Conditions: Glioblastoma
Keywords: Glioblastoma (GBM) Wilms Tumor 1 (WT1) Cancer Vaccines Neoplasms Astrocytoma Glioma Brain Cancer Brain Tumor Bevacizumab
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 221
Healthy volunteers: no

Brief summary:
This is an event driven, adaptive design, a randomized, active-controlled, multicenter, open-label, parallel groups, Phase 3 study of DSP-7888 Dosing Emulsion plus Bevacizumab versus Bevacizumab alone in patients with recurrent or progressive glioblastoma multiforme (GBM) following treatment with first line therapy consisting of surgery and radiation with or without chemotherapy.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: DSP-7888 Dosing Emulsion intervention 2: Bevacizumab
Intervention descriptions: intervention 1: DSP-7888 Dosing Emulsion will be administered i.d. every 7 ± 1 day for Doses 1 to 5, every 14 ± 3 days for Doses 6 to 15, and every 28 ± 7 days for Doses 16 and above. intervention 2: Bevacizumab will be administered intravenously every 14 ± 3 days at 10 mg/kg.

Protocol document:
Prot_000.pdf: 
 
 
 
CLINICAL STUDY PROTOCOL 
AMENDMENT 7 
A Randomized, Multicenter, Adaptive Phase 3 Study of DSP-7888 
Dosing Emulsion in Combination with Bevacizumab versus 
Bevacizumab Alone in Patients with Recurrent or Progressive 
Glioblastoma Following Initial Therapy 
 
 
 
Protocol Number: 
BBI-DSP7888-201G 
EudraCT Number: 
Not Applicable 
INC Research (A Syneos 
Health Group Company) 
Study Number: 
1009238 
Investigational Product: 
Nelatimotide and Adegramotide (Ombipepimut-S) 
(hereafter referred to as DSP-7888) Dosing Emulsion 
Phase: 
Phase 3 
Sponsor: 
Sumitomo Dainippon Pharma Oncology Inc. (SDP 
Oncology) 
640 Memorial Drive 
Cambridge, MA 02139 
USA 
Contract Research 
Organization: 
INC Research (A Syneos Health Group Company)  
3201 Beechleaf Court 
Suite 600 
Raleigh, NC 27604-1547 
United States 


 
 
Protocol Date: 
Amendment 1 
Amendment 2 
Amendment 3 
Amendment 4 
Amendment 5 
Amendment 6 
Amendment 7 
29 Mar 2017 (Version 1.0) 
30 Apr 2017 (Version 2.0) 
18 Sep 2017 (Version 3.0) 
06 Oct 2017 (Version 4.0 for South Korea Only) 
13 Oct 2017 (Version 5.0 for South Korea Only) 
03 Aug 2018 (Version 6.0) 
24 Jun 2019 (Version 7.0) 
05 Feb 2021 (Version 8.0) 
 
 
CONFIDENTIAL 
 
This protocol may not be reproduced or communicated to a third party without the 
written permission of Sumitomo Dainippon Pharma Oncology, Inc. 


 
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1 
PROTOCOL APPROVAL SIGNATURES 
 
 
 
 
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3 
SYNOPSIS 
Protocol Number: 
BBI-DSP7888-201G 
Protocol Title: 
A Randomized, Multicenter, Adaptive Phase 3 Study of DSP-7888 Dosing Emulsion in 
Combination with Bevacizumab versus Bevacizumab Alone in Patients with Recurrent or 
Progressive Glioblastoma Following Initial Therapy 
Investigational Product: 
DSP-7888 Dosing Emulsion 
Study Centers: 
Approximately 70 investigational sites in the US, Canada, Japan, Taiwan, and South Korea 
Phase: 
Phase 3 
Objectives: 
Primary objective:  The primary objective is to compare the overall survival (OS) between 
treatment with DSP-7888 Dosing Emulsion plus bevacizumab (Bev) versus Bev alone in 
patients with recurrent or progressive glioblastoma (GBM) following initial therapy. 
Key secondary objective: To compare the 12-month survival rate between treatment with 
DSP-7888 Dosing Emulsion plus Bev versus Bev alone. 
Other secondary objectives: 
• To compare the progression-free survival (PFS) of DSP-7888 Dosing Emulsion plus 
Bev to Bev alone 
• To compare the 6-month PFS of DSP-7888 Dosing Emulsion plus Bev to Bev alone  
• To compare the response rate of DSP-7888 Dosing Emulsion plus Bev to Bev alone  
• To compare the duration of response of DSP-7888 Dosing Emulsion plus Bev to 
Bev alone  


 
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• To describe the adverse event (AE) profile of DSP-7888 Dosing Emulsion plus Bev 
Exploratory objectives: 
• To describe the relationship between pharmacodynamic parameters such as Wilms’ 
Tumor 1 (WT1) peptide-specific cytotoxic T lymphocyte (CTL) activity and certain 
clinical findings (eg, OS, response) in patients receiving DSP-7888 Dosing 
Emulsion plus Bev 
• To describe the relationship between expression of WT1 by immunohistochemistry 
(IHC) and chromogenic in situ hybridization (CISH) in tumor tissue and certain 
clinical findings (eg, OS, response) in patients receiving DSP-7888 Dosing 
Emulsion plus Bev 
• To collect diffusion-weighted imaging (DWI) for future analysis of imaging 
findings and correlation with disease progression  
• To characterize the Neurological Assessment in Neuro-Oncology (NANO) scale 
score profile post DSP-7888 Dosing Emulsion plus Bev or Bev alone 
Study Design: 
This study is divided into 2 parts. Part 1 is a safety lead-in phase. Part 2 is a randomized, 
active-controlled, multicenter, open-label, parallel-group, adaptive Phase 3 study of 
DSP-7888 Dosing Emulsion plus Bev versus Bev alone in patients with recurrent or 
progressive GBM following treatment with first line therapy consisting of surgery and 
radiation with or without chemotherapy. An adaptive Phase 3 design with 2 interim 
analyses (IAs) and 1 final analysis (FA) is employed in Part 2 of this trial.   
Patients may have undergone a second surgery at the time of recurrence or progression but 
may not have received any other anti-neoplastic therapy.  Patients are randomized 1:1 to 
treatment with DSP-7888 Dosing Emulsion plus Bev or Bev alone. 
Potential study subjects first undergo pre-screening to determine appropriate human 
leukocyte antigen (HLA) type due to the nature of the vaccine DSP-7888.  DSP-7888 
Dosing Emulsion is active in subjects with HLA-A*02:01, HLA-A*02:06, or HLA-
A*24:02.  
Following HLA determination, a screening phase of up to 28 days determines eligibility.  
Following verification of eligibility and enrollment, DSP-7888 Dosing Emulsion is 
administered intradermally (i.d.) every 7 days (± 1 day) for 5 doses (the Induction Phase); 
then every 14 days (± 3 days) for Doses 6 to 15 (the Consolidation Phase), and then every 
28 days (± 7 days) for Doses 16 and above (the Maintenance Phase).  Bev is administered 
every 14 ± 3 days at the labeled dose of 10 mg/kg intravenously (i.v.).     


 
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Part 1: 
In Part 1, 3 patients will be treated with the combination of DSP-7888 Dosing Emulsion 
plus Bev in a single-arm manner.  DSP7888 Dosing Emulsion will be administered at a 
dose of 10.5 mg i.d. per the schedule described above and Bev at the dose and schedule 
described above.  If 0 of these first 3 patients experiences dose-limiting toxicity (DLT), 
then the study will proceed to Part 2, which will randomize patients to the combination of 
DSP-7888 Dosing Emulsion plus Bev or to Bev alone. 
If 1 of the first 3 patients experiences a DLT, then 3 more patients will be enrolled at the 
same treatment regimen.  If no additional DLTs are observed at the same dose (with 1/6 
DLTs), then the study will proceed to Part 2.  However, if 2 or more of the first 6 patients 
experience a DLT, then the dose of DSP-7888 Dosing Emulsion will be decreased to 3.5 
mg i.d., and an additional 3 patients will be treated with the combination of DSP-7888 
Dosing Emulsion plus Bev. 
If 0 of these 3 patients experiences DLT at this reduced dose of DSP-7888 Dosing 
Emulsion, then the study will proceed to Part 2.  If 1 of the 3 patients experiences a DLT at 
the reduced dose of DSP-7888 Dosing Emulsion, then 3 more patients will be enrolled at 
the same treatment regimen.  If no additional DLTs are observed at the same dose (with 1/6 
DLTs), then the study will proceed to Part 2.  However, if 2 patients or more experience a 
DLT at this reduced dose of DSP-7888 Dosing Emulsion plus Bev, then enrollment will be 
placed on hold until the Sponsor decides how best to proceed. 
In summary, if 0 of the first 3 patients or 1 of the first 6 patients experience a DLT, then the 
study will proceed to Part 2. The maximum tolerated dose (MTD) is decided only when 6 
patients are treated at a dose level with ≤ 1/6 DLT.  If at least 2/3 or 2/6 DLTs are observed, 
then the MTD has been exceeded.  Dosing should stop, and the dose should be de-escalated 
to DSP-7888 3.5 mg.  Then the process should be repeated at the reduced dose level of 
DSP-7888 3.5 mg. 
The patients who complete Part 1 of the study will not be randomized into Part 2.  Instead, 
they will continue to receive DSP-7888 Dosing Emulsion plus Bev and undergo the same 
assessments that are listed for Part 2 of the study. 
Dose-limiting toxicity will be evaluated and applied during the Induction Phase of Part 1 
(Day 1 through Day 29) and defined as the following AEs that are at least possibly related 
to the investigational agents per the Investigator and institutional guidelines: 
• The occurrence of any Grade 3 or higher hematologic AE lasting more than 7 days;  


 
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• Any Grade 3 or higher non-hematological AE that persists for more than 72 hours 
with the exceptions of transient nausea, vomiting, and diarrhea that are responding 
to supportive care; 
• Any Grade 3 or higher allergic and/or hypersensitivity reactions; and, 
• Any Grade 2 or higher autoimmune disease. 
Patients who discontinue Part 1 of the study for reasons other than DLT during the 
Induction Phase will be replaced. 
Part 2: 
Based on the results of the DLT evaluation in Part 1, a 10.5-mg dose of DSP-7888 Dosing 
Emulsion was determined as the dose for Part 2.   
In Part 2, patients are stratified prior to randomization based on the extent of surgical 
resection in primary therapy (gross total resection [GTR] versus not GTR) and Karnofsky 
Performance Status (KPS) scores (60 through 70 versus 80 through 100). 
Rescreening for patients in Part 2 is permitted for patients with laboratory values (aspartate 
aminotransferase [AST], alanine aminotransferase [ALT], bilirubin, creatinine) that are out 
of range to meet eligibility and for patients requiring dexamethasone doses in excess of 4 
mg/day (or equivalent) once the dose can be tapered to 4 mg/day (or equivalent) or less 
with stability in the judgement of the investigator. 
Patients will continue to receive DSP-7888 Dosing Emulsion plus Bev or Bev alone 
independent of radiological assessment / progression:  
1. Provided that the Investigator considers it to be safe for the patient 
2. Provided that the Investigator determines that there is potential benefit for the patient 
3. When the patient is willing to continue 
Safety is assessed by the recording of AEs at each contact with the patient, by findings of 
physical and neurological examinations, and by the results of laboratory determinations; the 
severity of AEs or abnormal laboratory results is based on the Common Terminology 
Criteria for Adverse Events (CTCAE) V4.03. 
The criteria for response and progression is based on the Modified Response Assessment in 
Neuro-Oncology (mRANO) criteria, and patients also undergo neurological assessments 
based on the NANO criteria.   


 
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Patients randomized to the Bev arm of the study undergo evaluations on a similar schedule 
as patients randomized to treatment with the combination of DSP-7888 Dosing Emulsion 
plus Bev.  
Patients undergo magnetic resonance imaging (MRI) and DWI to assess their disease 
progression.  Patients who are, in the opinion of the Investigator, clinically stable and in 
whom pseudo-progression is suspected will continue to be treated per protocol according to 
the treatment arm assigned and will have a second (confirmatory) scan performed 4-8 
weeks later.   
Patients who discontinue study treatment for any reason will continue to be followed up for 
efficacy (mRANO, NANO, KPS, etc.) until new treatment is commenced.   
All patients are followed up for OS, regardless of potential subsequent therapy.  
Patients’ immunological responses to DSP-7888 Dosing Emulsion are measured by a 
variety of assays including: 
• Measurement of WT1 peptide-specific CTL induction activity at various times 
using peripheral blood mononuclear cells of patients 
• Retrospective analysis of additional biomarkers from peripheral blood and archival 
tumor samples 
Formalin-fixed, paraffin-embedded (FFPE) archival tumor samples will be tested for 
expression of WT1 by IHC and CISH and compared to a variety of clinical outcomes in 
exploratory analyses.  Additional exploratory analyses will evaluate the role of DWI in 
predicting and diagnosing true progression of neoplastic disease in patients with GBM. 
Exploratory analyses will be performed to investigate the relationship between DSP-7888 
Dosing Emulsion activities and other HLA Class 1 haplotypes (A and B locus) as well as 
HLA Class 2. 
Companion diagnostics of HLA typing will be developed as part of this study.  
Number of Patients:  
Between 3 and 12 patients were planned to be enrolled in Part 1 of the study (Section 
8.1.1). As of Protocol Amendment 7, 4 patients had been enrolled into Part 1.  
For Part 2, the adaptive Phase 3 study design, if the study continues to the final analysis 
with appropriately 260 death events (Section 8.2.1), approximately 338 patients with GBM 
will be enrolled from approximately 70 investigational sites in the United States (US), 
Canada, Japan, Taiwan, and South Korea. Part 2 of the study may be concluded earlier with 
early efficacy at IA2 or may be concluded in the final analysis with re-estimated number of 


 
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death events.  Note that Part 2 of the study is an event-driven adaptive trial and statistical 
power of Part 2 is determined by the target number of death events instead of the number of 
patients. The actual number of randomized patients in Part 2 may be adjusted to observe the 
targeted number of events, depending on the outcome of the interim analyses and 
operational feasibility.   
Treatment: 
Part 1:  This part of the study is a safety run-in cohort to determine the recommended dose 
(RD) for Part 2.  The initial dose of DSP-7888 Dosing Emulsion is 10.5 mg.  Bev will be 
administered at a dose of 10 mg/kg by i.v. infusion. 
Note:  The dose of DSP-7888 Dosing Emulsion may be reduced for individual patients to 
3.5 mg or 1.75 mg if any dose reduction criterion is met.  
Part 2:  Based on the results of the DLT evaluation in Part 1, a 10.5 mg dose of DSP-7888 
Dosing Emulsion was determined as the dose for Part 2.  Bev is administered at a dose of 
10 mg/kg by i.v. infusion. 
Note:  The dose may be reduced for individual patients to 3.5 mg or 1.75 mg of DSP-7888 
Dosing Emulsion if any dose reduction criterion is met. 
Study Duration: 
The study duration for individual patients commences at date of pre-screening consent and 
completes at the date of End of Study visit. The study will continue until the target number 
of events is observed. The study may be terminated early for efficacy or futility at the 
planned interim analyses. Individual patient OS status will be followed until the end of the 
study.  
Study Population: 
The study will enroll patients with GBM whose tumors have recurred or progressed 
following initial treatment with surgery, radiation, and/or chemotherapy. 
Inclusion Criteria  
Patients must fulfill all the following requirements: 
1. Patients or their legal representatives must be able to provide written informed consent. 
2. Histologically confirmed diagnosis of supratentorial GBM (Grade 4 astrocytoma). 


 
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3. Radiographic evidence of first recurrence or progression of GBM following primary 
therapy consisting of surgery (biopsy or resection) and radiation with or without 
chemotherapy; patients may have undergone a second debulking surgery following 
initial recurrence or progression.  Patients whose tumors are O6-methyl-guanyl-methyl-
transferase (MGMT) methylated-promoter negative need not have received 
chemotherapy in the past to be eligible. 
4. Human leukocyte antigen type HLA-A*02:01, HLA-A*02:06, or HLA-A*24:02. 
5. Age ≥ 18. 
6. KPS score of ≥ 60. 
7. Serum creatinine value < 2X the upper limit of normal (ULN) for the reference 
laboratory. 
8. ALT and AST < 3X the ULN and total bilirubin < 2X the ULN for the reference 
laboratory. 
9. Men and women of childbearing potential must agree to use a reliable method of 
contraception (oral contraceptives, implantable hormonal contraceptives, or double 
barrier method) or agree to completely refrain from heterosexual intercourse for the 
duration of the study and for 180 days following the last dose of DSP-7888 Dosing 
Emulsion. 
10. Patients must have recovered from the effect of all prior therapy to Grade 2 or less. 
11. Patients must be at least 28 days from any major surgery, and any surgery incisions or 
wounds must be completely healed. 
12. Patients must be at least 12 weeks from the completion of prior radiation therapy (RT) 
in order to discriminate pseudo-progression of disease from progression. 
13. Patients must be at least 4 weeks from the completion of prior systemic or intracranial 
chemotherapy. 
14. Patients must stop Novo-TTF treatment one day prior to study therapy (no washout 
period is needed).  However, any wounds from TTF must be adequately healed per 
Inclusion Criterion #11. 
15. For patients who are not receiving therapeutic anticoagulation treatment, an 
international normalized ratio (INR) and a partial thromboplastin time (PTT) ≤ 1.5X the 
ULN; patients who are receiving anticoagulation treatment should be on a stable dose. 


 
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16. Patient’s left ventricular ejection fraction (LVEF) > 40%. 
17. Patient has a resting pulse oximetry of 90% or higher. 
Exclusion Criteria 
Patients will be excluded from the study if one or more of the following are applicable: 
1. Prior therapy with Bev. 
2. Patients with secondary GBM. 
3. Any anti-neoplastic therapy, including RT or laser interstitial thermal therapy, for first 
relapse or recurrence. 
4. Evidence of leptomeningeal spread (gliomatous meningitis) of tumor or any history, 
presence, or suspicion of metastatic disease extracranially. 
5. Evidence of impending herniation on imaging. 
6. Has known multifocal disease. Multifocal disease is defined as discrete sites of disease 
without contiguous T2/FLAIR abnormality that require distinct radiotherapy ports. 
Satellite lesions that are associated with a contiguous area of T2/FLAIR abnormality as 
the main lesion(s) and that are encompassed within the same radiotherapy port as the 
main lesion(s) are permitted. 
7. Patients with infections that have required treatment with systemic antibiotics within 
7 days prior to the first dose of protocol therapy. 
8. The need for systemic glucocorticoids in doses in excess of 4 mg/day of dexamethasone 
or in comparable doses with other glucocorticoids. 
9. Treatment with any investigational agents within 5 half-lives of the agent in question or, 
if the half-life is unknown, within 28 days of enrollment. 
10. Pregnant or lactating females. 
11. Prior history of malignancy within 3 years of enrollment other than basal or squamous 
cell carcinoma of the skin, cervical intra-epithelial neoplasia, in situ carcinoma of the 
breast, or localized prostate cancer treated with surgery or RT with a prostate specific 
antigen of < 0.01 ng/mL. 
12. Patients with active autoimmune diseases within 2 years of enrollment into the study 
including, but not limited to, rheumatoid arthritis, systemic lupus erythematosus, 


 
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systemic sclerosis, Sjogren’s syndrome, Wegener’s granulomatosis, ulcerative colitis, 
Crohn’s disease, myasthenia gravis, Graves’ disease, or uveitis except for psoriasis not 
requiring systemic therapy, vitiligo or alopecia areata, or hypothyroidism; if an 
autoimmune condition has been clinically silent for 12 months or greater, the patient 
may be eligible for enrollment. 
13. Patients on immunosuppressive therapies; the use of topical, inhalational, 
ophthalmologic, or intra-articular glucocorticoids or the use of physiologic replacement 
doses of glucocorticoids is permitted. 
14. Patients with primary immunodeficiency diseases. 
15. Patients with significant bleeding in the preceding 6 months prior to study enrollment or 
with known coagulopathies. 
16. History of abdominal fistula, intestinal perforation, or intra-abdominal abscess in the 
preceding 12 months prior to study enrollment  
17. Positive serology for human immunodeficiency virus (HIV) infection, active hepatitis 
B*, or untreated hepatitis C; patients who have completed a course of anti-viral 
treatment for hepatitis C are eligible.  
*In cases of negative results for HepB surface antigen with positive HepB core 
antibody, HBV deoxyribonucleic acid (DNA) testing is required. 
18. Patient has a medical history of frequent ventricular ectopy, eg, non-sustained 
ventricular tachycardia (VT). 
19. Significant cardiovascular disease, including New York Hospital Association Class III 
or IV congestive heart failure, myocardial infarction within 6 months of study 
enrollment, unstable angina, poorly controlled cardiac arrhythmias, or stroke in the 
preceding 6 months prior to study enrollment. 
20. Any other uncontrolled inter-current medical condition, including systemic fungal, 
bacterial, or viral infection; uncontrolled hypertension; diabetes mellitus; or chronic 
obstructive pulmonary disease requiring 2 or more hospitalizations in the preceding 
12 months prior to study enrollment. 
21. Any psychiatric condition, substance abuse disorder, or social situation that would 
interfere with a patient’s cooperation with the requirements of the study. 
22. Known sensitivity to Bev or any of the components of DSP-7888 Dosing Emulsion. 
23. Patient has a QTcF (QT corrected based on Fridericia’s equation) interval > 480 msec 
(CTCAE = Grade 2) or other factors that increase the risk of QT prolongation or 


 
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arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval 
syndrome) at screening.  (Patients with bundle branch block and a prolonged QTc 
interval should be reviewed by the Medical Monitor for potential inclusion.) 
24. Patient has dyspnea at rest (CTCAE ≥ Grade 3) or has required supplemental oxygen 
within 2 weeks of study enrollment. 
Primary Endpoint: 
The primary endpoint is OS and is defined as the interval between randomization and death 
from any cause.  Patients who are lost to follow-up will be censored on the last day they 
were known to be alive. 
Key Secondary Endpoint: 
The key secondary endpoint is the12-month survival rate and is defined as the proportion of 
patients alive 12 months after randomization. 
Other Secondary Endpoints: 
• PFS is defined as the interval between randomization and progression, determined 
by the central radiology review or death from any cause. 
• 6-month PFS rate is defined as the proportion of patients alive at 6 months after 
randomization and without progressive neoplastic disease.  
• The response rate is defined as the proportion of patients exhibiting a response 
(complete response [CR] plus partial response [PR]) based on the mRANO criteria 
as determined by the central radiology review. 
• The duration of response is defined as the interval between first documented 
oncological response and progression of disease or death from any cause, with 
response based on the mRANO criteria as determined by the central radiology 
review. 
Efficacy: 
Efficacy will be evaluated by comparing the OS between treatment with DSP-7888 Dosing 
Emulsion plus Bev versus Bev alone in patients with recurrent or progressive GBM 
following initial therapy. 


 
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Pharmacodynamics: 
The relationship between pharmacodynamic parameters such as WT1 peptide-specific CTL 
activity and certain clinical findings (eg, OS, response) in patients receiving DSP-7888 
Dosing Emulsion will be described if appropriate. 
The relationship between the expression of WT1 by IHC and CISH in tumor tissue and 
certain clinical findings (eg, OS, response) in patients receiving DSP-7888 Dosing 
Emulsion will be described if appropriate. 
Safety: 
The Sponsor will promptly review all serious life-threatening and fatal events (other than 
death due to disease progression) reported in the study and perform a causality assessment. 
Based on the causality assessment of life-threatening and fatal events that occur from the 
start of treatment with DSP-7888 Dosing Emulsion and up to 30 days from the last dose of 
DSP-7888 Dosing Emulsion (other than death due to disease progression), the Sponsor will 
determine whether the study will be suspended for safety review.  
The Sponsor will determine whether the study will be modified, continue enrollment or be 
terminated based on the following scenarios: 
• Any cases of death (other than death related to progressive disease) that occur from 
the start of treatment with DSP-7888 Dosing Emulsion and up to 30 days from the 
last DSP-7888 Dosing Emulsion administration and deemed by the Sponsor to be 
related to any of the study’s drugs. 
• If the percentage of patients presenting with drug‑related (assessed by Sponsor) 
Grade 4 or higher AE within a particular medical concept (eg, hypersensitivity) in 
this study is higher than that reported in patients treated with DSP-7888 Dosing 
Emulsion within the clinical program and as reported in the literature for GBM 
patients.  
The causality assessment and safety reviews will occur in the context of the Sponsor’s 
safety governance processes including the study team and senior leadership.  As part of the 
safety review, in addition to ongoing routine review of the safety data by the Independent 
Data Monitoring Committee (IDMC), the Sponsor may choose to consult with the IDMC 
on an ad hoc basis. 
Based on the safety review, the Sponsor will determine whether the study may continue 
(with or without a protocol amendment) or if it must be terminated.  


 
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Statistical Analysis: 
The OS will be estimated using Kaplan-Meier (KM) estimates and will be tested using a 
stratified log-rank test considering the randomization strata of extent of surgical resection in 
primary therapy (GTR versus not GTR) and KPS class (60 through 70 versus 80 through 
100) in the intent-to-treat (ITT) population. The 12-month OS rate will be estimated based 
on the 12-month KM estimate.  A comparison between treatments will be performed using 
a Z-test-statistic considering the respective Greenwood variances.  PFS and duration of 
response will be analyzed similarly to OS. The 6-month PFS rate will be analyzed similarly 
to the 12-month survival rate.  The proportion of patients who achieve CR or PR will be 
analyzed using a Cochran-Mantel-Haenszel method considering the 2 randomization 
factors.  Stratified Cox-Proportional-Hazards regression, stratified by the 2 randomization 
factors, will be used to assess the hazard ratio (HR) for the comparison of the treatments. 
Sample Size: 
Considering that the number of death events are 108 (observed at interim analysis 1 [IA1]), 
approximately 185 (interim analysis 2 [IA2]), and approximately 260 (FA), then the study 
will have approximately 90% power to detect a 34% reduction in the HR of DSP-7888 
Dosing Emulsion plus Bev versus Bev alone (ie, HR = 0.663, which corresponds to a 1-
year survival proportion of 45% in the DSP-7888 Dosing Emulsion plus Bev arm compared 
to 30% in the Bev alone arm). The number of death events at the FA could go up to 370 if 
event re-estimation is performed based on the conditional power calculated at IA2.  
Assuming an enrollment rate of 11 patients per month and patients are followed until the 
end of the study, with a 5% dropout rate per year, the study will require enrolling of 
approximately 338-480 patients.  
Note that Part 2 is an event-driven adaptive trial and statistical power of Part 2 is 
determined by the target number of death events instead of the number of patients.  The 
actual number of randomized patients in Part 2 may vary to observe the targeted number of 
events, depending on the outcome of the interim analyses, the duration of the study and 
operational feasibility. It is envisioned that approximately 215 patients will be enrolled at 
the second IA with 185 events, approximately 338 patients will be enrolled at the FA with 
260 events when there is no event number re-estimation. If the number of events at the FA 
reaches the cap of 370 with event number re-estimation, approximately 480 patients will be 
enrolled in the study assuming that the ratio of the number of events to the number of 
patients at the FA is approximately 0.77 (assume similar death event rate of 260/338 when 
the target event number is 260). 


 
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4 
TABLE OF CONTENTS 
1 
Protocol Approval Signatures .................................................................................. 3 
2 
Study Personnel .......................................................................................................... 4 
3 
Synopsis ........................................................................................................................ 5 
4 
Table of Contents...................................................................................................... 17 
5 
List of Abbreviations & Definitions....................................................................... 22 
6 
Introduction ............................................................................................................... 26 
6.1 
Disease ........................................................................................................................ 26 
6.1.1 
Current Therapy of Glioblastoma ............................................................ 26 
6.1.2 
Recent Studies in Recurrent Glioblastoma ............................................. 27 
6.1.3 
Wilms’ Tumor 1 (WT1) Antigen ............................................................. 28 
6.1.3.1 
Molecular Biology and Role in Oncogenesis ......................................... 28 
6.1.3.2 
WT1 in Glioblastoma ............................................................................... 28 
6.1.3.3 
Vaccine- and Immune-Based Clinical Studies in Recurrent 
Glioblastoma ............................................................................................. 28 
6.1.3.4 
Rationale for Use of Modified Radiographic Response 
Assessment (mRANO) ............................................................................. 30 
6.1.4 
DSP-7888 Dosing Emulsion .................................................................... 31 
6.2 
Rationale .................................................................................................................... 31 
7 
Study Objectives ....................................................................................................... 33 
7.1 
Primary Objective .................................................................................................... 33 
7.2 
Key Secondary Objective ........................................................................................ 33 
7.3 
Other Secondary Objectives ................................................................................... 33 
7.4 
Exploratory Objectives ............................................................................................ 33 
7.5 
Endpoints ................................................................................................................... 34 
7.5.1 
Primary Endpoint ...................................................................................... 34 
7.5.2 
Key Secondary Endpoint .......................................................................... 34 
7.5.3 
Other Secondary Endpoints...................................................................... 34 
8 
Investigational Plan .................................................................................................. 34 
8.1 
Overall Study Design and Plan:  Description ...................................................... 34 


 
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8.1.1 
Flow Chart for Part 1 of the Study........................................................... 39 
8.1.2 
Study Design for Part 2 of the Study ....................................................... 40 
8.1.3 
Schedule of Assessments ......................................................................... 41 
8.2 
Selection of Study Population ................................................................................. 45 
8.2.1 
Number of Planned Patients ..................................................................... 45 
8.2.2 
Inclusion Criteria ...................................................................................... 45 
8.2.3 
Exclusion Criteria ..................................................................................... 46 
8.2.4 
Reasons for Discontinuation of Protocol Therapy.................................. 48 
8.2.5 
Reasons for Discontinuation from the Clinical Study ............................ 50 
8.3 
Investigational Products .......................................................................................... 51 
8.3.1 
Identity of Investigational Products ......................................................... 51 
8.3.1.1 
DSP-7888 Dosing Emulsion .................................................................... 51 
8.3.1.2 
Bevacizumab ............................................................................................. 52 
8.3.2 
Dose Delay, Dose Reduction, and Study Stopping Criteria .................. 52 
8.3.2.1 
DSP-7888 Dosing Emulsion .................................................................... 52 
8.3.2.2 
Bevacizumab ............................................................................................. 54 
8.3.2.3 
Treatment of Injection Site Reactions ..................................................... 54 
8.3.3 
Grade 1 Injection Site Reactions ............................................................. 55 
8.3.4 
Grade 2/3 Injection Site Reactions .......................................................... 55 
8.3.5 
Study Stopping Rules ............................................................................... 56 
8.3.6 
Packaging and Labeling ........................................................................... 57 
8.3.7 
Method of Assigning Patients to Treatment Groups .............................. 57 
8.3.8 
Selection of Doses in the Study ............................................................... 57 
8.3.9 
Prior and Concomitant Therapy ............................................................... 58 
8.3.9.1 
Prohibited Medication/Therapy ............................................................... 58 
8.3.9.2 
Permitted Medication/Therapy ................................................................ 59 
8.3.10 
Treatment Compliance ............................................................................. 59 
8.3.11 
Blinding ..................................................................................................... 59 
9 
Study Procedures ...................................................................................................... 59 
9.1 
Timing of Study Procedures ................................................................................... 59 
9.1.1 
Pre-Screening Phase ................................................................................. 59 
9.1.2 
Pre-Treatment Screening Phase (Day -28 to -1) ..................................... 60 
9.1.3 
Induction Phase (Day 1, Day 8, Day 15, Day 22, and Day 29) ............. 61 
9.1.3.1 
Day 1, Day 15, and Day 29 Procedures .................................................. 62 
9.1.3.2 
Day 8 and Day 22 Procedures .................................................................. 62 
9.1.4 
Consolidation Phase (Days 43, 57, 71, 85, 99, 113, 127, 141, 
155, 169, and 183) .................................................................................... 63 
9.1.4.1 
Days 43, 71, 99, 127, and 155 Procedures .............................................. 63 
9.1.4.2 
Days 57, 85, 113, 141, and 169 Procedures ............................................ 63 


 
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9.1.4.3 
Day 183 Procedures .................................................................................. 64 
9.1.5 
Maintenance Phase (Day 197 and Thereafter) ........................................ 64 
9.1.6 
End of Treatment Visit ............................................................................. 65 
9.1.7 
Follow-Up after End of Treatment .......................................................... 66 
9.2 
Description of Study Procedures............................................................................ 68 
9.2.1 
Medical History ........................................................................................ 68 
9.2.2 
Karnofsky Performance Status Score ...................................................... 68 
9.2.3 
Clinical Laboratory Evaluation ................................................................ 68 
9.2.3.1 
Hematology ............................................................................................... 68 
9.2.3.2 
Coagulation Parameters ............................................................................ 68 
9.2.3.3 
Clinical Chemistry .................................................................................... 68 
9.2.3.4 
Urinalysis .................................................................................................. 69 
9.2.3.5 
Other Laboratory Variables...................................................................... 69 
9.2.4 
Vital Signs ................................................................................................. 69 
9.2.5 
Physical Examination ............................................................................... 69 
9.2.6 
Neurological Examination ....................................................................... 69 
9.2.7 
Tumor and Brain Imaging ........................................................................ 69 
9.2.8 
Other Safety Assessments ........................................................................ 70 
9.2.8.1 
Electrocardiogram..................................................................................... 70 
9.2.8.2 
Echocardiogram/MUGA .......................................................................... 70 
9.2.8.3 
Monitoring of QTc Intervals .................................................................... 70 
9.2.9 
Pharmacodynamic Testing ....................................................................... 70 
9.3 
Duration of Treatment............................................................................................. 71 
10 
Efficacy, Pharmacodynamics, and Safety Variables Assessed .......................... 71 
10.1 Efficacy Variables..................................................................................................... 71 
10.2 Pharmacodynamic Assessments ............................................................................. 72 
10.3 Safety Assessments ................................................................................................... 72 
10.3.1 
COVID-19 ................................................................................................. 72 
10.3.2 
Adverse Events ......................................................................................... 72 
10.3.2.1 
Adverse Event Definition ......................................................................... 72 
10.3.2.2 
Assessment of Severity ............................................................................ 73 
10.3.2.3 
Assessment of Causality........................................................................... 74 
10.3.2.4 
Action Taken ............................................................................................. 75 
10.3.2.5 
Follow-Up of Adverse Events ................................................................. 75 
10.3.2.6 
Documentation and Reporting of Adverse Events ................................. 75 
10.3.3 
Serious Adverse Events ............................................................................ 78 
10.3.3.1 
Serious Adverse Event Definition ........................................................... 78 
10.4 Pharmacodynamic Variables.................................................................................. 80 


 
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10.5 Independent Data Monitoring Committee ........................................................... 80 
10.5.1 
Appropriateness of Measurements .......................................................... 81 
11 
Statistical Analysis .................................................................................................... 82 
11.1 Statistical Methods ................................................................................................... 82 
11.1.1 
Statistical Hypotheses ............................................................................... 82 
11.1.2 
Level of Significance, Multiple Comparisons, and Multiplicity ........... 82 
11.2 Definition of Study Populations ............................................................................. 82 
11.2.1 
Determination of Number of Events, Power and Sample Size .............. 83 
11.3 Demographic and Other Baseline Characteristics .............................................. 83 
11.4 Planned Analyses ...................................................................................................... 84 
11.4.1 
Demographic and Other Baseline Characteristics .................................. 84 
11.4.2 
Planned Analysis for Primary Efficacy Endpoint ................................... 84 
11.4.3 
Planned Analysis for Key Secondary Efficacy Endpoint....................... 85 
11.4.4 
Planned Analysis for Other Secondary Efficacy Endpoints .................. 85 
11.4.5 
Planned Analysis for Pharmacodynamic Endpoints ............................... 86 
11.4.6 
Safety Analyses......................................................................................... 87 
11.4.7 
Additional Analyses ................................................................................. 88 
11.5 Periodic Safety Reviews ........................................................................................... 88 
11.6 Interim and Final Analyses ..................................................................................... 88 
11.7 Protocol Deviations .................................................................................................. 89 
11.8 General Considerations ........................................................................................... 89 
12 
Quality Assurance and Quality Control ............................................................... 90 
12.1 Audit and Inspection ................................................................................................ 90 
12.2 Monitoring ................................................................................................................. 91 
12.3 Data Management and Coding............................................................................... 91 
12.3.1 
Data Collection/Electronic Data Capture ................................................ 91 
12.3.2 
Records and Supplies ............................................................................... 92 
12.4 Drug Accountability ................................................................................................. 92 
12.5 Financing and Insurance ......................................................................................... 92 
12.6 Compensation............................................................................................................ 92 
13 
Ethics .......................................................................................................................... 93 


 
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13.1 Independent Ethics Committee or Institutional Review Board ........................ 93 
13.2 Regulatory Authorities ............................................................................................ 93 
13.3 Ethical Conduct of the Study .................................................................................. 93 
13.4 Informed Consent ..................................................................................................... 93 
13.5 Patient Confidentiality ............................................................................................. 94 
14 
Reporting and Publication, Including Archiving ................................................ 95 
15 
References .................................................................................................................. 96 
16 
Appendices ............................................................................................................... 100 
16.1 Performance Status Scores ................................................................................... 101 
16.2 The Modified Response Assessment in Neuro-Oncology (mRANO) 
Criteria ..................................................................................................................... 102 
16.3 The Neurological Assessment in Neuro-Oncology (NANO) Criteria ............. 108 
16.4 Glucocorticoid Dose Equivalents ......................................................................... 112 
16.5 Table of Tissue Samples and Informed Consents Required ............................ 113 
16.6 Investigator Signature Page .................................................................................. 114 
 
 
Table of Tables 
Figure 1: 
Part 1 Flow Chart ................................................................................... 39 
Figure 2: 
Part 2 Study Design ................................................................................ 40 
Figure 3: 
Adaptive Design for Part 2 of the Study ............................................. 88 
Figure 4: 
Post-Randomization Tumor Assessment Process Flow .................. 102 
Figure 5: 
Algorithm for Identification of Target Lesions................................ 103 
 
Table of Figures 
Figure 1: 
Part 1 Flow Chart ................................................................................... 39 
Figure 2: 
Part 2 Study Design ................................................................................ 40 
Figure 3: 
Adaptive Design for Part 2 of the Study ............................................. 88 
Figure 4: 
Post-Randomization Tumor Assessment Process Flow .................. 102 
Figure 5: 
Algorithm for Identification of Target Lesions................................ 103 
 


 
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5 
LIST OF ABBREVIATIONS & DEFINITIONS 
ADL 
activities of daily living 
AE 
adverse event 
AESI 
adverse event of special interest 
AKT 
serine/threonine kinase also known as protein kinase B 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
Bev 
Bevacizumab 
BBI 
Boston Biomedical, Inc. 
CBC 
complete blood (cell) count 
CFR 
Code of Federal Regulations 
cGCP 
current Good Clinical Practice 
CI 
confidence interval 
CISH 
chromogenic in situ hybridization 
CP 
conditional power 
CR 
complete response 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTL 
cytotoxic T lymphocyte 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DSP 
Sumitomo Dainippon Pharma 
DSP-7888 
adegramotide/nelatimotide (INN, International Non-Proprietary 
Names) or ombipepimut-S (USAN, United States Adopted 
Name)  
DSP-7888 Dosing 
Emulsion 
adegramotide/nelatimotide suspension with montanide 
DSP-7888-H  
DSP-7888 (adegramotide [INN]) helper peptide 
DSP-7888-K  
DSP-7888 (nelatimotide [INN]) cytotoxic T lymphocyte-
inducing (killer) peptide 


 
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DSP-7888-M 
water-in-oil emulsion of DSP-7888 with the immunogenicity 
enhancing adjuvant MONTANIDE ISA 51 VG 
DWI 
diffusion-weighted imaging 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EGFR 
epidermal growth factor receptor 
EGFRvIII 
epidermal growth factor receptor vIII tumor-specific oncogene 
EOT 
end of treatment 
FA 
final analysis 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed, paraffin-embedded 
GBM 
glioblastoma  
GTR 
gross total resection 
Hep 
hepatitis 
HIV 
human immunodeficiency virus 
HLA 
human leukocyte antigen 
HR 
hazard ratio 
IA 
interim analysis 
IA1 
interim analysis 1 
IA2 
interim analysis 2 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
i.d. 
intradermally 
IDH 
isocitrate dehydrogenase 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IGF1R 
type 1 insulin-like growth factor receptor 
IHC 
immunohistochemistry 


 
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INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRES 
internal ribosome entry site 
ISR 
injection site reaction 
ITT 
intent-to-treat 
i.v. 
intravenously 
KLH 
keyhole limpet hemocyanin 
KM 
Kaplan-Meier 
KPS 
Karnofsky Performance Status 
LLN 
lower limit of normal 
LVEF 
left ventricular ejection fraction 
MAP 
mitogen activated protein 
MDS 
myelodysplastic syndromes 
MGMT 
O6-methyl-guanyl-methyl-transferase 
MHC 
major histocompatibility complex 
mRANO 
Modified Response Assessment in Neuro-Oncology 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
MUGA 
multigated acquisition scan 
n 
number of patients with an observation 
NA 
not available, not applicable, or not able to assess 
NANO 
Neurological Assessment in Neuro-Oncology 
O2 
oxygen 
OK-432 
picibanil antitumor agent 
ORR 
overall response rate 
OS 
overall survival 
P53 
tumor suppressor protein 
PD 
progressive disease 
PDGF-A 
platelet-derived growth factor A 


 
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PE38QQR 
Pseudomonas aeruginosa exotoxin A 
PFS 
progression-free survival 
PFS6 
6-month progression-free survival 
PI3K 
phosphoinositide 3-kinase 
PIK3CA 
phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit 
alpha 
PP 
per protocol 
PR 
partial response 
PTT 
partial thromboplastin time 
PVS-RIPO 
poliovirus-rhinovirus IRES poliovirus open reading frame 
QTcF 
Fridericia's correction formula (msec) 
RANO 
Response Assessment in Neuro-Oncology 
RD 
recommended dose 
RNA 
ribonucleic acid 
RT 
radiation therapy 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SDP Oncology 
Sumitomo Dainippon Pharma Oncology, Inc 
SpO2 
oxygen saturation 
SUSAR 
suspected unexpected serious adverse reaction 
ULN 
upper limit of normal 
US 
United States 
VEGFR 
vascular endothelial growth factor receptor 
VT 
ventricular tachycardia 
WBC 
white blood (cell) count 
WHO 
World Health Organization 
Wnt 
Int/Wingless gene family combining nomenclature of integration 
1 (int 1) and Wingless (Wg) genes 
WT1 
Wilms’ Tumor 1 


 
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6 
INTRODUCTION 
6.1 
Disease 
It is estimated that in 2017, there will be 23,800 new cases of brain and nervous system 
tumors in the US alone; and there were 255,000 cases worldwide in 2012.1,2 The age 
adjusted incidence rate of brain tumor in the US is 6.4/100,000, and this rate has been 
relatively stable over several decades.3 Gliomas, sub-types of brain tumors, are malignant 
neoplasms of glial tissue and are derived from astrocytes.  The World Health Organization 
(WHO) further divides gliomas into several sub-types; GBM is classified as a Grade 4 
astrocytic tumor due to its highly malignant potential.4  Gliomas comprise 81% of all brain 
tumors, and GBMs comprise 45% of all gliomas.5  The incidence of GBM increases with 
age, starting around age 55, reaching a peak in the 75- to 84-year-old age group, after 
which the incidence declines. 6 
 
Even though GBM rarely spreads distantly, progressive expansion of the tumor within the 
fixed confines of the bony skull results in significant morbidity and mortality.  The survival 
of GBM is extremely poor; 5-year survival rates are consistently under 5%, whether in the 
US,6 the European Union7 or Asia.8 Glioblastoma, therefore, remains a disease with a 
significant unmet medical need. 
6.1.1 Current Therapy of Glioblastoma 
Following the initial diagnosis of GBM, a majority of patients undergo maximal resection, 
followed by RT and adjuvant temozolomide.  This recommendation is based on a 
randomized study comparing surgery, radiation, and temozolomide to surgery and radiation 
alone, where the 3 modality treatment regimen was shown to be statistically significantly 
better than surgery and radiation alone.9  Two-year survival for the 3 modality regimen was 
27.2% versus 10.9% for the 2 modality regimen; and these differences persisted over 5 
years of follow-up (HR = 0.6, p < 0.0001).  No new drugs or therapies have been shown to 
have clinical benefit in the first line treatment of GBM since the publication of these data.  
Bevacizumab (AVASTIN®) is approved for the second-line treatment of GBM.  This 
approval was based on 2 open-label studies conducted in patients with recurrent GBM.  The 
first study was a single-arm study of Bev in 48 patients with recurrent GBM (any 
recurrence).  In this study, the overall response rate (ORR) was 35%, the 6-month PFS was 
29%, and the median OS was 31 weeks.10  The second study randomized patients in first or 
second recurrence to Bev alone (n = 85) or the combination of Bev and irinotecan (n = 82).  
In the monotherapy arm, the ORR was 28%, the 6-month PFS was 43%, and the median 
OS was 37 weeks, consistent with the results of the first study.11  Several other studies 
involving the combination of Bev and other agents have not shown improvements on these 
results; and since the approval of Bev, there have been no other systemic therapies 
approved for the treatment of recurrent GBM. 


 
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6.1.2 Recent Studies in Recurrent Glioblastoma 
Despite continued efforts at discovering novel agents for the treatment of recurrent GBM, 
there is an obvious need for a treatment that can improve on the current treatment methods.  
Several recent studies conducted in patients with recurrent or progressive GBM illustrate 
the difficulty in developing new agents in this condition.  
The PRECISE Study was a global clinical Phase 3 study that randomized 296 patients with 
first recurrence of GBM to cintredekin besudotox (IL13-PE38QQR), administered via 
convection enhanced delivery directly into the brain parenchyma, or carmustine implant 
(GLIADEL WAFER®).  Cintredekin besudotox is a recombinant cytotoxin consisting of 
human interleukin-13 fused to Pseudomonas exotoxin A.  All patients underwent gross 
resection of tumor prior to receiving assigned treatment.  The primary endpoint of the study 
was OS.  After the protocol specified cut-off of 215 events, there was no difference in OS 
between the 2 arms (9.1 months for cintredekin besudotox versus 8.8 months for Gliadel, 
p = 0.48).12  
A second Phase 3 multicenter study compared treatment with enzastaurin, a protein kinase 
Cβ and phosphoinositide 3-kinase (PI3K)/serine-threonine kinase (AKT) inhibitor, to 
treatment with lomustine in patients with recurrent GBM.  The primary endpoint was PFS.  
A total of 266 patients were randomized 2:1 between enzastaurin and lomustine.  An IA for 
futility was performed after 115 patients had progression or had died.  There was no 
difference in PFS between the 2 treatment arms (1.5 months for enzastaurin, 1.6 months for 
lomustine).  There was also no difference in 6-month PFS (11.1% for enzastaurin, 19% for 
lomustine), median OS (6.6 months versus 7.1 months), or ORR (2.9% versus 4.3%).13 
A third Phase 3 multicenter study randomized 325 patients with recurrent GBM (2:2:1) 
manner to treatment with cediranib, a pan-vascular endothelial growth factor receptor 
(VEGFR) tyrosine kinase inhibitor, the combination of cediranib and lomustine and 
lomustine alone.  The primary endpoint of the study was PFS.  There were no differences in 
PFS between treatment with cediranib alone compared to lomustine (92 days for cediranib 
versus 82 days for lomustine, p = 0.90) or with cediranib in combination with lomustine 
compared to lomustine (125 days for the combination versus 82 days for lomustine alone, p 
= 0.16.).  There were also no differences in median OS (8.0 months for cediranib, 9.4 
months for the combination, and 9.8 months for lomustine) or ORR (15.3% for cediranib, 
17.2% for the combination, and 8.9% for lomustine).14  
These 3 contemporary, randomized Phase 3 studies in recurrent GBM clearly illustrate the 
challenge in developing new agents for the treatment of GBM. 


 
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6.1.3 Wilms’ Tumor 1 (WT1) Antigen 
6.1.3.1 Molecular Biology and Role in Oncogenesis 
The WT1 gene encodes a zinc-finger transcription factor that binds to both DNA and 
ribonucleic acid (RNA) and, under circumstances of normal embryogenesis, directs the 
development of several organs and tissues.  The WT1-null condition is lethal to developing 
embryos, in which there is a complete lack of development of the kidneys, the gonads, the 
heart, the spleen, and the adrenal glands.15  In healthy adults, expression of WT1 is limited 
to certain cells of the glomerulus, and reduced expression is associated with 
glomerulopathies.16  Although WT1 was originally thought to function solely as a tumor 
suppressor based on its activity in Wilms’ tumor, expression of WT1 in adult tumors points 
to its possible role as an oncogene.  In this respect, numerous target genes for WT1 have 
been discovered, including genes encoding growth factors and growth factor receptors 
(epidermal growth factor receptor [EGFR], type 1 insulin-like growth factor receptor 
[IGF1R], transforming growth factor beta, platelet-derived growth factor A [PDGF-A]; 
genes involved in wingless-related integration site (Wnt) pathway signaling; genes involved 
in differentiation; and genes involved in apoptosis (Bcl2, c-Myc).11,15  A metaanalysis has 
shown that expression of WT1 by neoplasms negatively impacts OS (metaHR 1.48, 95% 
confidence interval [CI] = 1.11, 1.97) as well as disease free, relapse-free, and PFS (meta 
HR = 2.14, 95% CI = 1.42, 3.21).11,17  Based on data from previous studies using WT1 
vaccines, as well as the immunogenicity, oncogenicity, and specificity of WT1, the 
National Cancer Institute selected WT1 as the highest priority tumor-associated antigen for 
vaccine development.18  
6.1.3.2 WT1 in Glioblastoma 
Approximately 80% of GBMs express WT1 as a tumor-associated antigen19 and WT1 
seems to contribute to the malignant nature of the disease.  When wild-type and WT1 
knockdown U87MG GBM cell lines were injected intracerebrally into new-born mice, all 
control animals were dead by Day 40, whereas all the animals harboring the knockdown 
cells were alive.  In addition, apoptosis related genes, including mitogen-activated protein 
(MAP) kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha 
(PIK3CA), and tumor suppressor protein (p53) were up regulated in the knockdown cells 
compared to the wild-type cells.20  In another set of experiments with GBM, compared to 
wild-type cells, WT1 knockdown cells had differential gene expression, with down 
regulation of several oncogenic genes, and up regulation of genes involved in tumor 
suppression.21  Therefore, WT1 would seem to be a critical oncologic element of GBM. 
6.1.3.3 Vaccine- and Immune-Based Clinical Studies in Recurrent Glioblastoma 
There have been several studies employing various vaccine strategies (peptide, dendritic, 
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progressive GBM.  Several recent studies, however, demonstrate the potential role of 
vaccine therapy in GBM. 
The ReACT study was a randomized, placebo-controlled study of rindopepimut, which 
consists of an EGFRvIII peptide conjugated to keyhole limpet hemocyanin (KLH), in 
combination with Bev versus KLH plus Bev, in patients with recurrent or progressive GBM 
following initial treatment with RT and temozolomide.  Patients treated with rindopepimut 
plus Bev (n = 36) had a 6-month PFS (PFS6, the study’s primary endpoint) of 28%, versus 
16% in the control arm (n = 37, p = 0.0658).  In the rindopepimut arm, 9/30 patients (30%) 
had a radiographic response (CR plus PR) versus 6/34 (18%) of patients in the control arm.  
OS was 11.3 months in the rindopepimut arm versus 9.3 months in the control arm 
(HR = 0.53, p = 0.0137).  Rindopepimut also elicited a brisk immunologic response as 
evidenced by measurement of anti-rindopepimut antibodies.22  
Poliovirus-rhino virus internal ribosome entry site poliovirus open reading frame 
(PVS RIPO) is an engineered recombinant live attenuated oncolytic virus containing the 
oral poliovirus Sabin type 1, where the internal ribosome entry site (IRES) has been 
replaced with the IRES from human rhinovirus type 2.  A Phase 1 study in patients with 
recurrent adult GBM enrolled 24 patients.  The median OS was 12.5 months; the 6-month 
OS was 83%, and the 12-month OS was 56%.  There have also been several long-term 
survivors (in excess of 22 months), and 2 patients have no evidence of disease.  The US 
Food and Drug Administration (FDA) granted PVS-RIPO breakthrough designation for the 
treatment of GBM.23  
A Phase 2 clinical study with a WT1 vaccine was conducted in Japan in 21 patients with 
recurrent GBM (the peptide in this study was different from the peptides contained in DSP-
7888 Dosing Emulsion).  The vaccine was administered i.d., and treatment was well 
tolerated with local erythema as the only vaccine-related AE.  Partial response was 
observed in 2 patients, and stable disease (SD) in 10 patients. The median PFS was 20 
weeks, and the PFS-6 was 33%. Two patients showed initial responses of progressive 
disease (PD); however, tumor stabilization occurred 6 months after the start of treatment in 
the trial, which could be suggestive of pseudo-progression. In addition, a decrease in tumor 
size was observed in one patient in the SD group (although not achieving the partial 
response requirements), which was observed 7 months after the initial WT1 vaccination.24 
Two patients showed complete responses that were indicative of pseudo-progression on 
Days 645 and 505.25 Finally, a second study of a WT1 vaccine was conducted in Japan in 
10 patients with recurrent malignant glioma.  This study employed dendritic cells pre-
incubated with 2 WT1 peptides, which were then injected i.d. in the axillary region along 
with OK-432 (picibanil antitumor agent), a streptococcal adjuvant.  Approximately 
1 to 2 x 107 cells were injected every 2 weeks for 5 to 7 administrations.  The study 
enrolled 10 patients; other than injection site reactions (ISRs), the vaccine was well 
tolerated.  Of the 6 patients with GBM, 2 had prolonged survival times of >46 months and 
>77 months.26,27  


 
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6.1.3.4 Rationale for Use of Modified Radiographic Response Assessment (mRANO) 
GBM often displays high vascularity.28 For this reason, contrast enhancement on imaging 
studies such as CT or MRI can be used to determine radiographic response or progression 
after treatment.  Several sets of radiographic criteria have been developed and used in GBM 
studies to determine tumor response, including the Macdonald criteria29  and the Response 
Assessment in Neuro-Oncology (RANO) criteria.30  RANO criteria were developed to 
correct deficiencies in the Macdonald criteria, including taking into account non-enhancing 
tumor progression and the phenomenon of pseudo-progression.  Pseudo-progression has 
emerged as a particularly important concept in GBM studies wherein an increase in contrast 
enhancement resulting from increased vascular permeability induced by anti-tumor 
treatment may be mistaken for tumor progression. 
The current study will use mRANO to evaluate tumor response.  It is recognized that 
RANO criteria have limitations, including reader discordance in bidimensional tumor 
measurements of contrast-enhancing tumors,31 and in the era of immunotherapy, 
inflammatory changes in the tumor as a result of immune activation may lead to ambiguous 
changes in T2 signal intensity that are difficult to interpret.32  mRANO criteria were 
developed to overcome these limitations.  The mRANO criteria allow for continuation of 
therapy for patients with apparent progression at first imaging or on a subsequent 
radiographic assessment following a period of SD, PR, or CR.  Specifically, the criteria 
allow patients with “preliminary progression” (defined as a ≥ 25% increase in sum of 
products of bidimensional measurements or ≥ 40% volume increase of enhancing lesions) 
to continue on treatment for at least 4 weeks, at which time a scan should be done to 
confirm or refute progression. Because delayed responses to WT1 vaccine therapy have 
been seen (even after apparent initial progression), using a set of radiographic assessment 
criteria such as mRANO will allow for better discrimination of patients with pseudo-
progression from true progression.  
Additionally, this protocol will not mandate discontinuation of treatment even if 
progression is confirmed by mRANO criteria.  Currently, there are no radiological 
assessment criteria that enable a clear differentiation of true progression from 
pseudo-progression.  In studies involving immune activation, pseudo-progression may limit 
greatly the ability to determine treatment benefit (or lack thereof).  Therefore, it is 
important to allow patients to continue on study treatment for as long as possible to 
differentiate pseudo-progression from true progression.  Thus, the current study will allow 
patients to continue receiving study treatment despite confirmed mRANO progression 
provided that the Investigator considers it to be safe, the Investigator determines that there 
is potential benefit, and the patient is willing to continue. 


 
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6.1.4 DSP-7888 Dosing Emulsion 
DSP-7888 is a synthetic peptide that consists of 2 synthetic peptide constructs:  DSP-7888-
K (major histocompatibility complex [MHC] Class I peptide; nelatimotide [INN]) and 
DSP-7888-H (MHC Class II peptide; adegramotide [INN]).  Both constructs are derived 
from the WT1 protein.  Specifically, DSP-7888-K is a conjugate consisting of the 
WT1126-134 peptide sequence and the modified WT1235-243 peptide sequence, whereas DSP-
7888-H corresponds to the WT134-51 sequence.  DSP-7888 Dosing Emulsion is an emulsion 
of these peptides formulated in a water/oil emulsion with DSP-7888-M, a solution that 
contains the well-known adjuvant montanide ISA 51 VG.  The emulsion acts as a depot and 
enhances the immunogenicity of the DSP-7888-K and DSP-7888-H peptides.  DSP-7888 
Dosing Emulsion is applicable for patients who have at least one of 3 HLA types:  HLA-
A*02:01, HLA-A*02:06, and HLA-A*24:02, which covers approximately 56% of the US 
population and 81% of the Japanese population.33  
DSP-7888 Dosing Emulsion is administered i.d. and is presented on the surface of antigen-
presenting cells as an MHC Class I peptide complex that can be recognized by CD8 
positive CTLs.  As a consequence, vaccination with DSP-7888 Dosing Emulsion may 
stimulate the host immune system to induce a CTL response against cancer cells 
overexpressing the WT1 protein, resulting in cell lysis and inhibition of cancer cell 
proliferation.  Addition of the MHC Class II peptide is expected to show efficacy over that 
observed with a treatment regimen of the MHC Class I peptide alone. 
DSP-7888 Dosing Emulsion is under clinical investigation in 3 studies:  A Phase 1 study in 
patients with a variety of advanced malignancies in the US, a Phase 1/2 study in patients 
with myelodysplastic syndrome (MDS) in Japan, and a Phase 1/2 study in children with 
malignant glioma in Japan.  DSP-7888 Dosing Emulsion has elicited delayed-type 
hypersensitivity reactions in patients who were immunized; and in the MDS study, 42% of 
immunized patients have demonstrated WT1 peptide-specific CTLs.26  
DSP-7888 Dosing Emulsion has been well tolerated thus far.  Overall, the most frequently 
observed AE is ISR.  In one case, in a Japanese patient with MDS, this progressed to 
cellulitis and pyoderma gangrenosum.  Of note, in the US Phase 1 study involving doses of 
3.5 mg or 10.5 mg, ISRs have been of Grade 1 or 2 in intensity, easily managed, and 
infrequently reported.  Review of the study patients with malignant glioma, both pediatric 
and adult, does not reveal any safety concerns specific to this population.  These studies are 
ongoing, and additional information regarding DSP-7888 Dosing Emulsion can be found in 
the current Investigator’s Brochure. 
6.2 
Rationale 
Glioblastoma, with its exceedingly poor prognosis, remains a disease with a significant 
unmet medical need; and there remains an ongoing need for new therapies in this disease.  


 
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A high percentage of GBM tumors express WT1, and WT1 may be critical to the 
maintenance of the oncologic state in GBM; therefore, it is a potentially important target 
for the development of anti-GBM therapies.  WT1 vaccines have demonstrated preliminary 
evidence of activity in patients with GBM, and DSP-7888 Dosing Emulsion has 
demonstrated safety in the doses proposed for this study.  The addition of Bev may further 
enhance the activity of a tumor vaccine.  VEGFA inhibits maturation of dendritic cells into 
functional cells and may also reduce the cytotoxic activity of T cells, so that inhibition by 
of VEGF-A may enhance these activities.  In addition, Bev can decrease the levels of 
myeloid derived suppressor cells.34  Therefore, Bev may create a more fertile 
immunological field for the activity of DSP7888 Dosing Emulsion. 
DSP-7888 Dosing Emulsion given i.d. in a dose of 10.5 mg has been shown to be safe and 
to induce immunological responses in patients tested with this dose thus far.  This dose and 
route of administration will therefore be employed in this study.  Bev is the standard of care 
for patients with recurrent or progressive GBM and, therefore, represents the appropriate 
comparator arm. 
A Phase 3 study assessed Bev plus radiotherapy or placebo in patients with glioblastoma; 
disease progression, OS, and quality of life were measured throughout the study.  For the 
combination of bevacizumab with standard radiotherapy, the study did not show improved 
OS; however, the study results showed a trend of improved PFS. Based on the above, the 
approved use of Bev as a single agent in recurrent GBM, and the unmet medical need in 
GBM, there is an appropriate medical and scientific rationale for the combination of DSP-
7888 Dosing Emulsion plus Bev in the treatment of recurrent or progressive GBM. 


 
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7 
STUDY OBJECTIVES 
7.1 
Primary Objective 
The primary objective is to compare the OS between treatment with DSP-7888 Dosing 
Emulsion plus Bev versus Bev alone in patients with recurrent or progressive GBM 
following initial therapy. 
7.2 
Key Secondary Objective 
To compare the 12-month survival rate between treatment with DSP-7888 Dosing 
Emulsion plus Bev versus Bev alone. 
 
7.3 
Other Secondary Objectives 
The other secondary objectives of the study are: 
• To compare the PFS of DSP-7888 Dosing Emulsion plus Bev to Bev alone 
• To compare the 6-month PFS rate of DSP-7888 Dosing Emulsion plus Bev to Bev 
alone  
• To compare the response rate of DSP-7888 Dosing Emulsion plus Bev to Bev alone  
• To compare the duration of response of DSP-7888 Dosing Emulsion plus Bev to 
Bev alone  
• To describe the AE profile of DSP-7888 Dosing Emulsion plus Bev 
7.4 
Exploratory Objectives 
The exploratory objectives of the study are: 
• To describe the relationship between pharmacodynamic parameters such as WT1 
peptide-specific CTL activity and certain clinical findings (eg, OS, response) in 
patients receiving DSP-7888 Dosing Emulsion plus Bev 
• To describe the relationship between expression of WT1 by IHC and CISH in tumor 
tissue and certain clinical findings (eg, OS, response) in patients receiving DSP-
7888 Dosing Emulsion plus Bev 
• To collect DWI for future analysis of imaging findings and correlation with disease 
progression  


 
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• To characterize the NANO scale score profile post DSP-7888 Dosing Emulsion plus 
Bev or Bev alone 
7.5 
Endpoints 
7.5.1 Primary Endpoint 
The primary endpoint is OS and is defined as the interval between randomization and death 
from any cause.  Patients who are lost to follow-up will be censored on the last day they 
were known to be alive. 
7.5.2 Key Secondary Endpoint 
The key secondary endpoint is the 12-month survival rate defined as the proportion of 
patients alive 12 months after randomization. 
 
7.5.3 Other Secondary Endpoints 
• PFS is defined as the interval between randomization and progression, determined 
by central radiology review, or death from any cause. 
• 6-month PFS rate is defined as the proportion of patients alive at 6 months after 
randomization and without progressive neoplastic disease.  
• The response rate is defined as the proportion of patients exhibiting a response (CR 
plus PR) based on the mRANO criteria as determined by the central radiology 
review. 
• The duration of response is defined as the interval between first documented 
oncological response and progression of disease or death from any cause, with 
response based on the mRANO criteria as determined by the central radiology 
review. 
 
8 
INVESTIGATIONAL PLAN 
 
8.1 
Overall Study Design and Plan:  Description 
This study is divided into 2 parts. Part 1 is a safety lead-in phase. Part 2 is a randomized, 
active-controlled, multicenter, open-label, parallel-group, adaptive Phase 3 study of DSP-
7888 Dosing Emulsion plus Bev versus Bev alone in patients with recurrent or progressive 
GBM following treatment with first line therapy consisting of surgery and radiation with or 


 
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without chemotherapy.  An adaptive Phase 3 design with 2 IAs and 1 FA is employed in 
Part 2 of this study (Section 11.6).   
Patients may have undergone a second surgery at the time of recurrence or progression but 
may not have received any other anti-neoplastic therapy.  Patients are randomized 1:1 to 
treatment with DSP-7888 Dosing Emulsion plus Bev or Bev alone. 
Potential study subjects first undergo pre-screening to determine appropriate HLA type due 
to the nature of the vaccine DSP-7888.  DSP-7888 Dosing Emulsion is active in subjects 
with HLA-A*02:01, HLA-A*02:06, or HLA-A*24:02. 
Following HLA determination, a screening phase of up to 28 days determines eligibility.  
Following verification of eligibility and enrollment, DSP-7888 Dosing Emulsion is 
administered i.d. every 7 days (± 1 day) for 5 doses (the Induction Phase); then every 14 
days (± 3 days) for Doses 6 to 15 (the Consolidation Phase), and then every 28 days 
(± 7 days) for Doses 16 and above (the Maintenance Phase).  Bev will be administered 
every 14 ± 3 days in the labeled dose of 10 mg/kg intravenously (i.v.). 
Part 1: 
In Part 1, 3 patients will be treated with the combination of DSP-7888 Dosing Emulsion 
plus Bev in a single-arm manner.  DSP7888 Dosing Emulsion will be administered at a 
dose of 10.5 mg i.d. in the schedule described above and Bev will be administered at the 
dose and schedule described above.  If 0 of these first 3 patients experiences a DLT, then 
the study will proceed to Part 2, which will randomize patients to the combination of DSP-
7888 Dosing Emulsion plus Bev or to Bev alone. 
If 1 of the first 3 patients experiences a DLT, then 3 more patients will be enrolled at the 
same treatment regimen.  If no additional DLTs are observed at the same dose (with 1/6 
DLTs), then the study will proceed to Part 2.  However, if 2 or more of the first 6 patients 
experience a DLT, then the dose of DSP-7888 Dosing Emulsion will be decreased to 
3.5 mg i.d., and an additional 3 patients will be treated with the combination of DSP-7888 
Dosing Emulsion plus Bev. 
If 0 of these 3 patients experiences a DLT at this reduced dose of DSP-7888 Dosing 
Emulsion, then the study will proceed to Part 2.  If 1 of the 3 patients experiences a DLT at 
the reduced dose of DSP-7888 Dosing Emulsion, then 3 more patients will be enrolled at 
the same treatment regimen.  If no additional DLTs are observed at the same dose (with 1/6 
DLTs), then the study will proceed to Part 2.  However, if 2 patients or more experience a 
DLT at this reduced dose of DSP-7888 Dosing Emulsion plus Bev, then enrollment will be 
placed on hold until the Sponsor decides how best to proceed. 
In summary, if 0 of the first 3 patients or 1 of the first 6 patients experiences a DLT, then 
the study will proceed to Part 2. The MTD is decided only when 6 patients are treated at a 


 
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dose level with ≤ 1/6 DLTs.  If at least 2/3 or 2/6 DLTs are observed, then the MTD has 
been exceeded.  Dosing should stop, and the dose should be de-escalated to DSP-7888 
Dosing Emulsion 3.5 mg.  Then the process should be repeated at the reduced dose level of 
DSP-7888 Dosing Emulsion 3.5 mg. 
The patients who complete Part 1 of the study will not be randomized into Part 2.  Instead, 
they will continue to receive DSP-7888 Dosing Emulsion plus Bev and undergo the same 
assessments that are listed in Section 8.1.3. 
Dose-limiting toxicity will be evaluated and applied during the Induction Phase of Part 1 
(Day 1 through Day 29) and defined as the following AEs that are at least possibly related 
to the investigational agents per the Investigator and institutional guidelines: 
• The occurrence of any Grade 3 or higher hematologic AE lasting more than 7 days;  
• Any Grade 3 or higher non hematological AE that persists for more than 72 hours 
with the exceptions of transient nausea, vomiting, and diarrhea that are responding 
to supportive care; 
• Any Grade 3 or higher allergic and/or hypersensitivity reactions; and, 
• Any Grade 2 or higher autoimmune disease. 
Patients who discontinue Part 1 of the study for reasons other than DLT during the 
Induction Phase will be replaced. 
Part 2: 
Based on the results of the DLT evaluation in Part 1, a 10.5 mg dose of DSP-7888 Dosing 
Emulsion was determined as the dose for Part 2.  In Part 2, patients are stratified prior to 
randomization based on the extent of surgical resection in primary therapy (GTR versus not 
GTR) and KPS (Appendix 16.1) scores (60 through 70 versus 80 through 100). 
Rescreening for patients in Part 2 is permitted for patients with laboratory values (AST, 
ALT, bilirubin, creatinine) that are out of range to meet eligibility and for patients requiring 
dexamethasone doses in excess of 4 mg/day (or equivalent) once the dose can be tapered to 
4 mg/day (or equivalent) or less with stability in the judgement of the investigator. 
Patients will continue to receive DSP-7888 Dosing Emulsion plus Bev or Bev alone 
independent of radiological assessment / progression:  
1. Provided that the Investigator considers it to be safe for the patient 
2. Provided that the Investigator determines that there is potential benefit for the patient 


 
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3. When the patient is willing to continue 
Safety is assessed by the recording of AEs at each contact with the patient, by findings of 
physical and neurological examinations, and by the results of laboratory determinations; the 
severity of AEs or abnormal laboratory results is based on the CTCAE V4.03. 
The criteria for response and progression is based on the mRANO criteria 
(Appendix 16.2),35 and patients also undergo neurological assessments based on the NANO 
criteria (Appendix 16.3).36  
Patients randomized to the Bev arm of the study undergo evaluations on a similar schedule 
as patients randomized to treatment with the combination of DSP-7888 Dosing Emulsion 
plus Bev. 
Patients will undergo MRI and DWI at Screening; after 8, 16, and 24 weeks on study; then 
every 12 weeks thereafter; and at the End of Treatment (EOT) visit to assess their disease 
progression.  Patients who are, in the opinion of the Investigator, clinically stable and in 
whom pseudo-progression is suspected will continue to be treated per protocol according to 
the treatment arm assigned and will have a second (confirmatory) scan performed 4-8 
weeks later.  Progressive disease may additionally be confirmed locally when available at 
the site by performing one of the following: single-photon emission computed tomography, 
perfusion MRI, MRI spectroscopy, 11C methionine positron-emission tomography, or 
pathology from available surgical/biopsy specimens to differentiate from pseudo-
progression. DWI-MRI assessment that is being provided from a central radiological 
review at the investigator’s request will be available to help differentiate progression from 
pseudo-progression.   
Patients who discontinue study treatment for any reason will continue to be followed up for 
efficacy (mRANO, NANO, KPS, etc.) until new treatment is commenced.  
All patients will be followed up for OS, regardless of potential subsequent therapy.  
Patients’ immunological responses to DSP-7888 Dosing Emulsion will be measured by a 
variety of assays including: 
• Measurement of WT1 peptide-specific CTL induction activity at various times 
using peripheral blood mononuclear cells of patients 
• Retrospective analysis of additional biomarkers from peripheral blood and archival 
tumor samples 
Formalin-fixed, paraffin-embedded archival tumor samples will be tested for expression of 
WT1 by IHC and CISH and compared to a variety of clinical outcomes in exploratory 
analyses.  Additional exploratory analyses will evaluate the role of DWI (conducted by 


 
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central radiology review) in predicting and diagnosing true progression of neoplastic 
disease in patients with GBM. Exploratory analyses will be performed to investigate the 
relationship between the activity of DSP-7888 Dosing Emulsion and other HLA Class 1 
haplotypes (A and B locus) as well as HLA Class 2. 
Companion diagnostics of HLA typing will be developed as part of this study.  
The study duration for individual patients commences at date of pre-screening consent and 
completes at the date of End of Study visit. The study may be terminated early for either 
efficacy or futility at IA1 and for efficacy only at IA2.  The study will continue until the target 
number of events is observed.   
A flow chart of Part 1 of the study is presented in Figure 1 (Section 8.1.1); a schema of the 
study is presented in Figure 2 (Section 8.1.2.); and a schedule of assessments is presented 
in Section 8.1.3. 


 
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8.1.1 Flow Chart for Part 1 of the Study 
Figure 1: 
Part 1 Flow Chart 
 
 
 
PART 1 OF THE STUDY – OPEN LABEL, SINGLE ARM 
 
 
 
 
 
 
 
 
 
 
3 Patients Dosed with DSP-7888 
Dosing Emulsion 10.5 mg i.d. plus 
Bevacizumab 10 mg/kg IV 
0 Patients 
Experience 
DLT 
1 Patient 
Experiences DLT 
3 Patients Dosed with DSP-7888 
Dosing Emulsion 3.5 mg i.d. plus 
Bevacizumab 10 mg/kg IV 
Study Placed 
on Hold 
Continue DSP-7888 Dosing Emulsion plus Bev; 
Undergo Same Procedures as in Part 2 Schedule of Assessments 
Initiate Part 2 of the Study (Randomized, 2 Arms) 
3 New Patients Dosed with DSP-7888 
Dosing Emulsion 10.5 mg i.d. plus 
Bevacizumab 10 mg/kg IV 
0 Patients 
Experience DLT 
1 Patient 
Experiences DLT 
0 Patients 
Experience DLT 
1 Patient 
Experiences DLT 
3 New Patients Dosed with DSP-7888 
Dosing Emulsion 3.5 mg i.d. plus 
Bevacizumab 10 mg/kg IV 
0 Patients 
Experience DLT 
1 Patient 
Experiences DLT 


 
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8.1.2 Study Design for Part 2 of the Study 
Figure 2: 
Part 2 Study Design 
 
 
 
PART 2 OF THE STUDY – RANDOMIZED, TWO ARMS 
     Arm 1:  DSP-7888 Dosing Emulsion plus Bevacizumab 
Arm 2:  Bevacizumab Alone 
DSP-7888 Dosing Emulsion Dose Day 
 
1 
8 
15 
22 
29 
43 
57 
71 
85 
99 
113 
127 
141 
155 
169 
183 
197 
211 
225 
239 
253 
267 
281+ 
 
 
 
 
 
 
 
1 
8 
15 
22 
29 
43 
57 
71 
85 
99 
113 
127 
141 
155 
169 
183 
197 
211 
225 
239 
253 
267 
281+ 
Bevacizumab Dose Day (All Patients) 
 
Induction 
Phase 
Consolidation Phase 
Maintenance Phase 


 
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8.1.3 Schedule of Assessments 
Procedures and 
Assessments 
Pre-
Screening Screening Induction Phase 
Consolidation Phase 
Maintenance Phase 
EOTv  
EOT 
F/Uw,x 
Day 
 
-28 to -1 
1 8 15 22 29 43 57 71 85 99 113 127 141 155 169 183 197 211 225 239 253 267 >281 
 
 
DSP-7888 Dosing Emulsiona 
 
 
X X X X X X X X X X X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Dose # 
 
 
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 
 
16 
 
17 
 
18 
 
19 
 
 
Bevb 
 
 
X 
 
X 
 
X X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Informed Consentc 
Xm 
Xn,s 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic Information 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical Historyd 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signse 
 
X 
X X X X X X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical Examination 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Neurological Examinationf 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X x 
Karnofsky Performance Status 
Score 
 
X 
X X X X X X X X X X X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X x 
ECG 
 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
X 
 
CBCg 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Coagulation Parametersh 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Chemistry Testsi 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Urinalysisj 
 
X 
X 
 
X 
 
X X X X X X X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Pregnancy Testk 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Serology for HIV, Hep B, Hep 
Cl 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HLA Typingm 
Xm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fresh/Archival Tumor Samplen 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Companion Diagnostics 
Sampleo 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Procedures and 
Assessments 
Pre-
Screening Screening Induction Phase 
Consolidation Phase 
Maintenance Phase 
EOTv  
EOT 
F/Uw,x 
Day 
 
-28 to -1 
1 8 15 22 29 43 57 71 85 99 113 127 141 155 169 183 197 211 225 239 253 267 >281 
 
 
DWI, Conventional MRI, and 
mRANOp 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
X x 
IDH 1/2 mutation and MGMT 
Promotor Methylation Statusq 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Event and Serious 
Adverse Event Reporting 
 
X 
X X X X X X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant Medications 
 
X 
X X X X X X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood Samples for CTL 
Inductionr,s 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
 
Blood Samples for 
Retrospective Biomarker 
Analysesr,t 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
 
Blood Samples for Additional 
HLA Haplotypes 
 
 
 
Xu  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Echocardiogram or MUGA 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulse Oximetry 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; Bev = bevacizumab; CBC = complete blood count; CTL = cytotoxic 
T lymphocyte; DWI = diffusion-weighted imaging; ECG = electrocardiogram; EOT = End of Treatment; F/U = follow up; Hep = hepatitis; HIV = human 
immunodeficiency virus; HLA = human leukocyte antigen; IDH = isocitrate dehydrogenase; IHC = immunohistochemistry; INR = partial thromboplastin 
time; MGMT = O6-methyl-guanyl-methyl-transferase; MRI = magnetic resonance imaging; MUGA = multigated acquisition scan; NANO = 
Neurological Assessment in Neuro-Oncology; PTT = partial thromboplastin time; mRANO = Modified Response Assessment in Neuro-Oncology; WBC 
= white blood cell. 
Note 1:  The windows for assessments are every 7 ± 1 day for Doses 1 to 5, every 14 ± 3 days for Doses 6 to 15, and every 28 ± 7 days for Doses 16 and 
above except for MRI procedures, which have an assessment window of ± 7 days around the scheduled visit day. 
a  DSP-7888 Dosing Emulsion will be administered i.d. every 7 ± 1 day for Doses 1 to 5, every 14 ± 3 days for Doses 6 to 15, and every 28 ± 7 days for 
Doses 16 and above. 
b  Bev will be administered intravenously every 14 ± 3 days at the labeled dose of 10 mg/kg. 
c  Informed consent must be obtained before performing any study-related procedures. 
d  Pertinent medical history will be taken during the screening phase. Prior cancer therapy data will be collected during the pre-screening phase. 
e  Vital signs will include systolic and diastolic blood pressures, pulse, respiratory rate, temperature, and weight. 


 
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f  Neurological examination will be based on NANO criteria. 
g  CBC will include determinations of hemoglobin, hematocrit, red blood cell, WBC, WBC differential, and platelet count.* 
h  Coagulation parameters will include INR and PTT.* 
i  Chemistry tests will include determinations of sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, glucose, AST, ALT, alkaline 
phosphatase, total bilirubin, uric acid, total protein, albumin, calcium, magnesium, and phosphorous.* 
j  Urinalysis includes pH; specific gravity; dipstick determinations of glucose, ketones, protein, blood or hemoglobin, and total bilirubin.  Microscopic 
examination must be performed for dipstick determinations of 2+ or greater.  A 24-hour urine for total protein must be collected and performed for a 
protein dipstick result of 2+ or greater.* 
k  Pregnancy may be determined via serum or urine test.* 
l  Serology will include HIV antibody, hepatitis B surface antigen, hepatitis B core antibody, and hepatitis C virus antibody tests.* 
* Although local laboratory results are permitted for treatment-related decisions, baseline eligibility will be based on the central laboratory results. 
m  HLA serotyping may be performed prior to Screening after obtaining pre-screening informed consent for HLA typing.  All HLA typing is to be 
performed in a central laboratory. 
n Tumor tissue will be collected (1) for WT1 by IHC and CISH,  and (2) for retrospective analysis of biomarkers. (1) For WT1 by IHC and CISH: Tumor 
tissue samples must be collected at Screening when available. Provision of tumor tissue is preferred but not mandatory to be eligible for the study.  
   (2) For Retrospective Biomarker analysis:  Additional informed consent will be needed from the patients prior to collection of samples, that they 
consent to some of their tumor tissue and additional blood samples will be used to test for as yet unspecified biomarkers  (this is an optional part of the 
study).  As these biomarkers are currently not determined, long-term storage of these samples will be required.  Patients should also give additional 
consent to this long-term storage.   
   WT1 by IHC and CISH will be performed even if the WT1 expression data are available from medical records.  
   After the last dose of study medication, if the patient is undergoing required medical procedures that would permit retrieval of tumor tissue, a sample of 
this tissue is requested (but not mandatory).  Additional informed consent is needed prior to collection of tumor tissue samples after the last dose of 
study medication at Screening. 
o  Blood samples will be collected at the same time as those for HLA typing from all the patients who undergo Pre-Screening. 
p  DWI-MRI, conventional MRI, and mRANO tumor assessments will be performed at Screening; after 8, 16, and 24 weeks on study; and then every 12 
weeks thereafter. Conventional MRI should be used for mRANO assessments at the clinical sites. DWI-MRI as well as conventional MRI should be 
provided to the central radiology review. 
q The analysis will be conducted only when the information is not available at enrollment.  
r  If blood is not collected at Screening, it may be obtained on Day 1 PRIOR to administration of protocol therapy.  In the Maintenance Phase, blood 
samples should be obtained at Day 253 and then every 12 weeks thereafter. 
s  Some aliquots of the CTL blood samples may be used to investigate other HLA Class 1 haplotypes in relation to DSP-7888 activities rather than 
separate samples being taken from the patient. 
t  Additional informed consent is needed prior to the collection of blood samples for retrospective biomarker analyses. 
u Blood will be collected from the DSP-7888 Dosing Emulsion plus Bev arm on C1D8. If this sample is not collected on this cycle day, then it should be 
collected at the next cycle visit. 
v  The EOT visit should occur within 28 days of the end of treatment, and prior to the initiation of any new post-study treatment. 


 
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w  Patients who discontinue treatment for PD and are treated with an alternative therapy should be followed up for survival (using direct methods [ie, 
telephone call or email to patient/patients’ relatives] or indirect methods [ie, medical record review or obituary listing review]) and post-treatment and 
anti-tumoral therapy every 3 months and/or on an ad hoc basis for safety or regulatory purposes, or a prespecified analysis; females of childbearing 
potential and female partners of male patients should be followed up for up to 90 days to ensure no pregnancy occurs.  
x  All other patients who discontinue treatment (including patients who discontinue treatment for PD and who will not receive further treatment, or where 
the Investigator believes it in the patient’s best interest to discontinue treatment), should be followed up for survival (using direct or indirect methods) 
and post-treatment and anti-tumoral therapy every 3 months and/or on an ad hoc basis for safety or regulatory purposes, or a prespecified analysis. In 
addition: KPS, NANO criteria assessment,  DWI-MRI, conventional MRI, mRANO assessment of response, and documentation of corticosteroid usage 
for mRANO assessment, should be performed on Day 57 ± 14 days, Day 113 ± 14 days and Day 169 ± 14 days, if withdrawal of study treatment occurs 
prior to these timepoints and until the patient receives further treatment for GBM; and, females of childbearing potential and female partners of male 
patients, should be followed up for up to 90 days to ensure no pregnancy occurs. 
 
 


 
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8.2 
Selection of Study Population 
8.2.1 Number of Planned Patients  
Between 3 and 12 patients were to be enrolled in Part 1 of the study (Section 8.1.1). As 
of Protocol Amendment 7, 4 patients had been enrolled into Part 1 of the study.  
Part 2 is an adaptive Phase 3 study in which approximately 215 to 480 patients with GBM 
will be enrolled from approximately 70 investigational sites in the US, Canada, Japan, 
Taiwan, and South Korea. 
Note that Part 2 of the study is an event-driven adaptive trial and statistical power of 
Part 2 of the study is determined by the target number of death events instead of the 
number of patients.  The actual number of randomized patients in Part 2 may vary to 
observe the targeted  number of OS events, depending on the outcome of the IAs, the 
duration of the study and operational feasibility of the trial. Details of statistical power, 
event number and sample size are provided in Section 11.2.1. 
8.2.2 Inclusion Criteria 
The study will enroll patients with GBM whose tumors have recurred or progressed 
following initial treatment with surgery, radiation, and chemotherapy.  To be eligible for 
study entry, patients must satisfy all of the following criteria: 
Note: The latest laboratory value should be used to determine eligibility if the 
laboratory tests are performed more than once during the Screening phase. Eligibility 
will always be determined by the results from the central laboratory. 
1. Patients or their legal representatives must be able to provide written informed 
consent. 
2. Histologically confirmed diagnosis of supratentorial GBM (Grade 4 
astrocytoma). 
3. Radiographic evidence of first recurrence or progression of GBM following 
primary therapy consisting of surgery (biopsy or resection) and radiation with or 
without chemotherapy; patients may have undergone a second debulking surgery 
following initial recurrence or progression.  Patients whose tumors are O6-
methyl-guanyl-methyl-transferase (MGMT) methylated-promoter negative need 
not have received chemotherapy in the past to be eligible. 
4. Human leukocyte antigen (HLA) type HLA-A*02:01, HLA-A*02:06, or 
HLA-A*24:02. 
5. Age ≥ 18. 
6. Karnofsky Performance Status (KPS) score of ≥ 60. 


 
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7. Serum creatinine value < 2X the upper limit of normal (ULN) for the reference 
laboratory. 
8. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3X the 
ULN and total bilirubin < 2X the ULN for the reference laboratory. 
9. Men and women of childbearing potential must agree to use a reliable method of 
contraception (oral contraceptives, implantable hormonal contraceptives, or 
double barrier method) or agree to completely refrain from heterosexual 
intercourse for the duration of the study and for 180 days following the last dose 
of DSP-7888 Dosing Emulsion. 
10. Patients must have recovered from the effect of all prior therapy to Grade 2 or 
less. 
11. Patients must be at least 28 days from any major surgery, and any surgery 
incisions or wounds must be completely healed. 
12. Patients must be at least 12 weeks from the completion of prior RT in order to 
discriminate pseudo-progression of disease from progression. 
13. Patients must be at least 4 weeks from the completion of prior systemic or 
intracranial chemotherapy. 
14. Patients must stop Novo-TTF treatment one day prior to study therapy (no 
washout period is needed).  However, any wounds from TTF must be adequately 
healed per Inclusion Criterion #11. 
15. For patients who are not receiving therapeutic anticoagulation treatment, an 
international normalized ratio (INR) and a partial thromboplastin time (PTT) 
≤ 1.5 × the ULN; patients who are receiving anticoagulation treatment should be 
on a stable dose. 
16. Patient’s left ventricular ejection fraction (LVEF) > 40%. 
17. Patient has a resting pulse oximetry of 90% or higher. 
8.2.3 Exclusion Criteria 
Patients will be excluded from the study if one or more of the following criteria are 
applicable: 
1. Prior therapy with Bev. 
2. Patients with secondary GBM. 


 
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3. Any anti-neoplastic therapy, including RT or laser interstitial thermal therapy, 
for first relapse or recurrence. 
4. Evidence of leptomeningeal spread (gliomatous meningitis) of tumor or any 
history, presence, or suspicion of metastatic disease extracranially. 
5. Evidence of impending herniation on imaging. 
6. Has known multifocal disease.  Multifocal disease is defined as discrete sites of 
disease without contiguous T2/FLAIR abnormality that require distinct 
radiotherapy ports. Satellite lesions that are associated with a contiguous area of 
T2/FLAIR abnormality as the main lesion(s) and that are encompassed within 
the same radiotherapy port as the main lesion(s) are permitted. 
7. Patients with infections that have required treatment with systemic antibiotics 
within 7 days prior to the first dose of protocol therapy. 
8. The need for systemic glucocorticoids in doses in excess of 4 mg/day of 
dexamethasone or in comparable doses with other glucocorticoids. 
9. Treatment with any investigational agents within 5 half-lives of the agent in 
question or, if the half-life is unknown, within 28 days of enrollment. 
10. Pregnant or lactating females. 
11. Prior history of malignancy within 3 years of enrollment other than basal or 
squamous cell carcinoma of the skin, cervical intra-epithelial neoplasia, in situ 
carcinoma of the breast, or localized prostate cancer treated with surgery or RT 
with a prostate specific antigen of <0.01 ng/mL. 
12. Patients with active autoimmune diseases within 2 years of enrollment into the 
study including, but not limited to, rheumatoid arthritis, systemic lupus 
erythematosus, systemic sclerosis, Sjogren’s syndrome, Wegener’s 
granulomatosis, ulcerative colitis, Crohn’s disease, myasthenia gravis, Graves’ 
disease, or uveitis except for psoriasis not requiring systemic therapy, vitiligo or 
alopecia areata, or hypothyroidism; if an autoimmune condition has been 
clinically silent for 12 months or greater, the patient may be eligible for 
enrollment. 
13. Patients on immunosuppressive therapies; the use of topical, inhalational, 
ophthalmologic, or intra-articular glucocorticoids or the use of physiologic 
replacement doses of glucocorticoids is permitted. 
14. Patients with primary immunodeficiency diseases. 


 
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15. Patients with significant bleeding in the preceding 6 months prior to study 
enrollment or with known coagulopathies. 
16. History of abdominal fistula, intestinal perforation, or intra-abdominal abscess in 
the preceding 12 months prior to study enrollment. 
17. Positive serology for human immunodeficiency virus (HIV) infection, active 
hepatitis B*, or untreated hepatitis C; patients who have completed a course of 
anti-viral treatment for hepatitis C are eligible. 
*In cases of negative results for HepB surface antigen with positive HepB core 
antibody, HBV DNA testing is required. 
18. Patient has a medical history of frequent ventricular ectopy, e.g., non-sustained 
ventricular tachycardia (VT). 
19. Significant cardiovascular disease, including New York Hospital Association 
Class III or IV congestive heart failure, myocardial infarction within 6 months of 
study enrollment, unstable angina, poorly controlled cardiac arrhythmias, or 
stroke in the preceding 6 months prior to study enrollment. 
20. Any other uncontrolled inter-current medical condition, including systemic 
fungal, bacterial, or viral infection; uncontrolled hypertension; diabetes mellitus; 
or chronic obstructive pulmonary disease requiring 2 or more hospitalizations in 
the preceding 12 months prior to study enrollment. 
21. Any psychiatric condition, substance abuse disorder, or social situation that 
would interfere with a patient’s cooperation with the requirements of the study. 
22. Known sensitivity to Bev or any of the components of DSP-7888 Dosing 
Emulsion. 
23. Patient has a QTcF (QT corrected based on Fridericia’s equation) interval 
> 480 msec (CTCAE = Grade 2) or other factors that increase the risk of QT 
prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family 
history of long QT interval syndrome) at screening.  (Patients with bundle 
branch block and a prolonged QTc interval should be reviewed by the Medical 
Monitor for potential inclusion.) 
24. Patient has dyspnea at rest (CTCAE ≥ Grade 3) or has required supplemental 
oxygen within 2 weeks of study enrollment. 
8.2.4 Reasons for Discontinuation of Protocol Therapy 
Patients have the right to withdraw fully or partially from the study at any time and for 
any reason without prejudice to his or her future medical care by the physician or at the 
institution. 


 
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Withdrawal of partial consent means that the patient does not wish to take 
investigational product any longer but is still willing to collaborate in providing further 
data by continuing on study (eg, participate in all subsequent study visits or procedures). 
Patients may decline to continue receiving investigational product at any time during the 
study.  These patients, as well as those who have stopped receiving investigational 
product for other reasons (eg, Investigator or Sponsor concern) should continue the 
schedule of study observations. 
Rescreening for patients in Part 2 will be permitted for patients with laboratory values 
(AST, ALT, bilirubin, creatinine) that were out of range to meet eligibility and for 
patients requiring dexamethasone doses in excess of 4 mg/day (or equivalent) once the 
dose can be tapered to 4 mg/day (or equivalent) or less with stability in the judgement of 
the investigator. 
Patients will continue to receive DSP-7888 Dosing Emulsion plus Bev or Bev alone 
independent of radiological assessment / progression:  
1. Provided that the Investigator considers it to be safe for the patient 
2. Provided that the Investigator determines that there is potential benefit for the 
patient 
3. When the patient is willing to continue 
Patients will be discontinued from protocol therapy for any of the following reasons: 
• The need for a prohibited treatment for a concomitant illness or AE 
• An AE that precludes further administration of DSP-7888 Dosing Emulsion or 
Bev (see Section 8.3.2.1) 
• Patient withdraws consent for continued administration of DSP-7888 Dosing 
Emulsion or Bev 
• The Investigator believes it is in the patient’s best interest to discontinue 
protocol therapy or to initiate alternative treatment for GBM  
• Pregnancy 
• Lost to follow-up (3 attempts to contact the patient must be made by the 
investigative site by phone or email before a patient is considered lost to 
follow-up) 
• Patient moves out of the Investigator’s catchment area or is unable to continue to 
come to the investigational site 


 
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8.2.5 Reasons for Discontinuation from the Clinical Study 
Reasons for discontinuation from the study include: 
• Patient withdraws consent for continued participation 
• Lost to follow-up 
• Death of the patient 
• The Sponsor deems it necessary to discontinue the study 
Withdrawal of full consent for a study means that the patient does not wish to receive 
further investigational treatment and does not wish to or is unable to continue further 
study participation.  Any patient may withdraw full consent to participate in the study at 
any time during the study.  The Investigator will discuss with the patient the most 
appropriate way to withdraw to ensure the patient’s health. 
Patients who do not comply with the protocol or who withdraw consent during the 
Induction Phase in Part 1 of the study will be replaced.  Patients who stop study drug for 
any other reason during Part 1 will not be replaced.  No patients will be replaced during 
Part 2 of the clinical study.  Patients are free to withdraw from the study at any time 
without providing reason(s) for withdrawal and without prejudice to further treatment.  
The reason(s) for withdrawal will be documented in the patient’s chart and in the 
electronic case report form (eCRF). 
Patients withdrawing from the study will be encouraged to complete the same final 
evaluations as patients completing the study according to this protocol, particularly 
safety evaluations.  The aim is to record data in the same way as for patients who 
complete the study. 
Reasonable efforts will be made to contact patients who are lost to follow-up.  These 
efforts must be documented in the patient’s file.  
The Sponsor has the right to terminate the study at any time in the case of serious 
adverse events (SAEs) or if special circumstances concerning the investigational 
product or the company itself occurs, making further treatment of patients impossible.  
In this event, the Investigator(s) will be informed of the reason for study termination. 
Full details will be recorded on the withdrawal page of the eCRF. 


 
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8.3 
Investigational Products 
8.3.1 Identity of Investigational Products 
8.3.1.1 DSP-7888 Dosing Emulsion 
DSP-7888 Dosing Emulsion will be administered at the study site by staff trained in the 
administration of intradermal drugs.  Patients will be treated with a dose of 10.5 mg 
(6.0 mg DSP-7888-K plus 4.5 mg DSP-7888-H) administered in 6 x 100 µL intradermal 
injections (Table 1) in the following schedule: 
• Induction Phase:  once every 7 ± 1 days (Doses 1 through 5)  
• Consolidation Phase:  once every 14 ± 3 days (Doses 6 through 15) 
• Maintenance Phase:  once every 28 ± 7 days until discontinuation (Dose 16 and 
thereafter) 
Table 1 
DSP-7888 Dosing Administration 
Administration 
Route 
Dose Level 
Number 
of 
Injection 
Sites 
Amount per 
Injection   
SITE (mL) 
Total Amount to 
Administer per 
Dosing DAY (mL) 
Intradermal 
10.5 mg 
6 
0.1 
0.6 
 
In the event of a DLT occurring during Part 1 of the study, the patient should be 
permanently removed from study treatment and should not be replaced.  In the event of 
a study drug-related AE occurring in Part 2 of the study, the dose modification criteria 
should be applied by the Investigator. 
Wherever possible, the posterior neck and posterior shoulder regions should be used 
primarily as injection sites with other areas surrounding regional lymph nodes in the 
upper arm, the lower abdomen, or the femoral area used if additional dosing sites are 
required.  To the extent possible, injections of study drug should be administered to 
separate parts of the body and separated from one another.  Rotation of injection sites is 
permitted.  Injection sites should not be chosen in the areas of any ongoing skin 
condition (eg, an area of psoriasis).   
A full description of DSP-7888 Dosing Emulsion preparation can be found in the Study 
Pharmacy Manual. 


 
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8.3.1.2 Bevacizumab 
Bev will be administered in a dose of 10 mg/kg by i.v. infusion every 14 ± 3 days.  The 
first infusion will be administered over 90 minutes; the second infusion may be 
administered over 60 minutes if the first infusion was well tolerated; and subsequent 
infusions may be administered over 30 minutes if the second infusion was well 
tolerated.  Additional information regarding Bev administration may be found in the 
AVASTIN® Full Prescribing Information or other local product information.  On the 
days when both DSP-7888 Dosing Emulsion and Bev are administered, DSP-7888 
Dosing Emulsion should be administered first.  Bev will be obtained by the clinical site, 
except in South Korea where different regulations apply. 
8.3.2 Dose Delay, Dose Reduction, and Study Stopping Criteria 
8.3.2.1 DSP-7888 Dosing Emulsion 
Part 1:  This part of the study is a safety run-in cohort to determine the RD for Part 2.  
The dose of DSP-7888 Dosing Emulsion is 10.5 mg.  Bev will be administered at a dose 
of 10 mg/kg by i.v. infusion. 
Any patient who experiences a DLT with DSP-7888 Dosing Emulsion should be 
permanently removed from the study treatment and should not be replaced. 
Note:  The dose of DSP-7888 Dosing Emulsion may be reduced for individual patients 
to 3.5 mg or 1.75 mg if any dose reduction criterion is met. 
Part 2:  Based on the results of the DLT evaluation in Part 1, a 10.5 mg dose of DSP-
7888 Dosing Emulsion was determined as the dose for Part 2.  Bev is administered at a 
dose of 10 mg/kg by i.v. infusion. 
Note:  The dose may be reduced for individual patients to 3.5 mg or 1.75 mg of DSP-
7888 Dosing Emulsion if any dose reduction criterion is met. 
The dose of DSP-7888 Dosing Emulsion should be held for any Grade 3 or Grade 4 
toxicity that is at least possibly related to DSP-7888 Dosing Emulsion, but that is not a 
DLT, with the exception of Grade 3 ISRs which do not require hospitalization, where 
patients may continue on DSP-7888 Dosing Emulsion without holding or reducing the 
dose per Investigator’s judgment on a case-by-case basis, after consultation with the 
Sponsor.  Dosing may be resumed at a reduced dose once the toxicity has reverted to 
Grade 2 or less. Treatment with Bev may be put on hold in case of Grade 3 or higher 
ISR, to avoid any delay in wound healing.  
For Grade 2 toxicity at least possibly related to DSP-7888 Dosing Emulsion, dosing 
may take place at a reduced dose according to Table 2 below.  On days when DSP-7888 
Dosing Emulsion is held for toxicity, Bev should be administered if scheduled for that 


 
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day.  If toxicities related to DSP-7888 Dosing Emulsion preclude administration of 
DSP-7888 Dosing Emulsion for 4 consecutive treatments, DSP-7888 Dosing Emulsion 
should be discontinued with continuation of Bev alone. However, if in the opinion of 
the Investigator the patient is clinically stable and receiving benefit from study drug, the 
patient may restart treatment with DSP-7888 Dosing Emulsion on a case-by-case basis, 
after consultation with the Sponsor. 
Dose reduction should be undertaken as shown in Table 2 and Table 3: 
Table 2 
Dose Reduction Schedule 
Starting Dose Level 
Reduced Dose Level 
Starting Dose Level # Injection Sites 
x Volume/Site 
Strategy 
Dose 
# Injection Sites 
x Volume/Site 
10.5 mg 
6 x 100 µL 
Dose Reduction 
3.5 mg 
2 x 100 μL 
3.5 mg 
2 x 100 µL 
Dose Reduction 
1.75 mg 
2 x 50 µL 
Note: A dose increase is not allowed after dose reduction.  A 2-step dose reduction is allowed. 
 
Table 3 
Dose Reduction Administration 
Administration 
Route 
Dose Level 
Number 
of 
Injection 
Sites 
Amount per 
injection   site 
(mL) 
Total Amount to 
administer per 
dosing day (mL) 
Intradermal 
3.5 mg 
2 
0.1 
0.2 
Intradermal 
1.75 mg 
2 
0.05 (50 µL) 
0.1 
 
After the Induction Phase, dose reduction is permitted due to ISRs if the Investigator or 
Sub-Investigator has judged that a dose reduction is medically required. 
Patients who experience Grade 3 or higher toxicities at a dose of 1.75 mg that are at 
least possibly related to DSP-7888 Dosing Emulsion will be removed from the protocol 
therapy, with the exception of patients with Grade 3 ISRs assessed as at least possibly 
related to DSP-7888 Dosing Emulsion not requiring hospitalization; these patients may 
continue on DSP-7888 Dosing Emulsion per Investigator’s judgment on a case-by-case 
basis, after consultation with the Sponsor. 


 
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8.3.2.2 Bevacizumab 
Bev toxicities should be managed according to the Full Prescribing Information or other 
local product information.  There are no dose reductions for Bev.  Treatment with Bev 
may be put on hold for Grade 3 or higher ulceration of injection sites due to DSP-7888 
Dosing Emulsion.  If a toxicity felt to be associated with Bev requires temporary 
discontinuation of Bev, DSP-7888 Dosing Emulsion will continue to be administered on 
schedule.  If toxicities related to Bev preclude administration of Bev for 6 consecutive 
weeks (3 treatment cycles of Bev), then Bev should be permanently discontinued.  For 
patients on the Bev alone arm, this will constitute discontinuation of protocol therapy.  
For patients randomized to the combination arm, treatment will continue with DSP-
7888 Dosing Emulsion alone. 
8.3.2.3 Treatment of Injection Site Reactions  
Injection site reactions will be graded according to the following criteria (Table 4).  The 
symptoms that occur with injection site reaction should be reported as “injection site 
reaction” (not described as “erythema,” “itching,” etc.). 
Table 4 
Grading of Injection Site Reactions 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Tenderness, 
erythema, warmth, 
pruritus, swelling 
Pain, induration, 
fatty 
degeneration, 
edema, phlebitis 
Ulcer, necrosis, 
abscess, erosion, or 
severe tissue injury, 
requiring surgical 
intervention or skin 
graft 
Life-threatening, 
required 
emergency care 
Mild; 
asymptomatic or 
mild symptoms; 
clinical or 
diagnostic 
observations only; 
intervention not 
indicated 
Moderate; 
minimal, local, or 
noninvasive 
intervention 
indicated; limiting 
age-appropriate 
instrumental 
ADLa 
Severe or medically 
significant but not 
immediately 
life-threatening; 
hospitalization or 
prolongation of 
hospitalization 
indicated; disabling; 
limiting self-care ADLb 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
ADL = Activities of Daily Living. 
a Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
b Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 


 
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Factors other than the appearance of the ISR should be taken into consideration when 
evaluating the severity of an ISR.  A pinpoint ulcer, for example, may not truly be 
indicative of a Grade 3 ISR, and other factors, such as the presence of fever, or the need 
for systemic analgesia, should also be considered in determining ISR severity and 
guiding decisions regarding discontinuation of DSP-7888 Dosing Emulsion. 
8.3.3 Grade 1 Injection Site Reactions 
Irrigation with physiological saline is recommended.  Topical steroids should be applied 
as appropriate.  A mid-strength Class 4 topical steroid is recommended (National 
Psoriasis Foundation, 1996-2016).  Examples include: 
• Flurandrenolide ointment, 0.05% 
• Mometasone furoate cream, 0.1% 
• Triamcinolone acetonide cream/spray, 0.1% 
• Fluocinolone acetonide ointment, 0.03% 
• Desoximetasone cream or ointment, 0.05% 
• Hydrocortisone valerate ointment, 0.2% 
Antiseptics that are susceptible to immunization should not be used. 
Application of topical antibiotics is not recommended, as it may worsen the reaction.  
However, the antibiotics may be used in the presence of infectious findings or positive 
culture results. 
8.3.4 Grade 2/3 Injection Site Reactions 
• In the presence of a Grade 2 ISR, the administration of DSP-7888 Dosing 
Emulsion may continue at a reduced dose of 3.5 mg (2.0 mg killer peptide plus 
1.5 mg helper peptide).  Further dose reduction to 1.75 mg as described above is 
permitted. 
• DSP-7888 Dosing Emulsion should be held in the presence of a Grade 3 ISR 
requiring hospitalization (as described above); once the ISR resolves to Grade 2 
or less, administration of DSP-7888 Dosing Emulsion may resume at a reduced 
dose of 3.5 mg (2.0 mg killer peptide plus 1.5 mg helper peptide).  Further dose 
reduction to 1.75 mg as described above is permitted. 
• Irrigation with physiological saline and use of topical steroids as described for 
Grade 1 ISRs above should be instituted. 


 
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• If an abscess forms, incision and drainage should be carried out to avoid 
exacerbation of the inflammatory response around the site.  After the drainage, 
the site should be washed with physiological saline followed by application of 
topical steroids as appropriate.  Most abscesses should be sterile, but cultures 
should be obtained. 
• Topical antibiotics should not be used unless cultures indicate infection. 
• Open areas may be protected with a non-stick dressing. 
If severe ISRs are observed, local (subcutaneous) injection of steroids may be 
considered. 
8.3.5 Study Stopping Rules 
The Sponsor will promptly review all serious life-threatening and fatal events (other 
than death due to disease progression) reported in the study and perform a causality 
assessment. 
Based on the causality assessment of life-threatening and fatal events that occur from 
the start of treatment with DSP-7888 Dosing Emulsion and  up to 30 days from the last 
dose of DSP-7888 Dosing Emulsion (other than death due to disease progression), the 
Sponsor will determine whether the study will be suspended for safety review.  
The Sponsor will determine whether the study will be modified, continue enrollment or 
be terminated based on the following scenarios: 
• Any cases of death (other than death related to progressive disease) that occur 
from the start of treatment with DSP-7888 Dosing Emulsion and up to 30 days 
from the last DSP-7888 Dosing Emulsion administration and deemed by the 
Sponsor to be related to any of the study’s drugs. 
• If the percentage of patients presenting with drug‑related (assessed by Sponsor) 
Grade 4 or higher AE within a particular medical concept (eg, hypersensitivity) 
in this study is higher than that reported in patients treated with DSP-7888 
Dosing Emulsion within the clinical program and as reported in the literature for 
GBM patients.  
The causality assessment and safety reviews will occur in the context of the Sponsor’s 
safety governance processes including the study team and senior leadership.  As part of 
the safety review, in addition to ongoing routine review of the safety data by the IDMC, 
the Sponsor may choose to consult with the IDMC on an ad hoc basis. 
Based on the safety review, the Sponsor will determine whether the study may continue 
(with or without a protocol amendment) or if it must be terminated. 


 
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8.3.6 Packaging and Labeling 
Sumitomo Dainippon Pharma Oncology, Inc. (SDP Oncology) will supply the bulk 
product.  The study packaging will be performed by a contract manufacturing 
organization (Almac) designated by Syneos (with Sponsor oversight) and SDP 
Oncology.  All packaging and labeling operations will be performed according to Good 
Manufacturing Practice for Medicinal Products and the relevant regulatory 
requirements. 
8.3.7 Method of Assigning Patients to Treatment Groups 
The study will be divided into 2 parts.  Part 1 will be a non-randomized, open-label 
Induction Phase where all patients will be treated with the combination of DSP-7888 
Dosing Emulsion plus Bev in a single-arm manner.  The objective of Part 1 is to 
establish the safety of the combination of DSP-7888 Dosing Emulsion plus Bev.  
Patients who discontinue Part 1 of the study for reasons other than DLT during the 
Induction Phase will be replaced. 
Once the safety of the combination of DSP-7888 Dosing Emulsion plus Bev has been 
established, Part 2 (the randomized part of the study) will begin.  In Part 2, patients will 
be stratified prior to randomization based on the extent of surgical resection in primary 
therapy (GTR versus not GTR) and KPS class (60 through 70 versus 80 through 100) 
and will be randomized in a 1:1 ratio for DSP7888 Dosing Emulsion plus Bev or Bev 
alone via the Endpoint Interactive Voice/Web Response System.  The treatment 
assignment is to be obtained in Part 2 after the study patient has passed all inclusion and 
exclusion criteria and has been enrolled in the study prior to the initiation of the study 
treatment or first dosing visit.  Withdrawn patients will not be replaced in Part 2 of the 
study. 
8.3.8 Selection of Doses in the Study 
DSP-7888 Dosing Emulsion has been evaluated in 2 doses in clinical studies in Japan 
and was evaluated in a Phase 1 study in the US.  Doses of 3.5 mg and 10.5 mg have 
been well tolerated in both Japanese and US study patients with little difference in the 
overall safety profiles of both doses observed to date.  Induction of cytotoxic T cell 
activity may occur more rapidly following the 10.5 mg dose, and so this dose was 
selected for investigation in this study. 
In Part 1 of study DSP-7888-201G, no DLTs were observed with 10.5 mg DSP-7888 
Dosing Emulsion, therefore, Part 2 proceeded with a dose of 10.5 mg DSP-7888 Dosing 
Emulsion i.d.  
The dose of Bev, 10 mg/kg i.v. every 14 days, is the currently approved dose for the 
treatment of recurrent GBM. 


 
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8.3.9 Prior and Concomitant Therapy 
The study will enroll patients with GBM whose tumors have recurred or progressed 
following initial treatment with surgery, radiation, and chemotherapy 
Patients should receive treatment for all inter-current medical conditions or AEs at the 
discretion of the Investigator in conformance with community or institutional medical 
standards. 
Patients may also receive anti-seizure medications and symptomatic treatments (e.g., 
analgesics, anxiolytics, and hypnotics) at the discretion of the Investigator. 
Patients may occasionally require systemic glucocorticoids of 4 mg/day of 
dexamethasone or equivalent for other glucocorticoids at the discretion of the 
Investigator to treat changes in neurological status; DSP-7888 Dosing Emulsion 
administration should continue at the discretion/judgement of the investigator while the 
patient is receiving corticosteroid treatment. Efforts must be made to taper any systemic 
glucocorticoids to doses of less than 4 mg/day of dexamethasone (or equivalent doses of 
other glucocorticoids per Appendix 16.4) as soon as possible; topical, inhalational, 
ophthalmologic, intra-articular, and replacement doses of glucocorticoids are permitted. 
If a patient requires doses of corticosteroids in excess of dexamethasone 4 mg/day (or 
equivalent) to manage neurological symptoms, please contact the medical monitor for 
discussion/approval.  
 
Patients with CTCAE ≥ 2 with hypomagnesemia (magnesium < 0.5 mmol/L) and/or 
hypokalemia (potassium < the lower limit of normal [LLN] - 3.0 mmol/L) should 
receive electrolyte supplementation. 
8.3.9.1 Prohibited Medication/Therapy 
• Patients may not receive any therapy directed at GBM including RT. 
• Patients may not receive cytotoxic agents, hormonal agents for anti-tumoral 
therapy, monoclonal antibodies, immunomodulatory agents, or investigational 
agents during the study. 
• Patients may not receive any immunosuppressive agents other than 
glucocorticoids as described in Section 8.3.9. 
• Patients should not receive live vaccines (eg, Flu-Mist®); vaccines containing 
killed organisms are permitted. 


 
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8.3.9.2 Permitted Medication/Therapy 
Patients on the study will be permitted to receive COVID-19 vaccinations that are 
authorized for use by the health authorities of the specific country or region; this should 
be discussed as necessary with the Medical Monitor on a case-by-case basis. For 
additional information refer to NCCN guidance.37 
 
8.3.10 Treatment Compliance 
The administration of investigational product will occur at the clinical site; therefore, 
the study staff will be able to confirm compliance. 
8.3.11 Blinding 
This is an open-label study. The primary endpoint of Part 2 of this study is OS, the 
assessment of which is unlikely impacted by the open-label nature of the study.   
To comply with ICH E6 (R2) Guideline for Good Clinical Practice (2016), which 
recommends the blinded review of planned analyses, and to minimize the risk of 
potential bias into interim and final analyses for the adaptive Phase 3 design in Part 2, 
blinding controls have been implemented on the aggregate data by treatment arm. 
Specifically, the IA results will be reviewed by the IDMC and will only be available to 
the IDMC and selected unblinded team members. The investigators, the patients, the 
Sponsor and CRO study personnel who interact with the site and other blinded partners 
do not have access to the IA results. 
 
9 
STUDY PROCEDURES 
9.1 
Timing of Study Procedures 
Patients will provide written informed consent before any study-related procedures are 
performed. 
The planned study assessments are in Section 8.1.3. 
9.1.1 Pre-Screening Phase 
Prior to the Screening Phase, the following activities will occur: 
• Record demographic data, such as ethnic origin, date of birth, and sex. 
• Perform HLA typing for subtype to determine the patient’s eligibility for the 
study. 


 
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• Collect blood for companion diagnostic development (blood samples will be 
collected at the same time as those for HLA typing). 
• Collect prior cancer therapy data. 
9.1.2 Pre-Treatment Screening Phase (Day -28 to -1) 
The Screening Phase may last up to 28 days prior to the first administration of study 
drug.  Procedures outlined in the Schedule of Assessments (Section 8.1.3) will be 
conducted during this time and will include the following activities and procedures: 
• Assess eligibility (according to the inclusion and exclusion criteria). 
• Obtain informed consent. 
• Collect pertinent medical history, including concomitant illnesses/diseases and 
concomitant medications (prescription medications, over-the-counter medicines 
and supplements, and alternative/herbal therapies). 
• Collect cancer treatment history and update prior cancer therapy data as needed. 
• Record vital signs. 
• Perform a physical examination. 
• Conduct a neurological examination based on the NANO criteria. 
• Assess KPS. 
• Perform an electrocardiogram (ECG). 
• Perform echocardiogram or multigated acquisition scan (MUGA). 
• Collect samples for hematology (complete blood count [CBC]) and serum 
chemistry tests. 
• Collect samples for urinalysis (24-hour urine protein as needed). 
• Assess coagulation parameters. 
• Conduct pregnancy test in women of childbearing potential. 
• Collect samples for serology tests for HIV antibody, hepatitis B surface antigen, 
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• Perform DWI-MRI, conventional MRI, and mRANO assessment of response. 
• Archival tumor tissue sample must be collected for WT1 by IHC and CISH 
where available.  Provision of tissue samples is preferred but not mandatory to 
be eligible for the study. WT1 IHC and CISH will be performed even if the data 
expression of WT1 are available from medical records.  
• Tumor tissue samples will be requested for retrospective biomarker analysis; 
however, this is optional and requires additional consent from the patient.  
• Assess isocitrate dehydrogenase (IDH) 1 and 2 mutations and MGMT promoter 
methylation status.  It is strongly encouraged for sites to provide archival tumor 
tissue (if available) if no information regarding IDH 1 and 2 mutation and 
MGMT promotor methylation status is available at enrollment.  
• Collect blood for CTL induction analysis (prior to drug administration). 
• Collect blood for retrospective analysis of biomarkers (prior to drug 
administration). Additional consent is needed prior to collection of blood 
samples for these biomarkers. 
• Pulse oximetry to measure O2 saturation (SpO2) 
• Report AEs and SAEs. 
• Patients should also be asked at this time for consent to provision of a sample of 
tumor tissue after the last dose of study medication, if the patient will be 
undergoing a medically necessary procedure (this is not mandatory). Patients 
can elect to participate or not participate in providing the optional tumor tissue 
throughout the study. 
Patients who fail the Screening Phase may be re-screened at a later date. Rescreening 
for patients in Part 2 will be permitted for patients with laboratory values (AST, ALT, 
bilirubin, creatinine) that were out of range to meet eligibility, and for patients requiring 
dexamethasone doses in excess of 4 mg/day (or equivalent) once the dose can be 
tapered to 4 mg/day (or equivalent) or less with stability in the judgement of the 
investigator. 
9.1.3 Induction Phase (Day 1, Day 8, Day 15, Day 22, and Day 29) 
In Part 1, all patients will be dosed with DSP-7888 Dosing Emulsion every 7 ± 1 day 
and with Bev every 14  ± 3 days during the Induction Phase of the study. 
In Part 2, patients randomized to the DSP7888 Dosing Emulsion plus Bev treatment 
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Induction Phase of the study.  All patients will be dosed with Bev every 14 ± 3 days 
during the Induction Phase. 
9.1.3.1 Day 1, Day 15, and Day 29 Procedures 
The following procedures will be performed for all patients on Day 1, Day 15, and 
Day 29 of the Induction Phase: 
• Record vital signs. 
• Assess KPS. 
• Collect samples for hematology (CBC) and serum chemistry tests. 
• Collect samples for urinalysis (24-hour urine protein as needed). 
• Administer DSP-7888 Dosing Emulsion plus Bev or administer Bev alone. 
• Report AEs and SAEs. 
• Record concomitant medications. 
• Conduct a physical examination (Day 29 only). 
• Conduct a neurological examination by NANO Criteria (Day 29 only). 
• Collect blood for CTL induction analysis (prior to drug administration).  (If 
blood is collected during Pre-Treatment Screening Phase, blood collection at 
Day 1 is not needed). 
• Collect blood for retrospective analysis of biomarkers from the patients who 
have provided consent at Screening (prior to drug administration).  (If blood is 
collected during the Pre-Treatment Screening Phase, blood collection at Day 1 is 
not needed). 
9.1.3.2 Day 8 and Day 22 Procedures 
Patients in the DSP-7888 Dosing Emulsion plus Bev treatment group will undergo the 
following assessments: 
• Record vital signs. 
• Assess KPS. 


 
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• Collect blood for additional HLA haplotypes (Day 8, or next cycle visit) prior to 
drug administration. 
• Administer DSP-7888 Dosing Emulsion. 
• Report AEs and SAEs. 
• Record concomitant medications. 
9.1.4 Consolidation Phase (Days 43, 57, 71, 85, 99, 113, 127, 141, 155, 169, 
and 183) 
All patients will be dosed every 14 ± 3 days during the Consolidation Phase of the 
study. The exception to this is the following:  
• DSP-7888 Dosing Emulsion will not be administered at Day 183. 
9.1.4.1 Days 43, 71, 99, 127, and 155 Procedures 
• Record vital signs. 
• Assess KPS. 
• Collect samples for urinalysis (24-hour urine protein as needed). 
• Administer DSP-7888 Dosing Emulsion plus Bev or administer Bev. 
• Report AEs and SAEs. 
• Record concomitant medications. 
9.1.4.2 Days 57, 85, 113, 141, and 169 Procedures 
• Conduct a physical examination. 
• Conduct a neurological examination by NANO Criteria. 
• Record vital signs. 
• Assess KPS. 
• Perform an ECG. 
• Collect samples for hematology (CBC) and serum chemistry tests. 
• Collect samples for urinalysis (24-hour urine protein as needed). 


 
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• Collect blood for CTL induction analysis (prior to drug administration) 
(Days 57, 85, 113, and 169 only). 
• Collect blood for retrospective analysis of biomarkers from the patients who 
have provided consent at Screening (prior to drug administration) (Days 57, 85, 
113, and 169 only).  
• Administer DSP-7888 Dosing Emulsion plus Bev or administer Bev. 
• Report AEs and SAEs. 
• Record concomitant medications. 
• Perform DWI-MRI, conventional MRI, and mRANO assessment of response 
(Days 57, 113, and 169 only). 
9.1.4.3 Day 183 Procedures  
• Record vital signs. 
• Assess KPS. 
• Report AEs and SAEs. 
• Record concomitant medications. 
• Administer Bev. 
9.1.5 Maintenance Phase (Day 197 and Thereafter) 
Patients in the DSP-7888 Dosing Emulsion plus Bev treatment group will be dosed with 
DSP-7888 Dosing Emulsion every 28 days ± 7 days and with Bev every 
14 days ± 3 days during the Maintenance Phase of the study.  Patients in the Bev alone 
treatment group will be dosed with Bev every 14 days ± 3 days during the Maintenance 
Phase. 
The following assessments will be conducted: 
• Conduct a physical examination (Day 197 and then every 4 weeks). 
• Conduct a neurological examination by NANO Criteria (Day 197 and then every 
4 weeks). 
• Record vital signs. 


 
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• Assess KPS (Day 197 and then every 4 weeks). 
• Collect samples for hematology (CBC) and serum chemistry tests (Day 197 and 
then every 4 weeks). 
• Collect samples for urinalysis (24-hour urine protein as needed) (Day 197 and 
then every 4 weeks). 
• Collect blood for CTL induction analysis (prior to drug administration) 
(Day 253 and then every 12 weeks thereafter). 
• Collect blood for retrospective analysis of biomarkers from the patients who 
have provided consent at Screening (prior to drug administration) (Day 253 and 
then every 12 weeks thereafter). 
• For patients in the DSP-7888 Dosing Emulsion plus Bev treatment group, 
administer DSP-7888 Dosing Emulsion every 28 days ± 7 days, and administer 
Bev every 14 days ± 3 days.  For patients in the Bev alone treatment group, 
administer Bev every 14 days ± 3 days. 
• Report AEs and SAEs. 
• Record concomitant medications. 
• Perform DWI-MRI, conventional MRI, and mRANO assessment of response 
(Day 253 and then every 12 weeks thereafter). 
9.1.6 End of Treatment Visit 
The reasons for the discontinuation of study treatment are described in Section 8.2.4.  
The following procedures should be conducted within 28 days after the last dose of 
study treatment (and prior to the initiation of any new post-study treatment): 
• Conduct a physical examination. 
• Conduct a neurological examination by NANO Criteria. 
• Record vital signs. 
• Assess KPS. 
• Perform an ECG. 
• Collect samples for hematology (CBC) and serum chemistry tests. 


 
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• Collect samples for urinalysis (24-hour urine protein as needed). 
• Collect blood for CTL induction analysis (prior to drug administration). 
• Collect blood for retrospective analysis of biomarkers from the patients who 
have provided consent at Screening (prior to drug administration). 
• Perform DWI-MRI, conventional MRI and mRANO assessment of response. 
• Report AEs and SAEs. 
• Record concomitant medications.   
• Tumor samples for WT1 by IHC and CISH and for retrospective analysis of 
biomarkers should be obtained from all patients who provide consent (per the 
point above).  Provision of tumor tissue samples after the last dose of study drug 
is optional and not mandatory. 
9.1.7 Follow-Up after End of Treatment 
As the primary endpoint is OS, it is critical to follow patients for survival accordingly to 
the schedule. 
The following survival follow-up methods are recommended: 
• Direct (ie, telephone call or email to the patient/patient’s relative, etc.), or 
• Indirect (ie, medical record review or obituary listing review, etc.). 
Patients who discontinue treatment for PD, and who are treated with alternative therapy 
will be followed for survival. 
• The following procedures will be performed: Survival follow-up (direct or 
indirect methods as specified above) and post-treatment anti-tumoral therapy 
every 3 months and/or on an ad-hoc basis for safety or regulatory purposes, or a 
prespecified analysis. 
• Follow-up of a patient for up to 90 days to ensure no pregnancy occurs in female 
patients of childbearing potential and in female partners of male patients. 
Patients who discontinue treatment for PD (and who will not receive further treatment), 
or due to the need for a prohibited treatment for a concomitant illness or AE, an AE that 
precludes further administration of DSP-7888 Dosing Emulsion or Bev, the patient 
withdraws consent for continued administration of DSP-7888 Dosing Emulsion or Bev, 


 
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the Investigator believes it is in the patient’s best interest to discontinue protocol 
therapy will undergo the following procedures: 
• Survival follow-up (direct or indirect methods as specified above) and post-
treatment anti-tumoral therapy every 3 months and/or on an ad-hoc basis for 
safety or regulatory purposes, or a prespecified analysis. 
• Assess KPS and conduct a neurological examination by NANO Criteria on Day 
57 ± 14 days, Day 113 ± 14 days and Day 169 ± 14 days if withdrawal of study 
treatment occurs prior to these time points and until the patient receives further 
treatment for GBM.  
• Perform DWI-MRI, conventional MRI, and mRANO assessment of response on 
Day 57 ± 14 days, Day 113 ± 14 days and Day 169 ± 14 days if withdrawal of 
study treatment occurs prior to these time points and until the patient receives 
further treatment for GBM. 
• Follow-up of a patient for up to 90 days to ensure no pregnancy occurs in female 
patients of childbearing potential and in female partners of male patients. 
If a patient wishes to withdraw their consent to both study drug and study assessments, 
they should be asked if they are willing to continue with survival follow-up (which can 
be conducted by telephone). If the patient wishes to withdraw their consent to further 
participation in the study entirely, including survival follow-up, this should be clearly 
documented in the patient’s notes and in the clinical study database.  
The status of ongoing, withdrawn (from the study), and “lost to follow-up” patients at 
the time of an OS analysis should be obtained by the site personnel by checking the 
patient’s notes, hospital records, contacting the patient’s current physician, and 
checking publicly available death registries. If the patient has actively withdrawn 
consent to the processing of their personal data, the vital status of the patient can be 
obtained by site personnel from publicly available resources where it is possible to do so 
under applicable local laws.  
Withdrawn patients will not be replaced. 
For patients who are lost to follow-up; who move out of the Investigator’s catchment 
area or are unable to continue to come to the investigational site; or in the event the 
Sponsor deems it necessary to discontinue the study, patients will be censored on the 
day the patient was last known to be alive or had not progressed. 


 
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9.2 
Description of Study Procedures 
9.2.1 Medical History 
The medical history will include all pertinent aspects of the patient’s past health, as well 
as aspects of the underlying GBM, including date of diagnosis, extent of surgery, 
MGMT promoter methylation and IDH-1 and -2 mutation, dose of RT administered, 
duration of chemotherapy, and date of recurrence or progression.  All concurrent 
medications including prescription medications, over-the-counter medicines and 
supplements, and alternative/herbal therapies will be recorded.  The medical history will 
be obtained during Screening. 
9.2.2 Karnofsky Performance Status Score 
Careful questioning, including time in bed or in a chair, ability to perform activities of 
daily living, degree of ambulatory ability, etc., will be assessed with the KPS. 
9.2.3 Clinical Laboratory Evaluation 
The hematology and clinical chemistry laboratory analyses will be performed at a 
central laboratory.  Reference ranges will be supplied and used by the Investigator to 
assess the laboratory data for clinical significance and pathological changes.  While the 
expectation is that samples will be analyzed by a central laboratory, local laboratories 
may be used as deemed necessary by the Investigator in order to make treatment related 
decisions.  Note that eligibility will always be determined from the central laboratory 
results.  If a sample is analyzed by a local laboratory, an aliquot will be also be sent to 
the central laboratory as required by this protocol. 
9.2.3.1 Hematology 
A CBC will include measures of the white blood cell count (WBC), red blood cell 
count, hemoglobin, hematocrit, WBC (total and differential), and platelet count.  A 
CBC will be performed according to the Schedule of Assessments in Section 8.1.3. 
9.2.3.2 Coagulation Parameters 
Coagulation parameters will include an INR and PTT.  Coagulation parameters will be 
obtained during Screening and then as clinically indicated. 
9.2.3.3 Clinical Chemistry 
Serum chemistry tests will include measures of creatinine, blood urea nitrogen, AST, 
ALT, alkaline phosphatase, total bilirubin, albumin, total protein, sodium, potassium, 
chloride, bicarbonate, glucose, uric acid, calcium, magnesium, and phosphorus.  Serum 
chemistries will be performed according to the Schedule of Assessments in Section 
8.1.3. 


 
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9.2.3.4 Urinalysis 
A urinalysis will include measurements of pH, specific gravity, and dipstick 
determinations of protein, glucose, ketones, blood (or hemoglobin) and total bilirubin.  
If any dipstick determinations are 2+ or greater, a microscopic examination of urine will 
be performed.  If a dipstick determination of protein is 2+ or higher, a 24-hour urine 
collection must be done.  Urine testing will be performed according to the Schedule of 
Assessments in Section 8.1.3. 
9.2.3.5 Other Laboratory Variables 
Screening for hepatitis B surface antigen, hepatitis C antibody, HIV will be performed 
at Screening/Baseline only. 
Pregnancy testing in women of childbearing potential may be obtained with a serum or 
urine beta human chorionic gonadotropin test.  A pregnancy test will be performed 
during Screening and then as clinically indicated. 
9.2.4 Vital Signs 
Vital signs will include systolic and diastolic blood pressures, pulse, respiratory rate, 
temperature, and weight.  Blood pressure and heart rate will be recorded in a 
standardized manner, ie, after the patient has rested in the sitting position for at least 
5 minutes. Pulse oximetry will also be measured at screening only. 
9.2.5 Physical Examination 
A physical examination will include examinations of the skin, particularly areas where 
DSP-7888 Dosing Emulsion has been administered; head, eyes, ears, nose, and throat; 
chest, including the lungs and the heart; abdomen; and extremities and areas of major 
lymph node chains.   
9.2.6 Neurological Examination 
A neurological exam will be based on the NANO criteria (Appendix 16.3) and will 
include assessments of gait, strength, ataxia, sensation, facial strength, visual fields, 
language, and level of consciousness. 
9.2.7 Tumor and Brain Imaging 
Conventional MRI and DWI scans will be obtained at Screening; at Weeks 8, 16, and 
24 of the study; and then every 12 weeks thereafter; and at EOT or as clinically 
indicated.  A radiology manual will describe in detail the techniques for obtaining, 
storing, transmitting, and interpreting the images (including mRANO evaluation).  
Clinical decisions (including mRANO assessments) will be made based on local 
interpretation of the MRIs.  In cases of suspected progression, confirmatory MRIs are to 


 
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be performed 4-8 weeks later (see Appendix 16.2).  Continuation of study treatment is 
independent from the radiological assessments. 
9.2.8 Other Safety Assessments 
9.2.8.1 Electrocardiogram 
A 12-lead ECG will be obtained during Screening, days 57, 85, 113, 141, 169, and 
EOT. 
9.2.8.2 Echocardiogram/MUGA 
An echocardiogram or MUGA will be conducted during Screening. 
9.2.8.3 Monitoring of QTc Intervals 
Rationale for Use of QTcF 
Per the FDA’s Guidance for Industry:  E14 Clinical Evaluation of QT/QTc Interval 
Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs, “Bazett’s 
correction is frequently used in clinical practice and in the medical literature.  In 
general, however Bazett’s correction overcorrects at elevated heart rates and 
undercorrects at heart rates below 60 beats per minute and hence is not an ideal 
correction.  Fridericia’s correction is more accurate than Bazett’s in subjects with such 
altered heart rates. 
Recommendations for the Management of Prolonged QTc Intervals and Electrolyte 
Imbalances 
Patients who experience prolongation of the QTc interval to > 480 msec (CTCAE 
Grade 2) should be promptly evaluated for causality of the QTc prolongation and 
managed according to the following guidelines: 
• Levels of electrolytes (potassium, calcium, and magnesium) should be checked 
and supplementation given to correct any values outside the normal range.  
Patients with CTCAE ≥ 2 with hypomagnesemia (magnesium < 0.5 mmol/L) 
and/or hypokalemia (potassium < LLN - 3.0 mmol/L) should receive electrolyte 
supplementation. 
• Concomitant therapies should be reviewed and adjusted as appropriate for 
medications with known QT prolonging effects. 
9.2.9 Pharmacodynamic Testing 
Peripheral blood mononuclear cells will be obtained for the evaluation of WT1 
peptide-specific CTL induction activity by tetramer assay.  Furthermore, if consent is 
given, analysis will be conducted of other biomarkers from tumor tissue and peripheral 


 
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blood samples, such as protein and gene expression analysis that may be important to 
the understanding of DSP-7888 Dosing Emulsion, but that have not yet been 
determined.  Providing informed consent for use of this sample for these research 
purposes is optional, and participation in the study is not dependent upon providing this 
sample. 
Immunohistochemistry of FFPE tumor tissue will be performed to evaluate expression 
of WT1 by IHC and CISH, even if those expression data are available from medical 
records. FFPE slides will be requested. 
Site study staff will ship tissue samples to the central laboratory.  Remaining tissue 
slides will be returned to the sites at the conclusion of testing or at a time requested by 
the study site. 
Specific shipping and processing instructions will be detailed in the study Laboratory 
Manual. 
9.3 
Duration of Treatment 
Patients will continue to receive DSP-7888 Dosing Emulsion plus Bev or Bev alone: 
independent of radiological assessment / progression:  
1. 
Provided that the Investigator considers it to be safe for the patient 
2. 
Provided that the Investigator determines that there is potential benefit for the 
patient 
3. 
When the patient is willing to continue 
 
10 EFFICACY, PHARMACODYNAMICS, AND SAFETY VARIABLES 
ASSESSED 
The planned schedule of assessments is available in Section 8.1.3. 
10.1 Efficacy Variables 
The primary efficacy variable will be the comparison of OS between treatment with 
DSP-7888 Dosing Emulsion plus Bev versus Bev alone in patients with recurrent or 
progressive GBM following initial therapy. 
The key secondary efficacy variable is the 12-month survival rate between treatment 
with DSP-7888 Dosing Emulsion plus Bev versus Bev alone. The other secondary 
efficacy variables include: 


 
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• PFS of DSP-7888 Dosing Emulsion plus Bev versus Bev alone 
• Six-month PFS of DSP-7888 Dosing Emulsion plus Bev versus Bev alone 
• Response rate of DSP-7888 Dosing Emulsion plus Bev versus Bev alone 
• Duration of response of DSP-7888 Dosing Emulsion plus Bev versus Bev alone 
10.2 Pharmacodynamic Assessments 
Pharmacodynamic assessments will include: 
• The evaluation of WT1 peptide-specific CTL induction activity 
• Immunohistochemistry and CISH to evaluate expression of WT1.  
10.3 Safety Assessments 
Safety will be evaluated based on the AEs recorded at each contact with the patient, 
physical examinations, and the results of laboratory tests; the severity of AEs or 
abnormal laboratory results will be based on the CTCAE V4.03. 
10.3.1 COVID-19 
Because much is still unknown about how SARs-CoV-2 affects the human body, 
patients who have tested positive for COVID-19 will be identified and relevant 
information collected.  All patients should provide documentation of any testing for 
COVID-19 if available, along with test results, both at screening for enrollment and/or 
during the study. Prior test results should be reported, if available, for any patient who 
has previously tested positive for COVID-19 SARS-CoV-2 titers (antiviral 
immunoglobulin G [IgG] and immunoglobulin M [IgM]).38 These data will be entered 
into the patient’s study-specific record. 
Any patient-reported illness of COVID-19 during the study should be recorded as an 
AE. If a patient reports infection with COVID-19, the investigator may discuss with the 
Medical Monitor whether the patient can continue on study. 
10.3.2 Adverse Events 
10.3.2.1 Adverse Event Definition 
An AE is defined as any untoward medical occurrence in a clinical study subject 
administered a medicinal product which does not necessarily have a causal relationship 
with this treatment.  An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not it is related to the 


 
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medicinal (investigational) product.  This includes an exacerbation of pre-existing 
conditions or events, inter-current illnesses, drug interaction or the significant 
worsening of the indication under investigation that is not recorded elsewhere in the 
eCRF under specific efficacy assessments.  Anticipated fluctuations of pre-existing 
conditions, including the disease under study, that do not represent a clinically 
significant exacerbation or worsening need not be considered AEs.  Disease progression 
and lack of efficacy are not considered to be an AE or SAE, and the duration of AE 
collection is until 30 days after the last dose of study drug. 
It is the responsibility of the Investigator to document all AEs that occur during the 
study from the time main consent is obtained until 30 days after the last dose of study 
drug.  When an SAE that is assessed as causally related (ie, Definite, Probable, or 
Possible) occurs after completion of the clinical study, the Investigator will report the 
event to the Sponsor as a spontaneous report.  Adverse events will be elicited by asking 
the subject a non-leading question, for example, “Have you experienced any new or 
changed symptoms since we last asked/since your last visit?”  Adverse events should be 
reported on the appropriate page of the eCRF. 
The Investigator is responsible for reviewing laboratory test results and determining 
whether an abnormal value in an individual study patient represents a change from 
values before the study.  In general, abnormal laboratory findings without clinical 
significance (based on the Investigator's judgement) should not be recorded as AEs; 
however, laboratory value changes requiring therapy or adjustment in prior therapy are 
considered AEs. 
Adverse reactions will be reported to the FDA according to 21 Code of Federal 
Regulations (CFR) 312.32. 
10.3.2.2 Assessment of Severity 
The severity of AEs or abnormal laboratory results will be based on the CTCAE V4.03 
(https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf).  
Each AE will be assigned a category by the Investigator as follows: 
Grade 1: 
An AE that is easily tolerated by the subject, causes minimal 
discomfort, and does not interfere with everyday activities 
Grade 2: 
An AE that is sufficiently discomforting to interfere with normal 
everyday activities; intervention may be needed 
Grade 3: 
An AE that prevents normal everyday activities; treatment or other 
intervention is usually needed 


 
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Grade 4: 
An AE that places the subject at immediate risk of death as the 
event occurred 
Grade 5: 
An AE that results in the death of the subject 
If there is a change in the severity of an AE, it must be recorded as a separate event. 
10.3.2.3 Assessment of Causality 
A suspected adverse reaction is any AE for which there is a reasonable possibility that 
the drug caused the AE.  For the purpose of IND safety reporting, “reasonable 
possibility” means there is evidence to suggest a causal relationship between the drug 
and the AE.  Inherent in this definition is the need for the Investigator and Sponsor to 
evaluate the available evidence and make a judgement about the likelihood that the drug 
actually caused the AE. 
Every effort will be made by the Investigator to assess the relationship of the AE, if any, 
to either or both of the drugs (i.e., DSP-7888 Dosing Emulsion and Bev) comprising 
protocol therapy.  Causality should be assessed using the following categories: 
Not Related to the Study Drug: 
Not Related: 
Clinical event with an incompatible time relationship to study drug 
administration, and that could be explained by underlying disease or 
other drugs or chemicals or is incontrovertibly not related to the study 
drug. 
Unlikely: 
Clinical event whose time relationship to study drug administration 
makes a causal connection improbable, but that could plausibly be 
explained by underlying disease or other drugs or chemicals. 
Related to the Study Drug: 
Possible: 
Clinical event with a reasonable time relationship to study drug 
administration, but that could also be explained by concurrent disease 
or other drugs or chemicals. 
Probable: 
Clinical event with a reasonable time relationship to study drug 
administration and is unlikely to be attributed to concurrent disease or 
other drugs or chemicals. 
Definite: 
Clinical event with plausible time relationship to study drug 
administration, and that cannot be explained by concurrent disease or 
other drugs or chemicals. 


 
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10.3.2.4 Action Taken 
The Investigator will describe the action taken in the appropriate section of the eCRF, as 
follows: 
• Dose not changed 
• Dose reduced 
• Drug interrupted 
• Drug withdrawn 
• Not applicable 
• Unknown 
10.3.2.5 Follow-Up of Adverse Events 
All Investigators should follow up patients with AEs until the event is resolved or until, 
in the opinion of the Investigator, the event is stabilized or determined to be chronic.  
Details of AE resolution must be documented in the eCRF. 
10.3.2.6 Documentation and Reporting of Adverse Events 
All AEs, whether serious or not, will be described in the source documents and the AE 
page of the eCRF.  A medical condition present at Screening that has increased in 
frequency or severity during the AE reporting period must also be recorded as an AE. 
Patients should be instructed to report any AE that they experience to the Investigator.  
Investigators should assess the patient for AEs at each visit.  AEs occurring during the 
clinical study and the follow-up period should be recorded on the appropriate AE page 
of the eCRF.  To capture the most potentially relevant safety information during a 
clinical study, it is important that Investigators use accurate AE terminology on eCRFs.   
Wherever possible, a specific disease or syndrome rather than individual associated 
signs and symptoms should be identified by the Investigator and recorded on the eCRF.  
However, if an observed or reported sign or symptom is not considered a component of 
a specific disease or syndrome by the Investigator, it should be recorded as a separate 
AE on the eCRF. 
Appropriate CTCAE terms for AEs should be used whenever possible.  If an 
appropriate CTCAE term is not available, then the verbatim term should be 
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The symptoms that occur with injection site reaction should be reported as “injection 
site reaction” (not described as “erythema,” “itching,” etc.). 
Information to be reported in the description of each AE must include at a minimum: 
• The patient’s study number 
• A medical diagnosis 
• Date of onset 
• Date of resolution  
• The severity of the event 
• Whether the event is serious  
• Action taken regarding study drug (none, dose reduction, temporary interruption, 
discontinuation) 
• The outcome of the event (patient recovered without sequelae, patient recovered 
with sequelae, event is ongoing, patient expired) 
• The relationship of the event to study drug 
Questions sometimes arise about when an abnormal laboratory value should be reported 
as an AE.  Although this decision is at the discretion of the Investigator, an abnormal 
laboratory value should be reported as an AE if it is clinically significant; if it is 
associated with clinical sequelae; if it is an SAE or important medical event; if it 
requires a discontinuation or change in protocol therapy; if it requires medical 
intervention; or if it results in study discontinuation. 
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the 
diagnosis or syndrome should be recorded as an AE.  It is more advantageous to report a 
laboratory abnormality as a clinical event with a medical term rather than an abnormal 
laboratory result per se (record thrombocytopenia rather than decreased platelet count). 
Progression of disease is considered an efficacy outcome parameter and should not be 
captured as an AE. 
The Investigator is responsible for ensuring that all AEs (as defined in Section 10.3.2 
and as further specified below) observed by the Investigator or reported by patients are 
collected and recorded in the patients’ medical records in the eCRF, and for SAEs, on 
the SAE report form.  These AEs will include the following: 


 
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• All non-serious AEs (as defined in Section 10.3.2.6) that occur after the patient 
has signed the main informed consent form (ICF) until 30 days after the last 
dose of study drug. 
• All SAEs (as defined in Section 10.3.3.1) that occur after the patient has signed 
the main ICF until 30 days after the last dose of study drug. 
The following AE attributes must be assigned by the Investigator:  AE diagnosis or 
syndrome(s) (if known, signs or symptoms if not known); event description (with detail 
appropriate to the event); dates of onset and resolution; severity; assessment of 
relatedness to the investigational product or active control, and action taken.  The 
Investigator may be asked to provide follow-up information, discharge summaries, and 
extracts from medical records or eCRFs. 
• Adverse events should be reported and documented in accordance with the 
procedures outlined below.  All AEs occurring during the study must be 
documented on the relevant eCRF pages.  The following data should be 
documented for each AE: 
• Description of the symptom event 
• Classification of “serious” or “not serious” 
• Severity 
• Date of first occurrence and date of resolution (if applicable) 
• Action taken 
• Causal relationship to DSP-7888 Dosing Emulsion alone 
• Causal relationship to Bev alone 
• Outcome of the event (unknown, recovered, not yet recovered, recovered with 
sequelae, death [with date and cause reported]) 
Patients should be advised to immediately alert the study staff if they experience AEs 
that could be new or worsening signs or symptoms of an acute cardiac and/or 
respiratory event: 
• Chest tightness/pain 
• Coughing or dyspnea 
• Wheezing 


 
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• Fatigue 
10.3.2.6.1 Reporting COVID-19 Infections 
Suspected or confirmed COVID-19 infections, including asymptomatic infections and 
positive COVID-19 tests, are Adverse Events of Special Interest (AESIs), and therefore 
immediately reportable events, even if the events do not meet SAE criteria.  
Serious COVID-19 events will be reported on an SAE Report Form within 24 hours of 
the Investigator’s awareness, according to Section 10.3.3.1.1.   
Non-serious COVID-19 events will be reported on a COVID-19 Report Form within 5 
calendar days of the Investigator’s awareness to the same email / fax for reporting SAEs 
described in Section 10.3.3.1.1. 
Updates or follow-up information for COVID-19 events should be reported on an SAE 
Report Form (serious events) or a COVID-19 Report Form (non-serious events) within 
the same timelines as initial reports. 
 
10.3.3 Serious Adverse Events 
10.3.3.1 Serious Adverse Event Definition 
An SAE is any untoward medical occurrence or effect that, at any dose: 
• Results in death. 
• Is life-threatening (an AE is life-threatening if the subject was at immediate risk 
of death from the event as it occurred, ie, it does not include a reaction that 
might have caused death if it had occurred in a more serious form). 
• Requires or prolongs inpatient hospitalization.  (Complications occurring during 
hospitalization are AEs and are SAEs if they cause prolongation of the current 
hospitalization.  Hospitalization for elective treatment of a pre-existing, 
non-worsening condition is not, however, considered an AE.  The details of such 
hospitalizations must be recorded on the medical history or physical examination 
pages of the eCRF). 
• Results in persistent or significant disability/incapacity.  (An AE is 
incapacitating or disabling if it results in a substantial and/or permanent 
disruption of the patient’s ability to carry out normal life functions). 
• Results in a congenital anomaly/birth defect. 
In addition, medical and scientific judgement is required to decide if prompt notification 
is required in situations other than those defined for SAEs above.  This may include any 


 
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event that the Investigator regards as serious that did not strictly meet the criteria above, 
but may have jeopardized the patient or required intervention to prevent one of the 
outcomes listed above, or that would suggest any significant hazard, contraindication, 
side effect, or precaution that may be associated with the use of the investigational 
product. 
Hospitalizations for elective or planned purposes, for the administration of protocol 
therapy, for the administration of blood products or ancillary therapies, for procedures 
such as endoscopy or placement of an intravascular access device, for purposes of 
disposition or respite care or that are less than 24 hours in duration would not fulfill the 
above definition of serious.  Complications arising from elective or planned 
hospitalizations that result in prolonged hospitalization would be considered SAEs. 
10.3.3.1.1 Reporting of Serious Adverse Events 
Any SAE must be reported by the Investigator if it occurs from the time the patient 
signs the main ICF until 30 days after the last dose of study drug, whether or not the 
SAE is considered to be related to the investigational product.  An SAE report consists 
of the SAE form, which includes the concomitant medication information.  A copy of 
these forms must be emailed within 24 hours to the attention of the Sponsor at: 
SDP Oncology Pharmacovigilance Department 
Email: BBISafety@bostonbiomedical.com 
Fax (back-up to email): (617) 674-8660 
 
The Investigator should not wait to receive additional information to document fully the 
event before notification of an SAE, though additional information may be requested.  
Where applicable, information from relevant laboratory results, hospital case records, 
and autopsy reports should be obtained. 
Instances of death, congenital abnormality, or an event that is of such clinical concern as 
to influence the overall assessment of safety if brought to the attention of the 
Investigator at any time after the cessation of study drug administration and linked by 
the Investigator to this study, should be reported to the study monitor. 
The Sponsor and/or INC Research (A Syneos Health Group Company) will promptly 
notify all relevant Investigators and the regulatory authorities of findings that could 
adversely affect the safety of patients, have an impact on the conduct of the study, or 
alter the Independent Ethics Committee (IEC)/Institutional Review Board (IRB) 
approval/favorable opinion of the study.  In addition, INC Research (A Syneos Health 
Group Company), on behalf of the Sponsor, will expedite the reporting to all concerned 
Investigators, to the IECs/IRBs, where required, and to the regulatory authorities of all 
adverse reactions that are both serious and unexpected. 


 
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Patients will be instructed that a known or suspected pregnancy occurring during the 
study, in patients or the female partners of male patients, should be confirmed and 
reported to the Investigator, who will then withdraw the patient from the study without 
delay.  Upon discontinuation from the study, only those procedures that would not 
expose the patient to undue risk will be performed.  The Investigator should also be 
notified of pregnancy occurring during the study but confirmed after completion of the 
study.  In the event that a patient is subsequently found to be pregnant after inclusion in 
the study, any pregnancy will be followed to term; and the status of mother and child 
will be reported to the Sponsor after delivery. 
10.3.3.1.2 Unexpected Adverse Reactions 
An unexpected adverse reaction is any untoward and unintended response that is related 
to the administration of the study drug at any dose that is not consistent with the 
applicable product information (Investigator’s Brochure for DSP-7888 Dosing 
Emulsion or local product information for Bev). 
All suspected unexpected serious adverse reactions (SUSARs) will be the subject of 
expedited reporting.  The Sponsor and/or INC Research (A Syneos Health Group 
Company) shall ensure that all relevant information about a SUSAR that is fatal or life-
threatening is reported to the relevant competent authorities and IEC/IRB within 7 days 
after knowledge by the Sponsor of such a case and that relevant follow-up information 
is communicated within an additional 8 days.  All other SUSARs will be reported to the 
relevant competent authorities and IEC/IRB within 15 days after knowledge by the 
Sponsor of such a case.  All Investigators should follow up SUSARs until the event is 
resolved or until, in the opinion of the Investigator, the event is stabilized or determined 
to be chronic.  Suspected unexpected serious adverse reactions that occur after the 
patient has withdrawn from the clinical study must be reported by the Investigator to the 
Sponsor. 
10.4 Pharmacodynamic Variables 
The relationship between pharmacodynamic parameters such as WT1 peptide-specific 
CTL activity and certain clinical findings (eg, OS, response) in patients receiving 
DSP-7888 Dosing Emulsion will be described if appropriate. 
The relationship between expression of WT1 by IHC and CISH in tumor tissue and 
certain clinical findings (eg, OS, response) in patients receiving DSP-7888 Dosing 
Emulsion will be described if appropriate. 
10.5 Independent Data Monitoring Committee 
To enhance the safety and integrity of the study data, an IDMC consisting of 
independent experts will be convened to periodically review the accumulating safety 
data and efficacy results of the interim analyses.  The specific responsibilities and 


 
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composition of the IDMC will be outlined in a separate document, the IDMC Charter.  
The charter will specify when the IDMC will convene to review accumulating safety 
data and to provide a recommendation on study continuation or early termination in 
case there is a concern regarding safety.  Results of the interim analyses of primary 
efficacy and other available data, including safety data, will be reviewed by the IDMC.  
More details for decision making based on the results of the IAs will be provided in the 
IDMC Charter. 
10.5.1 Appropriateness of Measurements 
The efficacy and safety assessments planned for this study are widely used and 
generally recognized as reliable, accurate, and relevant to the disease condition. 


 
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11 STATISTICAL ANALYSIS 
Detailed methodology for summary and statistical analyses of the data collected in this 
study will be documented in a statistical analysis plan (SAP), which will be maintained 
by the Sponsor. The SAP may modify the plans outlined in the protocol; however, any 
major modifications of the primary endpoint definition and/or its analysis will also be 
reflected in a protocol amendment. 
11.1 Statistical Methods 
The primary data from Part 1 of the study will be listed and summarized separately from 
the data from the randomized part of the study.  Only descriptive statistics will be used 
to present data from Part 1 of the study.  Summaries will be provided for each dose 
level. 
The methodology for the randomized Part 2 of the study is presented in the sections 
below. 
11.1.1 Statistical Hypotheses 
The primary statistical null hypothesis is that there is no difference between the 
2 treatment groups (DSP-7888 Dosing Emulsion plus Bev and Bev alone) with regards 
to OS.  This will be tested by a stratified log-rank test. 
The statistical null hypothesis for the key secondary endpoint is that there is no 
difference between the 2 treatment groups (DSP-7888 Dosing Emulsion plus Bev and 
Bev alone) with regards to 12-month OS rate. Treatment comparisons will be performed 
using the respective KM estimates and the respective variances according to the 
Greenwood’s formula to construct a standard normally distributed Z-statistic.39 
11.1.2 Level of Significance, Multiple Comparisons, and Multiplicity 
Primary efficacy and the key secondary endpoint will be tested using a 1-sided test with 
an overall significance level 2.5%. The Lan-DeMets error spending function based on 
O’Brien-Fleming stopping boundaries will be used to adjust the significance level for 
the interim and the final analysis. The key secondary endpoint will only be tested 
following the significance of the primary endpoint. The details of multiplicity 
adjustment for the adaptive design will be provided in the SAP.  
11.2 Definition of Study Populations 
The ITT population will consist of all randomized patients in Part 2 of the study, 
regardless of whether treatment is ever administered.  The primary efficacy endpoint of 
OS will be analyzed based on the ITT population. 


 
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The per protocol (PP) population will consist of all patients in the second part of the 
study who are eligible for enrollment into the study who receive at least one dose of 
study drug (DSP-7888 Dosing Emulsion or Bev), and who do not have major protocol 
deviations that may impact primary analysis of efficacy.  The determination of the PP 
population will be finalized following a complete data review by both INC Research 
(A Syneos Health Group Company) and Sponsor representatives prior to the database 
lock. 
The safety population will consist of all patients who receive at least one dose of study 
drug (either DSP-7888 Dosing Emulsion or Bev). 
The DLT population will consist of all patients in Part 1 of the study who receive the 
first 5 administrations of the combination of DSP-7888 Dosing Emulsion plus Bev or 
who are discontinued from the study during this time due to the occurrence of a DLT 
and who do not have major protocol deviations that may impact primary analysis of 
efficacy. 
11.2.1 Determination of Number of Events, Power and Sample Size 
Considering that the number of death events are 108 (observed at IA1), approximately 
185 (IA2), and approximately 260 (FA), the study will have approximately 90% power 
to detect a 34% reduction in the HR of DSP-7888 Dosing Emulsion plus Bev versus 
Bev alone (ie, HR = 0.663, which corresponds to a 1-year survival proportion of 45% in 
the DSP-7888 Dosing Emulsion plus Bev arm compared to 30% in the Bev alone arm). 
The number of death events at the FA could go up to 370 if event re-estimation is 
performed based on the conditional power calculated at IA2.  Assuming an enrollment 
rate of 11 patients per month and patients are followed until the end of the study, with a 
5% dropout rate per year, the study is expected to enroll approximately 338-480 
patients.   
Note that Part 2 is an event-driven adaptive trial and statistical power of Part 2 is 
determined by the target number of death events instead of the number of patients.  The 
actual number of randomized patients in Part 2 may vary to observe the targeted number 
of events, depending on the outcome of the interim analyses, the duration of the study 
and operational feasibility. It is envisioned that approximately 215 patients will be 
enrolled at the second IA with 185 events, approximately 338 patients will be enrolled 
at the FA with 260 events when there is no event number re-estimation. If the number of 
events at the FA reaches the cap of 370 with event number re-estimation, approximately 
480 patients will be enrolled in the study assuming that the ratio of the number of events 
to the number of patients at the FA is approximately 0.77 (assume similar death event 
rate of 260/338 when the target event number is 260).  
11.3 Demographic and Other Baseline Characteristics 
All demographic and baseline characteristics information will be summarized using the 
ITT population.  Extent of surgical resection in primary therapy (GTR versus not GTR) 


 
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and KPS class (60 through 70 versus 80 through 100) will be used as the stratification 
factors at randomization, and therefore will be considered to be the main covariate in 
the analysis of efficacy.  In addition, gender, and age groups (< 55, 55 through 64, 
65 through 74, 75 through 84, ≥ 85), and IDH mutation and MGMT methylation status 
will be considered to be relevant. 
11.4 Planned Analyses 
All efficacy analyses will be based on the ITT population.  Analyses will be repeated 
using the PP population.   
For survival-type endpoints (OS, PFS, duration of response), descriptive summary 
statistics that are of interest, point estimates, and 95% CI intervals for overall and PFS 
probabilities will be provided for each treatment group at 3, 6, 9, 12, 15, 18, 21, and 24 
months, if estimable.  These estimates will be computed from KM survival curves. 
11.4.1 Demographic and Other Baseline Characteristics 
All demographic and baseline characteristics information will be summarized using the 
ITT population.  Karnofsky Performance Status scores (classified as 60 through 70 
versus 80 through 100) and extent of surgical resection in primary therapy (GTR versus 
not GTR) will be used as stratification factors at randomization, and therefore will be 
considered to be the main covariate in the analysis of efficacy.  In addition, gender and 
age groups (< 55, 55 through 64, 65 through 74, 75 through 84, and ≥ 85) and IDH 
mutation and MGMT methylation status will be considered to be relevant. 
11.4.2 Planned Analysis for Primary Efficacy Endpoint 
The primary efficacy endpoint is OS.  The KM method will be used to estimate and 
visualize the distribution of OS by treatment group.  Additionally, KM curves and 
estimates by treatment group will be provided for the subgroups of patients within each 
randomization stratum (KPS 60 through 70, KPS 80 through 100, and extent of surgical 
resection in primary therapy [GTR versus not GTR]).  The primary treatment 
comparison will be based on a stratified logrank test considering the 2 randomization 
factors of KPS class and extent of surgical resection in primary therapy (GTR versus not 
GTR).  A stratified Cox’s regression model will be performed with treatment group as 
the independent variable and the 2 randomization variables of KPS class (60 through 70 
versus 80 through 100) and extent of surgical resection in primary therapy (GTR versus 
not GTR) as strata.  Hazard ratio and respective 95% CI obtained from the stratified 
Cox model will be provided.    
For patients who discontinue early or who complete without meeting the event 
(= death), the OS will be censored on the last day they were known to be alive. 


 
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11.4.3 Planned Analysis for Key Secondary Efficacy Endpoint 
The key secondary efficacy endpoint is 12-month survival rate which is defined as the 
proportion of patients alive 12 months after randomization.  Treatment comparisons will 
be performed using the respective KM estimate and the respective variances according 
to the Greenwood’s formula.38 
11.4.4 Planned Analysis for Other Secondary Efficacy Endpoints 
The other secondary efficacy endpoints are: 
• PFS is defined as the interval between randomization and progression, 
determined by central radiology review, or death from any cause.  Pseudo-
progression will not be considered as PD for the assessment of PFS, but only 
confirmed PD cases.  PFS will be analyzed similarly to OS. 
• Six-month PFS rate is defined as the proportion of patients alive at 6 months 
after randomization and without progressive neoplastic disease.   Six-month PFS 
will be estimated considering only progressions determined by central radiology 
review or death as events.  Six-month PFS will be analyzed similarly to 12-
month survival rate. 
• The ORR is defined as the proportion of patients who achieve CR or PR based 
on the mRANO criteria as determined by central radiology review.  The absolute 
and relative frequency of ORR (CR plus PR) will be presented by treatment 
group in overall and within each randomization stratum (KPS 60 through 70, 
KPS 80 through 100, and extent of surgical resection in primary therapy [GTR 
versus not GTR]) and will be compared by the Cochran-Mantel-Haenszel test 
accounting for randomization strata.  The odds ratio and CI obtained from the 
Cochran-Mantel-Haenszel will be provided. 
• The duration of response is defined as the interval between first documented 
oncological response and progression of disease or death from any cause, with 
response based on the mRANO criteria as determined by central radiology 
review.  Pseudo-progression will not be considered as PD for the assessment of 
duration of response endpoints, but only confirmed PD cases.  Duration of 
response will be analyzed similarly to OS. 
• For the calculation of PFS and duration of response, progression determined by 
central radiology review of the MRI results will be used as events. Table 5 
summarizes the calculation approach for PFS considering the various situations 
for censoring. This table follows the FDA Guidance for Industry Clinical Trial 
Endpoints for the Approval of Cancer Drugs and Biologics, May 2007.  Further 
details for the analysis of the PFS will be provided in the SAP. 


 
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Table 5: 
Calculation of PFS-Based Results of Centralized Review 
Situation 
Date of Progression or Censoring 
Outcome 
No baseline radiological 
assessments 
Randomization 
Censored 
Confirmed PD (by central 
radiology review) 
Date of radiological assessment showing 
PD 
Event 
No death or confirmed PD 
Date of last adequate radiological 
assessment 
Censored 
Treatment discontinuation 
for clinical (unconfirmed) 
progression 
Date of last adequate radiological 
assessment 
Censored 
Treatment discontinuation 
for toxicity or reason other 
than confirmed PD, 
clinical progression, or 
death 
Date of last adequate radiological 
assessment 
Censored 
New anticancer treatment 
started with no confirmed 
PD beforehand 
Date of last adequate radiological 
assessment before start of new treatment 
Censored 
Death during the study 
before confirmed PD 
Date of death 
Event 
Treatment discontinuation 
for other than confirmed 
PD or death, and no 
post-baseline radiological 
assessments 
Randomization 
Censored 
Note:  An adequate radiological assessment is one that is evaluable according to mRANO 
criteria by review of MRI results. 
 
11.4.5 Planned Analysis for Pharmacodynamic Endpoints 
Pharmacodynamic assessments will include: 
• The evaluation of WT1 peptide-specific CTL induction activity 
• Immunohistochemistry to evaluate expression of WT1 by IHC and CISH  


 
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To analyze the frequencies of the WT1-specific CTLs by tetramer assay, immunological 
responses would be defined to be positive when the frequencies of WT1-specific CTLs 
determined by tetramer assay increased significantly at least at one time point after the 
WT1 vaccination compared to those of WT1-specific CTLs before the WT1 
vaccination.  Possible correlations between clinical efficacy (eg, OS, ORR) and 
immunological responses would be examined in patients with both clinical and 
immunological responses available for assessment.  The results would be used to 
examine whether there is a significant correlation between increases in the frequencies 
of WT1 peptide-specific CTLs and clinical responses. 
For patients with tumor samples, a determination of expression of WT1 in tumor tissue 
from patients with solid tumors will be done by IHC and CISH.  These tumor tissue 
samples will be obtained before the first dose of study drug and after the last dose of 
study drug (optional).  The pathological assessment based on the proportion (%) of the 
stained tumor cells and the staining intensity for WT1 of each patient will be reported.  
Possible correlations between clinical efficacy (eg, OS, ORR) and the pathological 
assessment would be examined in patients with both clinical and immunological 
responses available for assessment. 
11.4.6 Safety Analyses 
Safety analysis and other summaries based on the safety population will be presented by 
actual treatment received.  Safety evaluation will include assessments of AEs, serum 
chemistry, hematology (CBC), urinalysis, coagulation parameters, pregnancy, 
neurological examination, KPS, study drug exposure, vital signs, physical examination, 
and ECG.   
Analyses of the safety parameters will be presented by visits and/or time points where 
data are collected.  For continuous variables, descriptive statistics will include the 
number of patients (n), mean, standard deviation, median, minimum, and maximum.  
Frequencies and percentages will be displayed for categorical data.  Percentages by 
categories will be based on the number of patients with no missing data, ie, will add up 
to 100%.  Categorical variables with a non-zero number of missing values will include 
an additional “Missing” category with no percentage provided (the category will be 
excluded from the distribution). 
Patient incidence rates of all treatment-emergent AEs will be tabulated by system organ 
class and preferred term.  Tables and/or narratives of “on-study” deaths and serious and 
significant treatment-emergent AEs, including early withdrawals due to AEs, also will 
be provided.  The extent of study exposure defined as the ([last exposure date] - [first 
exposure date] + 1) would also be summarized descriptively. 


 
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11.4.7 Additional Analyses 
Subgroup analyses will be presented for selected efficacy and safety outputs.  Relevant 
subgroups include, but are not limited to, geographic region, race, gender, age group, 
baseline KPS score, and extent of surgical resection in primary therapy (GTR versus not 
GTR).  Details of subgroup analyses as appropriate will be presented in the SAP. 
11.5 Periodic Safety Reviews 
Interim safety data will be provided to the IDMC that will periodically convene to 
review accumulating safety data and to provide a recommendation on study 
continuation or early termination in case there is a concern regarding safety.  The details 
of the data outputs that will be provided for the meetings will be referenced in the 
IDMC Charter. 
11.6 Interim and Final Analyses 
An adaptive design with 2 IAs and 1 FA is employed in Part 2 of this trial. Figure 3 
presents the 3 stages of the adaptive design for Part 2 of the Study.  
Figure 3: 
Adaptive Design for Part 2 of the Study 
 
 
Abbreviations: CP = conditional power; HR = hazard ratio; IA = interim analysis.  
 
Interim analysis 1 was carried out after 108 death events; IA2 will be carried out after 
approximately 185 death events and the FA will be carried out after approximately 260 
death events or the target re-estimated number of death events occur. The target death 
event re-estimation will be determined by calculating the conditional power (CP) based 
on the IA2 results. The CP is defined as the probability of establishing a significant 
treatment effect on OS at the FA conditional upon the OS data available at IA2. 
 
If the 1-sided p-value at IA1 is less than or equal to the prespecified significance 
levels11, an early efficacy would be claimed.  If the HR at IA1 is greater than 1, then the 


 
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study may be stopped for futility.  The futility boundary is non-binding and the totality 
of data including other efficacy and safety data may weigh in the futility decision 
making besides the futility criteria for the HR.  
 
Should the study neither stop for futility nor claim early efficacy at IA1, the study will 
continue to IA2. The IA2 decision rules are described as follows: if the 1-sided p-value 
at IA2 is less than or equal to the prespecified significance level s12, an early efficacy 
will be claimed. In this case, the primary endpoint is reached by IA2, and the study may 
be concluded to be successful and the CSR may be written based on IA2.  
 
If the early efficacy cannot be claimed at IA2, the event re-estimation will be performed 
using CP. This rule will be defined using 2 thresholds for CP, denoted by c1 and c2. 
These thresholds define the “underpowered zone” where it is most sensible to increase 
the number of OS events. The total number of events at the FA may be modified after 
IA2 as follows: 
• If CP ≤ c1, retain the original number of events (ie, 260 events). 
• If CP > c1 and CP ≤ c2, increase the number of events to achieve CP of 
90% or up to a pre-defined cap (ie, 370 events).  
• If CP > c2, retain the original number of events (ie, 260 events).  
When the FA is conducted and the 1-sided p-value is less than or equal to the pre-
specified significance level s3, then efficacy success in terms of the primary endpoint of 
OS will be claimed at the end of the study. 
Details of the adaptive design and the interim and final analyses including the 
specifications for c1, c2, s11, s12, and s13 will be provided in the SAP. 
 
11.7 Protocol Deviations 
All deviations related to study inclusion or exclusion criteria, conduct of the study, 
patient management, or patient assessment will be identified and evaluated before 
database lock and will be described in the final clinical study report. 
11.8 General Considerations 
Any change to the data analysis methods described in the protocol will require an 
amendment only if it changes a principal feature of the protocol.  Any other change to 
the data analysis methods described in the protocol and the justification for making the 
change will be described in the SAP and the clinical study report.  
For continuous variables, descriptive statistics will include the number of patients (n), 
mean, standard deviation, median, minimum, and maximum.  When needed, the use of 
other percentiles (eg, 10%, 25%, 75%, and 90%) will be mentioned in the relevant 


 
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section.  Frequencies and percentages will be displayed for categorical data.  
Percentages by categories will be based on the number of patients with no missing data, 
ie, will add up to 100%.  Categorical variables with a non-zero number of missing 
values will include an additional “Missing” category with no percentage provided (the 
category will be excluded from the distribution).  Fisher’s exact test will be used for 
unstratified comparison of categorical variables. 
Summaries based on the ITT and PP populations will be presented by planned treatment 
group, unless specifically stated otherwise.  Safety analyses and other summaries based 
on the safety population will be presented by actual treatment received.  All analyses 
will be performed using data pooled across sites.  Patient listings of all data from the 
eCRFs as well as any derived variables will be presented. 
All statistical comparisons will be made using 1-sided tests at the α = 0.025 significance 
level unless specifically stated otherwise, and CI will be calculated at 95%, 2-sided.   
All p-values will be rounded to 4 decimal places. 
Percentage values will be printed with 1 digit to the right of the decimal point (eg, 
52.3%, 8.9%).  Dates will be printed as DDMMMYYYY.  If only year and month are 
available, date will be displayed as MMMYYYY.  If only year is available, then just 
YYYY will be displayed.  Dates that are missing because they are not applicable for the 
patients are output as “NA,” unless otherwise specified. 
All analyses will be performed using data pooled across sites. 
All data processing, summarization, and analyses will be performed using SAS® 
Version 9.3 or higher. 
Specifications for table, figures, and data listing formats can be found in the SAP 
specifications for this study. 
All planned analyses will be conducted following a soft database lock.  A hard database 
lock will occur prior to the final analysis. 
12 QUALITY ASSURANCE AND QUALITY CONTROL 
12.1 Audit and Inspection 
Study centers and study documentation may be subject to Quality Assurance audit 
during the course of the study by the Sponsor or its nominated representative.  In 
addition, inspections may be conducted by regulatory authorities at their discretion. 


 
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12.2 Monitoring 
Data for each patient will be recorded on an eCRF.  Data collection must be completed 
for each patient who signs an ICF. 
In accordance with current Good Clinical Practice (cGCP) and ICH guidelines, the 
study monitor will carry out source document verification at regular intervals to ensure 
that the data collected in the eCRF are accurate and reliable. 
The Investigator must permit the monitor, the IEC/IRB, the Sponsor’s internal auditors, 
and representatives from regulatory authorities direct access to all study-related 
documents and pertinent hospital or medical records for confirmation of the data 
contained within the eCRFs. 
During the COVID-19 public health emergency, traditional on-site monitoring might be 
limited for reasons such as: (1) sites may not be able to accommodate monitoring visits 
(eg, due to staffing limitations or site closures); or, (2) monitors may not be able to 
travel to trial sites. When planned on-site monitoring visits are not possible, the reason 
should be documented and available for review by SDP Oncology and during FDA 
inspections. 
12.3 Data Management and Coding 
The Sponsor or INC Research (A Syneos Health Group Company) will be responsible 
for the activities associated with the data management of this study.  This will include 
setting up a relevant database and data transfer mechanisms, along with appropriate 
validation of data and resolution of queries.  Data generated within this clinical study 
will be handled according to the relevant standard operating procedures of the Data 
Management and Biostatistics Departments of INC Research (A Syneos Health Group 
Company). 
Medical coding will use Medical Dictionary for Regulatory Activities for concomitant 
diseases and AEs and WHO Drug Dictionary for medications. 
Missing or inconsistent data will be queried in writing to the Investigator for 
clarification.  Subsequent modifications to the database will be documented. 
12.3.1 Data Collection/Electronic Data Capture 
The Sponsor/INC Research (A Syneos Health Group Company) will provide eCRFs.  
The results from Screening including the pre-screening and data collected during the 
study (except clinical laboratory test results) will be recorded in the patient’s eCRF.  
The Investigator will review and sign all eCRFs.  
The study sites will use an electronic data capture (EDC) system that is compliant with 
relevant FDA regulatory requirements per 21 Code of Federal Regulations Part 11.  


 
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Password protected access to the EDC system will be enabled via a secure website.  
Data queries and data corrections will be handled through the same system.  All 
transactions within the EDC system are fully documented within an electronic audit 
trail.  Each set of completed eCRFs must be reviewed and electronically signed and 
dated by the Investigator. 
The source documents for the data recorded in the eCRF may include: 
• Outcome, severity, and seriousness of AEs 
• Causality of an AE to the study drug 
• Reason for concomitant medication use 
• Reason for change in dose of the study drug 
• Reason for patient’s discontinuation 
12.3.2 Records and Supplies 
12.4 Drug Accountability 
On receipt of the study drug, the Investigator (or designee) will conduct an inventory of 
the supplies and verify that study drug supplies are received intact and in the correct 
amounts before completing a supplies receipt.  The Investigator will retain a copy of 
this receipt at the study center and return the original receipt to the study monitor.  The 
study monitor may check the study supplies at each study center at any time during the 
study. 
It is the responsibility of the study monitor to ensure that the Investigator (or designee) 
has correctly documented the amount of the study drug received, dispensed, and 
returned on the dispensing log that will be provided.  A full drug accountability log will 
be maintained at the study center at all times.  The study monitor will also perform an 
inventory of study drug at the close-out visit to the study center.  All discrepancies must 
be accounted for and documented. 
12.5 Financing and Insurance 
Financing and insurance of this study will be outlined in a separate agreement between 
INC Research (A Syneos Health Group Company) and the Sponsor. 
12.6 Compensation 
The patient will be treated and/or compensated for any study-related illness/injury 
pursuant to the information provided in the Compensation for Injury section of the ICF. 


 
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13 ETHICS 
13.1 Independent Ethics Committee or Institutional Review Board 
Before initiation of the study at each study center, the protocol, the ICF, other written 
material given to the patients, and any other relevant study documentation will be 
submitted to the appropriate IEC/IRB.  Written approval of the study and all relevant 
study information must be obtained before the study center can be initiated or the study 
drug is released to the Investigator.  Any necessary extensions or renewals of IEC/IRB 
approval must be obtained for changes to the study such as amendments to the protocol, 
the ICF, or other study documentation.  The written approval of the IEC/IRB together 
with the approved ICF must be filed in the study files. 
The Investigator will report promptly to the IEC/IRB any new information that may 
adversely affect the safety of the patients or the conduct of the study.  The Investigator 
will submit written summaries of the study status to the IEC/IRB as required.  On 
completion of the study, the IEC/IRB will be notified that the study has ended. 
13.2 Regulatory Authorities 
Relevant study documentation will be submitted to the regulatory authorities of the 
participating countries, according to local/national requirements, for review and 
approval before the beginning of the study.  On completion of the study, the regulatory 
authorities will be notified that the study has ended. 
13.3 Ethical Conduct of the Study 
The Investigator(s) and all parties involved in this study should conduct the study in 
adherence to the ethical principles based on the Declaration of Helsinki, cGCP, ICH 
guidelines, and the applicable national and local laws and regulatory requirements. 
13.4 Informed Consent 
The process of obtaining informed consent must be in accordance with applicable 
regulatory requirement(s) and must adhere to cGCP. 
If an informed consent cannot be obtained and documented from a prospective trial 
participant (or legally authorized representative) as a signed paper copy, the consent 
form may be provided electronically by the Investigator or designee. 
Where a prospective trial participant (or legally authorized representative) is unable to 
print the informed consent document provided electronically by the Investigator or 
designee, an electronic signature process is not available, and the prospective trial 
participant must meet time-sensitive eligibility criteria, the Investigator may consider 
using the alternative process to satisfy FDA requirements for obtaining and 
documenting informed consent and IRB approval process (FDA Guidance on Conduct 


 
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of Clinical Trials of Medicinal Products during COVID-19 Public Health Emergency, 
July 2020). 
The Investigator is responsible for ensuring that no patient undergoes any study-related 
examination or activity before that patient has given written informed consent to 
participate in the study. 
The Investigator or designated personnel will inform the patient of the objectives, 
methods, anticipated benefits, and potential risks and inconveniences of the study.  The 
patient should be given every opportunity to ask for clarification of any points s/he does 
not understand and, if necessary, ask for more information.  At the end of the interview, 
the patient will be given ample time to consider the study.  Patients will be required to 
sign and date the ICF.  After signatures are obtained, the ICF will be kept and archived 
by the Investigator in the Investigator’s study file.  A signed and dated copy of the 
patient’s ICF will be provided to the patient or the patient’s legally authorized 
representative. 
It should be emphasized that the patient may refuse to enter the study or to withdraw 
from the study at any time, without consequences for further care or penalty or loss of 
benefits to which the patient is otherwise entitled.  Patients who refuse to give or who 
withdraw written informed consent should not be included or continue in the study. 
If new information becomes available that may be relevant to the patient’s willingness 
to continue participation in the study, a new ICF will be approved by the IEC(s)/IRB(s) 
(and regulatory authorities, if required).  The study patients will be informed about this 
new information and re-consent will be obtained. 
13.5 Patient Confidentiality 
Monitors, auditors, and other authorized agents of the Sponsor and/or its designee, the 
IEC(s)/IRB(s) approving this research, and the FDA, as well as that of any other 
applicable agency(ies), will be granted direct access to the study patient’s original 
medical records for verification of clinical study procedures and/or data, without 
violating the confidentiality of the patient to the extent permitted by the law and 
regulations.  In any presentations of the results of this study or in publications, the 
patient’s identity will remain confidential. 
All personal data collected and processed for the purposes of this study should be 
managed by the Investigator and his/her staff with adequate precautions to ensure the 
confidentiality of those data, and in accordance with the Health Insurance Portability 
and Accountability Act, applicable to national and/or local laws and regulations on 
personal data protection. 


 
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14 REPORTING AND PUBLICATION, INCLUDING ARCHIVING 
Essential documents are those documents that individually and collectively permit 
evaluation of the study and the quality of the data produced.  After completion of the 
study (end of study is defined as the date of the last visit of the last patient), all 
documents and data relating to the study will be kept in an orderly manner by the 
Investigator in a secure study file.  This file will be available for inspection by the 
Sponsor or its representatives.  Essential documents should be retained for 2 years after 
the final marketing approval in an ICH region or for at least 2 years since the 
discontinuation of the clinical development of the investigational product.  It is the 
responsibility of the Sponsor to inform the study center when these documents no 
longer need to be retained.  The Investigator must contact the Sponsor before destroying 
any study-related documentation.  In addition, all patient medical records and other 
source documentation will be kept for the maximum time permitted by the hospital, 
institution, or medical practice. 
The Sponsor must review and approve any results of the study or abstracts for 
professional meetings prepared by the Investigator(s).  This material shall be forwarded 
to the Sponsor at the earliest feasible time, but not less than 45 days before submission 
of any publication or any public presentation.  Published data must not compromise the 
objectives of the study.  Data from individual study centers in multicenter studies must 
not be published separately. 


 
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analysis of the Macdonald, RECIST, RANO, and RECIST + F criteria. Neuro-
Oncology. 2012;14(5):667-673. doi:10.1093/neuonc/nos070. 
32. Ellingson BM, Wen PY, Cloughesy TF. Modified Criteria for Radiographic 
Response Assessment in Glioblastoma Clinical Trials. Neurotherapeutics. 
2017;14(2):307-320. doi:10.1007/s13311-016-0507-6. 
33. Allele Frequency Net Database (AFND). 
http://www.allelefrequencies.net/default.asp.  
34. Elamin YY, Shereen R, Toomey S, et al. Immune effects of bevacizumab: 
killing two birds with one stone. Cancer Microenvironment 2015;8:15-21. 
35. Ellingson BM, Wen PY, Cloughesy TF. Modified criteria for radiographic 
response assessment in glioblastoma clinical trials. Neurotherapeutics. 
2017;14(2):307-320. doi:10.1007/s13311-016-0507-6. 


 
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36. Nayak L, DeAngelis L, Wen P, et al. The Neurologic Assessment in Neuro-
Oncology (NANO) Scale: a tool to assess neurological function for integration 
in the Radiologic Assessment in Neuro-Oncology (RANO) Criteria. Neuro 
Oncol 2014;16(Suppl2):ii76. 
37. National Comprehensive Cancer Network (NCCN): Cancer and COVID-19 
Vaccination Version 1.0; https://www.nccn.org/covid-19/pdf/COVID-
19_Vaccination_Guidance_V1.0.pdf 
38. Long QX, Liu BZ, Deng HJ, Wu GC, Deng K, Chen YK. Antibody responses to 
SARS-CoV-2 in patients with COVID-19. Nature Medicine 2020; 26:845-848. 
39. Collett D. Modelling survival data in medical research. London: Chapman & 
Hall, 1994. pp. 23-24. 
 


 
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16 APPENDICES 
16.1 
Performance Status Scores 
16.2 
The Modified Response Assessment in Neuro-Oncology (mRANO) Criteria 
16.3 
The Neurological Assessment in Neuro-Oncology (NANO) Criteria 
16.4 
Glucocorticoid Dose Equivalents 
16.5 
Table of Tissue Samples and Informed Consents Required 
16.6 
Investigator Signature Page 
 
 
 


 
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16.1 Performance Status Scores 
ECOG Performance Status Scale 
Karnofsky Performance Status Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal 
activity; minor signs or 
symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; 
some signs or symptoms of 
disease. 
70 
Cares for self, unable to carry 
on normal activity or to do 
active work. 
2 
In bed < 50% of the time.  
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional 
assistance, but is able to care 
for most of his/her needs. 
50 
Requires considerable 
assistance and frequent 
medical care. 
3 
In bed > 50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special 
care and assistance. 
30 
Severely disabled, 
hospitalization indicated.  
Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any self-
care.  Totally confined to bed or 
chair. 
20 
Very sick, hospitalization 
indicated.  Death not 
imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 


 
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16.2 The Modified Response Assessment in Neuro-Oncology (mRANO) Criteria  
Figure 4: 
Post-Randomization Tumor Assessment Process Flow 
 
 
Recurrence 
Study 
Entry 
Pre-Tx 
MRI (1) 
< 28 Days 
Therapy 
Randomization 
Post-Tx 
MRI (N) 
>25% Bidim or 
>40% Volume Increase 
(PD wrt Pre-Tx Baseline or 
Nadir) 
>50% Bidim or 
>65% Volume Decrease 
(PR/CR wrt Pre-Tx Baseline) 
SD wrt Pre-Tx 
Baseline 
Preliminary 
Progression (PD) 
Continue Therapy 
Preliminary 
Response (PR/CR) 
Continue Therapy 
Stable Disease (SD) 
Continue Therapy 
Post-Tx 
MRI (N +1) 
Post-Tx 
MRI (N +1) 
>25% Bidim or 
>40% Volume Increase 
(PD wrt Post-Tx MRI(N)) 
SD/PR/CR 
wrt Post-Tx MRI(N) 
>25% Bidim or 
>40% Volume Increase 
(PD wrt Post-Tx MRI(N)) 
Confirmed Progression (PD)
a 
Continue Therapy if Safe or 
STOP Therapy 
SD/PR/CR 
wrt Pre-Tx Baseline 
Confirmed PsP 
Continue Therapy 
Preliminary PD 
Continue Therapy 
Durable Response 
Continue Therapy 
Post-Tx 
MRI (M) 
>25% Bidim or 
>40% Volume Increase 
(PD wrt smaller of Nadir 
after PsP or MRI(N+1)) 
SD/PR/CR wrt smaller of 
Nadir or MRI(N+1) 
Confirmed Progression (PD)
 a 
Continue Therapy if Safe or 
STOP Therapy 
Stable Disease (SD) 
Continue Therapy 
a  Regular scan assessments (mRANO/NANO) should continue if patients do not receive any new treatment for their GBM. 
To ensure harmonization across this multinational study, bidimensional measurements (rather than volume) were recommended. 
The figure has been expanded from the original article: intext information has been added for clarification, based on communication with the lead author 
(Ellingson BM, Wen, PY, Cloughesy, TF. Modified Criteria for Radiographic Response Assessment in Glioblastoma Clinical Trials. Neurotherapeutics 2017;14:307-320). 
 


 
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Figure 5: 
Algorithm for Identification of Target Lesions 
 
Note that both perpendicular measurements should be greater than or equal to 10 mm; otherwise, the lesion should be classified 
as non-target. 
 


 
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Measurable Lesions 
Non-Measurable Lesions 
Target Lesions 
Contrast enhancing 
Lesions too small to be 
measured (less than 10 mm 
in either of the perpendicular 
dimensions) 
Up to a total of 5 measurable 
lesions should be defined and 
ranked from largest to 
smallest 
 
 
 
2 perpendicular diameters 
both > 10 mm* 
Lesions that lack contrast 
enhancement (non-enhancing 
disease) 
 
 
 
 
*If slice thickness plus 
interslice gap is >5 mm, 
minimum size for BOTH 
measurements should be 
2 x slice thickness + 2 x 
interslice gap. 
Lesions with poorly defined 
margins that cannot be 
measured or segmented with 
confidence 
 
 
 
 
e.g., slice thickness 5 mm, 
interslice gap 1.5 mm, 
minimum measurement = 
13 mm. 
 
 
 
 
 
 
Lesion Assessments: 
• Measure the sum of the products of the diameters of all target lesions 
• Assess non-target lesions (all enhancing non-target lesions, non-enhancing 
disease) 
• Look for new lesions (new measurable lesions should be added to the sum of 
bidimensional products) 
• Combine lesion assessments with neurological/clinical findings and steroid use 
to yield an overall response 
Complete Response (CR) Requires All of the Following: 
Disappearance of all enhancing measurable and non-measurable disease sustained for at 
least 4 weeks. The first scan exhibiting disappearance of all enhancing measurable and 
non-measurable disease is considered “preliminary CR”. If the second scan exhibits 
measurable enhancing disease with respect to the “preliminary CR” scan, then the 
response is not sustained, noted as pseudo-response and is now considered “preliminary 
PD” (note confirmed PD requires at least 2 sequential increases in tumor volume). If the 
second scan continues to exhibit disappearance of enhancing disease or emergence of 
non-measurable disease (less than 10mm bidimensional product), it is considered a 


 
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durable CR and the patient should continue on protocol therapy until reasons for 
discontinuing protocol therapy outlined in Section 8.2.4 are met..  
 
Patients must be off corticosteroids (or on physiologic replacement doses only). 
Stable or improved clinical assessments (i.e. neurological examinations). 
Note: Patients with non-measurable disease only at baseline cannot have CR; the best 
response possible is SD. 
Partial Response (PR) Requires All of the Following: 
A decrease of ≥50% in sum of products of perpendicular diameters or ≥65% decrease in 
total volume of all measurable enhancing lesions compared with baseline, sustained for 
at least 4 weeks. The first scan exhibiting ≥50% decrease in sum of products of 
perpendicular diameters or ≥65% decrease in total volume of all measurable enhancing 
lesions compared with baseline is considered “preliminary PR”. If the second scan 
exhibits PD with respect to the “preliminary PR” scan, then the response is not 
sustained, noted as pseudo-response and is now considered “preliminary PD” (note 
confirmed PD requires at least 2 sequential increases in tumor volume). If the second 
scan exhibits SD, PR, or CR, it is considered a durable PR and the patient should 
continue on protocol therapy until reasons for discontinuing therapy outlined in Section 
8.2.4 are met. 
Steroid dose should be the same or lower compared with baseline scan. 
Stable or improved clinical assessments. 
Note: Patients with non-measurable disease only at baseline cannot have PR; the best 
response possible is SD. 
Progressive Disease (PD) is Defined by Any of the Following: 
At least 2 sequential scans separated by ≥4 weeks both exhibiting ≥25% increase in sum 
of products of perpendicular diameters or ≥40% increase in total volume of enhancing 
lesions. The first scan exhibiting ≥25% increase in sum of products of perpendicular 
diameters or ≥40% increase in total volume of enhancing lesions should be compared to 
the smallest tumor measurement obtained either at baseline (if no decrease) or best 
response (on stable or increasing steroid dose) and is noted as “preliminary PD.” If the 
second scan ≥4 weeks later exhibits a subsequent ≥25% increase in sum of products of 
perpendicular diameters or ≥40% increase in total volume of enhancing lesions relative 
to the “preliminary PD” scan, it is considered “confirmed PD” and the patient should 
discontinue protocol therapy. If the second scan ≥4 weeks later exhibits SD or PR/CR, 
this scan showing “preliminary PD” is noted as “pseudo-progression” and the patient 
should continue on protocol therapy until a second increase in tumor size relative to the 


 
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pseudo-progression scan is observed. Note that any new measurable (>10 mm × 10 mm) 
enhancing lesions should not be immediately considered PD, but instead should be 
added to the sum of bidimensional products or total volume representing the entire 
enhancing tumor burden. 
In the case where the baseline or best response demonstrates no measurable enhancing 
disease (visible or not visible), then any new measurable (>10 mm x 10 mm) enhancing 
lesions are considered PD after confirmed by a subsequent scan ≥4 weeks exhibiting 
≥25% increase in sum of products of perpendicular diameters or ≥40% increase in total 
volume of enhancing lesions relative to the scan first illustrating new measurable 
disease. The first scan exhibiting new measurable disease is noted as “preliminary PD.” 
If the second scan ≥4 weeks later exhibits a subsequent ≥25% increase in sum of 
products of perpendicular diameters or ≥40% increase in total volume of enhancing 
lesions relative to the “preliminary PD” scan, it is considered “confirmed PD,” and the 
patient should discontinue protocol therapy if the definitions outlined in Section 8.2.4 
are met. If the second scan ≥4 weeks later exhibits SD, CR, PR, or becomes non-
measurable, this scan showing “preliminary PD” is noted as “pseudo-progression” and 
the patient should continue on protocol therapy until a second increase in tumor size 
relative to the “preliminary PD” or pseudo-progression, scan is observed. Note that any 
new measurable (>10 mm × 10 mm) enhancing lesions on the subsequent scan 
following the preliminary PD scan should not be immediately considered confirmed PD, 
but instead should be added to the sum of bidimensional products or total volume 
representing the entire enhancing tumor burden. 
Clear clinical deterioration not attributable to other causes apart from tumor (eg, 
seizures, medication adverse effects, therapy complications, stroke, infection) or 
attributable to changes in steroid dose. 
Failure to return for evaluation as a result of death or deteriorating condition. 
Stable Disease (SD) Requires All of the Following: 
Does not qualify for CR, PR, or PD as defined above. Note that this also applies to 
patients who demonstrate pseudo-response when the confirmation scan does not show 
PD or pseudo-progression when the confirmation scan does not show PR or CR. 
In the event that corticosteroid dose was increased (for new symptoms/signs) without 
confirmation of disease progression on neuroimaging, and subsequent follow-up 
imaging shows that the steroid increase was required because of disease progression, the 
last scan considered to show stable disease will be the scan obtained when the 
corticosteroid dose was equivalent to the baseline dose. 
 
 


 
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Overall Response Assessment:  
 
If there is uncertainty regarding whether there is progression, then PD confirmation is 
strongly encouraged by subsequent evaluations at 4-week intervals.  If the subsequent 
evaluation confirms PD, then the date of progression should be the time point of the first 
assessment where PD was suspected. 
 
 
 
 
 
 
 


 
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16.3 The Neurological Assessment in Neuro-Oncology (NANO) Criteria 
Scoring assessment is based on direct observation and testing performed during clinical 
evaluation and is not based on historical information or reported symptoms.  Please 
check 1 answer per domain.  Please check “Not assessed” if testing for that domain is 
not done.  Please check “Not evaluable” if a given domain cannot be scored accurately 
due to pre-existing conditions, co-morbid events and/or concurrent medications. 
 
Date Assessment Performed (day/month/year):  
 
 
 
 
 
 
Study time point (ie, baseline, cycle 1, day 1)  
 
 
 
 
 
 
Assessment performed by (please print name):  
 
 
 
 
 
 
 
 
 
 
 


 
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The Neurological Assessment in Neuro-Oncology (NANO) Criteria (continued) 
 
 
 
 
 


 
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The Neurological Assessment in Neuro-Oncology (NANO) Criteria (continued) 
 
 


 
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Definition of Neurologic Response:  
An overall NANO score will be determined following assessment of each domain and 
will include one of 5 possible outcomes: neurologic response; neurologic progression; 
neurologic stability; not assessed; and non-evaluable.   
NANO Category 
Description 
Neurologic Response 
≥2-Level improvement in at least 1 domain without worsening 
in other domains from baseline or best level of function 
Neurological Progression 
1) ≥2-Level worsening from baseline or best level of function 
within ≥1 domain; or  
2) Worsening to the highest score within ≥1 domain. 
Neurological Stability 
A score of neurologic function that does not meet criteria for 
neurologic response, neurologic progression, non-evaluable, or 
not assessed 
Non-Evaluable 
If it is more likely than not that a factor other than underlying 
tumor activity contributed to an observed change in neurologic 
function. Such factors may include changes in concurrent 
medications or a co-morbid event 
 
In general, the assessment and scoring of all domains is encouraged. 
 
 


 
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16.4 Glucocorticoid Dose Equivalents 
Equivalent Dose 
Steroid 
1.2 mg 
Betamethasone (long-acting) 
1.5 mg 
Dexamethasone (long-acting) 
8 mg 
Methylprednisolone (intermediate-acting) 
8 mg 
Triamcinolone (intermediate-acting) 
10 mg 
Prednisone (intermediate-acting) 
10 mg 
Prednisolone (intermediate-acting) 
40 mg 
Hydrocortisone (short-acting) 
50 mg 
Cortisone (short-acting) 
Source:  http://emedicine.medscape.com/article/2172042-overview.  
 
 


 
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16.5 Table of Tissue Samples and Informed Consents Required 
Sample 
Type 
Source 
Purposes 
Optional Tumor Sample 
Provision ICF 
Optional Biological Sample Storage ICF 
Tissue  
Archival 
sample - 
mandatory 
when available 
  
WT1 IHC/CISH 
IDH 1/2 mutation 
and MGMT 
Promotor 
Methylation Status* 
  
 
Retrospective 
biomarkers** 
 
Required if patient 
undergoes medically 
necessary neurosurgical 
procedures (End of Study 
only) 
Required for retrospective biomarkers and long term 
storage 
Blood 
Optional extra 
blood tests at 
times specified 
in the Schedule 
of Assessments  
Retrospective 
biomarkers** 
NA 
Required for retrospective biomarkers and long term 
storage 
Abbreviations: CISH = chromogenic in situ hybridization;  ICF = informed consent form; IDH = isocitrate dehydrogenase; IHC = 
immunohistochemistry; MGMT = O6-methyl-guanyl-methyl-transferase; WT1 = Wilms’ Tumor 1 
*WT1 IHC/CISH IDH 1/2 mutation and MGMT Promotor Methylation Status mandatory test if tissue samples available; therefore, these tests are 
covered by the main study informed consent form. 
** Retrospective biomarkers – optional test on tissue and blood samples also requiring consent for long-term storage. 


 
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16.6 Investigator Signature Page 
Protocol Title: 
A Randomized, Multicenter, Adaptive Phase 3 Study of DSP-7888 
Dosing Emulsion in Combination with Bevacizumab versus 
Bevacizumab Alone in Patients with Recurrent or Progressive 
Glioblastoma following Initial Therapy 
Protocol Number: 
BBI-DSP7888-201G 
Confidentiality and cGCP Compliance Statement 
I, the undersigned, have reviewed this protocol (and amendments), including 
appendices, and I will conduct the study as described in compliance with this protocol 
(and amendments), cGCP, and relevant ICH guidelines. 
Once the protocol has been approved by the IEC/IRB, I will not modify this protocol 
without obtaining prior approval of Boston Biomedical, Inc., and of the IEC/IRB.  I will 
submit the protocol amendments and/or any ICF modifications to Boston Biomedical, 
Inc., and IEC/IRB, and approval will be obtained before any amendments are 
implemented. 
I understand that all information obtained during the conduct of the study with regard to 
the patients’ state of health will be regarded as confidential.  No patients’ names will be 
disclosed.  All patients will be identified by assigned numbers on all eCRFs, laboratory 
samples, or source documents forwarded to the Sponsor.  Clinical information may be 
reviewed by the Sponsor or its agents or regulatory agencies.  Agreement must be 
obtained from the patient before disclosure of subject information to a third party. 
Information developed in this clinical study may be disclosed by Boston Biomedical, 
Inc., to other clinical Investigators, regulatory agencies, or other health authority or 
government agencies as required. 
Investigator Signature 
Date 
Printed Name 
Institution 
 

SAP_001.pdf: 
Sumitomo Dainippon Pharma Oncology, Inc. 
 
Protocol No: BBI-DSP-7888-201G 
Statistical Analysis Plan – Version 5.0 
 
 
 
Confidential & Proprietary 
 
Page 1 of 59 
STATISTICAL ANALYSIS PLAN 
 
VERSION: 5.0 
DATE OF PLAN: 
01 November, 2021 
 
STUDY DRUG: 
Nelatimotide and Adegramotide (Ombipepimut-S)  
(hereafter referred to as DSP-7888) Dosing Emulsion 
PROTOCOL NUMBER: 
 
Version 1.0 29MAR2017 
Protocol Amendment 1.0 (Version 2.0) 30 Apr 2017,  
Protocol Amendment 2.0 (Version 3.0) 18 Sep 2017,  
Protocol Amendment 3.0 (Version 4.0 for South Korea Only) 06 Oct 2017,  
Protocol Amendment 4.0 (Version 5.0 for South Korea Only) 13 Oct 2017, 
Protocol Amendment 5.0 (Version 6.0) 03 Aug 2018,  
Protocol Amendment 6.0 (Version 7.0) 24 Jun 2019,  
Protocol Amendment 7.0 (Version 8.0) 05 Feb 2021 
 
STUDY TITLE: 
A Randomized, Multicenter, Adaptive Phase 3 Study of DSP-7888 Dosing Emulsion in Combination with 
Bevacizumab versus Bevacizumab Alone in Patients with Recurrent or Progressive Glioblastoma 
following Initial Therapy 
 
SPONSOR: 
Sumitomo Dainippon Pharma Oncology Inc. (SDP Oncology) 
640 Memorial Drive 
Cambridge, MA 02139, USA 
 
This study is being conducted in compliance with good clinical practice, including the archiving 
of essential documents. 


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SIGNATURE PAGE 
 
This document has been prepared by: 
 
Zijing Zhang, PhD  
Associate Director of Biostatistics,  
SDP Oncology   
 
 
 
 
 
 
Signature 
 
Date 
Bo Xu, PhD  
Sr. Director of Biostatistics,  
SDP Oncology   
 
 
 
 
 
 
Signature 
 
Date 
This document has been reviewed and accepted by: 
 
Bo Jin, PhD 
Vice President, Head of Data Science, 
SDP Oncology  
 
 
 
 
 
 
Signature 
 
Date 
Claudia Lebedinsky, MD 
Vice President, Head of Clinical 
Development, SDP Oncology 
 
 
 
 
 
 
Signature 
 
Date 


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TABLE OF CONTENTS 
1. 
REVISION HISTORY .................................................................................................7 
2. 
PURPOSE ...................................................................................................................12 
2.1. 
Timing of Analysis .....................................................................................................12 
3. 
STUDY OBJECTIVES, HYPOTHESES AND DECISION RULES FOR 
PART 2 .......................................................................................................................13 
3.1. 
Primary Objective .......................................................................................................13 
3.2. 
Key Secondary Objective ...........................................................................................13 
3.3. 
Other Secondary Objectives .......................................................................................13 
3.4. 
Exploratory Objectives ...............................................................................................13 
4. 
STUDY DESIGN .......................................................................................................14 
4.1. 
Summary of Study Design ..........................................................................................14 
4.1.1. 
Study Part 1 (Safety Lead-In) .....................................................................................14 
4.1.1.1. 
Dose Limiting Toxicity (DLT) ...................................................................................15 
4.1.2. 
Study Part 2.................................................................................................................16 
4.1.3. 
Stopping Rules ............................................................................................................17 
4.2. 
Patient Selection and Study Duration .........................................................................17 
4.3. 
Hypotheses and Decision Rules in Part 2 ...................................................................17 
4.3.1. 
Statistical Hypotheses .................................................................................................17 
4.3.2. 
Adaptive Design .........................................................................................................18 
4.3.3. 
Determination of Number of Events, Number of Patients and Power .......................18 
4.3.4. 
Decision Rules for the Interim and Final Analyses ....................................................19 
4.3.5. 
Multiplicity Adjustment..............................................................................................20 
4.3.5.1. 
Efficacy Stopping Rules .............................................................................................20 
4.3.5.2. 
Adaptive Design and Combination P-Value Approach ..............................................21 
4.3.5.3. 
Hierarchical Testing Procedure ..................................................................................23 
4.4. 
Treatment Assignment & Blinding .............................................................................23 
4.5. 
Study Schedule of Assessments..................................................................................24 
5. 
ENDPOINTS ..............................................................................................................25 
5.1. 
Primary Endpoint ........................................................................................................25 
5.2. 
Key Secondary Endpoint ............................................................................................25 
5.3. 
Other Secondary Endpoints ........................................................................................25 
5.4. 
EXPLORATORY ENDPOINTS ................................................................................25 


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6. 
ANALYSIS SETS ......................................................................................................26 
6.1. 
Safety Set ....................................................................................................................26 
6.2. 
Intent-To-Treat Set .....................................................................................................26 
6.3. 
Per-Protocol Set ..........................................................................................................26 
6.4. 
Dose-Determining Set ................................................................................................26 
7. 
PROTOCOL DEVIATIONS ......................................................................................28 
8. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS ........................................29 
8.1. 
General Methods .........................................................................................................29 
8.2. 
General Data Handling ...............................................................................................30 
8.3. 
Key Definitions ...........................................................................................................30 
8.4. 
Missing Data ...............................................................................................................31 
8.4.1. 
Missing Partial Death Dates .......................................................................................31 
8.4.2. 
Missing Dates for Adverse Events (AEs) or Concomitant Medications ....................31 
8.4.3. 
Missing Post GBM Treatment Start Date ...................................................................32 
8.4.4. 
Censoring Rules for Time-to-Event Data ...................................................................32 
8.4.5. 
Missing Lab, Pharmacodynamic and Biomarker Data ...............................................35 
8.5. 
Analysis Visit Window ...............................................................................................35 
8.6. 
Pooling of Centers ......................................................................................................35 
8.7. 
Subgroups ...................................................................................................................35 
9. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION ...........................................................................................................37 
9.1. 
Patient Disposition and Withdrawals ..........................................................................37 
9.2. 
Demographic and Other Baseline Characteristics ......................................................37 
9.3. 
Medical / Surgery History ..........................................................................................38 
9.4. 
GBM History and Other Baseline Characteristics ......................................................38 
9.5. 
Medication ..................................................................................................................38 
9.5.1. 
Prior Medication .........................................................................................................39 
9.5.2. 
Concomitant Medication ............................................................................................39 
9.5.3. 
Prior Cancer Therapies ...............................................................................................39 
9.5.4. 
Prior Radiation Therapies ...........................................................................................39 
10. 
EFFICACY .................................................................................................................41 
10.1. 
Primary Efficacy Endpoint and Analysis ...................................................................41 
10.1.1. 
Primary Efficacy Analysis ..........................................................................................41 


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10.1.2. 
Sensitivity Analysis of Primary Endpoint ..................................................................41 
10.2. 
Key Secondary Efficacy Endpoint and Analysis ........................................................42 
10.2.1. 
12-Month Overall Survival Rate ................................................................................42 
10.3. 
Other Secondary Efficacy Endpoint and Analyses .....................................................43 
10.3.1. 
Progression-Free Survival (PFS) ................................................................................43 
10.3.2. 
Best Overall Response, Objective Response Rate (ORR) and Disease 
Control Rate ................................................................................................................43 
10.3.3. 
Duration of Response .................................................................................................44 
10.4. 
Exploratory Efficacy Endpoint and Analyses .............................................................45 
11. 
ANALYSIS OF BIOMARKER DATA .....................................................................46 
12. 
SAFETY .....................................................................................................................47 
12.1. 
Extent of Exposure .....................................................................................................47 
12.1.1. 
Exposure of DSP7888.................................................................................................47 
12.1.2. 
Exposure of Bevacizumab ..........................................................................................48 
12.2. 
Treatment Compliance ................................................................................................49 
12.3. 
Adverse Events / Adverse Drug Reactions .................................................................49 
12.4. 
Laboratory Evaluation ................................................................................................51 
12.5. 
Vital Signs ..................................................................................................................52 
12.6. 
Electrocardiogram .......................................................................................................53 
12.7. 
Karnofsky Performance Score ....................................................................................53 
12.8. 
Physical Examination .................................................................................................54 
12.9. 
Echocardiogram/Multigated Acquisition Scan ...........................................................54 
12.10. 
Oxygen Saturation ......................................................................................................54 
13. 
CHANGE FROM ANLAYSIS PLANNED IN PROTOCOL....................................55 
14. 
REFERENCE .............................................................................................................56 
15. 
APPENDIX.................................................................................................................57 
15.1. 
Tipping Point Sensitivity Analysis .............................................................................57 
15.1.1. 
Fitting a Bayesian Piecewise Exponential Model to the Analysis Data Set ...............58 
15.1.2. 
Generating Event Times for Patients Lost to Follow up ............................................58 
15.1.3. 
Analyzing Imputed Data .............................................................................................59 
 


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LIST OF TABLES 
Table 1: 
List of Abbreviation ......................................................................................................9 
Table 2: 
One-Sided Alpha Spending for the primary endpoint at Each Decision Point...........21 
Table 3: 
One-Sided Alpha Spending for the Primary Endpoint at IA2 Between 180 to 
190 Events ..................................................................................................................21 
Table 4:      One-sided significance levels for the key secondary endpoint at FA for 
various actual information fractions at IA2 ................................................................23 
Table 5:      Censoring Rules for Overall Survival for Part 2. .......................................................32 
Table 6:      PFS Censoring Rules by Confirmed PD for Part 2.....................................................33 
Table 7:      Preliminary PFS Censoring Rules for Part 2 ..............................................................34 
Table 8:      CTCAE Lab Grading Parameters. ..............................................................................51 
Table 9: 
Markedly Abnormal Ranges for Vital Signs ..............................................................53 
 
LIST OF FIGURES 
Figure 1:      Part 1 of the Study – Open Label, Single Arm ..........................................................15 
Figure 2:      Part 2 of the Study – Randomized, Two Arms ..........................................................17 
Figure 3:      Adaptive Design for Part 2 of the Study ...................................................................18 
 


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1. 
REVISION HISTORY 
Version # 
Date 
Revision Summary 
0.1 
31 Jul 2017 
Initial Release Version. Based on Protocol Amendment 1 
0.2 
23 Oct 2017 
Update with sponsor comments and with changes from Protocol 
Amendment 2.0 
0.3 
27 Aug 2018 
Update with sponsor comments and with changes from Protocol 
Amendments 3.0, 4.0 and 5.0 
0.4 
30 Sep 2018 
Update with sponsor comments 
1.0 
06 Dec 2018 
Update with sponsor comments 
2.0 
09 Jan 2020 
Add the IA/FA efficacy boundary adjustment 
Add CTL, WTL, HLA*A genotype correlation analysis 
Add tipping point sensitivity analysis 
Update the OS/PFS censoring rule 
3.0 
05 Feb 2021 
Update the statistical design to an adaptive Phase 3 design 
Designate 12-month OS rate as the key secondary endpoint 
4.0  
 
29 September 2021 
Clarification of conditional power (Section 4.3.4 ) 
Updated per protocol analysis set definition to include per 
protocol analysis set for PFS (Section 6.3 ) 
Clarify the baseline definitions for efficacy and safety parameters 
(Section 8.2 ) 
Update missing data imputation rules in Section 8.4 for missing 
or partial death date, post GBM treatment date and concomitant 
medication date.  
Update PFS definitions and censoring rules (Section 8.4.4 )   
Update baseline height definition (Section 9.2 )  
Update best overall response hierarchical order, reasons for NE, 
and definitions of ORR / DCR (Section 10.3.2 ) 
Clarify the biomarker analysis are exploratory endpoints and the 
analysis are exploratory in nature and removed biomarker 
analysis from SAP (Section 11) 
Update dose intensity definition (Section 12.1 ) 
Add the analysis for ISR (Section 12.3 ) 
Update lab CTCAE grading and summary (Section 12.4 ) 
Add the markedly abnormal ranges for vital signs (Section 12.5 ) 
Update the summary of ECG (Section 12.6 ) 


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Version # 
Date 
Revision Summary 
5.0  
01 November 2021 
Update PFS Derivation Rule (Section 8.4.4) to included 
preliminary PD followed by confirmed PD is an event.   
Update the test statistic of 12 month OS rate difference in 
the case that the log-log transformation is not appropriate 
(Section 10.2.1) .   
 
 
 


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Table 1: 
List of Abbreviation 
Abbreviation 
Description 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical 
BBI 
Boston Biomedical Inc. 
Bev 
Bevacizumab 
BMI 
Body Mass Index 
BOR 
Best Overall Response 
CI 
Confidence Interval 
CISH 
Chromogenic in situ Hybridization 
CP 
Conditional Power 
CR 
Complete Response 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTL 
Cytotoxic T Lymphocyte 
DCR 
Disease Control Rate 
DDS 
Dose-Determining Set 
DEC 
Dose Evaluation Committee 
DLT 
Dose Limiting Toxicity 
DSP 
Sumitomo Dainippon Pharma 
ECG 
Electrocardiogram 
FA 
Final Analysis 
FDA 
Food and Drug Administration 
GBM 
Glioblastoma Multiforme 
GTR 
Gross Total Resection 
HLA 
Human Leukocyte Antigen 
HR 
Hazard Ratio 
IA 
Interim Analysis 
ICH 
International Conference on Harmonization 
i.d. 
Intradermally 
IDH 
Isocitrate Dehydrogenase 
IDMC 
Independent Data Monitoring Committee 


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Abbreviation 
Description 
IHC 
Immunohistochemistry 
ISR 
Injection Site Reaction 
ITT 
Intent-to-Treat 
i.v. 
intravenously 
KPS 
Karnofsky Performance Status 
KM 
Kaplan-Meier 
LVEF 
Left Ventricular Ejection Fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGMT 
O-methyl-guanyl-methyl-transferase 
MTD 
Maximum Tolerated Dose 
MUGA 
Multigated Acquisition Scan 
N/A 
Not Applicable 
NANO 
Neurological Assessment in Neuro-Oncology 
NCI 
National Cancer Institute 
OS 
Overall Survival 
ORR 
Objective Response Rate  
PD 
Progressive Disease 
PFS 
Progression-Free Survival 
PMDA 
Pharmaceuticals and Medical Devices Agency 
PP 
Per-Protocol 
PR 
Partial Response 
PT 
Preferred Term 
QTc 
Corrected QT Interval 
QTcF 
Fridericia’s correction formula (msec) 
RANO 
Response Assessment in Neuro-Oncology 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SD 
Standard Deviation 
SD 
Stable Disease 
SDP Oncology 
Sumitomo Dainippon Pharma Oncology, Inc 
SOC 
System Organ Class 


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Abbreviation 
Description 
SS 
Safety Set 
TEAE 
Treatment Emergent Adverse Event 
USAN 
United States Adopted Name 
WHO 
World Health Organization 
WT1 
Wilm’s Tumor 1 


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2. 
PURPOSE 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, summary 
tables and figures which will be produced to support the completion of the Clinical Study Report 
(CSR), and the statistical methodologies that will be used, are complete and appropriate to allow 
valid conclusions regarding the study objectives according to International Council for 
Harmonization (ICH) E9, ICH E3 and ICH E6. This analysis plan is based on the latest version 
of both the protocol and case report forms.  Any ad hoc or unplanned analyses performed and not 
identified in this SAP will be documented separately.  
2.1. 
Timing of Analysis 
This study is divided into 2 parts. Part 1 is a safety lead-in phase. Part 2 is a randomized, active-
controlled, multicenter, open-label, parallel-group, adaptive Phase 3 study of DSP-7888 Dosing 
Emulsion plus Bev versus Bev alone in patients with recurrent or progressive GBM following 
treatment with first line therapy consisting of surgery and radiation with or without 
chemotherapy. An adaptive, phase 3 design with two interim analyses (IAs) and one final 
analysis (FA) is employed in Part 2 of this trial. More detail regarding the timing of the 
respective analyses can be found in Section 4.3 . Unless otherwise specified, the analysis 
includes all data collected in the database through the time of the data snapshot or database lock.  
Additional data collected after the database lock for final analysis of the study will be prepared 
as an addendum to the study report according to regulatory or scientific need.  
DSP7888 with United States Adopted Name (USAN) of Ombipepimut-S will be use in the SAP. 
Ombipepimut-S will be used in tables, figures, listings. 


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3. 
STUDY OBJECTIVES, HYPOTHESES AND DECISION RULES 
FOR PART 2  
3.1. 
Primary Objective 
• 
To compare the overall survival (OS) between treatment with DSP-7888 Dosing 
Emulsion plus bevacizumab (Bev) versus Bev alone in patients with recurrent or progressive 
glioblastoma (GBM) following initial therapy. 
3.2. 
Key Secondary Objective 
• 
To compare the 12-month survival rate between treatment with DSP-7888 Dosing 
Emulsion plus Bev versus Bev alone. 
3.3. 
Other Secondary Objectives 
• 
To compare the progression-free survival (PFS) of DSP-7888 Dosing Emulsion plus Bev 
to Bev alone; 
• 
To compare the 6-month PFS of DSP-7888 Dosing Emulsion plus Bev to Bev alone; 
• 
To compare the response rate of DSP-7888 Dosing Emulsion plus Bev to Bev alone; 
• 
To compare the duration of response of DSP-7888 Dosing Emulsion plus Bev to Bev 
alone; 
• 
To describe the adverse event (AE) profile of DSP-7888 Dosing Emulsion plus Bev 
3.4. 
Exploratory Objectives 
• 
To describe the relationship between pharmacodynamic parameters such as Wilms’ 
Tumor 1 (WT1) peptide-specific cytotoxic T lymphocyte (CTL) activity and certain clinical 
findings (e.g., OS, response) in patients receiving DSP-7888 Dosing Emulsion plus Bev;  
• 
To describe the relationship between expression of WT1 by immunohistochemistry (IHC) 
and chromogenic in situ hybridization (CISH) in tumor tissue and certain clinical findings 
(e.g., OS, response) in patients receiving DSP-7888 Dosing Emulsion plus Bev;  
• 
To collect diffusion-weighted imaging for future analysis of imaging findings and 
correlation with disease progression. 
• 
To characterize the NANO scale score profile post DSP-7888 Dosing Emulsion plus Bev 
or Bev alone treatment. 


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4. 
STUDY DESIGN 
4.1. 
Summary of Study Design 
This study will be divided into 2 parts. Part 1 is a safety lead-in phase. Part 2 is a randomized, 
active-controlled, multicenter, open-label, parallel group, adaptive Phase 3 study of DSP-7888 
Dosing Emulsion plus Bev versus Bev alone in patients with recurrent or progressive GBM 
following treatment with first line therapy consisting of surgery and radiation with or without 
chemotherapy.  
Patients may have undergone a second surgery at the time of recurrence or progression but may 
not have received any other anti-neoplastic therapy.  Patients are randomized 1:1 to treatment 
with DSP-7888 Dosing Emulsion plus Bev or Bev alone. 
Potential study subjects first undergo pre-screening to determine if they express the appropriate 
human leukocyte antigen (HLA) type.  The DSP-7888 Dosing Emulsion is to induce a CTL 
response against cancer cells in subjects who express HLA-A*02:01, HLA-A*02:06, or HLA-
A*24:02. 
Following the HLA determination, a screening phase of up to 28 days determines eligibility. 
Following verification of eligibility and enrollment, DSP-7888 Dosing Emulsion is administered 
intradermally (i.d.), based on the following schedule: 
• 
Induction Phase: once every 7 days (± 1 day) for (Doses 1 to 5);  
• 
Consolidation Phase: once every 14 days (± 3 days) for (Doses 6 to 15) except for Day 
183;  
• 
Maintenance Phase: once every 28 days (± 7 days) until discontinuation (Dose 16 and 
thereafter).  
Bev is administered every 14 ± 3 days at the labeled dose of 10 mg/kg intravenously (i.v.). 
4.1.1. 
Study Part 1 (Safety Lead-In) 
In Part 1, 3 patients will be treated with the combination of DSP-7888 Dosing Emulsion plus 
Bev in a single-arm manner. DSP-7888 Dosing Emulsion will be administered at a dose of 10.5 
mg i.d. per the schedule described above and Bev at the dose and schedule described above.  
If 0 of these first 3 patients experiences dose-limiting toxicity (DLT), then the study will proceed 
to Part 2, which will randomize patients to the combination of DSP-7888 Dosing Emulsion plus 
Bev or to Bev alone.  
If 1 of the first 3 patients experiences a DLT, then 3 more patients will be enrolled at the same 
treatment regimen. If no additional DLTs are observed at the same dose (with 1/6 patients 
experiencing a DLT), then the study will proceed to Part 2. However, if a total of 2 or more of 
the first 6 patients experience a DLT, then the dose of DSP-7888 Dosing Emulsion will be 
decreased to 3.5 mg i.d., and an additional 3 patients will be treated with the combination of 
DSP-7888 Dosing Emulsion plus Bev. If 0 of these 3 patients experiences DLT at this reduced 
dose of DSP-7888 Dosing Emulsion, then the study will proceed to Part 2 with DSP-7888 
administered at 3.5 mg i.d.. If 1 of the 3 additional patients experiences a DLT at the reduced 
dose of DSP-7888 Dosing Emulsion, then 3 more patients will be enrolled at the same treatment 


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regimen. If no additional DLTs are observed at the reduced dose (with 1/6 patients experiencing 
a DLT), then the study will proceed to Part 2 with DSP-7888 administered at 3.5 mg i.d.. 
However, if a total of 2 patients or more experience a DLT at this reduced dose of DSP-7888 
Dosing Emulsion plus Bev, then enrollment will be placed on hold until the sponsor decides how 
best to proceed.  
In summary, if 0 of the first 3 patients or 1 of the first 6 patients experience a DLT, then the 
study will proceed to Part 2. The maximum tolerated dose (MTD) is determined only when 3, in 
the event of zero DLTs, or 6, in the event of 1 DLT, patients are treated at a dose level with ≤ 1/6 
DLT. If at least 2/3 or 2/6 DLTs are observed, then the MTD has been exceeded. Dosing should 
stop, and the dose should be de-escalated to DSP-7888 3.5 mg. Then the process should be 
repeated at the reduced dose level of DSP-7888 3.5 mg. Part 1 of this study is presented in Figure 
1 below.  
Figure 1:      Part 1 of the Study – Open Label, Single Arm 
 
 
4.1.1.1. 
Dose Limiting Toxicity (DLT) 
Dose-limiting toxicities will be ascertained during the DLT Evaluation Period for the patients 
who are enrolled in Part 1, which extends from the day of the first dose of study drug to 
completion of fifth dose at the assigned dose level (Days 1 through 29). 
A dose limiting toxicity will be defined as any of the following AEs that are at least possibly 
related to the investigational agents per the Investigator and institutional guidelines: 
PART 1 OF THE STUDY – OPEN LABEL, SINGLE ARM 
 
 
 
 
 
 
 
 
 
 
3 Patients Dosed with DSP-7888 
Dosing Emulsion 10.5 mg i.d. plus 
Bevacizumab 10 mg/kg IV 
0 Patients 
Experience 
1 Patient 
Experiences DLT 
3 Patients Dosed with DSP-7888 
Dosing Emulsion 3.5 mg i.d. plus 
Bevacizumab 10 mg/kg IV 
Study Placed 
on Hold 
Continue DSP-7888 Dosing Emulsion plus Bev; 
Undergo Same Procedures as in Part 2 Schedule of Assessments 
Initiate Part 2 of the Study (Randomized, 2 Arms) 
3 New Patients Dosed with DSP-7888 
Dosing Emulsion 10.5 mg i.d. plus 
Bevacizumab 10 mg/kg IV 
0 Patients 
Experience DLT 
1 Patient 
Experiences DLT 
0 Patients 
Experience DLT 
1 Patient 
Experiences DLT 
3 New Patients Dosed with DSP-7888 
Dosing Emulsion 3.5 mg i.d. plus 
Bevacizumab 10 mg/kg IV 
0 Patients 
Experience DLT 
1 Patient 
Experiences DLT 


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• 
The occurrence of any Grade 3 or higher hematologic AE lasting more than 7 days;  
• 
Any Grade 3 or higher non hematological AE that persists for more than 72 hours with 
the exceptions of transient nausea, vomiting, and diarrhea that are responding to supportive 
care;  
• 
Any Grade 3 or higher allergic and/or hypersensitivity reactions;  
• 
Any Grade 2 or higher autoimmune disease.  
Patients who discontinue Part 1 of the study prior to the completion of the fourth dose for 
reasons other than DLT during the Induction Phase will be replaced.  
The review of the study data to determine DLTs, increase the number of subjects in a given dose 
cohort, adjust the study dose due to safety concerns, as well as the final determination of the dose 
for Part 2 will be decided by a Dose Evaluation Committee (DEC). The DEC will consist of the 
study Medical Monitor, relevant clinical investigators of the study patients and the Syneos 
Health, LLC team and BBI (now SPDO). 
4.1.2. 
Study Part 2  
Based on the results of the DLT evaluation in Part 1, a 10.5-mg dose of DSP-7888 Dosing 
Emulsion was determined as the dose for Part 2.   
In Part 2, patients are stratified prior to randomization based on the extent of surgical resection in 
primary therapy (gross total resection [GTR] versus not GTR) and Karnofsky Performance 
Status (KPS) (See Protocol Appendix 16.1) scores (60 through 70 versus 80 through 100) and 
randomized to either: 
a) DSP-7888 plus Bev, or 
b) Bev alone 
Patients randomized to the Bev arm of the study undergo evaluations on a similar schedule as 
patients randomized to treatment with the combination of DSP-7888 Dosing Emulsion plus Bev.  
Part 2 of this study is presented in Figure 2 .   


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Figure 2:      Part 2 of the Study – Randomized, Two Arms 
 
4.1.3. 
Stopping Rules 
Refer to protocol section 8.3.5. 
4.2. 
Patient Selection and Study Duration 
Between 3 and 12 patients were planned to be enrolled in Part 1 of the study (Section 4.1.1 ).  
Part 2 of the study is an event-driven adaptive trial and its statistical power is determined by the 
target number of death events instead of the number of patients. For Part 2, if the study continues 
to the final analysis with approximately 260 death events (Section 4.3.3 ), approximately 338 
patients with GBM will be enrolled from approximately 70 investigational sites in the United 
States (US), Canada, Japan, Taiwan, and South Korea. Part 2 of the study may be concluded 
sooner with early efficacy at IA2 (with approximately 185 death events from approximately 215 
patients) or may be concluded at the final analysis with a re-estimated number of death events 
(between approximately 260 and 370 death events from approximately 338 and 480 patients).  
Note that Part 2 of the study is an event-driven adaptive trial and the statistical power of Part 2 is 
determined by the target number of death events instead of the number of patients. The actual 
number of randomized patients in Part 2 may be adjusted to observe the targeted number of 
events, depending on the outcome of the interim analyses and operational feasibility. The study 
may be terminated early for either efficacy or futility at IA1 and for efficacy only at IA2 or the 
study will continue until the target number of events is observed.   
4.3. 
Hypotheses and Decision Rules in Part 2  
4.3.1. 
Statistical Hypotheses 
The primary study endpoint is OS in Part 2 of the study. The null and one-sided alternative 
statistical hypotheses in the terms of OS in Part 2 are:  
H0:  Hazard Rate of DSP-7888 Dosing Emulsion plus Bevacizumab = Hazard Rate of 
Bevacizumab alone 


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Ha: Hazard Rate of DSP-7888 Dosing Emulsion plus Bevacizumab < Hazard Rate of 
Bevacizumab alone  
The key secondary endpoint is 12-month OS rate in Part 2 of the study. The null and one-sided 
alternative statistical hypotheses are: 
H0: 12-month OS rate of DSP-7888 Dosing Emulsion plus Bevacizumab = 12-month OS 
rate of Bevacizumab alone 
Ha: 12-month OS rate of DSP-7888 Dosing Emulsion plus Bevacizumab > 12-month OS 
rate of Bevacizumab alone 
4.3.2. 
Adaptive Design 
An adaptive design with two interim analyses and one final analysis is employed in Part 2 of this 
trial.  Figure 3 presents the 3 stages of the adaptive design for Part 2 of the Study. 
Figure 3:      Adaptive Design for Part 2 of the Study 
 
 
 CP = conditional power; HR = hazard ratio; IA = interim analysis 
4.3.3. 
Determination of Number of Events, Number of Patients and Power 
Considering that the number of death events are 108 (observed at interim analysis 1 [IA1]), 
approximately 185 (IA2), and approximately 260 (FA), the study will have approximately 90% 
power to detect a 34% reduction in the HR of DSP-7888 Dosing Emulsion plus Bev versus Bev 
alone (i.e., HR = 0.663, which corresponds to a 1-year survival proportion of 45% in the DSP-
7888 Dosing Emulsion plus Bev arm compared to 30% in the Bev alone arm). The number of 
death events at the FA could go up to 370 if event re-estimation is performed based on the 
conditional power calculated at IA2. Assuming an enrollment rate of 11 patients per month and 
patients are followed until the end of the study, with a 5% dropout rate per year, the study will 
require enrolling of approximately 338 - 480 patients. 
Note that Part 2 is an event-driven adaptive trial and statistical power of Part 2 is determined by 
the target number of death events instead of the number of patients.  The actual number of 
randomized patients in Part 2 may vary to observe the targeted number of events, depending on 
the outcome of the interim analyses, the duration of the study and operational feasibility. It is 


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envisioned that approximately 215 patients will be enrolled at IA2 with approximately 185 
events, approximately 338 patients will be enrolled at the FA with 260 events if there is no event 
number re-estimation. If the number of events at the FA reaches the cap of 370 with event 
number re-estimation, approximately 480 patients will be enrolled in the study assuming that the 
ratio of the number of events to the number of patients at the FA is approximately 0.77 
(assuming similar to the death event rate of 260 events/338 patients when the target event 
number is 260). 
4.3.4. 
Decision Rules for the Interim and Final Analyses 
As shown in Figure 3, IA1 was carried out after 108 death events; IA2 will be carried out after 
approximately 185 death events; lastly, FA will be carried out after approximately 260 death 
events or re-estimated number of death events while capped at 370. The target death event re-
estimation will be determined by calculating the conditional power (CP) based on the IA2 
results. The conditional power is defined as the probability of establishing a significant treatment 
effect on OS at the final analysis conditional upon the OS data available at IA2. 
If the one-sided p-value at the IA1 is less than or equal to the prespecified significance level s11, 
an early efficacy success would be claimed in terms of the primary endpoint of overall survival. 
If the HR at the IA1 is greater than 1, then the study may be stopped for futility. The futility 
boundary is non-binding and the totality of data including other efficacy data and safety data 
may weigh in the futility decision making besides the futility criteria for the HR.  
Should the study neither stop for futility nor claim for early efficacy at the IA1, the study will 
continue to the IA2. The IA2 decision rules are described as follows:  
[1] If the one-sided p-value at the IA2 is less than or equal to the pre-specified significance 
level s12, an early efficacy success will be claimed in terms of the primary endpoint of overall 
survival. In this case, the primary endpoint is reached by the IA2, and the study may be 
concluded to be successful, and the clinical study report (CSR) may be written based on the IA2.  
[2] If the early efficacy success cannot be claimed at the IA2, the event re-estimation will be 
performed using CP. This rule will be defined using two thresholds for CP, denoted by 𝑐1 and 𝑐2. 
In this study 𝑐1 = 0.4 and  𝑐2 = 0.9.  These thresholds define the “underpowered zone” where it 
is most sensible to increase the number of OS events. The total number of events at FA may be 
modified after IA2 as follows: 
1) If CP ≤ 𝑐1, retain the original number of events (ie, 260 events). 
2) If CP > 𝑐1 and CP ≤ 𝑐2, increase the number of events to achieve conditional power 
of 90% or up to a pre-defined cap.  In this study the cap is set to be 370.   
3) If CP > 𝑐2, retain the original number of events (ie, 260 events).  
[3] When the FA is conducted and the one-sided p-value is less than or equal to the pre-
specified significance level s13, then efficacy success in terms of the primary endpoint of overall 
survival will be claimed at the end of the study. 
The CP will be computed at IA2 using the following approach. Let 𝑚2 denote the actual number 
of events at IA2 and 𝑛3 denote the planned number of events at FA prior to event count re-
estimation.  Also, let 𝑍 be the normally distributed interim test statistic (log-rank test) and 


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assume that a larger absolute value of this test statistic, |Z|, corresponds to a beneficial treatment 
effect.  Conditional power at IA2 is given by  
CP = Φ(𝑎|𝑍| −𝑏𝑧1−𝑠13,), 
where  
𝑎= √
𝑛3 −𝑚2
𝑚2
+ √
𝑚2
𝑛3 −𝑚2
,  𝑏= √
𝑛3
𝑛3 −𝑚2
, 
𝑧1−𝑠13 is the 100(1 −𝑠13) percentile of the standard normal distribution and Φ(𝑥) is the 
cumulative distribution function of the standard normal distribution. The conditional power 
formula assumes that the future survival data are consistent with the observed data at IA2.   
The CP function above is a monotone function of the interim hazard ratio.  To prevent the 
potential back calculation of the interim HR, the event count adjustment rule may be modified to 
be a non-monotone function.   
The details of the modified event count adjustment rule will not be described here in the SAP, 
will be provided to IDMC in a separate document, and will not be shared with the blinded study 
team, site and other blinded partners. This procedure is introduced to minimize the risk of the 
treatment effect being revealed to blinded partners by the event number re-estimation. The 
decision of event count adjustment will also consider other factors including potential clinical 
benefit and operational feasibility. 
4.3.5. 
Multiplicity Adjustment  
This adaptive design guarantees overall Type I error rate control in the strong sense with respect 
to all sources of multiplicity in this trial, ie, data-driven design adaptation and analysis of two 
endpoints. The combination function approach (Wassmer and Brannath, 2016) will be used to 
ensure strong Type I error rate control for the adaptive design. The hierarchical testing approach 
will be applied to testing of the primary endpoint and the key secondary endpoint using the 
method introduced in Maurer and Bretz (2013). 
4.3.5.1. 
Efficacy Stopping Rules 
The efficacy stopping rule (to claim efficacy success) for the primary and key secondary 
endpoints will be derived using the O’Brien-Fleming type alpha-spending function. This 
approach will be defined to be consistent with the efficacy stopping rule that was applied at IA1 
as shown below.   
The overall Type I error rate in the trial will be controlled at a one-sided 𝛼= 0.025. The one-
sided alpha levels at IA1, IA2 and FA will be computed using the Lan-DeMets error spending 
function approach with an O’Brien-Fleming stopping boundary (Jennison and Turnbull, 2000).  
The results for one-sided alpha levels for the primary endpoint that are obtained by EAST 6.5 are 
shown in Table 2 . The same alpha-spending function with the same information fraction at IA1 
and IA2 will be used for the key secondary endpoint, resulting the same boundaries for the key 
secondary endpoint, ie, s21 = s11 = α1 = 0.0005 and 𝑠22 = 𝑠12.  


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Table 2: 
One-Sided Alpha Spending for the primary endpoint at Each Decision Point 
 
Analysis 
α spending  
at each planed analysis 
(𝜶𝒊, i=1,2,3) 
Cumulative 
α spent 
P-value 
boundary for 
success 
(𝒔𝟏𝒊, i=1,2,3) 
IA1: 108 events 
0.0005 
0.0005 
0.0005 
IA2: 185 events 
0.0074 
0.0079 
0.0077 
FA: 260 events 
0.0171 
0.025 
0.0226 
 
This flexible approach of alpha-spending function determines the rate or fraction at which the 
overall type I error (alpha) is to be spent during a trial. In case the actual number of events 
observed at IA2 deviates from 185 events, Table 3 provides the corresponding IA2 p-value 
boundaries for the primary endpoint that will be used for IA2 according to the actual events 
number at IA2 between 180 to 190 events. 
Table 3: 
One-Sided Alpha Spending for the Primary Endpoint at IA2 Between 180 to 
190 Events 
IA2 
Event number 
α spending 
at IA2 
(𝛼2) 
Cumulative 
α spent 
P-value 
boundary for 
success 
(𝑠12) 
180 
0.0066 
0.0071 
0.0069 
181 
0.0067 
0.0072 
0.0071 
182 
0.0069 
0.0074 
0.0072 
183 
0.0070 
0.0076 
0.0074 
184 
0.0072 
0.0077 
0.0075 
185 
0.0074 
0.0079 
0.0077 
186 
0.0075 
0.0081 
0.0079 
187 
0.0077 
0.0082 
0.0081 
188 
0.0079 
0.0084 
0.0082 
189 
0.0081 
0.0086 
0.0084 
190 
0.0082 
0.0087 
0.0086 
4.3.5.2. 
Adaptive Design and Combination P-Value Approach 
To define the decision rules that will be applied at IA2 and FA, consider the log-rank test 
statistics for testing the primary hypothesis of no treatment effect at these decision points, 


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denoted by 𝑍12 and 𝑍13, respectively (a one-sided version of the log-rank test statistic that 
follows a normal distribution is assumed).   
The stagewise test statistics are defined as follows: 
• Stage 2: 𝑍12
∗= 𝑍12 
• Stage 3: 𝑍13
∗=
𝑍13√𝑚3−𝑍12√𝑚2
√𝑚3−𝑚2
, 
where 𝑚2 is the actual number of events at IA2 and 𝑚3 is the actual number of events at the FA. 
The stagewise test statistics are independent of each other under the null hypothesis of no effect. 
The stagewise p-values are computed from the null distributions of the stagewise test statistics, 
namely, the one-sided Stage 2 and 3 p-values are denoted by 𝑝12
∗ and 𝑝13
∗, respectively. 
In addition, let 𝑍22
∗ and 𝑍23
∗ denote the stagewise test statistics for the key secondary endpoint. 
The corresponding one-sided Stage 2 and 3 p-values will be denoted by 𝑝22
∗ and 𝑝23
∗, 
respectively. 
If the trial continues to FA, the significance of the treatment effect on the primary and key 
secondary endpoints will be evaluated at FA as follows. First, the combination p-values will be 
derived for the two endpoints using the weighted inverse-normal combination function, ie, 
𝑐(𝑥, 𝑦) = 1 −Ф (√𝑤Ф−1(1 −𝑥) + √1 −𝑤Ф−1(1 −𝑦)), 
where Ф(𝑥) denotes the cumulative distribution function of the standard normal distribution, and 
𝑤 and 1 −𝑤 are the pre-defined weights assigned to Stage 2 and 3 in the adaptive design, ie, 
0.71 (185/260) and 0.29.   
Using combination p-value, a significant effect will be established for the primary endpoint at 
FA if  
𝑐(𝑝12
∗, 𝑝13
∗) ≤𝑠13, 
where 𝑠13 is the significance level for the primary endpoint at FA. 
If this condition is met at FA and thus the primary hypothesis is rejected, a significant effect will 
be established for the key secondary endpoint at FA if 
𝑐(𝑝22
∗, 𝑝23
∗) ≤𝑠23. 
where 𝑠23 is the significance level for the key secondary endpoint at FA (Table 4). 
The significance levels for the key secondary endpoint at FA will be derived as follows. First of 
all, the one-sided significance level at IA1 and IA2, denoted by 𝑠21  and  𝑠22, are set to the same 
value as the significance level for the primary endpoint, i.e., 𝑠21 = 𝑠11 = 0.0005 and 𝑠22 = 𝑠12 
The significance level at FA, denoted by 𝑠23, is computed from 
𝑃(𝑃2 > 𝑠22, 𝑃3 ≤𝑠23) = 𝛼3, 
where 𝑃2 and 𝑃3 denote the random variables that have the same bivariate distribution as the one-
sided p-values for the key secondary endpoint at IA2 and FA under the null hypothesis of no 
treatment effect.  This significance level is easily computed from the joint distribution of 𝑍22 and 
𝑍23 under the secondary hypothesis of no effect for this endpoint. This distribution will depend 


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on the estimated information level at IA2 and FA, i.e., 𝐼2 and 𝐼3, namely, 𝑍22 and 𝑍23 both 
follow standard normal distributions and the correlation between 𝑍22 and 𝑍23 is equal to the 
actual information fraction at the interim analysis, i.e., √𝐼2/𝐼3, where the information is the 
reciprocal of the variance .  
𝐼= [∑((
σ̂𝑖1
𝑙𝑜𝑔[OS
̂ 𝑖1])
2
+ (
σ̂𝑖2
𝑙𝑜𝑔[OS
̂ 𝑖2])
2
)
𝑖
]
−1
 
Note that, if the number of events is increased in the trial, the information value 𝐼3 needs to be 
computed at the planned FA after 260 events. 
For illustration, Table 4 defines the significance level for the key secondary endpoint at FA (𝑠23) 
for selected values of the actual information fraction (𝐼2/𝐼3) under the assumption that the 
information fraction at IA2 is set to be 0.71. 
Table 4:      One-sided significance levels for the key secondary endpoint at FA for various 
actual information fractions at IA2 
Assumed information  
fraction at IA2 
Actual information  
fraction at IA2 
P-value boundary for 
success (significance 
level, 𝒔𝟐𝟑) 
0.71 
0.60 
0.0214 
0.71 
0.65 
0.0219 
0.71 
0.70 
0.0224 
0.71 
0.75 
0.0229 
0.71 
0.80 
0.0234 
 
4.3.5.3. 
Hierarchical Testing Procedure 
The hierarchical testing strategy for the primary and key secondary endpoints will be defined 
using the method introduced in Maurer and Bretz (2013). The key secondary endpoint will be 
tested sequentially beginning with the primary endpoint. It is important to point out that the 
common alpha spending function for the primary and key secondary endpoints, ie, the Lan-
DeMets function with an O’Brien-Fleming stopping boundary, satisfies the condition (well-
ordered condition) imposed in Maurer and Bretz (2013). 
4.4. 
Treatment Assignment & Blinding 
The study will be divided into 2 parts. Part 1 will be a non-randomized, open-label safety lead in 
Phase where all patients will be treated with the combination of DSP-7888 Dosing Emulsion plus 
Bev in a single-arm manner. Patients who discontinue Part 1 of the study for reasons other than 
DLT during the Induction Phase will be replaced.  
Once the safety of the combination of DSP-7888 Dosing Emulsion plus Bev has been 
established, Part 2 (the randomized part of the study) will begin. In Part 2, patients will be 
stratified prior to randomization based on the extent of surgical resection in primary therapy 


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(GTR versus not GTR) and KPS class (60 through 70 versus 80 through 100) and will be 
randomized in a 1:1 ratio for DSP-7888 Dosing Emulsion plus Bev or Bev alone via the 
Endpoint Interactive Voice/Web Response System. The treatment assignment is to be obtained in 
Part 2 after the study patient has passed all inclusion and exclusion criteria and has been 
randomized in the study prior to the initiation of the study treatment or first dosing visit. 
Withdrawn patients will not be replaced in Part 2 of the study.  
This is an open label study. The primary endpoint of Part 2 of this study is OS, the assessment of 
which is unlikely impacted by the open-label nature of the study.  
To comply with ICH E6 (R2) Guideline for Good Clinical Practice (2016), which recommends 
the blinded review of planned analyses, and to minimize the risk of potential bias into interim 
and final analyses for the adaptive Phase 3 design in Part 2, blinding controls have been 
implemented on the aggregate data by treatment arm.  Specifically, the IA results will be 
reviewed by the IDMC and will only be available to the IDMC and selected unblinded team 
members. The investigators, the patients, the study personnel who interact with the site and other 
blinded partners do not have the access to the IA results.  
A blinding plan that details the blinding controls for the sponsor and its partners will be 
summarized in separate document. 
4.5. 
Study Schedule of Assessments 
Schedule of Assessments is provided in the protocol section 8.1.3. 


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5. 
ENDPOINTS 
5.1. 
Primary Endpoint 
The primary endpoint is OS and is defined as the interval between randomization and death from 
any cause. Patients who are lost to follow-up will be censored on the last day they were known to 
be alive. 
5.2. 
Key Secondary Endpoint 
The 12-month OS rate is defined as the proportion of patients alive 12 months after 
randomization. 
5.3. 
Other Secondary Endpoints 
• 
PFS is defined as the interval between randomization and progression, determined by 
central radiology review (the local investigator assessment will be used at IA) or death from 
any cause.  
• 
6-month PFS rate is defined as the proportion of patients alive at 6 months after 
randomization and without progressive neoplastic disease.  
• 
The objective response rate is defined as the proportion of patients exhibiting a response 
(complete response [CR] plus partial response [PR]) based on the mRANO criteria as 
determined by the central radiology review (the local investigator assessment will be used at 
IA).  
• 
The duration of response is defined as the interval between first documented oncological 
response and progression of disease or death from any cause, with response based on the 
mRANO criteria as determined by the central radiology review (the local investigator 
assessment will be used at IA). 
• 
To describe the adverse event (AE) profile of DSP-7888 Dosing Emulsion plus Bev 
alone. 
5.4. 
EXPLORATORY ENDPOINTS  
In addition, exploratory endpoints include evaluating the amount of immune response by:  
• 
Measurement of WT1 peptide-specific cytotoxic T lymphocyte (CTL) induction activity 
at each assessment time for patients receiving DSP-7888 Dosing Emulsion plus Bev.  
• 
Determination of expression of WT1 protein via immunohistochemistry (IHC) and WT1 
mRNA via Chromogenic in situ Hybridization (CISH) in tumor tissue from patients receiving 
DSP-7888 Dosing Emulsion plus Bev. 
• 
Diffusion-weighted imaging results. 
• 
NANO scale score. 


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6. 
ANALYSIS SETS 
6.1. 
Safety Set  
The Safety Set (SS, also called Safety Population) for Part 1 will include all patients who were 
administered at least one dose of study medication in Part 1.  The Safety Set for Part 2 will 
include all randomized patients who were administered at least one dose of study medication in 
Part 2. Patients will be analyzed according to treatment received. The SS will be used for all 
analyses of safety endpoints and for the presentation of patients in all patient listings, unless 
otherwise specified  
6.2. 
Intent-To-Treat Set  
The Intent-to-Treat (ITT) Set (also called intent-to-treat population) will include all randomized 
patients in Part 2 of the study only, regardless of whether they received a dose of study drug or 
not. Patients will be analyzed according to their assigned treatment. The ITT Set will be used for 
all analyses of study disposition, baseline demographics, medical history, protocol deviations and 
efficacy endpoints et al. The presentation of patients in all efficacy listings will be based on the 
ITT Set.   
6.3. 
Per-Protocol Set 
The Per-Protocol (PP) Set (also called per-protocol population) will consist of all patients in Part 
2 of the study who received at least one dose of study drug (DSP-7888 Dosing Emulsion or Bev), 
and who do not have major protocol deviations that may impact the primary analysis of efficacy. 
Per-Protocol Set may be different depending on the Efficacy Endpoints as follows:  
• 
Per-Protocol Set for the Overall Survival Endpoint (PP-OS) 
• 
Per-Protocol Set for the Progression Free Survival Endpoint (PP-PFS) 
• 
Per-Protocol Set for the Overall Response Endpoints (PP-OR) 
The criteria of protocol deviations and reasons for exclusion from the PP Population will be 
finalized prior to the database lock and unblinding (for IA2 and FA). Reasons for exclusion from 
PP Population may include, but not limited to, the following: 
• 
Not meeting inclusion criterion 
• 
Meeting exclusion criterion 
• 
Meeting withdrawal criterion (e.g., a subject is subsequently found to be pregnant after 
inclusion in the study) 
Protocol deviations will be identified and maintained in a separate document, and the list of 
patients with protocol deviations including those with major protocol deviations that may be 
excluded from efficacy analysis will be finalized before database lock and unblinding.   
6.4. 
 Dose-Determining Set 
The Dose-Determining Set (DDS, also called DLT population) will consist of all patients in Part 
1 of the study only who received the first 5 administrations of the combination of DSP-7888 


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Dosing Emulsion plus Bev or who are discontinued from the study during Part 1 due to the 
occurrence of a DLT. 


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7. 
PROTOCOL DEVIATIONS 
The Investigator will notify the Sponsor or designee of any deviations from the protocol. Such 
contact with the Sponsor will be made as soon as possible to permit a decision as to whether the 
patient (for whom the deviation from the protocol was affected) is to continue in the study. The 
case records will describe both the details of and rationale for the protocol deviation. 
Major Protocol Deviations (PD) in the ITT population will be summarized, and all PDs in the 
ITT population will be listed.  


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8. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS 
8.1. 
General Methods 
Statistical analysis of data from this study will be performed using SAS version 9.3 or more 
recent version. 
Unless otherwise specified, study Part 1 summaries will be presented by dose level. Study Part 2 
summaries will be presented by treatment groups. Summaries based on the ITT and PP 
populations will be presented by planned treatment groups, unless specifically stated otherwise. 
Safety analyses and other summaries based on the safety population will be presented by actual 
treatment received. 
Statistical analyses will be descriptive in nature. Continuous variables will be summarized using 
the number of observations (n), mean, standard deviation (SD), median, minimum, and 
maximum. When needed, the use of other percentiles (e.g., 10%, 25%, 75%, and 90%) will be 
mentioned in the relevant section. Categorical variables will be summarized using number of 
observations (n), frequency and percentages of patients.  
For categorical variables, a Fisher’s exact test will be used for unstratified analyses of categorical 
variables and the Cochran-Mantel-Haenszel test will be used for stratified analyses. The Kaplan-
Meier (KM) product limit method will be used to provide the survival estimates and the survival 
curves for the time to event variables for each treatment group and for subgroup of patients 
within each actual stratum [KPS (60 through 70, and 80 through 100), and extent of surgical 
resection in initial therapy (GTR versus not GTR)]. Treatment comparisons for time-to-event 
analyses will be performed using a stratified log-rank test. For patients who discontinue early or 
who are in the study without meeting criteria for the event, the time-to-event will be censored. 
More detailed censoring rules for OS and PFS are described in Section 7.3 of this document. 
Hazard ratios and their corresponding 95% confidence intervals will be estimated based on a 
stratified Cox’s regression model using treatment group as the independent variable and the 
randomization stratification variables as strata.   
Patient’s tumor response will be assessed based on the mRANO (Neurotherapeutics. 2017 Apr; 
14(2): 307–320) as assessed by both study investigators and by a central blinded review. See 
study Protocol Amendment 6, Sections 16.2 and 16.3 for details on tumor response 
determinations that are fully captured on the case report forms (CRFs) of the study.  
One-sided p-values will be presented for treatment comparisons in the primary endpoint of OS 
and the key secondary endpoint of 12-month OS rate in Part 2. Confidence intervals (CIs) will be 
calculated at 95%, 2-sided.  
All p-values will be rounded to 4 decimal places. P-values rounding to less than 0.0001 will be 
presented as “<0.0001”. 
Percentage values will be rounded to one decimal point (e.g., 52.3%, 8.9%). Dates will be printed as 
DDMMMYYYY. If only year and month are available, date will be displayed as --MMMYYYY. If only 
year is available, then just ----YYYY will be displayed.  
All analyses will be performed using data pooled across sites.  
All relevant patient data will be included in listings.  


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8.2. 
General Data Handling 
Baseline measurements for Part 2:  
For efficacy parameters: for example, baseline weight, KPS score, NANO, tumor scans, baseline 
will be defined as the last non-missing value within 35 days prior to or on the randomization 
date; when such a parameter within 35 days prior to or on the randomization date is missing, and 
patients receive treatment, then the first parameter recorded prior to or on first dose date (if on 
first dose date, visit = screen/prescreen visit) but after randomization can be used if it is 
available. If patients didn’t receive any treatment, then the parameter recorded at the screening 
visit unless it occurs more than 35 days prior to randomization will be used.   
For safety parameters, such as labs, ECG, physical exams and vital signs, the last non-missing 
record prior to first dose date or on first dose date (record from “screen/pre-screening visit” and 
the time is not after Bev administration time) will be used as baseline. Baseline window of 28 
days prior to first dose date will be used. 
Baseline for Part 1 will follow the Part 2 safety baseline definition.   
For the safety parameters: unless otherwise specified, post baseline reporting period includes 
non-missing records collected from after first dose of study treatment until 30 days following last 
dose of study medication (DSP7888 and/or Bevacizumab).  
Scheduled and unscheduled visits post baseline: unless otherwise specified, for the summary by 
visit post baseline, only scheduled visits will be included; for summary of the maximum or 
maximum changes post baseline, both scheduled visits and unscheduled visits will be included. 
All records (scheduled and unscheduled) regardless of post baseline reporting period will be 
listed in the data listings.   
8.3. 
Key Definitions 
The reference date for calculating Study day for Part 1 and safety measurements of Part 2 is the 
date of the first dose of study drug, which will be considered Day 1 in the study. Specifically, 
study days for post-baseline data will be calculated as follows:  
Date of interest – Date of first dose + 1, if date of interest on or after the first dose date; or  
Date of interest – Date of first dose, if date of interest prior to the first dose date.  
For Part 2 efficacy measurements (such as PFS and OS), randomization date will be used as the 
reference date.  
Duration of exposure for each patient is the length of time from the first dose date of study drug 
to the date of last dose of study drug, and will be calculated using the formula below: 
Date of last dose of study treatment – Date of first dose of study treatment + 1.  


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8.4. 
Missing Data 
8.4.1. 
Missing Partial Death Dates 
It is recommended that the database be designed to mandate a complete death date. If there is a 
record for death, but the date is missing or is partial, it will be imputed based on the last contact 
date.   
If the entire date is missing, the death date will be imputed as the day after the date of last 
contact.  
If the day or both day and month are missing, the death date will be derived as below: 1) impute 
partial dates to be 1st day of the month if day of death is missing, or January 1st if both day and 
month of death are missing, 2) compare the imputed dates with one day after the last known to 
be alive date, select the latest date. For example, if a patient with partial death date is known to 
be March2020, and its last known to be alive date is March 16,2020, then considering the rules 
of both 1) and 2), its death date will be imputed as March 17 2020. 
8.4.2. 
Missing Dates for Adverse Events (AEs) or Concomitant Medications 
Partial or incomplete start/end dates in the adverse events (AE) or concomitant medications 
datasets will be imputed to help determine treatment-emergent adverse events and (prior or 
concomitant) medications. 
For incomplete start dates for AE or concomitant medications, use the following imputation 
rules: 
• 
Missing day - Impute the 1st of the month unless month is same as month of first dose of 
study drug then impute using the day of first dose date  
• 
Missing day and month – impute 1st January unless year is the same as first dose date 
then impute using the first dose date  
• 
Completely missing – impute using first dose date unless the end date suggests it must 
have started prior to first dose, in which case impute the missing date with 01JAN of the 
same year as the first dose date.  
When imputing a start date, ensure that the new imputed date is sensible i.e. is prior to the end 
date of the AE or medication.  If the imputed start date is after the end date, then the start date 
will be assumed equal to the end date. 
For incomplete end dates for AE or concomitant medications, use the following imputation rules:  
• 
Missing day - Impute the last day of the month unless month and year are the same as the 
month and year of the last dose of study drug, then impute last dose date  
• 
Missing day and month – impute 31st December unless year is the same as last dose date 
then impute last dose date  
• 
Completely Missing – need to look at whether the AE/medication is still ongoing before 
imputing a date and also when it started in relation to study drug. If the ongoing flag is not 
missing, then assume that AE is still present/medication is still being taken (i.e. do not 
impute a date). If the AE/medication is not ongoing and the start date is prior to first dose 


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date, then impute the end date using 1st dose date.  If it started on or after first dose date, then 
impute a date that is after the last dose date. 
When imputing an end date, ensure that the new imputed date is sensible i.e. is after the start date 
of the AE or medication. If the imputed end date is before the start date, then the end date will be 
assumed equal to the start date. 
8.4.3. 
Missing Post GBM Treatment Start Date 
For data collected from Post GBM Treatment CRF form start date:   
For treated patients:   
= 01JanYYYY, if only Year is available. After imputation if it is before last dose date, it will 
be set to last dose of study treatment + 1 
= 01MMMYYYY, if only day is missing.  After imputation if it is before last dose date, it 
will be set to last dose of study treatment + 1 
= last dose date + 1 if complete missing.   
For randomized but not treated patients:   
= 01JanYYYY, if only Year is available. After imputation if it is before randomization, it 
will be set to randomization date.  
= 01MMMYYYY, if only day is missing.  After imputation if it is before randomization, it 
will be set to randomization date.  
= randomization date if complete missing.   
For concomitant procedure:  
If the start date is completely or partially missing, then the imputed start date is: 
= 01JanYYYY, if only Year is available. After imputation if it is before randomization, it 
will be set to randomization date.  
= 01MMMYYYY, if only day is missing.  After imputation if it is before randomization, it 
will be set to randomization date.  
= randomization date if complete missing.   
8.4.4. 
Censoring Rules for Time-to-Event Data 
For time-to-event efficacy analyses, endpoints will be defined using the censoring rules 
presented in the following Table 5 Table 6 Table 7 for Part 2. 
Table 5:      Censoring Rules for Overall Survival for Part 2.   
  
Description 
Situation 
Date of Events or 
Censoring 
Outcome 
Overall Survival 
The interval 
between 
randomization and 
death from any 
cause 
Date of death 
Date of death 
Event 
Alive as of the last 
known follow-up, 
Date of last known 
to be alive 
Censored 


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Description 
Situation 
Date of Events or 
Censoring 
Outcome 
discontinued or lost 
to follow-up 
 
Table 6:      PFS Censoring Rules by Confirmed PD for Part 2 
Hierarchy 
Censoring 
Situation 
Date of Events or 
Censoring 
Outcome 
1 
No baseline assessment of target lesion and non-
target lesion within 35 days from randomization 
Date of Randomization 
Censored 
1st Confirmed PD within 2 assessment intervals [1] 
following previous adequate overall response 
assessment [2] or randomization if no previous 
adequate overall response assessment after 
randomization 
Date of response 
assessment of 1st 
Confirmed PD  
Event 
2 
New anti-cancer treatment started and no 
confirmed PD or death prior to that  
Date of previous 
adequate overall 
response assessment 
prior to start of new 
therapy  
Censor  
3 
Confirmed PD after 2 assessment intervals 
following previous adequate overall response 
assessment   
Date of previous 
adequate overall 
response assessment [3]  
Censor 
Preliminary PD following by death / confirmed PD 
within one assessment interval [4] 
Date of Preliminary PD 
Event 
For patient without confirmed PD, but death 
reported within 2 assessment intervals following 
previous adequate overall response assessment or 
randomization if no previous adequate overall 
response assessment after randomization    
Date of death 
Event 
4 
Have baseline target lesion or non-target lesion 
assessment performed within 35 days from 
randomization but no post-baseline overall 
response assessment (no confirmed PD by default) 
and no death within 2 assessment intervals 
following randomization  
Date of Randomization 
Censored 
5 
no confirmed PD and no death reported within 2 
assessment intervals following previous adequate 
overall response assessment or randomization if no 
previous adequate overall response assessment 
after randomization    
Date of latest adequate 
assessment or 
randomization date, 
whichever is later 
Censored  
  
Only mRANO assessments prior to new anti-cancer treatment will be used for deriving the PFS.   
[1]As mRANO tumor assessments will be performed at Screening; after 8, 16, and 24 weeks on 
study; and then every 12 weeks thereafter, two assessment intervals are 126 days (16 weeks+ 14 
days) if previous assessment is within 105 days (16 weeks – 7 days) from randomization; or 154 
days (20 weeks + 14 days) if previous assessment is after 105 days but prior to 161 (24 weeks – 


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7 day) days from randomization, or 182 days (24 weeks + 14 days) if previous assessment is 
after 161 days from randomization.  
[2]Adequate overall response assessments include the overall assessment of Confirmed CR, 
Confirmed PR, Preliminary CR, Preliminary PR, Pseudo Response, SD, Confirmed PsP, 
Preliminary PD, Confirmed PD (NE or NA is not included).  
[3] Date of overall response assessment is the last date from tumor scan, NANO/KPS assessment 
from the same visit.   
[4] One assessment interval is 70 days (8 weeks + 14 days) if previous assessment is prior to 161 
days (24 weeks – 7 day) from randomization, or 98 days (12 weeks + 14 days) if previous 
assessment is after 161 days from randomization. 
The censoring reason will be assigned according to the hierarchy order.  
Preliminary Progression Free Survival is the interval between the date of randomization and 
the date of 1st progressive disease including Preliminary PD / Confirmed PD / Confirmed PsP or 
death, whichever is first reported.   
Events and Sequential Censoring Rules for PD for preliminary PFS.  
Table 7:      Preliminary PFS Censoring Rules for Part 2 
Hierarchy 
Censoring 
Situation 
Date of Events or 
Censoring 
Outcome 
1 
No baseline assessment of target lesion and non-target 
lesion within 35 days from randomization 
Date of 
Randomization 
Censored 
1st PD [1] within 2 assessment intervals [2] following 
previous adequate overall response assessment [3] or 
randomization if no previous adequate overall response 
assessment after randomization 
Date of response 
assessment of 1st 
PD [1] 
Event 
2 
New anti-cancer treatment started and no PD [1]or death 
prior to that  
Date of previous 
adequate overall 
response 
assessment prior to 
start of new 
therapy 
Censor  
3 
PD [1] after 2 assessment intervals following previous 
adequate overall response assessment   
Date of previous 
adequate overall 
response 
assessment [4] 
Censor 
For patient without PD [1], but death reported within 2 
assessment intervals following previous adequate overall 
response assessment or randomization if no previous 
adequate overall response assessment after randomization   
Date of death 
Event 
4 
Have baseline conventional MRI or CT scan performed 
within 35 days from randomization but no post-baseline 
overall response assessment (no PD [1] by default) and no 
death within 2 assessment intervals following 
randomization 
Date of 
Randomization 
Censored 


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5 
no PD [1] and no death reported within 2 assessment 
intervals following previous adequate overall response 
assessment or randomization if no previous adequate 
overall response assessment after randomization    
Date of latest 
adequate 
assessment or 
randomization 
date, whichever is 
later 
Censored  
  
PD includes Preliminary PD / Confirmed PD / Confirmed PsP.  
[1]As mRANO tumor assessments will be performed at Screening; after 8, 16, and 24 weeks on 
study; and then every 12 weeks thereafter, two assessment intervals are 126 days (16 weeks+ 14 
days) if previous assessment is within 105 days (16 weeks – 7 days) from randomization; or 154 
days (20 weeks + 14 days) if previous assessment is after 105 days but prior to 161 (24 weeks – 
7 day) days from randomization, or 182 days (24 weeks + 14 days) if previous assessment is 
after 161 days from randomization.  
[3] Adequate overall response assessments include the overall assessment of Confirmed CR, 
Confirmed PR, Preliminary CR, Preliminary PR, Pseduo Response, SD, Confirmed PsP, 
Preliminary PD, Confirmed PD (NE or NA is not included).  
[4] Date of overall response assessment is the last date from tumor scan, NANO/KPS assessment 
from the same visit.  
The censoring reason will be assigned according to the hierarchy order.   
For Part 1 patients, the first dose date will be used instead of randomization date in the above 
algorithm. 
8.4.5. 
Missing Lab, Pharmacodynamic and Biomarker Data 
Unless otherwise specified, missing lab, pharmacodynamic and biomarker data will be treated as 
such and no imputed values will be derived. 
8.5. 
Analysis Visit Window 
No analysis windows are planned for the study regarding data collected outside the protocol 
specified windows, see Section 3.9 for the detailed schedule of assessments and protocol 
windows. Analyses will not exclude patient data due to the patient’s failure to comply with the 
visit scheduled, as data will be summarized based on the CRF study visit in which it was 
collected. 
8.6. 
Pooling of Centers 
No pooling of sites is planned for this study. Patients from all sites will be pooled together for 
data analysis. 
8.7. 
Subgroups  
Subgroup analysis will be presented for the primary endpoint by strata for randomization for the 
following 4 subgroups: 
• KPS 60 to 70  


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• KPS 80 to 100  
• Gross total resection  
• Not gross total resection 
• Country (United States, Canada, Japan, Korea, Taiwan),  
• Geographic region (North America, Asia),  
• Race (Caucasian, Asian, Black, Other),  
• Sex (male, female, other) where “other” will includes patients with “unknow” or 
“other” or missing category.   
• Age Group (<55, 55 through 64, 65 through 74, 75 through 84, ≥85),  
• HLA (HLA-A*02 Positive Only, HLA-A*24 Positive Only, Both Positive),  
• IDH Mutation (IDH1 Mutation: Yes, No, Missing; IDH2 Mutation: Yes, No, Missing, 
IDH1 or IDH2 Mutation: Yes, No, Missing),  
• MGMT Methylation: Yes, No, Missing,  
• Corticosteroids Use at Baseline: Yes, No 
• Patients Who Had a Surgery After Most Recent Recurrence: Yes, No 
If total number of patients in any subgroup is less than 10, no p-value or KM curve will be 
provided.   
Subgroup analyses (e.g., Japan, Non-Japan) for efficacy and safety endpoint will be performed 
for Pharmaceuticals and Medical Devices Agency (PMDA) submission.  Those analyses may not 
be included in the CSR.  


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9. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS 
AND MEDICATION 
9.1. 
Patient Disposition and Withdrawals 
The number of patients pre-screened for HLA type, the number of patients formally screened for 
the study, the number of patients screen failed, and the number of patients randomized will be 
summarized. Additionally, frequency counts and percentages of all patients who are randomized 
but did not take study drug, and patients who are dosed but discontinue investigational product 
will be presented by dose level and overall in study Part 1; and by treatment group and overall in 
study Part 2 for patients in the ITT Set. All patients who discontinue investigational product will 
be identified, and their reason for ending the investigational product will be summarized.  
Follow up time (months) defined by [last contact date (patients who still alive) or death date 
(patients who dead) - randomization date + 1]/30.4375 will be summarized.   
A listing of all study patients, whether they discontinued the investigational product or not, and 
the reasons for investigational product discontinuations will be provided for the Safety Set . 
The reasons for exclusion from analysis sets (including PP set) will be tabulated by study 
treatment and listed. 
9.2. 
Demographic and Other Baseline Characteristics 
Age (years) will be calculated as the number of years between the date of birth and the date of 
informed consent: 
Age at screening = (screening informed consent date – date of birth +1)/365.25 and truncated to 
complete years 
If height is recorded in inches (in), then height will be summarized in cm using the following 
conversion: 
 
Height (cm) = Height (in) x 2.54 
For Part 1, baseline height is defined as the last non-missing measurement prior to the first dose 
of study drug but within baseline window. In the event such a value is missing, the first 
measurement after the first dose of study drug is used.  
For Part 2, baseline height is defined as the last non-missing measurement on or prior to the date 
of randomization but within baseline window. In the event such a value is missing, the first 
measurement after randomization is used. 
If weight is recorded in pounds (lb), then weight will be summarized in kilograms (kg) using the 
following conversion: 
 
Weight (kg) = Weight (lb) x 0.4536 
Body Mass Index (BMI) in kg/m2 will be calculated as: Weight (kg)/[Height (m)2] 
Demographic and baseline characteristic data (sex, race, ethnicity, age (years), height (cm), 
weight (kg), BMI (kg/m2), and HLA Class I results) will be summarized by dose level in Part 1 
Safety Set, and by treatment group and overall in Part 2 ITT Set.   


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All demographic and baseline characteristic data will also be listed. 
9.3. 
Medical / Surgery History 
Medical/surgical history including diagnosis, signs & symptoms, procedures, the onset date, and 
status (ongoing or resolved) will be collected.  
Medical/surgical history recorded at screening will be summarized by dose level in Part 1 Safety 
Set, and by treatment group and overall in Part 2 ITT Set via descriptive statistics. The number 
and percentage of patients reporting each System Organ Class (SOC) and/or Preferred Term (PT) 
will be presented. Patients with multiple occurrences of the same event will be counted only once 
within the given preferred term. Similarly, at the SOC level, a patient will be counted only once 
if the patient experienced more than one event within the given SOC. 
The medical/surgical history that is specifically related to GBM as indicated by the “related to 
GBM” checkbox on the medical/surgical history CRF will be summarized separately from all 
other medical history.   
Medical/Surgical history listings will be sorted by treatment group or dose level depending on 
the study part, patient number, onset date, end date, SOC, and PT. 
9.4. 
GBM History and Other Baseline Characteristics 
GBM history including date of initial diagnosis of primary site, date of most recent 
recurrence/relapse/progression and recurrent type will be obtained. The time in months since 
initial GBM diagnosis to randomization, the time in months since Initial GBM diagnosis to most 
recent recurrent/relapse/progression, the time in months since most recent 
recurrent/relapse/progression to Randomization,  the frequency of most recent recurrent/type will 
be summarized by dose level in Part 1 Safety Set, and by treatment group and overall in Part 2 
ITT Set. The date of initial diagnosis of primary site, date of most recent 
recurrence/relapse/progression and recurrent type will be listed by treatment group or dose level 
depending on the study part as captured on the CRF. 
The type of primary surgery performed will also be summarized based on the data entered into 
the Gross Total Resection CRF (number of patients who had a gross total resection vs. Not gross 
total resection).  Of those who did not have a gross total resection, the number who had a partial 
resection vs. Number who had no resection at all will be summarized.   
In addition, MGMT promoter methylation, isocitrate dehydrogenase (IDH) 1 mutation and IDH 
2 mutation data obtained during screening will be listed. The use of corticosteroids at baseline 
and the sum of NANO overall scale score at baseline will be summarized by dose level in Part 1 
Safety Set, and by treatment group and overall in Part 2 ITT Set. 
9.5. 
Medication 
Medications will be coded using WHO Drug Dictionary Enhanced (WHO-DDE) -B2 201609.    
Medications will be summarized using Anatomical Therapeutic Chemical (ATC) classification 
level 2 and Preferred base. All medications will be summarized by dose level in Part 1 Safety 
Set, and by treatment group and overall in Part 2 Safety Set. The analysis will be sorted by order 


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of decreasing frequency of ATC classification level 2 and preferred base in DSP-7888 Dosing 
Emulsion plus Bev arm.   
Missing or partial start/end dates of medications will be imputed using the approach discussed in 
Section 8.4 .   
Medication data collected on the study include systemic anti-cancer medications received prior 
to randomization, prior and concurrent medications that are not anti-cancer, and systemic anti-
cancer medications received after discontinuing protocol treatment.   
Prior and concomitant medication data for medications that are not anti-cancer  will be listed and 
will include the primary indication for use, start date, end date, ATC classification level 2, 
preferred base, dose, dose unit, and route of administration. Medications will be flagged as being 
either prior medications, concomitant medications, or both. Within patients, medications will be 
ordered by start date, end date, ATC classification level 2 and preferred base. 
9.5.1. 
Prior Medication 
Prior medications are defined as medications that are not anti-cancer with at least one dose taken 
before the date of the first dose of the study drug. 
9.5.2. 
Concomitant Medication 
Concomitant medications are defined as medications that are not anti-cancer with at least one 
dose taken between the date of first dose (inclusive) and the date of last dose (inclusive) of study 
drug. 
Concomitant medications will be summarized by dose level in Part 1 Safety Set, and by 
treatment group and overall in Part 2 Safety Set using the ATC classification level 2 terms. If a 
patient has taken a medication more than once, the patient will only be counted once in the total 
for the summary. 
9.5.3. 
Prior Cancer Therapies 
Prior cancer therapies (also known as prior systemic anti-cancer medications) will be 
summarized and listed separately from prior and concomitant medications that are not anti-
cancer. The classification of the cancer therapies includes type of prior cancer therapy, regimen, 
start/end date, and best response captured on the Prior Cancer Therapy eCRF page. The 
categorization of prior systemic anti-cancer therapies was performed by the study sponsor.   
For prior systemic anti-cancer medications, the number and percentage of patients that received 
each specific agent (as defined by preferred base) and best response will be summarized by dose 
level in Part 1 Safety Set, and by treatment group and overall in Part 2 ITT Set. Prior cancer 
therapies will also be listed and include the regimen as entered by the site, the type of prior 
cancer therapy entered, the categorization provided by the sponsor, start/stop dates,  preferred 
base and best response, et al  . The listing will be ordered by treatment group or dose level 
depending on the study part, patient, and the start date of the therapy. 
9.5.4. 
Prior Radiation Therapies 
Prior radiation therapies will be summarized and listed separately from other prior and 
concomitant medications. The summary of prior radiotherapy includes number of fractions, 


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fractional dose received (Gy), total dose received, best response, and reason for stopping 
captured on the Prior Radiation Therapy eCRF page.  The specific type of radiotherapy received 
and the anatomic site will not be summarized but will be listed. 
Time (months) since stop date of radiotherapy to first Dose date, number of fractions, total dose 
(Gy) and best response will be summarized by dose level in Part 1 Safety Set, and by treatment 
group and overall in Part 2 ITT Set. 
The number and percentage of patients who had prior radiation therapy and best response will be 
summarized. Continuous variables such as the number of fractions, the time (months) since stop 
date of radiotherapy to first Dose date and total dose received will be summarized via descriptive 
statistics using the number of observations (n), mean, standard deviation (SD), median, 
minimum, and maximum.  
Prior radiation therapies will also be listed and include the type of prior radiation therapy 
received, anatomic site, start date, stop date, number of fractions, fractional dose received, total 
dose received, best response, reason for stopping. The listing will be ordered by treatment group 
or dose level, depending on the study part, patient, and the start date of the therapy. 


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10. 
EFFICACY  
All continuous variables will be summarized using the number of observations (n), mean, 
standard deviation (SD), median, minimum, and maximum. Categorical efficacy variables will 
be summarized using frequency counts and percentages. The analysis will be presented by 
treatment group and overall in Part 2 ITT Set. Analysis of the primary efficacy endpoint and 
selected secondary efficacy endpoints will be repeated using the PP Set. 
10.1. 
Primary Efficacy Endpoint and Analysis 
10.1.1. 
Primary Efficacy Analysis 
The primary efficacy endpoint is OS. The primary statistical null hypothesis is that there is no 
difference between the 2 treatment groups (DSP-7888 Dosing Emulsion plus Bev and Bev alone) 
with regards to OS. This will be tested by the stratified log-rank test based on the actual 
stratification variables at baseline.  
The KM method will be used to estimate and visualize the distribution of OS by treatment group. 
Additionally, KM curves and estimates by treatment group will be provided for the subgroups of 
patients (subgroups are defined in SAP Section 8.7). Descriptive summary statistics that are of 
interest, point estimates and 95% confidence intervals for overall survival will be provided for 
each treatment group at 3, 6, 9, 12, and additional months if estimable. These estimates will be 
computed from Kaplan-Meier survival curves for each treatment group. The primary treatment 
comparison will be based on a stratified log-rank test considering the 2 actual stratification 
factors of KPS class and extent of surgical resection in primary therapy (GTR versus not GTR). 
A stratified Cox’s regression model will be performed with treatment group as the independent 
variable and the 2 stratification factors of KPS class (60 through 70 versus 80 through 100) and 
extent of surgical resection in primary therapy (GTR versus not GTR) as strata. The hazard ratio 
and respective 95% CI obtained from the stratified Cox model will be provided.  
10.1.2. 
Sensitivity Analysis of Primary Endpoint 
Sensitivity Analysis of OS includes:  
The analyses of OS in the per-protocol population and safety set will be performed.  An un-
stratified log-rank test and Cox PH model may be used as sensitivity analyses for OS.  A 
stratified log-rank test/stratified Cox PH model may be performed based on randomization 
stratification factors for ITT set.   
Evaluation of the impact of new anti-cancer therapy on OS may be performed.  The patients who 
receive subsequent (new) anti-cancer therapy may be censored at the time of new anti-cancer 
therapy. If applicable, other sensitivity analyses including the time-dependent Cox PH model 
may be used to adjust for the impact of new anti-cancer therapy. 
Subgroup analysis will be performed considering the subgroup specified in Section 8.7 other 
subgroups where appropriate. 
For each subgroup level, the median OS (or other quartiles) and a 2-sided 95% CI will be 
provided for each arm. The difference in OS between Arm 1 and Arm 2 may be analyzed by 
unstratified log-rank test. The nominal 2-sided p-value may be provided in an exploratory basis. 


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The estimated hazard ratio and 2-sided 95% CI may be provided based on un-stratified Cox PH 
model.  
Forest plots of hazard ratios from the primary analysis or other subgroup analyses will be 
provided where appropriate. 
A sensitivity analysis using stratified multivariate Cox proportional hazards model will be 
performed to account for potential imbalance for IDH/MGMT between two treatment arms by 
including the IDH mutation and/or MGMT methylation as covariates; potential treatment by 
covariate interaction effects may be explored as appropriate. Subgroup analysis for MGMT 
methylation and IDH mutation for the primary and key secondary efficacy endpoints will also be 
conducted.   
At the final analysis, in the case there is significantly high dropout rate, e.g. (15% or higher 
overall) , when the primary endpoint is statistically significant, a tipping point sensitivity 
analysis may be carried out. See Section 15.1 for more detail. 
In addition, the assumptions used in the primary analysis may be assessed using the method 
proposed in He, Fang and Su (2013) and He and Su (2015).  The methodology is aimed at 
evaluating the significance of treatment effect in the presence of delayed effects as well as 
important deviations from the assumption of a constant hazard ratio function.  The methodology 
will be applied as follows: 
• 
Step 1. The survival data in the two treatment arms will be examined to determine 
whether one or more change points in the hazard ratio function exist. The changing point 
search will be limited to median survival from ITT set with pooling both arm togethers.  
• 
Step 2. If at least one change point is identified, the changes points will be used to 
partition the trial period (up to the last event or censored observation) into multiple intervals.  
Since the hazard ratio function is expected to be close to a constant within each interval, 
interval-specific inferences will be performed, e.g., the log-rank test will be applied to 
compute the interval-specific treatment effect p-value and the Cox proportional hazards 
model will be used to estimate the interval-specific hazard ratio. 
Additional sensitivity analysis may be performed using appropriate methods from the class of 
weighted log-rank tests (Zucker and Lakatos, 1990), including generalized piecewise weighted 
log-rank tests (Xu et al., 2018) with parameters that match the observed deviations from the 
assumed constant hazard ratio function. 
10.2. 
Key Secondary Efficacy Endpoint and Analysis 
10.2.1. 
12-Month Overall Survival Rate 
The 12-month OS rate is defined as the proportion of patients alive 12 months after 
randomization on the KM curve. 
Treatment comparisons will be performed using the KM estimates and the respective variances 
according to the Greenwood’s formula to construct a standard normally distributed Z-statistic. 
Let OS
̂ 𝑖1and OS
̂ 𝑖2 denote the KM estimates of the 12-month OS rates for the two arms from 
Stratum 𝑖 (Arm 1: DSP-7888+Bev; Arm 2: Bev only) and σ̂𝑖1and σ̂𝑖2 denote the standard errors. 
The stratified test statistic TOS12 is obtained by  


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𝑇𝑂𝑆12 =
∑(𝑙𝑜𝑔(−𝑙𝑜𝑔[OS
̂𝑖1]) −𝑙𝑜𝑔(−𝑙𝑜𝑔[OS
̂𝑖2]))
𝑖
√∑((
σ̂𝑖1
𝑙𝑜𝑔[OS
̂𝑖1])
2
+ (
σ̂𝑖2
𝑙𝑜𝑔[OS
̂𝑖2])
2
)
𝑖
 
which asymptotically follows a standard normal distribution N(0,1) under the null hypothesis. 
𝜎̂𝑖𝑘
2 = ∑
𝑑𝑗𝑖𝑘
𝑌𝑗𝑖𝑘(𝑌𝑗𝑖𝑘−𝑑𝑗𝑖𝑘)
𝑡𝑗≤𝑡
 
where 𝑘= 1 indicates Arm 1, and 𝑘= 2 indicates Arm 2,  𝑑𝑗𝑖𝑘 is the number of events in strata 𝑖 
and Arm 𝑘 and 𝑌𝑗𝑖𝑘 is the number of patients at risk at event time 𝑡𝑗 in strata 𝑖 and Arm 𝑘 (Klein 
2007). Please note the log-log transformation is not appropriate when either of OS
̂ 𝑖1 or OS
̂ 𝑖2or 
both are 0 or 1. In this case the linear transformation will be used. The test statistic is defined as  
𝑇𝑂𝑆12 =
∑( OS
̂ 𝑖1 −OS
̂ 𝑖2)
𝑖
√∑((OS
̂ 𝑖1σ̂𝑖1)
2 + (OS
̂ 𝑖2σ̂𝑖2)
2)
𝑖
 
 
10.3. 
Other Secondary Efficacy Endpoint and Analyses 
10.3.1. 
Progression-Free Survival (PFS) 
This is defined as the interval between randomization and disease progression, determined by 
central review, or death from any cause, whichever comes first. The disease progression is based 
on mRANO criteria with confirmed PD.  See Section 8.4.4 for the detailed events/censoring 
rules for PFS.  The PFS based on the investigator assessment will be used as the primary analysis 
at IA and used as a sensitivity analysis to assess the robustness of the study conclusion on PFS at 
FA. Progression-free survival will be analyzed similar as OS.  
The 6-Month Progression Free Survival 
The six-month PFS rate is defined as the proportion of patients alive at 6 months after 
randomization and without progressive disease. Six-month PFS will be estimated considering 
only confirmed progressions by central review or death as events. Six-month PFS will be 
analyzed similarly to 12-month overall survival rate. The six-month PFS rate based on 
investigator assessment will be used as the primary analysis at IA and maybe used as a 
sensitivity analysis at FA.   
10.3.2. 
Best Overall Response, Objective Response Rate (ORR) and Disease Control 
Rate 
The best overall response (BOR) is the best response designation recorded from randomization 
until end of study or start of new anti-cancer treatment whichever occurs first. The best overall 
response will be derived based on following order: Confirmed CR > Confirmed PR > 
Preliminary CR > Preliminary PR > Pseudo Response > SD > confirmed Pseudo Progression > 
Preliminary PD > Confirmed PD. All other cases will be categorized as NE. The reasons for NE 
will be summarized below:  
• No baseline assessment  


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• New anti-cancer therapy started before first post baseline assessment  
• Death before mRANO assessment post baseline 
• No post baseline assessment or all post-baseline assessment have overall response of 
NE/NA 
• SD too early (< 28 days)  since randomization date) 
• PD* too late (> 119 days) since randomization date) 
*PD too late (> 119 days) since randomization date will include preliminary PD and confirmed 
PD.   
Pictorial presentations to examine changes in tumor burden such as spider and waterfall plots 
will also be provided.  
The ORR is defined as the proportion of patients who achieve Confirmed CR or Confirmed PR 
based on the mRANO criteria as determined by the central review. Confirmed CR or Confirmed 
PR by the local investigator assessment will be used at IAs and may be included as supportive 
analysis at FA. The absolute and relative frequency of ORR will be presented by treatment group 
and within each randomization stratum (KPS 60 through 70, KPS 80 through 100, and extent of 
surgical resection [GTR versus not GTR]). Comparison of responses among the treatment groups 
will be done using stratified 1-sided Cochran-Mantel-Haenszel method, based on actual 
stratification factors. Treatment Difference of ORR and its 95% CI based on harmonic mean 
method adjusting actual stratification factors will be provided. For the analysis of ORR in the 
subgroups, differences between the two arms may be compared using a 1-sided Z-test via normal 
approximation. Treatment difference and its 95% CI based on normal approximation 
(unstratified) may be provided.  
Disease Control Rate (DCR) is defined as the proportion of patients with BOR of Preliminary 
CR, Confirmed CR, Preliminary PR, Confirmed PR, Pseudo Response, Confirmed Pseudo 
Progression or SD. 
 
BOR/ORR/DCR will be based on the central review at FA. Local investigator assessment will be 
used at IAs and may be included as supportive analysis at FA. DCR will be analyzed similarly as 
ORR. 
10.3.3. 
Duration of Response 
The duration of response (DOR) is defined as the interval between first documented response 
(Confirmed CR and Confirmed PR) based on the mRANO criteria as determined by the central 
radiology review and progression of disease or death from any cause. DOR will only be 
calculated for patients with ORR.  Censoring rules is identical to the censoring rules presented 
for PFS.  Central review assessment will be used at FA and local investigator assessment will be 
used at IAs and may be included as supportive analysis at FA. Descriptive analysis for DOR 
based on KM method may be included. 


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10.4. 
Exploratory Efficacy Endpoint and Analyses 
The overall NANO score categories (Neurologic Response, Neurological Progression, 
Neurological Stability) will be summarized by visit and will be listed as appropriate. Overall 
NANO score changes over time may be evaluated graphically.   
Corticosteroid systemic use (prior to treatment, on or after treatment, both prior and on or after 
treatment, or no prior or on/after treatment) will be summarized by arm for ITT set. Duration of 
Patients remaining off Corticosteroids for treatment of GBM will be summarized by arm. 
Corticosteroids use over time may be tabulated or presented graphically.   


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11. 
ANALYSIS OF BIOMARKER DATA 
Biomarker data are exploratory endpoints and may include but are not limited to the following: 
• 
Measurement of WT1 peptide-specific CTL induction activity   
• 
Expression of WT1 via Chromogenic in situ Hybridization (CISH) and/or WT1 protein 
via immunohistochemistry (IHC) in tumor tissue  
Analysis of biomarker data will be exploratory in nature. 


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12. 
SAFETY 
The population used for safety analyses will be the Safety Set (SS). Safety will be assessed based 
on treatment exposure, adverse event (AE) or adverse drug reactions (ADR) reports, clinical 
laboratory data, ECG parameters, physical examinations, and vital signs. Analyses of the safety 
parameters will be presented by visits and/or time points where applicable. For continuous 
variables, descriptive statistics will include the number of patients (n), mean, standard deviation, 
median, minimum, and maximum. Frequencies and percentages will be displayed for categorical 
data. Percentages by categories will be based on the number of patients with no missing data, 
i.e., will add up to 100%. Categorical variables with a non-zero number of missing values will 
include an additional “Missing” category with no percentage provided (the category will be 
excluded from the distribution).  
No inferential testing will be performed on safety data, which will be summarized by dose level 
in Part 1 and by treatment group in Part 2 Safety Set. 
For patients who have a dose reductions/modification, all AEs (due to drug or otherwise) will be 
assigned to the associated initial dose combination/dose level. 
Safety data will be presented graphically as deemed appropriate. This may include, but is not 
restricted to, presentation of parameters against time or shift plots. Appropriate scatter- or box- 
plots will also be considered to investigate trends in parameters compared to baseline. 
12.1. 
Extent of Exposure 
Study drug exposure including cumulative dose and duration of exposure will be summarized by 
study part and treatment group. Duration of exposure (i.e., weeks on study drug) will be 
calculated as the number of weeks from first to last dose date, (last exposure date - first exposure 
date + 1)/7. The number of patients with a dose reduction or dose interruption in each dose group 
or treatment group will also be summarized. The relative dose intensity defined as the actual 
dose intensity (ADI) delivered divided by the planned dose intensity (PDI) multiplied by 100 
will also be presented.   
12.1.1. 
Exposure of DSP7888  
• 
Intended Treatment Duration (weeks) = (last dose date of DSP7888 + intended timing 
OR last dose of bevacizumab + intended timing which comes later– first dose date of 
DSP7888 or bevacizumab which comes first)/7. Intended timing is 7 days for induction 
phase, and 14 days for consolidation phase and 28 days for maintenance phase for DSP7888, 
and 14 days for Bev. 
• 
Actual Cumulative Dose (mg) = Sum of all administered dose of DSP7888 (mg) 
• 
Actual Dose Intensity (mg/week), ADI = Actual Cumulative Dose (mg) / Intended 
Treatment Duration (weeks) 
• 
Cumulative Planned Dose = Sum of all protocol-defined planned doses (mg) during the 
intended treatment duration period 
• 
Planned Dose Intensity (mg/week), PDI = Cumulative planned dose (mg) / Intended 
Treatment Duration (weeks) 


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• 
Relative Dose Intensity (%), RDI = 100 * ADI (mg/week) / PDI (mg/week) 
Dose exposure of DSP7888 will also be summarized by phase: Induction Phase, Consolidation 
Phase, Maintenance Phase. 
For the induction phase:   
• 
Intended Treatment Duration (weeks) in the induction phase = (first dose date of 
DSP7888 in the consolidation phase - first dose date of DSP7888 in the induction phase )/7 
or ( last dose date of DSP7888 in the induction phase - first dose date of DSP7888 in the 
induction phase + 7) /7 if patients didn’t enter the consolidation phase   
• 
Actual Cumulative Dose (mg) in the induction phase = Sum of all administered doses of 
DSP7888 (mg) in the induction phase 
• 
Actual Dose Intensity (mg/week), ADI in the induction phase = Actual Cumulative Dose 
(mg) / Intended Treatment Duration (weeks) in the induction phase 
• 
Relative Dose Intensity (%), RDI in the induction phase = 100* ADI (mg/week) / 10.5 
(mg/week) 
For the consolidation phase:  
• 
Intended Treatment Duration (weeks) in the consolidation phase = (first dose date of 
DSP7888 in the maintenance phase - first dose date of DSP7888 in the consolidation phase) 
/7 or ( last dose date of DSP7888 in the consolidation phase - first dose date of DSP7888 in 
the consolidation phase + 14) /7 if patients didn’t enter the maintenance phase  
• 
Actual Cumulative Dose (mg) in the consolidation phase = Sum of all administered doses 
of DSP7888 (mg) in the consolidation phase 
• 
Actual Dose Intensity (mg/week), ADI in the consolidation phase = Actual Cumulative 
Dose (mg) /Intended Treatment Duration (weeks) in the consolidation phase 
• 
Relative Dose Intensity (%), RDI in the consolidation phase = 100* ADI (mg/week) / 
5.25 (mg/week) 
For the maintenance phase,   
• 
Intended Treatment Duration (weeks) in the maintenance phase = (last dose date of 
DSP7888 in the maintenance phase - first dose date of DSP7888 in the maintenance phase + 
28) /7  
• 
Actual Cumulative Dose (mg) in the maintenance phase = Sum of all administered doses 
of DSP7888 (mg) in the maintenance phase 
• 
Actual Dose Intensity (mg/week), ADI in the maintenance phase = Actual Cumulative 
Dose (mg) / Intended Treatment Duration (weeks) in the maintenance phase 
• 
Relative Dose Intensity (%), RDI in the maintenance phase = 100* ADI (mg/week) / 
2.625 (mg/week) 
12.1.2. 
Exposure of Bevacizumab 
• 
Intended Treatment Duration (weeks) = (last dose date of DSP7888 + intended timing 
OR last dose of bevacizumab +intended timing which comes later – first dose date of 


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DSP7888 or bevacizumab which comes first).  Intended timing is 7 days for induction phase, 
and 14 days for consolidation phase and 28 days for maintenance phase for DSP7888, and 14 
days for Bev.  
• 
Actual Cumulative Dose (mg/kg) = Sum of all administered doses of bevacizumab 
(mg/kg) that the patient received.  Actual dose received (mg) for each visit will be converted 
to dose in mg/kg by dividing the weight. The weight is derived on the last available weight 
prior to or on each date of Bevacizumab dosing.    
• 
Actual Dose Intensity (mg/kg/week), ADI = Actual Cumulative Dose (mg/kg) / Intended 
Treatment Duration (weeks) 
• 
Planned Dose Intensity (mg/kg/week), PDI = 5 mg/kg/week  
• 
Relative Dose Intensity (%), RDI = 100* ADI (mg/kg/week) / PDI (mg/kg/week) 
12.2. 
Treatment Compliance 
N/A. All patients will be administered study drug in clinic  
12.3. 
Adverse Events / Adverse Drug Reactions 
Adverse events will be collected throughout the study, commencing from the time the informed 
consent form is obtained until 30 days after the last dose of study drug. When an SAE that is 
assessed as causally related (i.e., Definite, Probable, or Possible) occurs after completion of the 
clinical study, the Investigator will report the event to the Sponsor as a spontaneous report.   
All adverse events that occur after administration of the first dose of study drug or that are 
present at baseline but worsen in severity after the first dose of study drug up to 30 days after the 
last dose of study treatment (or up to any time if a serious AE and considered related to study 
drug) will be considered as Treatment-Emergent Adverse Events (TEAEs). Any AEs that is not 
TEAE but occur after 30 days during the Post-Protocol Therapy will be considered as Post-AEs. 
The emphasis for AE analysis will be based on treatment-emergent AE (TEAE), however all 
AEs will be listed regardless of TEAE or not.   
Adverse events will be summarized by dose level for Part 1 and by arm for Part 2.   
Adverse events will be summarized by the SOC and PT based on the MedDRA dictionary 
version 19.1 or later.  
For summaries of AEs by SOC and PT, a patient will be counted once at the SOC level and once 
at each PT within the SOC level. For summaries by SOC, PT, and maximum CTCAE grade, a 
patient will be counted once at the highest CTCAE grade level for which the event occurred at 
the SOC level and the highest CTCAE grade level for each unique PT within that SOC level. 
Therefore, patients may only contribute once to each PT and once to each SOC level summary.    
The summaries presenting frequency of AEs by SOC and PT will be ordered by descending 
frequency of SOC and then, within an SOC, by overall descending frequency of PT in DSP-7888 
Dosing Emulsion plus Bev arm.   
The following AE tables will be provided: 


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• 
An overall summary of the number and percentage of patients reporting TEAEs, 
treatment-related TEAEs, serious TEAEs, Grade 3 (or worse) TEAEs, AEs considered as 
DLTs ( Section 4.1.1.1  for definition of DLTs), TEAEs leading to dose withdrawn, and fatal 
AEs  
• 
TEAEs by SOC and PT 
• 
TEAEs by PT 
• 
Serious TEAEs, by SOC and PT 
• 
Serious TEAEs, by PT 
• 
DLTs  
• 
Study-treatment-related AEs, by SOC and PT 
• 
TEAEs by CTCAE Grade, by SOC and PT 
• 
TEAEs by Worst Grade 
• 
TEAEs leading to death, by SOC and PT  
• 
TEAEs of grade 3 or higher, by SOC and PT 
• 
TEAEs of grade 3 or higher on worst grade and by PT 
• 
TEAEs leading to withdrawal of study medication, by SOC and PT. 
• 
TEAEs leading to dose modification or interruption of study medication by SOC and PT 
For patients who have a dose modification, all AEs (due to drug or otherwise) will be assigned to 
the initial dose group.  
Listings will be provided for AEs marked as DLTs. TEAEs will be flagged in listings. 
In addition, Exposure Adjusted Incidence Rate (EAIR; He et al., 2015) of selected AEs may be 
summarized. 
Serious Adverse Event (SAE) and Death 
Treatment emergent SAEs and treatment emergent SAEs related to DSP-7888 will be 
summarized by SOC, PT and maximum CTCAE grade.  
The number and percentages of patients who died on treatment, as well as the primary cause of 
death will be summarized. On-treatment death is defined as death within 30 days of last dose of 
study drug (DSP-7888 or Bev). A listing of death data will also be provided.  
Injection Site Reaction (ISR) 
The predominant adverse effect observed with DSP-7888 is injection site reaction. The Preferred 
Terms of TEAEs within the High Level Group Term of “Administration Site Reaction” 
(MedDRA version 19.1) will be used to identify events of injection site reaction occurring in the 
pivotal study and across the program. 
Below analysis will be provided for ISR: 
• 
ISR by SOC, PT, and maximum CTCAE Grade 


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• 
ISR by SOC, PT, and maximum CTCAE Grade by subgroup of Geographic Region, 
Race, Country, and HLA type.   
• 
Onset time of first ISR for patients with at least one ISR: Time to onset is analyzed for 
patients with at least one ISR from the first dose of the DSP-7888 to the first occurrence 
of ISR regardless of CTCAE grade. 
• 
Onset time of first ISR: Time to first ISR is defined as the time from the first dose of the 
DSP-7888 to the first occurrence of ISR . For patients with no ISR, the onset time will be 
censored as data cutoff date, end of study date, death date, or safety follow-up completion 
date (end of treatment date + 30 days) whichever is shorter. 
• 
Onset time of the first Grade 3 or higher ISR for patients with at least one Grade 3 or 
higher ISR: Time to onset is analyzed for patients with at least one Grade 3 or higher ISR 
from the first dose of DSP-7888 to the first occurrence of the Grade 3 or higher ISR. 
• 
Onset time of the first Grade 3 or higher ISR: Time to first Grade 3 or higher ISR is 
defined as the time from the first dose of DSP-7888 to the first occurrence of the Grade 3 
or higher ISR. For patients with no Grade 3 or higher ISR, the onset time will be 
censored as data cutoff date, end of study date, death date, or safety follow-up completion 
date (end of treatment date + 30 days) whichever is shorter. 
• 
Duration of Grade 3 or higher ISR and Duration of ISR may be analyzed in the CSR.  
A listing of ISR will also be provided. 
12.4. 
Laboratory Evaluation 
All samples will be analyzed at a central laboratory and collected per Schedule of Assessments 
in Section 3.9. Local laboratories may be used as deemed necessary by the Investigator in order 
to make treatment related decisions. 
The results of laboratory parameters will be graded according to NCI CTCAE v4.03 for below 
parameters (Table 8 ).  For patients with both baseline and post baseline assessments, a summary 
of shift from baseline CTCAE grade to maximum postbaseline CTCAE grade will be provided. 
All records on or after the first dose (scheduled and unscheduled) until 30 days following the last 
dose of study drug will be considered as post baseline. Additional parameters may be added for 
the shift tables. Both scheduled and unscheduled laboratory test results will be included in the 
shift tables.  
Table 8:      CTCAE Lab Grading Parameters.  
↓ 
↑ 
HEMATOLOGY Anemia 
 
HEMATOLOGY White blood cell decreased 
 
HEMATOLOGY Lymphocyte count decreased  
HEMATOLOGY Neutrophil count decreased 
 
HEMATOLOGY Platelet count decreased 
 
CHEMISTRY 
  
Alanine aminotransferase increased 


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CHEMISTRY 
Hypoalbuminemia 
  
CHEMISTRY 
  
Alkaline phosphatase increased 
CHEMISTRY 
  
Aspartate aminotransferase increased 
CHEMISTRY 
  
Blood bilirubin increased 
CHEMISTRY 
  
Blood Urea Nitrogen Increased  
CHEMISTRY 
Hypocalcemia 
Hypercalcemia 
CHEMISTRY 
  
Creatinine increased 
CHEMISTRY 
Hypoglycemia 
Hyperglycemia 
CHEMISTRY 
Hypomagnesemia  
Hypermagnesemia  
CHEMISTRY 
Hypophosphatemia 
  
CHEMISTRY 
Hypokalemia 
Hyperkalemia 
CHEMISTRY 
Hyponatremia 
Hypernatremia 
Blood Urea Nitrogen Increased is not in CTCAE grading, SDPO will define as use mg/dL as 
grade 1 is 23 - 26, grade 2 is 27-31, grade 3, >31 
Listings of hematology and biochemistry, urinalysis and coagulation will be provided, including 
the test result, units, normal range, change from baseline, and CTCAE grade if available.  
An eDISH (evaluation of Drug-Induced Serious Hepatotoxicity) plot for patients in Part 1 and 
Part 2 will be provided. A listing of liver function test results that corresponding to the eDISH 
plot will be provided by patients and potential Hy’s law cases if any will be flagged in the listing.   
12.5. 
Vital Signs 
 
Body temperature will be summarized in °C. If body temperature is recorded as °F, then 
temperature will be converted to °C using: 
Temperature (°C) = 5/9 (Temperature [°F]-32). 
 
Summaries of post baseline markedly abnormal vital signs, including systolic blood pressure, 
diastolic blood pressure, pulse rate, weight change, and temperature will be presented. Markedly 
abnormal ranges for vital signs parameters are given in Table 9 . Post baseline includes non-
missing records from both scheduled and unscheduled visits after the first dose of study drug 
until 30 days following the last dose of study treatment. 


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Table 9: 
Markedly Abnormal Ranges for Vital Signs 
Parameter 
Markedly Abnormal (Low) 
Markedly Abnormal (High) 
Systolic Blood 
Pressure 
• 
Absolute value ≤ 90 mmHg for 
post baseline, or  
• 
a decrease from baseline ≥20 
mmHg for change from baseline 
• 
Absolute value ≥ 180 mmHg for 
post baseline, or  
• 
an increase from baseline ≥20 
mmHg for change from baseline 
Diastolic Blood 
Pressure 
• 
Absolute value ≤ 50 mmHg for 
post baseline, or   
• 
a decrease from baseline ≥15 
mmHg for change from baseline 
• 
Absolute value ≥ 105 mmHg for 
post baseline, or  
• 
an increase from baseline ≥ 15 
mmHg for change from baseline 
Pulse 
• 
Absolute value ≤ 50 bpm for post 
baseline, or   
• 
a decrease from baseline ≥ 15 
bpm for change from baseline 
• 
Absolute value ≥ 120 bpm for 
post baseline, or   
• 
an increase from baseline ≥ 
15bpm for change from baseline 
Weight Change 
Weight loss from baseline ≥ 20%  
Weight gain from baseline ≥ 20% 
Temperature 
≤ 35C post baseline only 
≥ 40C post baseline only 
A listing of vital signs results will also be presented using the Safety Set.  
12.6. 
Electrocardiogram 
A 12-lead Electrocardiogram (ECG) with categorical results (normal; abnormal, not clinically 
significant; abnormal, clinically significant) will be summarized in the shift summary from 
baseline to worst post baseline. Post baseline includes non-missing records collected (scheduled 
and unscheduled) after the first dose of study treatment until 30 days following the last dose of 
study treatment. QT measurements corrected by heart rate will be used for the data analysis and 
interpretation. QTc interval will be calculated using Fridericia’s correction. The formula is: 
Fridericia’s correction: QTcF = QT ∕RR0.33 
where unit of QT is milliseconds (msec) and unit of RR is second (sec). The number and 
percentage of patients in QT and QTcF (QT and QTcF interval: ≤ 450 msec, > 450 - ≤ 480 msec, 
> 480 - ≤ 500 msec, and > 500 msec) will be summarized at baseline and maximum post 
baseline. Categories of maximum changes from baseline (≤ 30 msec, > 30 - ≤ 60 msec, > 60 
msec) will be summarized as well. 
An ECG result listing that including QT, QTc, and Heart Rate will also be provided. 
12.7. 
Karnofsky Performance Score 
Summary tables by visit and change from baseline by visit for Karnofsky performance 
assessment (see Table below) will be provided.   


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All Karnofsky performance scores will be listed by treatment group and dose level. 
12.8. 
Physical Examination 
Physical examination, including documentation of body system, normal/abnormal and 
abnormality description and neurological examination will be presented in individual subject 
data listings.   
12.9. 
Echocardiogram/Multigated Acquisition Scan 
Echocardiogram and multigated acquisition scan (MUGA) will be assessed at baseline. Results 
including LVEF (%) will be listed. 
12.10. 
Oxygen Saturation 
Oxygen saturation will be assessed at baseline. Results will be listed. 


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13. 
CHANGE FROM ANLAYSIS PLANNED IN PROTOCOL 
No major change from planned analyses was made.   


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14. 
REFERENCE 
1. 
Protocol BBI-DSP7888-201G Original Protocol 29MAR2017 
2. 
Protocol BBI-DSP7888-201G Protocol Amendment 1 Version 2.0 FINAL 30APR2017 
3. 
Protocol BBI-DSP7888-201G Protocol Amendment 2 Version 3.0 FINAL 18SEP2017 
4. 
Protocol BBI-DSP7888-201G Protocol Amendment 3 Version 4.0 FINAL 06OCT2017 
5. 
Protocol BBI-DSP7888-201G Protocol Amendment 4 Version 5.0 FINAL 13OCT2017 
6. 
Protocol BBI-DSP7888-201G Protocol Amendment 5 Version 6.0 FINAL 08JUL2018 
7. 
Protocol BBI-DSP7888-201G Protocol Amendment 6 Version 7.0 FINAL 24JUN2019 
8. 
Protocol BBI-DSP7888-201G Protocol Amendment 7 Version 8.0 FINAL 05FEB2021 
9. 
Independent Radiology Review Imaging Charter Version 2 22JUL2020 
10. 
Cui, L., Hung, H. M. J., Wang, S. (1999). Modification of sample size in group sequential 
clinical trial. Biometrics. 55, 853-857. 
11. 
Shen, Y., Cai, J. (2003). Sample size re-estimation for clinical trials with censored 
survival data. Journal of the American Statistical Association. 98, 418-426. 
12. 
Wassmer G, Brannath W.  Group Sequential and Confirmatory Adaptive Designs in 
Clinical Trials. New York: Springer, 2016. 
13. 
Willi Maurer & Frank Bretz (2013) Multiple Testing in Group Sequential Trials Using 
Graphical Approaches, Statistics in Biopharmaceutical Research, 5:4, 311-320, DOI: 
10.1080/19466315.2013.807748 
14. 
He X, Chen L, Lei L, Xia HA, Lee MLT (2015) A Simple Method for Estimating 
Confidence Intervals for Exposure Adjusted Incidence Rate and Its Applications to Clinical 
Trials. J Biom Biostat 6: 238. 
15. 
He P, Fang L, Su Z. A sequential testing approach to detecting multiple change points in 
the proportional hazards model. Statistics in Medicine.2013; 32:1239-1245. 
16. 
He P, Su Z. A novel design for randomized immuno-oncology clinical trials with 
potentially delayed treatment effects. Contemporary Clinical Trials Communications. 2015;1:28-
31 
17. 
Klein, J.P., Logan, B., Harhoff, M. and Andersen, P.K. (2007), Analyzing survival curves 
at a fixed point in time. Statist. Med., 26: 4505-4519. 
18. 
Zucker DM, Lakatos E. Weighted log rank type statistics for comparing survival curves 
when there is a time lag in the effectiveness of treatment. Biometrika. 1990; 77:853-864. 
19. 
Xu Z, Park Y, Zhen B, Zhu B. Designing cancer immunotherapy trials with random 
treatment time-lag effect. Statistics in Medicine. 2018; 37: 4589-4609 


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15. 
APPENDIX 
15.1. 
Tipping Point Sensitivity Analysis 
To quantify the robustness of the primary study objective to departures from the censoring at 
random (CAR) assumption, sensitivity analyses under the censoring not at random (CNAR) 
assumption will be conducted for patients who discontinued from the study, e.g., lost to follow 
up. 
Sensitivity analyses will be conducted using a multiple imputation (MI) framework with a 
Bayesian Piecewise Exponential Proportional Hazards model (PEPHM) as the imputation model 
and the primary analysis model (e.g., the Cox proportional hazards model) as the analysis model.  
Sensitivity analysis will proceed as follows. 
1. Fitting Bayesian PEPHM with the number of intervals k from 3 to 10 to the analysis data 
set using PROC PHREG in SAS (BAYES statement), separately by treatment arm with 
the same covariates that are used in the primary analysis model.  The cut-points are 
determined in a data-driven way to ensure an about equal number of events per interval 
within each treatment arm.  
2. Sampling from posterior distribution of the model parameters (interval-specific hazards 
and regression coefficients, m=1,000 draws). 
3. Generating event times for patients who discontinued early from the study (lost to follow 
up) using imputation from the posterior predictive distribution of missing data for the 
same arm, with covariate-specific hazard functions multiplied by a treatment-specific 
sensitivity parameter δ𝑖 (𝑖= 0,1). For each draw from the posterior predictive 
distribution, simulate missing event times for each patient starting from the time this 
patient discontinued from the study (𝐶𝑖) and retain this value as an imputed time to event 
or censor at the end of the follow-up period (Tmax) if it exceeds Tmax. This results in 
forming m imputed data sets. 
4. Analyzing each imputed data set using the primary analysis model and computing the log-
hazard ratios, log(HR), and associated standard errors for the treatment effect 
5. Combining the m estimated log-hazard ratios and associated standard errors within single 
MI-inference, including the point estimate, confidence interval and p-value using Rubin’s 
combination rules (using PROC MIANALYZE). 
A tipping point analysis will be conducted by executing Steps 1-5 for different values of the 
sensitivity parameters δ0 and δ1, for the control and treatment arm, respectively. For each 
setting, a p-value is computed, and values of the sensitivity parameters are identified when the 
null hypothesis fails to be rejected (assume original test without imputation reject the null 
hypothesis).  Most of time, the delta is varied only in the treatment arm (δ1 > 1), which implies 
an increased hazard for patients after their discontinuation from the treatment, as prior to 
discontinuation.  both δ0 and δ1  can vary resulting in a two-dimensional map for the sensitivity 
analysis p-values. δ >1 implies an increased hazard for patients after their discontinuation from 
the treatment, while <1 implies a decreased hazard after discontinuation. 


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Another type of sensitivity analysis that can be easily implemented using the outlined framework 
is control-based imputation.  For this type of sensitivity analysis, times to event in both arms (in 
Step 3) are computed from the survival distribution estimated from the control arm (Step 1). 
The details on Steps 1-5 are provided as follows. 
15.1.1. 
Fitting a Bayesian Piecewise Exponential Model to the Analysis Data Set 
The imputation model will have a hazard function ℎ(𝑡) incorporating 𝑝 baseline covariates, 
𝑋1, 𝑋2, . . , 𝑋𝑝, i.e., 
ℎ(𝑡) = ℎ0(𝑡) exp(𝑋𝑇𝜷), 
Where 
• t is the time since randomization.  
• Piecewise baseline hazard ℎ0(𝑡) = ∑
𝜆0𝑖𝐼(𝜏𝑖−1 < 𝑡≤𝜏𝑖)
𝑘
𝑖=1
, 𝑖= 1, . . , 𝑘 , the k 
intervals defined as 0 = 𝜏0 < 𝜏1 < ⋯< 𝜏𝑘−1 < 𝜏𝑘= ∞ , 𝜆0𝑖 are constant baseline 
hazards for the ith interval and 𝐼(∙) is the indicator function. 
• Default diffuse priors for 𝜆0𝑖 are gamma G (10-4, 10-4), i.e., the prior mean is set to 1 
and the prior variance is set to 104.  Default priors for the regression coefficients 𝜷 
are independent normal N (0,106).  Sampling from the posterior distribution of the 
parameters 𝜆0𝑖 and 𝜷 will be carried out via MCMC with default options for the 
number of burn-in iterations (NBI), number of iterations (NMC) and thinning 
(THINNING).  If the diagnostics suggest the presence of autocorrelation, the thinning 
parameter should be increased accordingly.   
15.1.2. 
Generating Event Times for Patients Lost to Follow up 
Event times are generated from the piecewise exponential distribution using the inversion 
method that can be easily implemented with SAS custom code following the steps detailed below 
for each trial arm: 
1. Set a sensitivity parameter 𝛿≥1.  Note that setting 𝛿= 1 corresponds to imputation under CAR. 
2. Draw 𝜆̃0𝑗, 𝑗= 1, . . , , 𝑘 and 𝜷̃ from the posterior distributions of 𝝀0 and 𝜷 (as explained in Section 
1). 
3. For patients to be imputed, evaluate 𝑆𝝀̃0,𝜷̃(𝑐𝑖|𝒙𝑖), i.e., the survival function at 𝑐𝑖, the time when 
the ith patient was censored (early discontinued), with the parameters 𝝀̃0, 𝜷̃. Let 𝜏𝑗−1 < 𝑐𝑖≤𝜏𝑗, 
𝑗= 1, . . , 𝑘 (𝜏0=0 and 𝜏𝑘= ∞). Then 
𝑆𝝀̃0,𝜷̃(𝑐𝑖|𝒙𝑖) = ∏exp(−(𝜏𝑙−𝜏𝑙−1)𝛿𝜆̃0𝑙exp (𝒙𝒊
𝑻𝜷̃))
𝑗−1
𝑙=1
× exp(−(𝑐𝑖−𝜏𝑗−1)𝛿𝜆̃0𝑗exp (𝒙𝒊
𝑻𝜷̃)) 
4. For the ith censored patient, simulate uniform values from 𝑢𝑖~𝑈(𝑝𝑖, 1), where 𝑝𝑖= 1 −
𝑆𝝀̃0,𝜷̃(𝑐𝑖|𝒙𝑖).  
5. Compute the event time 𝑡̃𝑖 by using the inverse of the CDF for the time to event evaluated at 𝝀̃0, 𝜷̃ 


Sumitomo Dainippon Pharma Oncology, Inc. 
 
Protocol No: BBI-DSP-7888-201G 
Statistical Analysis Plan – Version 5.0 
 
 
 
Confidential & Proprietary 
 
Page 59 of 59 
𝑡̃𝑖=
{
  
 
  
 
−log(1 −𝑢𝑖)
𝜆1(𝒙𝑖)
, 0 < 𝑢𝑖< 1 −𝑆1(𝒙𝑖)
𝜏𝑗−1 −log(1 −𝑢𝑖) + ∑
(𝜏𝑙−𝜏𝑙−1)𝜆𝑙(𝒙𝑖)
𝑗−1
𝑙=1
𝜆𝑗(𝒙𝑖)
, 1 −𝑆𝑗−1(𝒙𝑖) ≤𝑢𝑖< 1 −𝑆𝑗(𝒙𝑖), 𝑗= 2, . . , 𝑘−1
𝜏𝑘−1 −log(1 −𝑢𝑖) + ∑
(𝜏𝑙−𝜏𝑙−1)𝜆𝑙(𝒙𝑖)
𝑘−1
𝑙=1
𝜆𝑘(𝒙𝑖)
, 1 −𝑆𝑘−1(𝒙𝑖) ≤𝑢𝑖≤1
 
where the piecewise constant covariate adjusted hazards are 𝜆𝑗(𝒙𝑖) = 𝛿𝜆̃0𝑗exp (𝑋𝑇𝜷̃), and the 
associated survival function is 𝑆𝑗(𝒙𝑖) = ∏
exp(−(𝜏𝑙−𝜏𝑙−1)𝜆𝑙(𝒙𝑖))
𝑗
𝑙=1
.  
Note that the sensitivity parameter 𝛿 is incorporated into the hazard function 𝜆𝑗(𝒙𝑖).  When 
performing imputation under the sensitivity analysis, 𝛿 can be treatment-specific, i.e., 𝛿 >1 in the 
treatment arm (assuming a higher hazard for patients after discontinuation compared to a patient 
with the same covariates who remained on treatment) and 𝛿=1 in the control arm.  
6 Compare the simulated time 𝑡̃𝑖with the maximum follow up time 𝑇𝑚𝑎𝑥. If the time exceeds 
𝑇𝑚𝑎𝑥, censor the ith patient at 𝑇𝑚𝑎𝑥. 
15.1.3. 
Analyzing Imputed Data  
Each imputed data set is analyzed using the primary analysis model, e.g., the proportional 
hazards Cox model, for several values of 𝛿. The resulting point estimates and standard errors are 
combined using PROC MIANALYZE to produce the final estimates of the treatment effect and 
p-values. The p-values are reported as a function of the sensitivity parameter 𝛿 and regions of 
𝛿’s are found where the p-value becomes non-significant (tipping point analysis).