma, whole blood DNA), 1 – 10 
mL Heparin/Green top (for flow cytometry and DC activation assay), 1 – 10 mL Streck tube (for 
plasma and germline DNA).  
Minimum measurements on core needle tumor biopsies  
Immune phenotyping analysis by CyTOF and/or single cell RNAseq 
Minimum measurements on whole blood PBMC collected for biomarker evaluation 
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Dendritic Cell activation assay 
Phenotyping analysis of immune cells using multicolor flow cytometry 
Immune repertoire TCR sequencing 
Exploratory Biomarker Research including Pharmacogenomic Study 
Blood samples including pharmacogenomic samples (PG samples) for the development of 
exploratory predictive biomarkers will be collected prior to the first dose of study drug, on Cycle 
1 Day 4, then on Day 1 of every cycle for Q4W, or every 2 cycles for Q3W during Treatment 
Phase, and at the EOT assessment. Subjects will be required to provide a fresh biopsy of tumor 
before treatment, and within 7 days prior to Cycle 3 Day 1 of the study treatment for biomarker 
analyses. Biomarker discovery and/or validation will be performed to identify blood or tumor 
biomarkers which may be useful to predict subject response to the study treatment, as determined 
by evaluation of response-related and/or safety-related outcomes as well as for potential use in 
diagnostic development. Blood samples from subjects receiving study treatment may be analyzed 
using RNAseq, Flow cytometry, multiplex bead-based immunoassay, or other assays/methods or 
new technology. In addition, biomarkers identified in other plinabulin clinical studies may also 
be assessed in the biomarker samples collected from subjects enrolled in this study.  
A blood sample for peripheral blood mononuclear cells (PBMCs) and plasma isolation will be 
collected from enrolled subjects. Cell free nucleic acid isolated from plasma samples may be 
used to obtain ctDNA and explore tumor genetic alterations such as mutations observed in 
archival tumor samples as well as those which develop during drug treatment. 
The PG samples may be used to identify genetic factors that may influence a subject’s exposure 
to the study drug, as well as genetic factors that may have an effect on clinical response or 
potential AEs related to study treatment, and to explore the role of genetic variability in 
response. Samples may be analyzed to determine a subject’s genotypes or sequence for a number 
of genes or non-coding regulatory regions. The research may include the investigation of 
polymorphisms in genes that are likely to influence the study drug pharmacokinetics or 
therapeutic response. 
The decision to perform exploratory biomarker analysis may be based on the clinical outcome of 
this study and/or the signals observed in other clinical studies or other information available at 
that time. 
Any leftover samples from the translational study will be stored for up to 15 years from the study 
closure for future research. The samples may be used to study the mechanism of the study 
treatment or to explore the predictive and response biomarkers for the diseases or the treatment.  
7.2. 
Adverse and Serious Adverse Events 
7.2.1. 
Definition of Adverse Events 
7.2.1.1. 
Adverse Event (AE) 
An AE is the development of an undesirable medical condition or the deterioration of a 
pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered casually related to the product. In clinical studies, an AE can include 
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an undesirable medical condition occurring at any time, including baseline or washout periods, 
even if no study treatment has been administered. 
All AEs encountered during the clinical study will be reported in the electronic CRF MOCLIA. 
All SAEs will be reported on eSAE. 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.  
The MD Anderson Cancer Center will collect all deaths on study regardless of its potential 
relationship to disease progression. 
The Investigator is responsible for assessing the severity of the AE and/or the adverse drug 
reaction, the causal relationship between any events and the clinical study procedure, activities or 
device. Additionally, the Investigator is responsible for providing appropriate treatment for the 
event and for adequately following the event until resolution.   
Attribution - the determination of whether an AE is related to a medical treatment or procedure 
will be as follows: 
• Definite - the AE is clearly related to the investigational agent(s) 
• Probable - the AE is likely related to the investigational agent(s) 
• Possible - the AE may be related to the investigational agent(s) 
• Unlikely - The AE is doubtfully related to the investigational agent(s) 
• Unrelated - The AE is clearly NOT related to the investigational agent(s).  
 
7.2.1.2. 
Serious Adverse Event (SAE) 
Serious Adverse Event (SAE) Reporting Requirements for M D Anderson Sponsor  
An AE or suspected adverse reaction is considered “serious” if, in the view of either the 
investigator or the sponsor, it results in any of the following outcomes: 
• Death 
• A life-threatening AE 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• A congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse (21 CFR 312.32). 
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• Important medical events as defined above, may also be considered SAEs. Any important 
medical event can and should be reported as an SAE if deemed appropriate by the Principal 
Investigator or the Investigational New Drug (IND) Sponsor, IND Office. 
• All events occurring during the conduct of a protocol and meeting the definition of a SAE 
must be reported to the Institutional Review Board (IRB) in accordance with the 
timeframes and procedures outlined in “The University of Texas M. D. Anderson Cancer 
Center Institutional Review Board Policy on Reporting Adverse Events for Drugs and 
Devices”. 
• Serious Adverse Events will be captured from the time of the first protocol-specific 
intervention, through 90 days after the subject’s last dose, or 30 days following the last 
dose if the subject initiates new anti-cancer therapy, whichever is earlier; unless the subject 
withdraws consent.  
• Serious Adverse Events must be followed until clinical recovery is complete and laboratory 
tests have returned to baseline, progression of the event has stabilized, or there has been 
acceptable resolution of the event. 
• All SAEs, expected or unexpected/ initial or follow up, must be reported to the IND Office 
within 5 working days of knowledge of the event regardless of the attribution. 
• Death or life-threatening events that are unexpected, possibly, probably, or definitely 
related to drug must be reported (initial or follow up) to the IND Office within 24 hours of 
knowledge of the event. 
• Additionally, any Serious Adverse Events that occur after the 90-day time period or 
30 days following the last dose if the subject initiates new anticancer therapy, that are 
related to the study treatment must be reported to the IND Office. This may include the 
development of a secondary malignancy. 
• The electronic SAE application (eSAE) will be utilized for safety reporting to the IND 
Office and MD Anderson IRB.  
• All events reported to the supporting company must also be reported to the IND Office. 
 
Reporting to FDA: 
• SAEs will be forwarded to FDA by the IND Sponsor according to 21 CFR 312.32. 
 
It is the responsibility of the Principal Investigator and the research team to ensure Serious 
Adverse Events are reported according to the Code of Federal Regulations, Good Clinical 
Practices, the protocol guidelines, the sponsor’s guidelines, and Institutional Review Board 
policy. 
7.2.1.3. 
Other Adverse Event (OAE) 
OAEs will be identified by the Drug Safety Physician from the sponsor and if applicable also by 
the Clinical Study Team Physician during the evaluation of safety data for the Clinical Study 
Report (CSR). Significant AEs of particular clinical importance, other than SAEs and those AEs 
leading to discontinuation of the patient/subject from the study, will be classified as OAEs. For 
each OAE, a narrative may be written and included in the CSR. 
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7.3. 
Relationship to Study Drug 
An Investigator who is qualified in medicine must make the determination of relationship to the 
investigational product for each AE (Unrelated, Possibly Related, Probably Related or Related). 
The Investigator should decide whether, in his or her medical judgment, there is a reasonable 
possibility that the event may have been caused by the investigational product. If no valid reason 
exists for suggesting a relationship, then the AE should be classified as “unrelated.” If there is 
any valid reason, even if undetermined, for suspecting a possible cause-and-effect relationship 
between the investigational product and the occurrence of the AE, then the AE should be 
considered “related.” 
If the relationship between the AE/SAE and the investigational product is determined to be 
“possible” or “probable” the event will be considered to be related to the investigational product 
for the purposes of expedited regulatory reporting. 
7.4. 
Recording Adverse Events 
AEs spontaneously reported by the patient and/or in response to an open question from the study 
personnel or revealed by observation will be recorded during the study at the investigational site. 
Abnormal values that constitute an SAE or lead to discontinuation of administration of study 
drug must be reported and recorded as an AE. Information about AEs will be collected from the 
first administration of study drug (Study Day 1) until 30 days after the last infusion of study 
treatment, or initiation of another anti-cancer therapy. SAE information will be collected from 
time of signing of the informed consent through 90 days after the subject’s last dose, or 30 days 
following the last dose if the subject initiates new anticancer therapy. The AE term should be 
reported in standard CTCAE v5.0terminology when possible. For each AE, the Investigator will 
evaluate and report the onset (date and time), resolution (date and time), intensity, causality, 
action taken, serious outcome (if applicable), and whether or not it caused the patient to 
discontinue the study. 
Whenever possible, the intensity of clinical AEs will be graded according to NCI CTCAE (v5.0) 
grading system. AEs not listed on the NCI-CTCAE grading system will be graded on a 3-point 
scale (mild, moderate, severe) as described below, and reported in detail as indicated on the CRF 
(Study Manual). 
Severity Grading for AEs not listed in NCI-CTCAE (v5.0): 
• Grade 1: Mild (awareness of sign or symptom, but easily tolerated) 
• Grade 2: Moderate (discomfort sufficient to cause interference with normal activities) 
• Grade 3: Severe (incapacitating, with inability to perform normal activities, 
hospitalization may be indicated) 
• Grade 4: Life Threatening (extreme limitation in activity; significant assistance 
required; significant medical intervention or therapy required; hospitalization indicated) 
• Grade 5: Death 
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It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 7.2.1.2. An AE of severe intensity 
may not be considered serious. 
Should a pregnancy occur to female participants or female partners of a male participant during 
the study treatment or within 3 months of last plinabulin dose, it must be reported to the MD 
Anderson Cancer Center safety group within 24 hours of awareness using the MD Anderson 
Cancer Center’s pregnancy form. Pregnancy in itself is not regarded as an AE unless there is a 
suspicion that an investigational product may have interfered with the effectiveness of a 
contraceptive medication.  
The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth or 
congenital abnormality) must be followed up and documented even if the patient was 
discontinued from the study. 
All reports of congenital abnormalities/birth defects are SAEs. Spontaneous miscarriages should 
also be reported and handled as SAEs. Elective abortions without complications should not be 
handled as AEs. 
This Phase 1b/2 study will follow the recommended AE data collection guidelines as indicated in 
Table 9. 
Table 9: 
Recommended Adverse Event Reporting Guidelines 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
Phase I 
Phase I 
Phase I 
Phase II   
 
Phase I 
Phase II   
Phase III 
Phase I  
Phase II   
Phase III 
Unlikely 
Phase I 
Phase I 
Phase I  
Phase II   
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Possible 
Phase I 
Phase II   
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Probable 
Phase I 
Phase II  
 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Definitive 
Phase I 
Phase II  
 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II  
Phase III  
Phase I 
Phase II   
Phase III 
7.5. 
Reporting Serious Adverse Events 
All SAEs are collected from the time of signing of the consent form through 90 days after the 
subject’s last dose, or 30 days following the last dose if the subject initiate’s new anticancer 
therapy. Any SAEs considered possibly or probably related to the investigational product and 
discovered by the Investigator at any time after the study should be reported. Any SAE judged 
by the investigator to be related to the study treatment or any protocol-required procedure should 
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be reported to the MD Anderson Cancer Center and BeyondSpring Pharmaceuticals regardless of 
the length of time that has passed since study completion. 
All SAEs must be reported to The MD Anderson Cancer Center BeyondSpring Pharmaceuticals 
within 24 hours of the first awareness of the event. The Investigator must complete, sign and date 
the SAE pages, verify the accuracy of the information recorded on the SAE pages with the 
corresponding source documents, and send a copy by email or fax to: 
BeyondSpring Pharmaceuticals: 
SAE Email Address: ICON-Safety-CentralReceipt@iconplc.com 
or by fax to 215-616-3096 (ICON- PV) 
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8. 
STATISTICAL METHODS 
All statistical analyses will be performed by the MD Anderson Cancer Center or designee after 
the study is completed. Details of the analyses will be included in a separate Statistical Analysis 
Plan (SAP). 
8.1. 
Study Endpoints and Analysis 
8.1.1. 
Primary Endpoint and Analysis 
1. 
Safety and tolerability; AEs will be evaluated according to CTCAE version 5.0 
2. 
The objective tumor response rate (complete response + partial response), assessed 
according to irRECIST criteria 
8.1.2. 
Secondary Endpoints and Analysis 
1. 
Disease control rate (complete response, partial response + stable disease) assessed 
according to irRECIST criteria) 
2. 
Progression-free survival (PFS)  
3. 
Overall Survival (OS) 
8.1.3. 
Exploratory Endpoints and Analysis 
1. Gene mutation density 
2. Immune repertoire TCR sequencing change in peripheral blood 
3. Immune phenotypes in tumor tissue, including DC, T cells, TAMs, pre and post treatment 
4. Phenotypes of immune cells in peripheral blood 
5. Dendritic cell activation in peripheral blood 
6. Predictive and Response Biomarker analysis taking account of the collected biomarkers 
8.2. 
Statistical Analysis Sets and Considerations 
8.2.1. 
Analysis Sets 
Modified Intent-to-Treat Analysis Set 
Modified Intent-to-Treat population (mITT Population): All safety subjects who provide post 
treatment tumor assessments or present clinical disease progression post treatment without any 
formal post treatment tumor assessments. The efficacy analysis will be based on the mITT 
population. 
Safety Analysis Set 
The safety analysis set comprises all patients who received at least one dose of study medication. 
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Per Protocol Analysis Set 
Per Protocol Population (PP Population) will include all mITT population without major protocol 
deviation. The criteria for PP Population exclusion will be documented before data base is 
locked. 
8.2.2. 
Patient Disposition 
Descriptive summaries will be generated to describe the disposition of all enrolled patients. 
8.2.3. 
Demographics and Other Baseline Characteristics 
Demographic and other baseline characteristics will be described. 
8.2.4. 
Study Treatment Exposure 
Study treatment exposure will be summarized. 
8.2.5. 
Efficacy Analyses Displays 
Data will be tabulated by treatment sequence, 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. Analyses will be 
performed based on observed data, and missing values will not be imputed unless otherwise 
stated in the SAP. 
ORR will be defined as percent of subjects achieved complete response (CR) or partial response 
(PR).  
Disease control rate defined as percent of subjects achieved CR, PR, and stable disease 
PFS is defined as the time from the first study dose date to the date of first documentation of 
confirmed disease progression or death (whichever occurs first). 
OS is measured from the start date of the treatment period until date of death from any cause. 
Subjects who are lost to follow-up and the subjects who are alive at the date of data cutoff will 
be censored at the date the subject was last known alive. 
Chi-square or Fisher’s exact test is used to compare ORR and disease control rate between two 
arms in phase 2. ORR and disease control rate are estimated with 95% confidence interval. 
The time-to-event endpoints including overall survival, progression free survival will be 
analyzed using Kaplan-Meier method or Cox regression. 
The mITT Subjects without any post treatment tumor assessments will be treated as non-
responders. 
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Additional details are provided in the SAP. 
8.3. 
Safety Analyses 
Medical history and AE data will be graded by system organ class (SOC) and NCI CTCAE v5.0 
terminology.   
All treatment emergent adverse events (TEAEs) will be graded according to NCI CTCAE 
version 5.0 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 
plinabulin due to safety concerns will be summarized.  
In Phase 1, BOIN study design is used to determine the MTD. In Phase 2, Bayesian toxicity 
monitoring is used. 
8.3.1. 
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 
sequences. 
8.3.2. 
Extent of Exposure 
Refer to the SAP for details. 
8.3.3. 
Adverse Events 
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized CTCAE v5.0 terminology. 
8.3.4. 
Laboratory Analyses 
Continuous variables will be analyzed using t-tests with unequal variances. Proportions for 
comparing independent treatment arms will be analyzed using the Wilson score test. Other 
categorical data will be analyzed using non-parametric statistical methods. 
8.3.5. 
Vital Signs 
Descriptive statistics and shift tables will be used for the evaluations. 
8.3.6. 
Performance Status 
Patients will be graded according to the ECOG Performance Status scale and criteria as 
described in Table 10 and per the timings presented in Table 7. 
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Table 10: 
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 housework) 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities; up and 
about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled; cannot perform any self-care; totally confined to bed or chair 
ECOG = Eastern Cooperative Oncology Group 
8.4. 
Sample Size Considerations 
Phase 1: 
We will employ the BOIN design (Liu and Yuan, 2015, Yuan et al., 2016) to find the 
MTD/RP2D. The BOIN design is implemented in a simple way similar to the traditional 3+3 
design, but is more flexible and possesses superior operating characteristics that are comparable 
to those of the more complex model-based designs, such as the continual reassessment method 
(CRM) (Zhou et al., 2018). 
The target DLT rate for the MTD is ɸ = 0.25 and the maximum sample size is 12. We will enroll 
and treat patients in cohorts of size 3. DLTs are defined in Section 2.6.1, and only those DLTs 
that occur within the first cycle will be used for dose finding. As shown in Figure 1, the BOIN 
design uses the following rule, optimized to minimize the probability of incorrect dose 
assignment under the alternatives ɸ1 = 0.6ɸ and ɸ2 = 0.6ɸ, to guide dose escalation/de-
escalation: 
• 
if the observed DLT rate at the current dose is ≤ 0.197, escalate the dose to the next 
higher dose level. 
• 
if it is ≥ 0.298, de-escalate the dose to the next lower dose level. 
• 
otherwise, stay at the current dose. 
For the purpose of overdose control, doses j and higher levels will be eliminated from further 
consideration if Pr(pj > 0.25 | data) > 0.95 and at least 3 patients have been treated at dose level j, 
where pj is the true DLT rate of dose level j, j = 1, …, 2. This posterior probability is evaluated 
based on the beta-binomial model yj | pj ~ binomial(pj) with pj ~ uniform(0, 1), where yj is the 
number of patients experienced DLT at dose level j. When the lowest dose is eliminated, stop the 
trial for safety. The probability cutoff 0.95 is chosen to be consistent with the common practice 
that when the target DLT rate ɸ ≤ 1/6, a dose with 2/3 patients experiencing DLT is eliminated. 
The above dose escalation/de-escalation and elimination rule can be equivalently presented in 
Table 11, which will be used to conduct the trial. 
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The steps to implement the BOIN design are described as follows: 
1. Patients in the first cohort are treated at dose level 2. There are only 2 doses (30 mg/m2 
and 20 mg/m2) specified in the protocol, and we will begin at the higher dose, dose level 
2 = 30 mg/m2. 
2. To assign a dose to the next cohort of patients, conduct dose escalation/de-escalation 
according to the rule displayed in Table 11. When using Table 11, please note the 
following: 
a. “Eliminate” means eliminate the current and higher doses from the trial to prevent 
treating any future patients at these doses because they are overly toxic. 
b. When we eliminate a dose, automatically de-escalate the dose to the next lower 
level. When the lowest dose is eliminated, stop the trial for safety. In this case, no 
dose should be selected as the MTD. 
c. If none of the actions (i.e., escalation, de-escalation, or elimination) is triggered, 
treat the new patients at the current dose. 
d. If the current dose is the lowest dose and the rule indicates dose de-escalation, 
treat the new patients at the lowest dose unless the number of DLTs reaches the 
elimination boundary, at which point terminate the trial for safety. 
e. If the current dose is the highest dose and the rule indicates dose escalation, treat 
the new patients at the highest dose. 
3. Repeat step 2 until the maximum sample size of 12 is reached, or stop the trial early if the 
number of patients treated at the current dose ≥ 9 and the decision according to Table 11 
is to stay at the current dose. 
 
Table 11: 
Dose escalation/De-escalation Rule for the BOIN Design 
Actions* 
The number of patients treated at the current dose 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Escalate if # of DLT ≤ 
0 
0 
0 
0 
0 
1 
1 
1 
1 
De-escalate if # of DLT ≥ 
1 
1 
1 
2 
2 
2 
3 
3 
3 
Eliminate if # of DLT ≥ 
NA 
NA 
3 
3 
3 
4 
4 
4 
5 
* When none of the actions (i.e., escalate, de-escalate or eliminate) is triggered, stay at the current dose for treating 
the next cohort of patients. Note that “# of DLT” is the number of patients with at least 1 DLT, and “NA” means that 
a dose cannot be eliminated before treating 3 patients. 
 
After the trial is completed, select the MTD based on isotonic regression as specified in Liu and 
Yuan (2015). This computation is implemented by the "Estimate MTD" tab of the BOIN Design 
Desktop Program (Venier et al., 2020). Specifically, select as the MTD the dose for which the 
isotonic estimate of the DLT rate is closest to the target DLT rate. If there are ties, select the 
higher dose level when the isotonic estimate is lower than the target DLT rate and select the 
lower dose level when the isotonic estimate is greater than or equal to the target DLT rate. 
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Figure 1 
Flowchart for trial conduct using the BOIN design. 
 
Once we determine the MTD, an additional 10 patients will be enrolled for additional experience 
with safety and efficacy in each of the eight cancer cohorts and to determine the recommended 
Phase 2 dose (RP2D). The RP2D will be selected based on both safety and totality of clinical 
evidence (e.g., PK/PD data), and is not necessarily the MTD. We will use the elimination 
boundaries in Table 12 for DLT monitoring. 
Selection of cohort that will advance into Phase 2 will be based on the following consideration: 
1. The cohort with the best response rate, within a 9-week window after RT plus plinabulin 
with 2 cycles (3 weeks Anti-PD-1/PD-L1 mAb dosing) of Anti-PD-1/PD-L1 mAb, will 
advance into Phase 2, if deemed well-tolerated. In consultation with the sponsor and 
using the totality of clinical evidence, other cohort(s) instead may be selected to advance 
into Phase 2. The final selection of the group to go into Phase 2 will be determined by a 
Safety Monitoring Committee 
2. The response evaluation will be based on a minimum of 5 subjects and up to 10 subjects 
per cohort, unless enrollment of a given cohort is very slow and incomplete at the time 
sufficient response data is available on other cohorts, in which case that given cohort 
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could be closed for further patient accrual.  
 
Table 12 shows the operating characteristics of the dose finding based on 1000 simulations of the 
trial using the BOIN Design Desktop Program (Venier et al., 2020). The operating characteristics 
show that the design selects the true MTD, if any, with high probability and allocates more 
patients to the dose levels with the DLT rate closest to the target of 0.25. 
Table 12: 
BOIN Operating Characteristics Table 
  
Dose Level 
Number of patients 
% Early stopping 
  
-1 
1 (starting) 
Scenario 1 
True DLT Rate 
0.2 
0.25 
11 
2.4 
Selection % 
40.5 
57.1 
% Pts Treated 
36.7 
63.3 
Scenario 2 
True DLT Rate 
0.25 
0.3 
11.1 
5 
Selection % 
52.3 
42.7 
% Pts Treated 
43 
57 
Scenario 3 
True DLT Rate 
0.3 
0.35 
11.2 
8.8 
Selection % 
60.6 
30.6 
% Pts Treated 
48.9 
51.1 
DLT: dose-limiting toxicity 
 
Phase 2: 
102 Patients will be 1:1 randomized to the control and experimental arms.  
Arm A: Radiation Therapy + Plinabulin + anti-PD-1/PD-L1 mAb (experimental) 
Arm B: Radiation Therapy + anti-PD-1/PD-L1 mAb (control) 
Because the experimental combination arm is not expected to be worse than the control arm, no 
futility monitoring is planned. Assuming the ORR is 5% in control arm and 15% in experimental 
arm, based on Chi-squared test. A sample size of 51 evaluable patients in each group is required 
to detect the difference with one sided type I error 0.2 and power 80%. 
The BOIN elimination rule, e.g., if Pr(DLT rate >0.25 | interim data) > 0.95, then stop the 
accrual, will be used to ensure patient safety in both arms. The posterior probability calculation 
is based on the uniform prior for the DLT rate. The monitoring will start from the 11th patient 
and carried out every 10 patients. The target toxicity (DLT) rate is 25%. 
Table 13: 
Toxicity Stopping Boundaries 
Number of patients 
Number of toxicities are considered too toxic 
11 
6–11 
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Number of patients 
Number of toxicities are considered too toxic 
21 
9– 21 
31 
12– 31 
41 
15– 41 
51 
18– 51 
Below shows the operating characteristics of the safety monitoring rule based on 10000 
simulations.  
 
True DLT rate 
 
0.1 
0.2 
0.3 
0.4 
0.5 
Pr(stopping) 
0 
0.03 
0.31 
0.78 
0.98 
Average 
sample size 
51 
50 
42.9 
28.8 
18.6 
 
The Investigator is responsible for completing an efficacy/safety summary report and submitting 
it to the IND Office Medical Affairs and Safety Group, for review and approval. 
Phase 1b: 
A Cohort summary will be submitted after the first 3 evaluable patients complete two doses of 
PD1/PDL1 and every 3 evaluable patients thereafter. Approval from IND office is required prior 
to expanding/changing dose levels. 
Ph1b expansion: 
A Cohort summary will be submitted after the first 3 evaluable patients per cohort complete two 
doses of PD1/PDL1, and every 3 evaluable patients, per cohort thereafter. During every 
submission, response assessed at 9 weeks will be included in the summary.  
Phase 2: 
Efficacy/safety summary will be submitted after the first 11 evaluable patients per arm, complete 
two doses of PD1/PDL1, and every 10 evaluable patients per arm, thereafter. During every 
submission, the response assessment (done at 8 weeks) of previously submitted patients will be 
provided. 
A copy of the summary report should be placed in the Investigator’s Regulatory Binder under 
“sponsor correspondence”. 
8.5. 
Withdrawal 
If a patient discontinues treatment due to any other reason than disease 
progression/death/withdrawal of informed consent, the disease evaluations shall continue until 
disease progression. This includes subjects who wish to discontinue treatment but agree that 
further data is captured for the purpose of the study (partial withdrawal). 
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9. 
DATA INTEGRITY AND QUALITY ASSURANCE 
9.1. 
Source Documents 
Study data will be collected on source documents. The Investigator is responsible for assuring 
that collected data are complete and accurate. Source documentation (the point of initial 
recording of a piece of data) should support data collected on the eCRF. Source documents 
include all recordings of observations or notations of clinical activities and all reports and 
records necessary for the evaluation and reconstruction of the clinical study. 
9.2. 
Data Collection and Case Report Form Monitoring 
All subjects will be registered in the Clinical Oncology Research System (CORe). 
All data obtained for this study will be entered in a Code of Federal Regulations Title 21 
(21 CFR) Part 11-compliant Data Management System provided by MD Anderson Cancer 
Center or its designee. These data will be recorded with an electronic data capture (EDC) system 
(Moclia). The Investigator will ensure the accuracy and completeness of the data reported to the 
MD Anderson Cancer Center. All data entry, modification or deletion will be recorded 
automatically in an electronic audit trail. 
The Investigator will provide access to his/her original records to permit a representative from 
the MD Anderson Cancer Center to verify the proper transcription of data. Data reported in the 
eCRFs should be consistent with and substantiated by the subject’s medical record and original 
source documents. The eCRF data will be monitored by the MD Anderson Cancer Center or 
designee. The MD Anderson Cancer Center will retain the final eCRF data and audit trail. A 
copy of all completed eCRFs will be provided to the investigator. 
9.3. 
Study Records Retention 
Study documents should be retained indefinitely. No records will be destroyed without the 
written consent of MD Anderson Cancer Center.   
9.4. 
Audits and Inspections 
Authorized representatives of the MD Anderson Cancer Center, a regulatory authority, an IEC or 
an IRB may visit the site to perform audits or inspections, including source data verification. The 
purpose of a MD Anderson Cancer Center audit or inspection is to systematically and 
independently examine all study-related activities and documents to determine whether these 
activities were conducted, and data were recorded, analyzed, and accurately reported according 
to the protocol, Good Clinical Practice guidelines of the International Conference on 
Harmonization, and any applicable regulatory requirements. The investigator should contact the 
MD Anderson Cancer Center immediately if contacted by a regulatory agency about an 
inspection.   
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9.5. 
Institutional Review Board (IRB) 
The Principal Investigator must obtain IRB approval for the investigation. Initial IRB approval, 
and all materials approved by the IRB for this study including the patient consent form and 
recruitment materials must be maintained by the Investigator and made available for inspection. 
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10. 
ETHICAL CONSIDERATIONS, COMPLIANCE STATEMENT 
ND REGULATORY COMPLIANCE 
10.1. 
Ethical Considerations 
A copy of the protocol, informed consent forms (ICFs), other information to be completed by 
subjects, such as questionnaires and any proposed advertising or recruitment materials, will be 
submitted to the regulatory authority(ies) and ECs. 
All subsequent amendments to the protocol, informed consent documents, and other study 
documentation referenced above must be submitted and approved in accordance with country 
specific requirements. 
Periodic study status reports, as applicable, will be submitted to the ECs in accordance with 
country specific regulations. The PI will be responsible for obtaining EC approval of the annual 
continuing review throughout the duration of the study. 
The PI will notify the local ECs of violations from the protocol and SAEs. 
Subjects will be informed that medical care will not be affected by their agreement or refusal to 
participate in this study, and that they are free to withdraw from the study at any time without 
prejudice to the clinician patient relationship. 
The final study protocol, including the final version of the ICF, must be approved or given a 
favorable opinion in writing by an IRB or IEC as appropriate. The Investigator must submit 
written approval to the MD Anderson Cancer Center before he or she can enroll any patient into 
the study. 
The Principal Investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements. In addition, the IRB or IEC must approve all 
advertising used to recruit patients for the study. The protocol must be re-approved by the IRB or 
IEC upon receipt of amendments and annually, as local regulations require. 
The Principal Investigator is also responsible for providing the IRB with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product. The MD Anderson Cancer Center will provide this information to the Principal 
Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. 
10.2. 
Good Clinical Practice 
This study will be conducted in compliance with the protocol, the ethical principles that have 
their origin in the Declaration of Helsinki (October 2013), the ICH consolidated Guideline E6 for 
Good Clinical Practice (GCP) (CPMP/ICH/135/95), and FDA GCP Regulations: C21 CFR, Parts 
11, 50, 54, 56 and 312 as appropriate.  
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The MD Anderson Cancer Center will ensure that the study complies with all local, federal, or 
country regulatory requirements as applicable. Throughout the study, the MD Anderson Cancer 
Center and its designee will work with the Investigator(s) to ensure proper study protocol 
implementation and adherence to regulatory requirements as listed in the study protocol. 
10.3. 
Delegation of Investigator Duties 
The PI should ensure that all persons assisting with the study are adequately qualified, trained, 
and informed about the protocol, any amendments to the protocol, the study treatments, and their 
study related duties and functions. 
The PI should maintain a list of sub-investigators and other appropriately qualified persons to 
whom he/she has delegated significant study related duties. 
10.4. 
Subject Confidentiality 
The Investigators and the MD Anderson Cancer Center will preserve the confidentiality of all 
subjects taking part in the study, in accordance with GCP and local regulations. 
The Sponsor will observe the rules laid down in the European Data Protection Directive 
95/46/EC on the protection of individuals regarding the processing of personal data and the free 
movement of such data. 
The Investigator must ensure that the subject’s anonymity is maintained. On the CRF/eCRF or 
other documents submitted to MD Anderson Cancer Center, subjects should be identified by a 
unique subject identifier as designated by the MD Anderson Cancer Center. Documents that are 
not for submission should be kept in strict confidence by the Investigator. 
In compliance with federal regulations/ICH GCP Guidelines, it is required that the Investigator 
and institution permit authorized representatives of the MD Anderson Cancer Center, of the 
regulatory agency(s), and the EC direct access to review the subject’s original medical records 
for verification of study-related procedures and data. The Investigator is obligated to inform the 
subject that his/her study-related records will be reviewed by the above-named representatives 
without violating the confidentiality of the subject. 
10.5. 
Written Informed Consent 
Before a subject’s participation in the study, it is the Investigator’s responsibility to obtain freely 
given consent, in writing, from the subject, or legally acceptable representative, after adequate 
explanation of the aims, methods, anticipated benefits, and potential hazards of the study and 
before any protocol-specific screening procedures or any study drugs are administered. A legally 
acceptable representative is an individual or other body authorized under applicable law to 
consent, on behalf of a prospective subject, to the subject’s participation in the clinical study. 
The written ICF should be prepared in the local language(s) of the potential subject population. 
In obtaining and documenting informed consent, the Investigator should comply with the 
applicable regulatory requirements, and should adhere to GCP and to the ethical principles that 
have their origin in the Declaration of Helsinki. The consent form and any revision(s) should be 
approved by the EC prior to being provided to potential subjects. 
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The subject’s written informed consent should be obtained prior to his/her participation in the 
study, and should be documented in the subject’s medical records, as required by 21 CFR Part 
312.62. The ICF should be signed and personally dated by the subject, or a legally acceptable 
representative, and by the person who conducted the informed consent discussion (not 
necessarily the Investigator). The original signed ICF should be retained in accordance with 
institutional policy, and a copy of the signed consent form should be provided to the subject or 
legal representative. The date and time (if applicable) that informed consent was given should be 
recorded on the CRF. 
10.6. 
Regulatory Compliance 
MD Anderson has a legal responsibility to notify the FDA as well as all sites, about the safety of 
the drug. 
The study protocol, subject information and consent form, the IB, any subject diary card or 
written instructions to be given to the subject, available safety information, subject recruitment 
procedures (e.g., advertisements), information about payments and compensation available to the 
subjects and documentation evidencing the Investigator’s qualifications should be submitted to 
the EC for ethical review and approval according to local regulations, prior to the study start.  
The written approval should identify all documents reviewed by name and version. 
Changes in the conduct of the study or planned analysis will be documented in a protocol 
amendment and/or the SAP. 
The Investigator must submit and, where necessary, obtain approval from the EC for all 
subsequent protocol amendments and changes to the informed consent document or changes of 
the investigational site, facilities or personnel. The Investigator should notify the EC of 
deviations from the protocol or SAEs occurring at the site, in accordance with local procedures. 
As required by local regulations, MD Anderson Cancer Center will ensure all legal aspects are 
covered, and approval of the appropriate regulatory bodies obtained, prior to study initiation, and 
that implementation of changes to the initial protocol and other relevant study documents happen 
only after the appropriate notification of or approval by the relevant regulatory bodies. 
The Investigator(s)/institution(s) will permit study related monitoring, audits, IRB/IEC review 
and regulatory inspection(s), providing direct access to source data/documents. Copies of the 
notification to the EC must be sent to the MD Anderson Cancer Center. 
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11. 
STUDY ADMINISTRATIVE INFORMATION 
11.1. 
Financial Disclosure 
The disclosed financial interest of the PI must be collected before screening of the first study 
subject. The PI should promptly update this information if any relevant changes occur during the 
study period and 1 year following overall study completion. 
11.2. 
Study Registration and Results Disclosure 
The MD Anderson Cancer Center may provide study information for inclusion in national 
registries per local regulatory requirements. 
Results of this study will be disclosed per the relevant national regulatory requirements. 
11.3. 
Use of Stored Samples and Data 
Stored samples will be labeled with study and subject information and kept in a locked room 
with limited access. Electronic data will be kept in password protected computers at the 
laboratory at MD Anderson Cancer Center or designee as applicable, for data analysis. Samples 
and corresponding data will be tracked using the laboratory’s tracking system. 
Prior MD Anderson Cancer Center and IRB approval are required before using or sharing study 
samples or data in ways not specified in the study protocol. 
Any loss or unanticipated destruction of samples (e.g., freezer malfunction) or data (e.g., loss of 
a data sheet with individually identifiable information) that violates or compromises the 
scientific integrity of study data must be reported to the MD Anderson Cancer Center and the 
IRB. 
Unless otherwise directed by the subject, at the completion (termination) of the study, samples 
will continue to be stored indefinitely. In all cases, samples will be stored until the completion 
(termination) of the study. At any time, subjects may inform the Investigator that they do not 
wish to have their samples stored beyond the completion (termination) of the study. In this case, 
the Investigator will request that all known remaining samples be destroyed to MD Anderson 
Cancer Center and report the disposition of samples to the requesting subjects and the IRB. 
11.4. 
Disposition of Stored Samples and Data 
Access to stored samples will be limited by using a locked room. Data will be kept in password 
protected computers at the laboratory and then transferred to the vendor for data analysis. 
Samples and corresponding data acquired will be tracked using the laboratory’s specimen 
tracking system. 
In the future, other Investigators may wish to study these samples and/or data. In that case, IRB 
approval and MD Anderson Cancer Center approval must be obtained before any sharing of 
samples and/or data. Any clinical information shared about the sample would similarly require 
prior MD Anderson Cancer Center and IRB approval. 
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Any loss or unanticipated destruction of samples (e.g., due to freezer malfunction) or data (e.g., 
loss of a data sheet with individually identifiable information) that results in a violation that 
compromises the scientific integrity of the data collected for the study will be reported to the MD 
Anderson Cancer Center and the IRB. 
At the completion (termination) of the study, samples will continue indefinitely. 
Additionally, subjects may decide at any point not to have their samples stored for a period of up 
to 15 years beyond the duration of the study. In this case, the PI will request the destruction of all 
known remaining samples and report what was done to both the subject and to the IRB. This 
decision will not affect the subject’s participation in this protocol. 
11.5. 
Subject Identification and Confidentiality 
A subject number will be recorded in the eCRF, and if the subject name appears on any other 
document (e.g., laboratory report), it must be obliterated on the copy of the document to be 
supplied to the MD Anderson Cancer Center. All records will be kept confidential to the extent 
provided by federal, state, and local laws. The subjects will be informed that representatives of 
the MD Anderson Cancer Center, EC/IRB, or regulatory authorities may inspect their medical 
records to verify the information collected, and that all personal information made available for 
inspection will be handled in strictest confidence and in accordance with local data protection 
laws. 
The PI will maintain a personal subject identification list (subject numbers with the 
corresponding subject names) to enable records to be identified. 
11.6. 
Protocol Amendments 
Any substantial change or addition to this protocol requires a written protocol amendment that 
must be approved by the MD Anderson Cancer Center, before implementation. Amendments 
significantly affecting the safety of subjects, the scope of the investigation, or the scientific 
quality of the study, require additional approval by the applicable regulatory authority(ies), 
central ECs, and local IRBs/ECs. Copies of the applicable written approvals must be given to the 
site monitor or their designee. 
These requirements for approval should in no way prevent any immediate action from being 
taken by the Investigator or by the MD Anderson Cancer Center in the interests of preserving the 
safety of all subjects included in the study. If an immediate change to the protocol is felt to be 
necessary by the Investigator and is implemented by him/her for safety reasons, the study MD 
Anderson Cancer Center or its agent should be notified and the applicable regulatory 
authority(ies)/central ECs/local IRBs/ECs should be informed within 10 working days. Any 
other regional reporting requirements must be adhered to. 
Amendments affecting only administrative aspects of the study do not require formal protocol 
amendments or regulatory authority/central EC/local IRB/IEC approval, but the regulatory 
authority(ies)/central ECs/local IRBs/ECs must be kept informed of such administrative changes 
in accordance with country specific requirements. 
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11.7. 
Audits and Inspections 
Domestic and foreign regulatory authorities, the IRB/IEC, and an auditor authorized by the MD 
Anderson Cancer Center may request access to all source documents, CRFs, and other study 
documentation for onsite audit or inspection. Direct access to these documents must be 
guaranteed by the Investigator, who must provide support always for these activities. Medical 
records and other study documents may be copied during audit or inspection if subject names are 
obliterated on the copies to ensure confidentiality. 
If an inspection is requested by a regulatory authority, the Investigator will inform the study MD 
Anderson Cancer Center, immediately that this request has been made. 
The MD Anderson Cancer Center will be allowed to conduct site visits to the investigation 
facilities for the purpose of monitoring any aspect of the study. The Investigator agrees to allow 
the monitor to inspect the drug storage area, study drug stocks, drug accountability records, 
subject charts and study source documents, and other records relative to study conduct. 
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12. 
REFERENCES 
Asensi V, Valle E, Meana A, et al. In Vivo Interleukin-6 Protects Neutrophils from Apoptosis in 
Osteomyelitis. Infection and Immunity, July 2004, p. 3823–3828. 
Deng L, Liang H, Burnette B et al. Irradiation and anti-PD-L1 treatment synergistically promote 
antitumor immunity in mice. J of Clin Inves. 2014;124(2): 687-695. 
Dinarello CA. A clinical perspective of IL-1β as the gatekeeper of inflammation. Eur J Immunol. 
2011 May;41(5):1203-17. 
Dovedi SJ, Adlard AL, Lipowska-Bhalla G et al. Acquired resistance to fractionated 
radiotherapy can be overcome by concurrent PD-L1 blockade. Cancer Research. 2014; 74(19): 
5458-5468  
Eisenhauer, EA, et al. New response evaluation criteria in solid tumours: revised RECIST 
guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
Kaminski MS, Tuck M, Estes J et al. 131I-tositumomab therapy as initial treatment for follicular 
lymphoma. N Engl J Med. 2005. 352:441-449. 
Kashyap AS, Fernandez-Rodriguez L, Zhao Y et al. GEF-H1 signaling upon microtubule 
destabilization is required for dendritic cell activation and specific anti-tumor responses. Cell 
Reports. 2019. 28:3367-3380. 
Kennedy NJ, Sluss HK, Jones SN et al. Suppression of Ras-stimulated transformation by the 
JNK signal transduction pathway. Genes & Dev., 2003; 17: 629-637 
La Sala G, Olieric N, Sharma A et al. Structure, thermodynamics, and kinetics of plinabulin 
binding to two tubulin isotypes. Chem, 2019; 5: 2969-2986 
Lloyd GK, Muller P, Kashyap A et al. Plinabulin: Evidence for an immune-mediated mechanism 
of action, AACR Tumor Microenvironment Event 2016 
Liu S. and Yuan, Y. Bayesian Optimal Interval Designs for Phase I Clinical Trials. Journal of the 
Royal Statistical Society: Series C, 2015; 64, 507-523. 
Nicholson B, Lloyd GK, Miller BR, 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. 
Postow MA, Harding J, and Wolchok JD. Targeting immune checkpoints: releasing the restraints 
on anti-tumor immunity for patients with melanoma. Cancer J. 2012; 18(2):153-159. 
Seung SK, Curti B, Crittenden M and Urba W. Radiation and immunotherapy. 
OncoImmunology. 2012; 1(9):1645-1647. 
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.  
Yuan Y., Hess K.R., Hilsenbeck S.G. and Gilbert M.R. Bayesian Optimal Interval Design: A 
Simple and Well-performing Design for Phase I Oncology Trials, Clinical Cancer Research, 
2016; 22(17), 4291-4301. 
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Zhou, H., Yuan, Y., and Nie, L. Accuracy, safety, and reliability of novel phase I trial designs. 
Clinical Cancer Research, 2018;  24(18), 4357-4364. 
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13. 
APPENDICES 
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APPENDIX A. CTCAE VERSION 5.0 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Refere
nce_5x7.pdf 
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APPENDIX B. IMMUNE-RELATED RESPONSE EVALUATION 
CRITERIA IN SOLID TUMORS 
Investigators should follow the guidelines provided here which are an adaptation of RECIST and 
irRC. The following guide represents a summary of irRECIST and is meant to help investigators 
in providing more objective and reproducible immune therapy related tumor response 
assessments in solid tumors. 
The key changes for irRECIST are: 
• irRECIST allows the site to select up to ten (10) target lesions at baseline, five 
(5) per organ, if clinically relevant via CT/MRI scans or by electronic calipers 
for skin lesions. The ability to continue treatment, if clinically stable, until 
repeat imaging scans ≥4 weeks later (in most cases at the next scanning time 
point 6 weeks later) to confirm Progressive Disease(irPD) 
 
irRECIST Lexicon 
1. Baseline Assessments 
Measurable 
(Target) lesions 
Measurable lesions must be accurately measured in at least one dimension 
with a minimum size of: 
•     10 mm in the longest diameter (LDi) by CT or MRI scan (or no less than 
double the slice thickness) for non-nodal lesions and ≥15 mm in short axis 
(SDi) for nodal lesions 
•     10 mm in LDi for clinical lesions (must be measured using electronic 
calipers) 
•     Identify up to 10 lesions, not more than 5 from one organ system. Lymph 
nodes are considered one organ system 
•     Likely to be reproducible across all time points 
•     Representative of tumor burden 
•     May include lesions in previously irradiated areas ONLY if there is 
demonstrated progression in that lesion after irradiation 
•     Sum of diameters (SOD) of all target lesions including nodal and non-
nodal are reported as baseline SOD, which is used for assessing tumor 
response at follow-up time points 
Bone lesions 
Regardless of the imaging modality, blastic bone lesions will not be selected 
as target lesions. Lytic or mixed lytic-blastic lesions with a measurable soft 
tissue component ≥10 mm can be selected as target lesions. 
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Cystic and 
Necrotic 
Lesions as 
Target Lesions 
Lesions that are partially cystic or necrotic can be selected as target lesions. 
The longest diameter of such a lesion will be added to the SOD of all target 
lesions at baseline. If other lesions with a nonliquid/nonnecrotic component 
are present, those should be preferred. 
Lesions with 
Prior Local 
Treatment 
During target lesion selection the radiologist will consider information on the 
anatomical sites of previous intervention (eg, previous irradiation, 
RF-ablation, TACE, surgery). Lesions undergoing prior intervention will not 
be selected as target lesions unless there has been a demonstration of 
progression in the lesion. 
Nonmeasurable 
(Nontarget) 
lesions 
Nontarget lesions will include: 
• Measurable lesions not selected as target lesions. There is no limit to 
the number of nontarget lesions that can be recorded at baseline 
• Other types of lesions that are confidently felt to represent neoplastic 
tissue but are difficult to measure in a reproducible manner. These 
include bone metastases, leptomeningeal metastases, malignant 
ascites, pleural or pericardial effusions, ascites, inflammatory breast 
disease, lymphangitis cutis/pulmonis, cystic lesions, ill-defined 
abdominal masses, etc. 
• Multiple non target lesions from the same organ may be captured as a 
single item on the eCRF (e.g., multiple liver metastases) 
Nontarget lesions should be reported as present at baseline 
SOD baseline 
Sum of diameters at baseline = LDi of all non-nodal + SDi of all nodal target 
lesions 
2. Time point Assessments After Baseline 
Target lesion 
measurements 
Locate image that optimizes the LDi of the non-nodal target lesion or short 
axis of target node(s). There is no need to go to an identical slice from 
baseline. 
Measure the respective LDi and SDi for all target lesions and calculate time 
point SOD (SOD timepoint). 
Special consideration for target lesions: 
• If target lesion is too small to measure, a default value of 5mm should 
be entered on eCRF. 
• If target lesion is 5-10mm, actual diameter should be entered in the 
eCRF. 
• If target lesion splits into 2 or more lesions, then the LDi of split 
lesions will be added and entered in place of that lesion. 
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• If two target lesions merged to form one lesion than LDi of one should 
be entered as “0mm” while the other lesion should have the diameter 
of the merged lesion. 
Nontarget 
Lesion 
Assessment 
Nontarget lesions are evaluated qualitatively as present, absent, not evaluable 
(NE) or unequivocal progression. The response of nontarget lesions primarily 
contributes to the overall response assessments of irCR. Nontarget lesions do 
not affect irPR and irSD assessments. Only a massive and unequivocal 
worsening of nontarget lesions alone, even in the presence of stable disease or 
a partial response in the target lesion is indicative of irPD. irCR is not 
possible unless all nontarget lesions are absent 
3. irRECIST Overall Tumor Assessment 
irCR 
•      Complete disappearance of all measurable and non-measurable lesions 
(from baseline) and there are no unequivocal new lesions (unconfirmed irCR). 
•      Lymph nodes must decrease to <10 mm in short axis. 
•      Confirmation of response is required ≥4 weeks later, preferably at next 
time point, to be considered a confirmed irCR. 
irPR 
• If the SODtimepointof TLs decreases by ≥30 % compared to SODbaseline and 
there are no unequivocal new lesions, and no progression of nontarget 
disease, it is an irPR (unconfirmed). 
• Confirmation is required ≥4 weeks later, preferably at next time point, to 
be considered a confirmed irPR. 
irSD 
Failure to meet criteria for irCR or irPR in the absence of irPD. 
•      If the sum of the TLs and the status of the nontarget lesions do not reach 
the criteria to meet irPR or irPD (increase ≥20% and at least 5 mm absolute 
increase in SOD compared to nadir†) the response is irSD. 
•      irSD = neither 30% decrease compared to SODbaseline or 20% increase and 
at least 5 mm absolute change compared to nadir. 
•      †SODnadir: Lowest measure SOD of TLs at any time point from baseline 
onward. 
irPD 
Minimum 20% increase and a minimum 5 mm absolute increase in SOD 
compared to nadir, or irPD for nontarget lesion(s) or unequivocal new 
lesion(s). 
• Confirmation of progression is recommended at a minimum of 4 
weeks after the first irPD assessment (preferably at next tumor 
assessment time point). 
• The decision to continue study treatment after the first evidence of PD 
is at the investigator’s discretion based on the clinical status of the 
subject as described in table below 
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Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
1st radiologic 
evidence of 
PD 
Repeat 
imaging at 
>4 weeks 
(next TA 
time point) 
to confirm 
PD 
May continue 
study treatment 
at the 
Investigator’s 
discretion while 
awaiting 
Repeat 
imaging at >4 
weeks to 
confirm PD 
per physician 
Discontinue treatment 
confirmatory 
scans 
discretion 
only 
Subsequent 
scan confirms 
PD 
No 
additional 
imaging 
required 
Discontinue 
treatment 
No additional 
imaging 
required 
N/A 
Subsequent 
scan 
shows 
SD, PR or CR 
Continue 
regularly 
scheduled 
imaging 
assessments 
Continue study 
treatment at the 
Investigator’s 
discretion 
Continue 
regularly 
scheduled 
imaging 
assessments 
May restart study 
treatment if condition 
has improved and/or 
clinically stable per 
investigator’s 
discretion 
Subjects may continue receiving study treatment while waiting for 
confirmation of irPD if they are clinically stable as defined by the following 
criteria: 
• Absence of signs and symptoms (including worsening of laboratory 
values) indicating disease progression 
• No decline in ECOG performance status 
• Absence of rapid progression of disease 
• Absence of progressive tumor at critical anatomical sites (e.g., cord 
compression) requiring urgent alternative medical intervention 
If irPD is confirmed and the subject is experiencing extraordinary clinical 
benefit, site must contact sponsor to discuss continuing treatment 
irNE 
Used in exceptional cases where insufficient data exists due to poor quality of 
scans or missed scans or procedure 
 
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Derivation of irRECIST overall responses 
Measurable 
response 
Non-measurable response 
  
Target 
Lesions (% 
change in 
SOD)a 
Nontarget Lesions Status 
New Lesions 
Status 
Overall 
Response 
(irRECIST) 
↓100 
Absent 
Absent 
irCRb 
↓100 
Present/NE 
Absent 
irPRb 
↓≥30 
Present/Absent/NE 
Absent 
irPRb 
↓<30 
to <20 
Present/Absent/NE 
Absent 
irSD 
↓100 
Present/Absent/NE 
Present 
irPDb 
↓≥30 
↓<30 
to <20 NE 
↓100 
Unequivocal Progression 
Any 
irPDb 
↓≥30 
↓<30 
to <20 
NE 
  
 
≥20 
from nadir 
Any 
Any 
irPDb 
NE 
Present/Absent/NE 
Absent 
irNEb 
irNE = immune-related not evaluable, irPD = immune-related progression disease, NE = Not evaluable  
a: Decreases assessed relative to baseline, including measurable lesions only. 
b: Assuming response (irCR) and progression (irPD) are confirmed by a second, consecutive assessment at least 4 weeks apart.  
 
 
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