Clinical trial NCT02026271
Conditions: Glioblastoma Multiforme Anaplastic Oligoastrocytoma
Sponsor: Alaunos Therapeutics
Start date: 2015-06-01; Completion date: 2019-08-01
Enrollment: 40 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This research study involves an investigational product: Ad-RTS-hIL-12 given with veledimex for production of human IL-12. IL-12 is a protein that can improve the body's natural response to disease by enhancing the ability of the immune system to kill tumor cells and may interfere with blood flow to the tumor.

The main purpose of this study is to evaluate the safety and tolerability of a single tumor injection of Ad-RTS-hIL-12 given with oral veledimex.

Detailed description:
Eligible patients will be stratified to one of two groups, according to clinical indication for tumor resection. Patients who are scheduled for a standard of care craniotomy and tumor resection will receive one dose of veledimex before the resection procedure. Ad-RTS-hIL-12 will be administered by free-hand injection. Patients will continue on oral veledimex for 14 days.

Patients not scheduled for tumor resection will receive Ad-RTS-hIL-12 by stereotactic injection and then will continue on oral veledimex for 14 days.

The study is divided into three periods: the screening period, the treatment period and the follow-up period.

Arms: arm 1: varying doses of intratumoral Ad-RTS-hIL-12 (INXN-2001) and oral veledimex (activator ligand).
Interventions: intervention 1: Ad-RTS-hIL-12 intervention 2: veledimex
Intervention descriptions: intervention 1: * 2.0 x 10\^11 viral particles (vp) per injection or 1.0 x 10\^12 viral particles (vp) per injection
* one intratumoral injection of Ad-RTS-hIL-12 intervention 2: * 4 doses (20mg/day, 40mg/day, 80mg/day, and 120mg/day)
* 14 oral daily doses of veledimex
* 1 Expansion cohort at a single dose level at or below MTD

Protocol documents:
Prot_000.pdf: 


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PROTOCOL SYNOPSIS 
Clinical Protocol ATI001-102 
Title 
A Phase I Study of Ad-RTS-hIL-12, an Inducible Adenoviral Vector Engineered to Express hIL-12 in the 
Presence of the Activator Ligand Veledimex in Subjects with Recurrent or Progressive Glioblastoma or 
Grade III Malignant Glioma 
Protocol Number 
ATI001-102 
Clinical Phase 
Phase I 
Investigational Product(s) 
Adenovirus-
-human interleukin-12 (Ad-RTS-hIL-12) and veledimex (RTS 
activator ligand) 
Ad-RTS-hIL-12 is a replication-incompetent adenoviral vector containing the hIL-12 gene under the control of 
the RTS inducible promoter turned on in the presence of the activator ligand, veledimex.  Veledimex is a small 
molecule RTS specific transcription factor that stabilizes the RTS promoter components and allows 
transcription of the hIL-12 target gene.  Since target gene expression is dependent on the dose and frequency 
of veledimex administration, the expression of hIL-12 can be modulated (turned on and off) by the veledimex 
dose and schedule. 
Research Hypothesis 
Among subjects with recurrent or progressive glioblastoma or Grade III glioma, Ad-RTS-hIL-12 and 
veledimex can be safely administered and can induce signals of immune activity. 
Primary Objective 
• 
To determine the safety and tolerability of varying dose levels of intratumoral Ad-RTS-hIL-12 and 
oral veledimex doses in subjects with recurrent or progressive glioblastoma or Grade III malignant 
glioma 
Secondary Objectives 
• 
To determine the veledimex maximum tolerated dose (MTD) when given with varying doses of 
intratumoral Ad-RTS-hIL-12 
• 
To determine the veledimex pharmacokinetic (PK) profile 
• 
To determine the veledimex concentration ratio between the brain tumor and blood 
• 
To evaluate cellular 
 immune responses elicited by Ad-RTS-hIL-12 and veledimex 
• 
To determine investigator assessment of response, including tumor objective response rate (ORR) 
and progression-free survival (PFS) 




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Group 2:  Subjects who will NOT undergo tumor resection: 
Subjects who will not undergo tumor resection will receive Ad-RTS-hIL-12 by standard stereotactic surgery 
on Day 0.  Ad-RTS-hIL-12 (2 × 1011 vp or 1 × 1012 vp) will be administered by stereotactic injection. The day 
of Ad-RTS-hIL-12 administration is designated as Day 0.  In Cohorts 1 and 2, it will be delivered into 
approximately two intratumoral sites for a total volume of 0.1 mL.  In Cohorts 3, 4, 5 and 6 it will be delivered 
into multiple intratumoral sites in a divided dose to deliver 0.5 mL volume in approximate aliquots of 0.1 mL 
at each site. The total amount delivered to each site will be recorded in the CRF. In the event that less than the 
planned total injected volume is administered, the reason will be provided.  Care should be taken to avoid 
intraventricular or basal cisternal injection or other critical locations. 
After the Ad-RTS-hIL-12 injection, veledimex will be administered orally for 14 days.  The first veledimex 
dose is to be given on as Day 1, preferably with food.  Subsequent veledimex doses are to be taken once daily, 
in the morning and within approximately 30 minutes of a regular meal. 
Subject enrollment into Group 2 will start no earlier than after two subjects have completed 28 days in 
Group 1, Cohort 1.  Enrollment into Group 2 cohorts is otherwise independent of enrollment into Group 1 
cohorts.   
This study will explore four veledimex dose cohorts; 20 mg, 40 mg, 80 mg, and 120 mg.  Subject enrollment 
and veledimex dose escalation will proceed according to a standard 3+3 design modified to independently 
evaluate two stratified subject groups that may exhibit different safety and tolerability profiles.  In each cohort, 
the first subject will be monitored for the 14 days of treatment and will be observed an additional 7 days post 
the last veledimex dose before the second and third subjects are enrolled in that same cohort.  The 
dose-limiting toxicity (DLT) evaluation period is defined as 28 days post Ad-RTS-hIL-12 injection (Day 0 – 
Day 28).  Determination of safety and recommendation to dose escalate will occur after all dosed subjects in a 
cohort have been evaluated for at least 28 days post Ad-RTS-hIL-12 injection.  The details on the dose 
escalation schedule are provided in Section 6.2 Table 5 and the dose escalation decision rules provided in 
Section 6.3 and summarized in Table 6.   
 
Study Oversight for Safety Evaluation: 
This study will implement an independent data and safety monitoring board (DSMB) to provide unbiased and 
objective input on the safety evaluation of the high grade glioma population.  In the context of an open label 
study, the responsibility of the DSMB is to provide an objective determination of safety at the end of each 
dose cohort and make a recommendation to proceed to the next higher veledimex dose level or to discontinue 
the study.  A separate charter will describe the activities of this committee.  
The first level of safety oversight will occur through the site investigator and medical monitor.  A formal 
Safety Review Committee (SRC) comprised of the study investigators, the medical monitor and other 
appropriate sponsor representatives will provide the overall safety oversight.  Additional external medical and 
scientific experts may also be invited to participate in the reviews as needed.  A separate charter will outline 
the SRC activities. Briefly, the SRC will evaluate patient safety within each cohort, and within each 
stratification group of the same cohort.  If no significant safety events occur with the first patient of each 
cohort, the second and third subjects will be enrolled and treated.  If a significant safety event occurs with the 
first patient in each cohort, the SRC will convene to evaluate the safety event(s) and make a recommendation 
and decision on the enrollment of the second and third subjects in that same cohort.  At the end of each cohort 
(Group 1 and 2 separately), the SRC will convene to review the safety data after the final patient in a cohort, 
within a group, has completed veledimex dosing and has been monitored for 28 days after the Ad-RTS-hIL-12 
injection. 
 At the end of each cohort, the safety summary will be communicated to the DSMB.  The DSMB, will be 
guided by a DSMB charter and, within three days of receipt, will evaluate the safety data and make a 


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recommendation to the SRC regarding continuation to the next dose cohort, amendment of the dose escalation 
schedule, or discontinuation of the study.  The DSMB recommendation will be communicated to the SRC and 
appropriate action will be taken.  A written record of the DSMB recommendation will be provided to the SRC 
and maintained on file with the sponsor. See Section 3.3. 
Dose-limiting toxicity (DLT) is defined as: 
An event, occurring within the first 28 days (Day 0 - Day 28) that meets one of the following conditions: 
• 
Any local reaction that requires operative intervention and felt to be attributable to Ad-RTS-hIL-12 
and/or veledimex 
• 
Any local reaction that has life-threatening consequences requiring urgent intervention or results in 
death and felt to be attributable to Ad-RTS-hIL-12 and/or veledimex 
• 
Any Grade 3 or greater non-hematological adverse event that is at least possibly related to the study 
drug 
• 
Any Grade 4 hematologic toxicity that is at least possibly related to the study drug and lasts at least 5 
days  
• 
Grade 3 or higher thrombocytopenia at least possibly related to the study drug 
Note: Diagnostic brain tumor biopsy is not considered a DLT.  Seizures, headache and cerebral edema are 
commonly observed in this population and will be recorded according to grade of toxicity, but will not be 
considered a DLT unless they are deemed as most likely to be drug-related as the main contributory factor. 
Expansion cohorts are not prospectively planned in this study.  A decision to enroll additional subjects, as part 
of an expansion cohort, at the determined veledimex MTD and the Ad-RTS-hIL-12 dose will be made by the 
SRC only after the MTD has been identified for one or both groups and safety evaluated.  If an expansion 
cohort is implemented, the veledimex dose may be delayed or reduced for individual subjects in the event of 
toxicity.  If ≥ 33% of subjects in the expansion cohort experience DLTs, according to the definition used in the 
dose-escalation phase, additional subjects may be enrolled at the next lower dose tested in the dose escalation 
phase, or at an intermediate dose, as recommended by the SRC.  All DLTs should be reported to the sponsor 
within 24 hours of investigator/site awareness. 
Number of Centers 
Approximately 8 to 12 centers 
Number of Subjects 
Up to 72 subjects may be enrolled.   


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Study Population 
The eligible study population includes adult subjects with recurrent or progressive glioblastoma or Grade III 
malignant glioma (anaplastic astrocytoma, anaplastic oligodendroglioma, and anaplastic oligoastrocytoma,) 
for which there is no alternative curative therapy. 
Inclusion Criteria: 
1. Male or female subject ≥ 18 and ≤ 75 years of age 
2. Provision of written informed consent for tumor resection, stereotactic surgery, tumor biopsy, samples 
collection, and treatment with investigational products prior to undergoing any study-specific procedures 
3. Histologically confirmed supratentorial glioblastoma or other World Health Organization (WHO) 
Grade III or IV malignant glioma from archival tissue 
4. Evidence of tumor recurrence/progression by MRI according to response assessment in neuro-oncology 
(RANO) criteria after standard initial therapy 
5. Previous standard of care antitumor treatment including surgery and/or biopsy and chemoradiation.  At the 
time of registration, subjects must have recovered from the toxic effects of previous treatments as 
determined by the treating physician.  The washout periods from prior therapies are intended as follows: 
(windows other than what is listed below should be allowed only after consultation with the Medical 
Monitor) 
a. Nitrosoureas:  6 weeks 
b. Other cytotoxic agents:  4 weeks 
c. Antiangiogenic agents, including bevacizumab:  4 weeks 
d. Targeted agents, including small-molecule tyrosine kinase inhibitors:  2 weeks 
e. Experimental immunotherapies (e.g., PD-1, CTLA-4):  3 months 
f. Vaccine-based therapy:  3 months 
6. Able to undergo standard MRI scans with contrast agent before enrollment and after treatment 
7. Karnofsky Performance Status ≥ 70 
8. Adequate bone marrow reserves and liver and kidney function, as assessed by the following laboratory 
requirements: 
a. Hemoglobin ≥ 9 g/L 
b. Lymphocytes > 500/mm3 
c. Absolute neutrophil count ≥ 1500/mm3 
d. Platelets ≥ 100,000/mm3 
e. Serum creatinine ≤ 1.5 x upper limit of normal (ULN) 
f. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x ULN.  For subjects with 
documented liver metastases, ALT and AST ≤ 5 x ULN 
g. Total bilirubin < 1.5 x ULN 
h. International normalized ratio (INR) and activated partial thromboplastin time within normal 
institutional limits 


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9. Male and female subjects must agree to use a highly reliable method of birth control (expected failure rate 
less than 5% per year) from the Screening Visit through 28 days after the last dose of study drug.  Women 
of childbearing potential (perimenopausal women must be amenorrheic for at least 12 months to be 
considered of non-childbearing potential) must have a negative pregnancy test at screening. 
Exclusion Criteria: 
1. Radiotherapy treatment within 4 weeks or less prior to starting first veledimex dose 
2. Subjects with clinically significant increased intracranial pressure (e.g., impending herniation or 
requirement for immediate palliative treatment) or uncontrolled seizures 
3. Known immunosuppressive disease, autoimmune conditions, and/or chronic viral infections [e.g., human 
immunodeficiency virus (HIV), hepatitis] 
4. Use of systemic antibacterial, antifungal, or antiviral medications for the treatment of acute clinically 
significant infection within 2 weeks of first veledimex dose.  Concomitant therapy for chronic infections is 
not allowed.  Subjects must be afebrile prior to Ad-RTS-hIL-12 injection; only prophylactic antibiotic use 
is allowed perioperatively. 
5. Use of enzyme-inducing antiepileptic drugs (EIAED) within 7 days prior to the first dose of study drug.  
Note:  Levetiracetam (Keppra®) is not an EIAED and is allowed 
6. Other concurrent clinically active malignant disease, requiring treatment, with the exception of 
non-melanoma cancers of the skin or carcinoma in situ of the cervix or nonmetastatic prostate cancer 
7. Nursing or pregnant females 
8. Prior exposure to veledimex 
9. Use of medications that induce, inhibit, or are substrates of CYP450 3A4 within 7 days prior to veledimex 
dosing without consultation with the Medical Monitor 
10. Presence of any contraindication for a neurosurgical procedure 
11. Unstable or clinically significant concurrent medical condition that would, in the opinion of the 
investigator or medical monitor, jeopardize the safety of a subject and/or their compliance with the 
protocol.  Examples include, but are not limited to, unstable angina, congestive heart failure, myocardial 
infarction within 2 months of screening, ongoing maintenance therapy for life-threatening ventricular 
arrhythmia or uncontrolled asthma. 


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Investigational Product(s), Dose and Mode of Administration 
Adenovirus-
human interleukin-12 (Ad-RTS-hIL-12) and veledimex (RTS 
activator ligand) 
Ad-RTS-hIL-12 is a replication-incompetent adenoviral vector containing the hIL-12 gene under the control of 
the RTS inducible promoter activated in the presence of the activator ligand, veledimex.  Veledimex is a small 
molecule RTS specific transcription factor that stabilizes the RTS promoter components and allows 
transcription of the hIL-12 target gene.  Since target gene expression is dependent on the dose and frequency 
of veledimex administration, the expression of hIL-12 can be modulated (turned on and off) by the optimal 
veledimex dose and schedule. 
Ad-RTS-hIL-12 Dose: 
This study will explore varying dose levels of Ad-RTS-hIL-12.  The Ad-RTS-hIL-12 will be administered by 
either 
 injection into residual tumor sites immediately after tumor resection (Group 1) or by 
stereotactic injection at intratumoral sites (Group 2). 
Veledimex Dose Cohorts post Ad-RTS-hIL-12 injection 
Veledimex will be administered orally.  Group 1 will receive veledimex 3 (± 2) hours before the planned 
craniotomy (first dose prior to craniotomy will be a dose specific to cohort), and will resume veledimex dosing 
as appropriate for the cohort after Ad-RTS-hIL-12 administration.  Group 2 will receive veledimex only after 
Ad-RTS-hIL-12 administration at dose levels specific to their cohort.  Group 2 will start recruitment only after 
the first two subjects have completed 28 days in Group 1, Cohort 1. 
This study will explore the following dose cohorts given after Ad-RTS-hIL-12 administration: 
Cohort 
Ad-RTS-hIL-12a 
(Day 0) 
Veledimexb 
Group 1 (Days 0 through 14) 
Group 2 (Days 1 through 14) 
Dose (vp) 
Total Daily Dose (mg) 
1 
2 x 1011 
20 
2 
2 x 1011 
40 
3 
1 × 1012 
20 
4 
1 × 1012 
40 
5 
1 × 1012 
80 
6 
1 × 1012 
120 
Ad-RTS-hIL-12 = Adenovirus-
-human 
interleukin-12, PK = pharmacokinetics, vp = viral particles 
a: Intratumoral injection 
b: Dose levels may be modified based on additional clinical and nonclinical PK 
data (Section 6.4) 
 










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TABLE OF CONTENTS 
1. 
INTRODUCTION ................................................................................................................................................... 21 
1.1 
DISEASE BACKGROUND ..................................................................................................................................... 21 
1.2 
INTERLEUKIN-12 AND CANCER IMMUNOTHERAPY .......................................................................................... 21 
1.3 
LOCAL IL-12 DELIVERY AND DEVELOPMENT OF AN INDUCIBLE IL-12 IMMUNOTHERAPY ........................... 22 
1.4 
ADENOVIRAL VECTORS FOR GENE THERAPY .................................................................................................. 23 
1.4.1 
Adenoviral Safety ............................................................................................................................................ 23 
1.4.2 
Safety of Intratumoral Injection of IL-12 Gene Vectors .................................................................................. 24 
 
 
 
 
 
 
 
1.5.3 
Veledimex ........................................................................................................................................................ 26 
 
 
 
 
1.7 
RATIONALE FOR STARTING DOSE AND DOSE ESCALATION SCHEDULE GLIOBLASTOMA PATIENT STARTING 
DOSE RATIONALE .............................................................................................................................................. 31 
 
 
 
 
 
 
 
2. 
STUDY OBJECTIVES ............................................................................................................................................ 34 
2.1 
PRIMARY OBJECTIVE ........................................................................................................................................ 34 
2.2 
SECONDARY OBJECTIVES .................................................................................................................................. 34 
3. 
STUDY DESIGN ..................................................................................................................................................... 35 
3.1 
OVERALL STUDY DESIGN .................................................................................................................................. 35 
3.2 
DOSE ESCALATION COHORTS ........................................................................................................................... 36 
3.3 
STUDY OVERSIGHT FOR SAFETY EVALUATION ................................................................................................ 37 
4 
SUBJECT SELECTION ......................................................................................................................................... 38 
4.1 
INCLUSION CRITERIA ........................................................................................................................................ 38 
4.2 
EXCLUSION CRITERIA ....................................................................................................................................... 39 
4.3 
SUBJECT ENROLLMENT ..................................................................................................................................... 39 
4.4 
WITHDRAWAL OF SUBJECTS FROM STUDY TREATMENT AND/OR STUDY ....................................................... 39 
4.5 
REPLACEMENT OF SUBJECTS ............................................................................................................................ 40 
4.6 
PREMATURE TERMINATION OF STUDY OR STUDY SITE ................................................................................... 40 
5 
INVESTIGATIONAL PRODUCT ......................................................................................................................... 41 
5.1 
PREPARATION OF AD-RTS-HIL-12 ................................................................................................................... 41 
5.2 
PREPARATION OF VELEDIMEX .......................................................................................................................... 41 
5.3 
HANDLING AND STORAGE ................................................................................................................................. 41 
5.4 
MONITORING OF SUBJECT ADHERENCE AND MANAGING MISSED VELEDIMEX DOSES ................................. 41 
5.5 
DISPOSITION OF UNUSED DRUG ........................................................................................................................ 41 
5.6 
ACCOUNTABILITY AND DISPENSATION ............................................................................................................. 42 
6 
TREATMENT PLAN .............................................................................................................................................. 43 
6.1 
AD-RTS-HIL-12 DOSAGE AND ADMINISTRATION PROCEDURES ..................................................................... 43 
6.2 
VELEDIMEX DOSAGE AND ADMINISTRATION ................................................................................................... 44 
6.3 
DOSE ESCALATION DECISION RULES ............................................................................................................... 45 


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6.4 
MODIFICATION OF DOSE ESCALATION SCHEDULE .......................................................................................... 47 
6.5 
DOSE LIMITING TOXICITY ................................................................................................................................ 48 
6.6 
MAXIMUM TOLERATED DOSE ........................................................................................................................... 48 
6.7 
DOSE MODIFICATIONS AND DOSE DELAYS ....................................................................................................... 48 
6.8 
SAFETY MONITORING AND ADVERSE EFFECT MANAGEMENT ........................................................................ 49 
6.9 
SEVERITY GRADING AND MANAGEMENT OF LOCAL REACTIONS ................................................................... 49 
6.10 
PROPHYLACTIC ANTIPYRETIC AND/OR ANALGESIC ADMINISTRATION .......................................................... 49 
7 
CONCOMITANT THERAPY ................................................................................................................................ 51 
7.1 
PERMITTED MEDICATIONS ................................................................................................................................ 51 
7.2 
PROHIBITED MEDICATIONS ............................................................................................................................... 51 
8 
STUDY PROCEDURES ......................................................................................................................................... 52 
8.1 
WRITTEN INFORMED CONSENT ........................................................................................................................ 52 
8.2 
SUBJECT REGISTRATION ................................................................................................................................... 52 
8.3 
SCHEDULE OF PROCEDURES AND OBSERVATIONS ........................................................................................... 52 
8.3.1 
Study Tests, Exams, and Procedures ............................................................................................................... 52 
8.3.2 
Screening Period:  Assessments ...................................................................................................................... 54 
8.3.3 
Treatment Period:  Day 0 (Ad-RTS-hIL-12 injection) .................................................................................... 55 
8.3.4 
Treatment Period:  Day 1 ................................................................................................................................. 55 
8.3.5 
Treatment Period:  Day 2 ................................................................................................................................. 55 
8.3.6 
Treatment Period:  Day 3 ................................................................................................................................. 56 
8.3.7 
Treatment Period:  Days 4 through 6 ............................................................................................................... 56 
8.3.8 
Treatment Period: Day 7 .................................................................................................................................. 56 
8.3.9 
Treatment Period:  Days 8 through 13 ............................................................................................................. 57 
8.3.10 
Treatment Period:  Day 14 ............................................................................................................................... 57 
8.3.11 
Follow-up Period:  Day 15 .............................................................................................................................. 58 
8.3.12 
Follow-up Period:  Day 28 (± 7 days) ............................................................................................................. 58 
8.3.13 
Follow-up Period:  Day 56 (± 7 days) and every 8 weeks (± 7 days) thereafter .............................................. 58 
8.3.14 
Unscheduled Visits Collections ....................................................................................................................... 58 
9 
TUMOR RESPONSE ASSESSMENTS................................................................................................................. 59 
9.1 
TUMOR RESPONSE ............................................................................................................................................. 59 
9.2 
TUMOR RESPONSE EVALUATION AND PSEUDO-PROGRESSION ........................................................................ 59 
10 
SAFETY ASSESSMENTS ...................................................................................................................................... 60 
10.1 
ADVERSE EVENTS AND DEFINITIONS ................................................................................................................ 60 
10.2 
EVALUATION OF ADVERSE EVENTS .................................................................................................................. 60 
10.3 
DETERMINATION OF SERIOUSNESS ................................................................................................................... 61 
10.3.1 
Serious Adverse Event ..................................................................................................................................... 61 
10.3.2 
Non-Serious Adverse Event............................................................................................................................. 62 
10.4 
DETERMINATION OF SEVERITY ......................................................................................................................... 62 
10.5 
DETERMINATION OF CAUSALITY ...................................................................................................................... 62 
10.6 
DOCUMENTING ADVERSE EVENTS .................................................................................................................... 63 
10.7 
REPORTING DOSE-LIMITING TOXICITIES AND SERIOUS ADVERSE EVENTS ................................................... 64 
10.8 
SPONSOR AND INVESTIGATOR RESPONSIBILITY FOR REPORTING ADVERSE EVENTS .................................... 65 


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10.9 
FOLLOW-UP INFORMATION FOR ADVERSE EVENTS ......................................................................................... 65 
10.10 PREGNANCIES .................................................................................................................................................... 65 
10.11 OVERDOSE .......................................................................................................................................................... 65 
11 
IMMUNE RESPONSE AND PHARMACOKINETIC ASSESSMENTS ........................................................... 67 
11.1 
SERUM CYTOKINE 
 
 FROM BLOOD ..................................................... 67 
 
 
 
 
 
 
 
 
11.4 
VELEDIMEX PHARMACOKINETIC ASSESSMENT ............................................................................................... 68 
11.5 
VELEDIMEX ........................................................................................................................................................ 68 
 
 
 
 
12 
STATISTICAL METHODS ................................................................................................................................... 69 
12.1 
POPULATIONS FOR ANALYSIS ............................................................................................................................ 69 
12.2 
SAMPLE SIZE AND POWER CALCULATIONS ...................................................................................................... 69 
12.3 
ENDPOINTS ......................................................................................................................................................... 70 
12.3.1 
Primary Endpoint ............................................................................................................................................. 70 
12.3.2 
Secondary Endpoints ....................................................................................................................................... 70 
12.4 
ANALYSES .......................................................................................................................................................... 70 
12.4.1 
Baseline Characteristics ................................................................................................................................... 70 
12.4.2 
Safety Analyses ............................................................................................................................................... 70 
12.4.3 
Tumor Response Analyses............................................................................................................................... 71 
12.4.4 
Multi-Center Study .......................................................................................................................................... 72 
12.4.5 
Adjustments for Covariates ............................................................................................................................. 72 
12.4.6 
Procedures for Handling Missing, Unused, and Spurious Data ....................................................................... 72 
12.5 
PROCEDURES FOR REPORTING DEVIATIONS TO ORIGINAL STATISTICAL ANALYSIS PLAN ........................... 72 
13 
STUDY MANAGEMENT ....................................................................................................................................... 73 
13.1 
ELECTRONIC CASE REPORT FORMS AND SOURCE DOCUMENTATION ............................................................ 73 
13.2 
GOOD CLINICAL PRACTICE ............................................................................................................................... 73 
13.3 
SPONSOR MONITORING ..................................................................................................................................... 73 
13.4 
DURATION OF THE STUDY ................................................................................................................................. 74 
13.5 
RECORDS RETENTION ....................................................................................................................................... 74 
13.6 
INSTITUTIONAL REVIEW BOARD/ INDEPENDENT ETHICS COMMITTEE .......................................................... 74 
13.7 
CONFIDENTIALITY AND HIPAA ........................................................................................................................ 75 
13.8 
INFORMED CONSENT ......................................................................................................................................... 75 
13.8.1 
FDA Informed Consent Requirements ............................................................................................................ 75 
13.8.2 
Subject Informed Consent Form ...................................................................................................................... 76 
14 
PROTOCOL APPROVAL PAGE ......................................................................................................................... 77 
15 
REFERENCES ........................................................................................................................................................ 78 
16 
APPENDICES .......................................................................................................................................................... 81 
16.1 
KARNOFSKY PERFORMANCE STATUS ............................................................................................................... 81 
16.2 
PROHIBITED ENZYME-INDUCING ANTIEPILEPTIC DRUGS AND ENZYME-INHIBITING ANTIEPILEPTIC DRUGS
 ............................................................................................................................................................................ 82 
16.3 
RECOMMENDED REGIMEN FOR ANTIPYRETIC AND/OR ANALGESIC PROPHYLAXIS ....................................... 82 


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16.4 
UPDATED RESPONSE CRITERIA FOR HIGH-GRADE GLIOMA:  RESPONSE ASSESSMENT IN NEURO-ONCOLOGY 
WORKING GROUP (ATTACHED) ........................................................................................................................ 82 
16.5 
IMMUNOTHERAPY RESPONSE ASSESSMENT IN NEURO-ONCOLOGY: A REPORT OF THE RANO WORKING 
GROUP (ATTACHED) .......................................................................................................................................... 82 
 
 




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ABBREVIATIONS 
Abbreviation 
Definition 
Ad 
Adenovirus 
AE 
adverse event 
ALT 
alanine transaminase 
ALP 
alkaline phosphatase 
ALVAC 
canarypox virus 
aPTT 
activated partial thromboplastin time 
AST 
aspartate transaminase 
AUC 
area under the curve 
AUClast 
area under the curve up to the last measureable concentration 
BBB 
blood brain barrier 
BID 
bis in die (twice daily) 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
Cmax 
maximum plasma concentration observed 
CD 
cluster of differentiation 
CL 
Clearance 
CR 
complete response 
CRF 
case report form 
CRP 
C-reactive protein 
CSF 
cerebrospinal fluid 
CTCAE 
Common Terminology Criteria For Adverse Events 
DLT 
dose-limiting toxicity 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
EcR 
ecdysone receptor 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EIAED 
enzyme-inducing antiepileptic drugs 
EMCV 
encephalomyocarditis virus 
ESR 
erythrocyte sedimentation rate 
ESP 
Evaluable Safety Population 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HED 
human equivalent dose 


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Abbreviation 
Definition 
HGG 
high-grade gliomas 
HIPAA 
Health Insurance Portability and Accountability Act 
hIL-12 
human interleukin-12 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
INF-β 
interferon-beta 
IFN-γ 
interferon-gamma 
IHC 
Immunohistochemistry 
IL 
Interleukin 
IV 
Intravenous 
INF 
Interferon 
INR 
international normalized ratio 
IP-10 
interferon gamma-induced protein 10 
IRB 
Institutional Review Board 
IRES 
internal ribosome entry site 
LDH 
lactate dehydrogenase 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NK 
natural killer 
ORR 
objective response rate 
OS 
overall survival 
OSP 
Overall Safety Population 
PD 
progressive disease 
PFS 
progression-free survival 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PKP 
Pharmacokinetic Population 
PO 
per oral 
PR 
partial response 
QD 
quaque die (every day) 
QT interval 
measure of the time between the start of the Q wave and the end of the T wave in the 
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Abbreviation 
Definition 
QTc interval 
corrected measure of the time between the start of the Q wave and the end of the T wave 
in the electrical cycle of the heart 
RANO 
response assessment in neuro-oncology (immune response assessment in neuro-oncology 
(iRANO)) 
rAD 
recombinant adenovirus 
RBC 
red blood cell  
 
 
RXR 
retinoid X receptor 
SAE 
serious adverse event 
SD 
stable disease 
SPD 
sum of products of diameters 
SRC 
safety Review Committee 
t1/2 
terminal phase half-life 
TEAE 
treatment-emergent adverse event 
TGFβ 
transforming growth factor β 
Th1 
T-helper cell type 1 
TNFα 
tumor necrosis alpha 
Tmax 
time at which the maximum concentration is observed 
ULN 
upper limit of normal 
UA 
unable to assess 
Vd 
volume of distribution 
Vp 
viral particles 
WBC 
white blood cell 
WHO 
World Health Organization 


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1. 
INTRODUCTION 
1.1 
Disease Background 
High-grade gliomas (HGG) are the most common primary brain tumors and account for approximately 
85% of all newly diagnosed malignant brain tumors annually.  The HGG category typically describes 
World Health Organization (WHO) classified Grade 3 and 4 tumors of which glioblastomas make up 
60% to 70%, anaplastic astrocytomas 10% to 15%, and several other anaplastic subtypes the rest 
(Central Brain Tumor Registry).  WHO Grade 4 gliomas include glioblastoma (also known as 
glioblastoma multiforme), giant cell glioblastoma, and gliosarcoma, while Grade 3 gliomas include 
anaplastic forms of astrocytoma, oligodendroglioma, and oligoastrocytoma (Louis 2007).  
Glioblastoma is by far the most frequent malignant glioma and is associated with a particularly 
aggressive course and dismal prognosis.  The current standard of care treatment is based on surgical 
resection with the intent to remove as much of the tumor as is feasible.  Resection is then followed by 
radiotherapy and concomitant adjuvant temozolomide.  However, such aggressive treatment is 
associated with only modest improvements in survival.  Newly diagnosed glioblastoma subjects have a 
median overall survival (OS) of 11 to 17 months and 2-year OS rate between 15% and 27%.  To date, 
no salvage treatment has been validated by Phase III data for recurrent or progressive glioblastoma.  
For such subjects, the median OS is 6 to 7 months, and median progression-free survival (PFS) is 
2 to 3 months. 
The lack of standard and validated salvage therapies has prompted the use of nitrosureas, 
temozolomide rechallenge, bevacizumab, and other targeted agents that are unsatisfactory treatment 
options.  This likely reflects the complexities of disease heterogeneity, and the treatment limitations of 
brain tumors given the low activity of antineoplastic agents, de novo or acquired drug resistance, the 
sensitivity of the brain to irreversible damage in response to treatment and the presence of the blood 
brain barrier (BBB), which maintains the brain as a privileged compartment.  Surgical resection may 
be offered for subjects with recurrent disease, with the goal of alleviating mass effect, improving 
symptoms, and achieving cytoreduction.  Surgical resection, however, is limited by the infiltrative 
nature of the disease and the lack of clear margins delimitating the tumor.  Given the poor overall 
prognosis and lack of effective treatments, new therapeutic approaches for malignant gliomas are 
needed. 
A role for immunotherapy has been explored in treating brain tumors.  Localized activation of immune 
modulators is particularly compelling since the specificity and efficiency of the immune system against 
tumors may spare normal cells and minimize toxicity from systemic agents.  Early clinical trials for 
multiple vaccine platforms have demonstrated feasibility and safety, and suggested that future studies 
should be explored in the setting of minimal disease, combining immunotherapeutic approaches with 
surgery, radiation and chemotherapy (Mitchell et al. 2008). 
1.2 
Interleukin-12 and Cancer Immunotherapy 
Interleukin-12 (IL-12) is a pro-inflammatory cytokine and has been recognized as a master regulator of 
cell mediated immunity in response to intracellular pathogens and neoplastic transformation.  
Structurally, IL-12 is a heterodimeric protein composed of p35 and p40 subunits covalently linked to 
form the biologically active IL-12p70 molecule (Carra et al. 2000).  The expression of the p40 subunit 
is tightly regulated and requires specific priming and amplification signals through complex 
combinatorial matching of Toll receptor agonists and specific cytokines, thus limiting the cell types 
that can produce native biologically active IL-12 to activated antigen-presenting cells, neutrophils, and 


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macrophages (Trinchieri 2003).  On a secondary level, IL-12 production can also be negatively 
regulated through various mechanisms including production of IL-10 and transforming growth factor β 
(TGFβ). 
Initial studies identified that IL-12 was produced by innate immune cells in response to pathogens and 
that it led to the production of interferon gamma (INF-γ) and tumor necrosis alpha (TNFα) by T and 
natural killer (NK) cells (Micallef et al.1996, Trinchieri 2003).  When it was discovered that IL-12 
could drive naïve T-helper cell differentiation to the inflammatory T-helper cell type 1 (Th1) 
phenotype (Hsieh et al. 1993), a role for IL-12 was established as a bridge between innate immune 
cells and the adaptive immune response through polarization of naïve CD4+ cells.  More recent data 
demonstrate additional functional roles of IL-12 directly influencing CD8+ T-cell differentiation 
(Curtsinger et al. 2003, Kalinski et al. 1999) and the reactivation and survival of memory CD4+ T-cells 
(Yoo et al. 2002).  This is particularly important in the context of the tumor microenvironment where 
high levels of IL-12 have been shown to repolarize antigen-experienced CD4+ T-cells back to the 
functional antitumor Th1 phenotype (Wesa et al. 2007). 
Evidence that IL-12 is able to trigger innate and adaptive immunity and modulate the tumor 
microenvironment supports the relevance of IL-12 as an important immunotherapeutic agent.  Its 
ability to activate and recruit dendritic cells that facilitate the cross-priming of tumor antigen-specific 
T-cells, along with its influence on NK and CD8+ T-cell cytotoxic activities and antigen-specific 
antitumor responses (Mosmann et al. 1989, Trinchieri 1995, Tsung et al. 1997, Mailliard et al. 2002) 
warrant further study in cancer therapy.  Additionally, IL-12 has also been shown to stimulate the 
production of superoxides and nitric oxide and possess potent antiangiogenic activity through INF-γ 
(Voest et al. 1995, Wigginton et al. 1996, Coughlin et al. 1998).  The potent antitumor activity of IL-12 
has been well documented in various cancer mouse models including melanoma, mammary carcinoma, 
sarcoma, and colon and renal carcinoma (Colombo et al 2002).  The potent nature of its biological 
activity and signaling complexity has also prompted the study of different delivery mechanism with a 
focus on intratumoral delivery and tumor microenvironment modulation. 
Based on such data, human studies of IL-12 as an anticancer agent were initiated.  The first of these 
studies was a Phase I dose escalation of intravenous (IV) administered recombinant human IL-12 in 
subjects with either melanoma or renal cell carcinoma.  The study reported a transient complete 
response in melanoma and a partial response in renal cell carcinoma with significant toxicities.  The 
Phase II trial observed similar toxicities, and two IL-12 related deaths prompted the Food and Drug 
Administration (FDA) to suspend the trial (Atkins et al 1997, Leonard et al 1997).  Additional studies 
confirmed that systemic administration of recombinant IL-12 resulted in significant toxicity, limiting 
its potential for clinical development (Salem et al. 2006).  These results prompted the investigation of 
alternative delivery routes focusing on locoregional administration either by subcutaneous injection or 
intratumoral delivery implementing IL-12 as a direct anticancer therapeutic or as an adjuvant to 
vaccination. 
1.3 
Local IL-12 Delivery and Development of an Inducible IL-12 Immunotherapy 
The potent effects of cytokines, particularly IL-12, as mediators of an anticancer immune response 
remain compelling.  This is especially true since the advent of immunotherapies such as anti-CTLA-4 
and anti-PD1 antibodies provide proof of concept that inhibiting immune checkpoints translates into 
clinical benefit.  IL-12 biology including the level of activation, location of initial expression, immune 


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effector function, and biologically active combination with other cytokines remain incompletely 
understood. 
Several human studies that have implemented the local delivery of cytokines or chemotherapeutic 
agents have already shown that such an approach reduces systemic toxicity and produces signals of 
clinical benefit.  One particularly relevant trial implemented a gene transfer strategy to express 
interferon beta (INF-β) locally in glioma tumors, and thus achieved high intratumoral INF-β 
expression without systemic toxicity.  The INF-β was constitutively expressed through a 
replication-defective serotype 5 adenoviral vector under the control of a cytomegalovirus promoter 
achieving transduction of both dividing and non-dividing cells.  The investigators reported the 
approach proved feasible and well tolerated; however, although the INF-β transduction was variable 
among subjects, it was associated with apoptosis (Chiocca et al. 2008). 
In the current Phase I study, we are exploring a local treatment strategy for high-grade gliomas with 
the goal of extending the IL-12 therapeutic window and reducing its systemic toxicity.  This strategy 
employs an inducible serotype 5 adenoviral vector (Ad-RTS-hIL-12) expressing the human 
interleukin 12 (hIL-12) gene under an inducible promoter named 
 
(RTS®).  The replication-incompetent Ad-RTS-hIL-12 vector is injected locally in the tumor lesion and 
initiates hIL-12 transcription only in the presence of the promoter specific oral activator ligand, 
veledimex.  With this system, the IL-12 expression level can be modulated by the dose and frequency 
of veledimex administration, making it feasible to lower or terminate IL-12 expression in the event of 
severe or unexpected toxicities. 
1.4 
Adenoviral Vectors for Gene Therapy 
1.4.1 Adenoviral Safety 
Adenoviral vectors have been used extensively to deliver a variety of gene products to human subjects, 
including cancer subjects.  Although adenoviral vectors are immunogenic, virtually all recipients have 
pre-existing humoral immunity to adenoviruses and they are generally considered a safe and well 
tolerated vehicle for gene delivery.  To date, numerous studies utilized adenoviral vectors to achieve 
intratumoral expression of a variety of genes.  In a Phase I/II clinical trial of subjects with prostate 
cancer, direct intraprostatic injection of a replication-defective adenoviral vector encoding bacterial 
nitroreductase (dose levels 5 x 1010-1 × 1012 viral particles [vp]) was well tolerated, with minimal 
adverse events (AEs) (Patel et al. 2009).  A Phase I study of subjects with oral leukoplakia 
implemented multiple intraepithelial injections of recombinant adenovirus (rAd)-p53 (1 x 108 vp/cm2) 
and demonstrated good tolerance of the vector, with no evidence of dose-limiting toxicity (DLTs) 
(Zhang et al. 2009).  Another Phase I/II study of subjects with chemoradiation-resistant advanced 
esophageal carcinoma, intratumoral injections of adenovirus vector containing p53 (Ad.5CMV-p53) 
were well tolerated at doses ranging from 10 x 1011 to 25 x 1011 vp, with no DLTs, and generally mild 
to moderate adverse events (AEs) (Shimada et al. 2006).  The most common AEs were fever (all 10 
subjects), pain (30% of subjects), and hyperglycemia, which was attributed to the use of total parental 
nutrition (30% of subjects).  Hypocalcemia was reported in two subjects (20%) and one subject each 
(10%) experienced activated partial thromboplastin time (aPTT) elongation, abnormally high serum 
amylase, and abnormally high serum creatinine. 
In a Phase I study of subjects with advanced pancreatic, colorectal, or primary liver tumors, 
intratumoral injection of an adenoviral vector encoding hIL-12 (Ad.IL-12) was well tolerated at doses 
of up to 3 × 1012 vp.  Common AEs were similar to symptoms observed with gene delivery by other 


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adenoviral vectors, including transient, mild to moderate fever, malaise, sweating, and lymphopenia 
(Sangro et al. 2004). 
A recent randomized, open-label, Phase III study compared a regimen of surgical resection, 
adenovirus-mediated gene therapy (intraoperative perilesional sitimagene ceradenovec), intravenous 
ganciclovir, and standard of care interventions versus surgical resection plus standard of care 
interventions in 250 subjects with newly diagnosed high-grade glioma amenable to resection.  Results 
showed that although the time to death or re-intervention was prolonged, OS was not improved for the 
investigational regimen relative to the standard of care regimen (Westphal et al. 2013).  However, the 
authors concluded that the treatment had a positive risk benefit ratio, with similar AEs (hemiparesis 
[often transient], hyponatremia, and seizures) compared with the standard of care regimen.  Neither 
cerebral hemorrhages nor hematomas were observed. 
1.4.2 Safety of Intratumoral Injection of IL-12 Gene Vectors 
In contrast with the systemic toxicity resulting from administration of recombinant IL-12 protein, local 
administration of IL-12 via injection of plasmid or adenoviral vectors containing the hIL-12 gene has 
proven to be well tolerated in subjects with various cancers, and therefore appears to provide an 
effective delivery method for this potent immunomodulatory cytokine.  Several studies have 
investigated the safety of intratumoral expression of IL-12 in subjects with metastatic melanoma.  A 
Phase I study investigated intratumoral expression of IL-12 together with the co-stimulatory molecule 
B7.1 via two separate canarypox virus viral vectors (ALVAC) in subjects with metastatic melanoma 
and reported mild to moderate injection site reactions, fever, chills, myalgia, and fatigue as AEs 
(Triozzi et al. 2005).  However, all subjects also developed antibodies to ALVAC.  Notably, serum 
IL-12 and INF-γ levels were not increased after treatment.  Another Phase I trial showed that delivery 
by electroporation of a plasmid containing IL-12 to tumors in subjects with metastatic melanoma 
resulted in minimal systemic toxicity, with transient pain after electroporation being the most common 
AE (Daud et al. 2008).  Results from another Phase I study showed that intratumoral injection of DNA 
encoding hIL-12 in subjects with metastatic melanoma was well tolerated overall (Heinzerling et al. 
2005).  Eight of nine subjects experienced a transient response at the intratumoral injection site, and 
some subjects who had tumor responses also showed some increases in systemic in IL-12, interferon 
gamma-induced protein 10 (IP-10), and IFN-γ. 
Localized production of IL-12 also has been reported as well tolerated in subjects with other 
malignancies.  For example, a Phase I study in 17 subjects with metastatic pancreatic, colorectal, or 
primary liver cancer examined intratumoral injection of dendritic cells engineered to secrete IL-12 via 
a rAD vector (Mazzolini et al. 2005).  In that study, the most common AEs were lymphopenia, fever, 
and malaise.  Subjects also developed antibodies to the adenoviral capsid proteins.  Intraperitoneal 
injection of a plasmid containing the hIL-12 gene in women with chemotherapy-resistant, recurrent, 
ovarian cancer also was found to be generally safe and well tolerated (Anwer et al. 2010).  Low-grade 
fever and abdominal pain were the most common AEs.  Plasmid DNA was not detected in the subjects’ 
serum samples, and treatment-related increases in IFN-γ levels were observed in pleural fluid, but not 
in serum.  Similar data were reported in a study of subjects with advanced pancreatic, colorectal, or 
primary liver malignancies who received intratumoral injections of adenoviral vectors encoding hIL-12 
at doses ranging from 2.5 × 1010 to 3 × 1012 vp (Sangro et al. 2004).  In that study, treatment was well 
tolerated and a maximum tolerated dose (MTD) was not reached.  Transient lymphopenia was 
observed in 86% of subjects, and the severity was increased at higher vector doses.  Transient, mild to 
moderate fever, sometimes accompanied by malaise and sweating, was observed in ~ 60% of subjects 
during the first 2 days after the injection.  Five of the 21 subjects (24%) experienced nausea and/or 




















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2. 
STUDY OBJECTIVES 
2.1 
Primary Objective 
• To determine the safety and tolerability of varying doses of antitumoral Ad-RTS-hIL-12 plus 
oral veledimex doses in subjects with recurrent or progressive glioblastoma or Grade III 
malignant glioma. 
2.2 
Secondary Objectives 
• To determine the MTD of veledimex when administered with varying doses of intratumoral 
Ad-RTS-hIL-12 dose  
• To determine the veledimex PK profile 
• To determine the veledimex concentration ratio between brain tumor and blood 
• To evaluate cellular 
 immune responses elicited by Ad-RTS-hIL-12 and 
veledimex 
• To determine investigator assessment of response including tumor Objective Response Rate 
(ORR) and PFS 
• 
To determine OS 
 
 




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in the CRF. In the event that less than the planned total injected volume is administered, the reason will 
be provided. The day of Ad-RTS-hIL-12 administration is designated as Day 0. 
For Cohorts 3, 4, 5 and 6, immediately after tumor resection, Ad-RTS-hIL-12 1 x 1012 vp will be 
administered by 
 injection into multiple sites in a divided dose within the residual tumor (day 
of Ad-RTS-hIL-12 administration is designated as Day 0).  The planned total injected volume for these 
cohorts is 0.5 mL given in approximate aliquots of 0.1 mL at each injection site.  The total amount 
delivered to each site will be recorded in the CRF. In the event that less than the planned total injected 
volume is administered, the reason will be provided. When available, an intra-operative magnetic 
resonance imaging (MRI) can be performed to guide the Ad-RTS-hIL-12 injection to areas of contrast 
enhancing tumor tissue. 
After the Ad-RTS-hIL-12 injection, veledimex will be administered orally for 14 days.  The first 
postresection veledimex dose is to be given on Day 1, preferably with food.  Subsequent veledimex 
doses are to be taken once daily, in the morning and within approximately 30 minutes of a regular 
meal. 
Group 2:  Subjects who will NOT undergo tumor resection: 
Subject enrollment into Group 2 will start no earlier than after two subjects have completed 28 days in 
Group 1, Cohort 1.  Enrollment into Group 2 cohorts is otherwise independent of enrollment into 
Group 1 cohorts.   
Subjects who will not undergo tumor resection will receive Ad-RTS-hIL-12 by standard stereotactic 
surgery on Day 0.  Tumor biopsy is recommended to reconfirm malignant glioma.  Ad-RTS-hIL-12 
(2 × 1011 vp or 1 × 1012 vp) will be administered by stereotactic injection. The day of Ad-RTS-hIL-12 
administration is designated as Day 0.   In Cohorts 1 and 2, it will be delivered into approximately two 
intratumoral sites for a total volume of 0.1 mL. In Cohorts 3, 4 and 5 it will be delivered into multiple 
sites in a divided dose to deliver up to 0.5 mL volume in approximate aliquots of 0.1 mL at each site.  
Care should be taken to avoid intraventricular or basal cisternal injection or other critical locations. 
After the Ad-RTS-hIL-12 injection, veledimex will be administered orally for 14 days.  The first 
veledimex dose is to be given on Day 1, preferably with food.  Subsequent veledimex doses are to be 
taken once daily, in the morning and within approximately 30 minutes of a regular meal. 
This study will explore four veledimex dose cohorts of 20 mg, 40 mg, 80 mg and 120 mg once daily 
(Table 5). 
3.2 
Dose Escalation Cohorts 
This study will implement a standard 3 + 3 design modified to independently evaluate two stratified 
subject groups that may exhibit different safety and tolerability profiles.  The dose escalation rules 
apply to subjects who have received Ad-RTS-hIL-12 and at least one veledimex dose post 
Ad-RTS-hIL-12 administration. In each cohort, the first subject will be monitored for the 14 days of 
treatment and will be observed an additional 7 days post last veledimex dose before the second and 
third subjects are enrolled in that same cohort.  The DLT evaluation period is defined as 28 days post 
Ad-RTS-hIL-12 injection (Day 0 – Day 28).  Determination of safety and recommendation to dose 
escalate will occur after all dosed subjects in a cohort have been evaluated for at least 28 days post 


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Ad-RTS-hIL-12 injection.  The details on the dose escalation schedule are provided in Section 6.2 and 
the dose escalation decision rules provided in Section 6.3.  
3.3 
Study Oversight for Safety Evaluation 
This study will implement an independent DSMB to provide additional unbiased and objective input 
on the safety evaluation of study population.  In the context of an open label study, the responsibility of 
the DSMB is to provide an objective determination of safety at the end of each dose cohort and make a 
recommendation to proceed to the next higher veledimex dose level, amend the dose escalation 
schedule or discontinue the study.  A separate DSMB charter will describe the activities of this 
committee. 
The first level of safety oversight will occur through the site investigator and medical monitor.  A 
formal SRC, guided by the SRC charter, will include the study investigators, the medical monitor and 
other appropriate sponsor representatives and will provide overall safety oversight.  Additional 
external medical and scientific experts may also be invited to participate in the reviews as needed and 
appropriate and as decided by the SRC.  The SRC will evaluate patient safety within each cohort, and 
within each stratification group of the same cohort.  If no significant safety events occur with the first 
patient of each cohort, the second and third subjects will be enrolled and treated.  If a significant safety 
event occurs with the first patient in each cohort, the SRC will convene to evaluate the safety event(s) 
and make a recommendation and decision on the enrollment of the second and third subjects in that 
same cohort 
At the end of each cohort (Group 1 and Group 2 separately), the SRC will convene to review all the 
safety data from each patient treated in that cohort, separately for each group.  At the end of each 
cohort, the SRC will provide the safety summary and a recommendation to the DSMB.  The DSMB, 
within 3 days of receipt, will evaluate the safety data and make a recommendation to the SRC 
regarding continuation to the next dose cohort, amendment of the dose escalation schedule, or 
discontinuation of the study.   
The DSMB recommendation will be communicated to the SRC and appropriate action will be taken.  
A written record of the DSMB recommendation will be provided to the SRC and maintained on file 
with the sponsor. 
 
 
 


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4 SUBJECT SELECTION 
The eligible study population includes adult subjects with recurrent or progressive glioblastoma or 
Grade III malignant glioma (anaplastic astrocytoma, anaplastic oligodendroglioma, and anaplastic 
oligoastrocytoma) for which there is no alternative curative therapy. 
4.1 
Inclusion Criteria 
1. Male or female subject ≥ 18 and ≤ 75 years of age 
2. Provision of written informed consent for tumor resection, stereotactic surgery, tumor biopsy, 
samples collection, and treatment with investigational products prior to undergoing any 
study-specific procedures 
3. Histologically confirmed supratentorial glioblastoma or other WHO Grade III or IV malignant 
glioma from archival tissue 
4. Evidence of tumor recurrence/progression by MRI according to response assessment in 
neuro-oncology (RANO) criteria after standard initial therapy 
5. Previous standard of care antitumor treatment including surgery and/or biopsy and chemoradiation.  
At the time of registration, subjects must have recovered from the toxic effects of previous 
treatments as determined by the treating physician.  The washout periods from prior therapies are 
intended as follows: (windows other than what is listed below should be allowed only after 
consultation with the Medical Monitor) 
a. Nitrosoureas:  6 weeks 
b. Other cytotoxic agents:  4 weeks 
c. Antiangiogenic agents including bevacizumab:  4 weeks 
d. Targeted agents including small-molecule tyrosine kinase inhibitors:  2 weeks 
e. Experimental immunotherapies (e.g., PD-1, CTLA-4):  3 months 
f. Vaccine-based therapy:  3 months 
6. Able to undergo standard MRI scans with contrast agent before enrollment and after treatment 
7. Karnofsky performance status ≥ 70 
8. Adequate bone marrow, liver, and kidney function, as assessed by the following laboratory 
requirements: 
a. Hemoglobin ≥ 9 g/L 
b. Lymphocytes > 500/mm3 
c. Absolute Neutrophil Count ≥ 1,500/mm3 
d. Platelets ≥ 100,000/mm3 
e. Serum creatinine ≤ 1.5 x upper limit of normal (ULN) 
f. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x ULN.  For subjects 
with documented liver metastases, ALT and AST ≤ 5 × ULN 
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h. International normalized ratio (INR) and aPTT normal institutional limits 
9. Male and female subjects must agree to use a highly reliable method of birth control (expected 
failure rate less than 5% per year) from the Screening Visit through 28 days after the last dose of 
study drug.  Women of childbearing potential (perimenopausal women must be amenorrheic for at 
least 12 months to be considered of non-childbearing potential) must have a negative pregnancy 
test at screening. 
4.2 
Exclusion Criteria 
1. Radiotherapy treatment within 4 weeks or less prior to veledimex dosing 
2. Subjects with clinically significant increased intracranial pressure (e.g., impending herniation or 
requirement for immediate palliative treatment) or uncontrolled seizures 
3. Known immunosuppressive disease, autoimmune conditions, and/or chronic viral infections [e.g., 
human immunodeficiency virus (HIV), hepatitis] 
4. Use of systemic antibacterial, antifungal, or antiviral medication for the treatment of acute 
clinically significant infection within 2 weeks of first veledimex dose.  Concomitant therapy for 
chronic infections is not allowed.  Subject must be afebrile prior to Ad-RTS-hIL-12 injection; only 
prophylactic antibiotic use is allowed perioperatively. 
5. Use of enzyme-inducing antiepileptic drugs (EIAED) within 7 days prior to the first dose of study 
drug.  Note:  Levetiracetam (Keppra®) is not an EIAED and is allowed 
6. Other concurrent clinically active malignant disease, requiring treatment, with the exception of 
non-melanoma cancers of the skin or carcinoma in situ of the cervix or nonmetastatic prostate 
cancer 
7. Nursing or pregnant females 
8.  Prior exposure to veledimex 
9. Use of medications that induce, inhibit, or are substrates of cytochrome p450 (CYP450) 3A4 
within 7 days prior to veledimex dosing without consultation with the Medical Monitor 
10. Presence of any contraindication for a neurosurgical procedure 
11. Unstable or clinically significant concurrent medical condition that would, in the opinion of the 
investigator or medical monitor, jeopardize the safety of a subject and/or their compliance with the 
protocol.  Examples include, but are not limited to:  unstable angina, congestive heart failure, 
myocardial infarction within 2 months of screening, ongoing maintenance therapy for 
life-threatening ventricular arrhythmia, or uncontrolled asthma. 
4.3 
Subject Enrollment 
Up to 72 subjects may be enrolled.   
4.4 
Withdrawal of Subjects from Study Treatment and/or Study 
The sponsor may terminate this study at any time.  The investigator and/or the subject have the right to 
terminate the subject’s participation in the study at any time.  Efforts should be made to ask subjects 
who discontinue study drug to be available to complete the Follow-up assessments. 


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A subject may withdraw or be withdrawn from the study treatment prematurely for any of the 
following reasons: 
• Principal Investigator (PI) determines further participation is not in subject’s best interest (e.g., 
subject experiences rapid clinical deterioration in the absence of confirmed disease 
progression) 
• Subject has confirmed disease progression 
A subject must be withdrawn in the event of any of the following: 
• Subject withdraws informed consent. 
• Any treatment-related AEs that meet withdrawal criteria 
• Substantial noncompliance with study requirements 
• Subjects with a confirmed positive pregnancy test 
• Any intercurrent illness that would, in the judgement of the investigator or sponsor’s medical 
monitor, affect assessments of clinical status to a significant degree and require discontinuation 
of protocol therapy 
• Subjects who did not receive the Ad-RTS-hIL-12 injection 
• Note:  Any subject who wishes to withdraw from the study treatment may do so at any time, but will 
be asked to be available for the safety, tumor response, and survival Follow-up assessments. 
Every effort should be made to follow subjects who withdraw from study treatment for ongoing 
treatment-related AEs.  Subjects who withdraw during the treatment period should continue to have 
study assessments as clinically indicated.  
4.5 
Replacement of Subjects 
Subjects who withdraw from the study during the DLT evaluation period (Days 0 to 28) for reasons 
other than toxicity or disease progression may be replaced.  All dosed subjects will be included in the 
overall safety assessment. 
4.6 
Premature Termination of Study or Study Site 
The sponsor has the right to close the study at any time, although this should occur only after mutual 
consultation between the sponsor and the investigators.  The Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC) must be informed of such action.  Should the study or center be 
closed prematurely, all study materials (completed, partially completed, and blank case report forms 
(CRF), study medication, etc.) must be stored or disposed of according to the sponsor’s instructions.  
Events that may trigger premature termination of the study or closure of a center include, but are not 
limited to the following:  new toxicity findings; decision to re-challenge patient who has experienced a 
Grade 4 event; interim analysis results; noncompliance with the protocol; changes in the development 
plans for the study drug; slow recruitment; and poor-quality data. 


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5 INVESTIGATIONAL PRODUCT 
The investigational product has two components:  the Adenovirus-
 
human interleukin-12 (Ad-RTS-hIL-12) and veledimex (RTS activator ligand).  
Ad-RTS-hIL-12 is a replication-incompetent adenoviral vector containing the hIL-12 gene under the 
control of the RTS inducible promoter activated in the presence of the activator ligand, veledimex.  
Veledimex is a small molecule RTS specific transcription factor that stabilizes the RTS promoter 
components and allows transcription of the hIL-12 target gene.  Since target gene expression is 
dependent on the dose and frequency of veledimex administration, the expression of hIL-12 can be 
modulated (turned on and off) by the optimal veledimex dose and schedule. 
Please refer to the Pharmacy Manual for additional information. 
5.1 
Preparation of Ad-RTS-hIL-12 
Ad-RTS-hIL-12 will be supplied in single-dose vials.  Information regarding the preparation of the 
Ad-RTS-hIL-12 dose is provided in the Pharmacy Manual. 
5.2 
Preparation of Veledimex 
Sponsor will provide veledimex capsules to be dispensed by the study site pharmacy to subjects for 
oral administration. 
5.3 
Handling and Storage 
Study drugs must be stored in a restricted access area under the storage conditions indicated in the 
Investigator’s Brochure or Pharmacy Manual.  All necessary precautions while handling potentially 
toxic compounds must be strictly followed. 
5.4 
Monitoring of Subject Adherence and Managing Missed Veledimex Doses 
The first veledimex dose following Ad-RTS-hIL-12 injection is expected to be administered when the 
subject is at the clinical site, under careful medical supervision by the clinic staff to ensure that the 
subject does not have difficulty swallowing the capsules. Thereafter, subjects may be allowed to 
self-administer the remaining once daily doses as described.  Subjects are to be instructed to take the 
appropriate number of capsules in the same way for each of the remaining treatment period days, and 
may be reminded to do so by phone on non-visit days. 
Subjects should NOT make up any missed doses. 
Subjects should be instructed to document veledimex dosing compliance in a subject diary, including 
the time subject took the once daily dose, the time subject ate breakfast, the number of capsules taken, 
whether subject missed any veledimex doses, and the study day and reason for any missed doses.  
Study drug container(s) with any remaining capsules should be returned to the study staff on Day 15, 
so that staff can properly assess dose compliance. 
5.5 
Disposition of Unused Drug 
All unused study drug should be destroyed at the study site in accordance with standard institutional 
practice and in accordance with United States Occupational Safety and Health Administration 


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procedures, after full accountability has been documented. Any study drug destruction at study site 
must be documented and the records maintained in the investigator’s study file. 
5.6 
Accountability and Dispensation 
The investigator must maintain accurate records accounting for the receipt and dispensation of study 
drugs.  The investigational materials are to be prescribed only by the investigator or the 
sub-investigators named on FDA Form 1572, and may only be dispensed by authorized personnel at 
the institution(s) listed therein.  Under no circumstances will the PI allow the investigational drug(s) to 
be used for purposes or in subjects other than as directed by the protocol. 
 
 


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6 TREATMENT PLAN 
6.1 
Ad-RTS-hIL-12 Dosage and Administration Procedures 
Subjects will be stratified according to clinical indication for standard of care tumor resection.  
Subjects who are scheduled for standard of care craniotomy and tumor resection (Group 1) will receive 
one veledimex dose before the resection procedure.  Samples [tumor, CSF (if available), and blood] 
will be collected during the resection procedure just prior to Ad-RTS-hIL-12 injection to determine the 
veledimex concentration ratio between brain tumor, CSF, and blood.  After Ad-RTS-hIL-12 injection, 
subjects will start oral veledimex for 14 days.  Subjects not scheduled for tumor resection (Group 2) 
will receive Ad-RTS-hIL-12 by stereotactic injection first, and then will receive oral veledimex for 
14 days. 
In the event that Ad-RTS-hIL-12 injection is not performed, subject will not continue with 
postresection veledimex dosing. 
Subjects Undergoing Tumor Resection (Group 1): 
• Subjects will be given a cohort-specific dose of veledimex by mouth, on an empty stomach 
(excluding other medications) 3 (± 2) hours before craniotomy.  The actual time of veledimex 
administration should be noted and recorded. 
• Surgical planning will be performed on a diagnostic MRI acquired prior to the surgery as per 
standard of care. 
• At the time of tumor resection, tumor, CSF (if available), and blood samples will be collected. 
• Immediately after tumor resection, when available, an intraoperative MRI can be performed to 
identify contrast enhancing or T2/FLAIR hyper intense residual tumor.  If intraoperative MRI 
is not available, the neurosurgeon will select sites for injection. 
• Subjects in Cohorts 1 and 2 will receive Ad-RTS-hIL-12 2 x 1011 vp.  This will be administered 
by 
 injection into approximately two sites within the residual tumor for a total volume 
of 0.1 mL selected by the neurosurgeon.  When available an intra-operative MRI can be 
performed to guide the Ad-RTS-hIL-12 injection to areas of contrast-enhancing tumor tissue. 
• For Cohorts 3, 4, 5 and 6, immediately after tumor resection, Ad-RTS-hIL-12 1 x 1012 vp will 
be administered by 
 injection into multiple sites in a divided dose within the residual 
tumor at sites selected by the neurosurgeon.  The planned total injected volume for these 
cohorts is 0.5 mL given in approximate aliquots of 0.1 mL at each injection site. When 
available, an intra-operative MRI can be performed to guide the Ad-RTS-hIL-12 injection to 
areas of contrast-enhancing tumor tissue. 
• The day of Ad-RTS-hIL-12 administration is designated as Day 0. 
• After tumor resection and Ad-RTS-hIL-12 injection, veledimex will be administered orally for 
14 days.  The first postresection veledimex dose is to be given on Day 1, preferably with food.  
Subsequent veledimex doses are to be taken once daily, in the morning and within 
approximately 30 minutes of a regular meal. 
 
 


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Subjects NOT Undergoing Tumor Resection (Group 2): 
• Surgical planning will be performed on a diagnostic MRI acquired prior to the stereotactic 
procedure. 
• On the day of Ad-RTS-hIL-12 administration (Day 0), subjects will be anesthetized and 
prepared for standard stereotactic surgery. 
• Subjects in Cohorts 1 and 2 will receive Ad-RTS-hIL-12 2 x 1011 vp.  It will be administered 
by stereotactic injection into approximately two intratumoral sites to deliver up to 0.1 mL 
volume. In Cohorts 3,4,5 and 6, Ad-RTS-hIL-12 1 × 1012 vp will be administered by 
stereotactic injection into multiple sites in a divided dose to deliver up to 0.5 mL volume in 
approximate aliquots of 0.1 mL at each site. Care should be taken to avoid intraventricular or 
basal cisternal injection or other critical location.  In case of multifocal tumors, one leading 
lesion should be selected for injection. 
• After the Ad-RTS-hIL-12 injection, veledimex will be administered orally for 14 days.  The 
first veledimex dose is to be given on Day 1, preferably with food.  Subsequent veledimex 
doses are to be taken once daily, in the morning and within approximately 30 minutes of a 
regular meal. 
Subjects should be carefully monitored for possible local reactions and/or hypersensitivity reactions, 
according to standard practice.  Intracranial bleeding or other procedure-related events should be 
evaluated before the first veledimex dose is given post Ad-RTS-hIL-12 administration.  Any changes 
in neurological status should be reported to the investigator immediately, either during hospitalization 
or once subject is discharged.  Subjects should be instructed to call the study physician or study nurse 
if they develop any symptoms after they are released from the hospital. 
Proper hydration is critical while subjects are on veledimex.  It is important that subjects are 
instructed repeatedly to maintain adequate oral hydration on and between veledimex doses.  
Study sites must closely monitor subjects for proper hydration.  Blood pressure should be 
monitored regularly. 
Administration of prophylactic antipyretics is strongly recommended during the first week after 
Ad-RTS-hIL-12 injection. 
6.2 
Veledimex Dosage and Administration 
Subjects Undergoing Tumor Resection (Group 1): 
• Before Ad-RTS-hIL-12 administration:  a cohort-specific oral dose of veledimex 3 (± 2) hours, 
on an empty stomach (excluding other medications), before craniotomy and tumor resection. 
• After Ad-RTS-hIL-12 administration:  Dose veledimex as assigned by dose cohort.  The first 
postresection veledimex dose is to be given on Day 1, preferably with food.  Subsequent 
veledimex doses are to be taken once daily, in the morning and within approximately 
30 minutes of a regular meal. 
Subjects NOT Undergoing Tumor Resection (Group 2) 


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• After Ad-RTS-hIL-12 administration:  Group 2 will start dosing subjects only after two 
subjects have completed 28 days in Group 1, Cohort 1. Veledimex dose will be administered as 
assigned by dose cohort.  The first veledimex dose is to be given on Day 1, preferably with 
food.  Subsequent veledimex doses are to be taken once daily, in the morning and within 
approximately 30 minutes of a regular meal. 
Subjects in Group 1 will receive up to a total of 15 veledimex doses:  The initial veledimex dose 
(cohort-specific) will be administered 3 (± 2) hours before the craniotomy procedure and before 
Ad-RTS-hIL-12 administration, and up to 14 veledimex doses after Ad-RTS-hIL-12 administration.  
Subjects in Group 2 will receive up to a total of 14 veledimex doses after Ad-RTS-hIL-12 
administration.  All veledimex doses will be recorded and safety monitored. 
Dose Escalation Schedule 
Four veledimex dose levels will be explored in this study.  Each dose cohort is expected to enroll at 
least three subjects, per group, in each dose level.  The prospectively defined veledimex dose levels are 
20 mg, 40 mg, 80 mg, and 120 mg.  The veledimex dose is to be taken by mouth once daily in the form 
of veledimex capsules .  The dose escalation cohorts are outlined in Table 5. 
TABLE 5  VELEDIMEX DOSE-ESCALATION COHORTS POST AD-RTS-HIL-12 
INJECTION 
Cohort 
Ad-RTS-hIL-12a 
(Day 0) 
Veledimexb 
Group 1 (Days 0 through 14) 
Group 2 (Days 1 through 14) 
Dose(vp) 
Total Daily Dose (mg) 
1 
2 x 1011 
20 
2 
2 x 1011 
40 
3 
1 x 1012 
20 
4 
1 x 1012 
40 
5 
1 x 1012 
80 
6 
1 x 1012 
120 
vp = viral particle 
a:  Intratumoral Injection 
b:  Dose levels may be modified based on additional clinical and nonclinical data (Section 6.4) 
The DSMB will review the safety data at the end of each dose cohort and provide a recommendation 
before any new subjects can be enrolled in the next higher dose cohort (Sections 3.2 and 3.3).  
6.3 
Dose Escalation Decision Rules 
This study has been designed to assess the safety and tolerability of varying doses of Ad-RTS-hIL-12 
and veledimex.  The dose escalation rules apply to subjects who have received Ad-RTS-hIL-12 and at 
least one veledimex dose post Ad-RTS-hIL-12 administration.  The veledimex dose escalation 


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schedule will follow a 3 + 3 design modified to independently evaluate two stratified subject groups 
that may exhibit different safety and tolerability profiles.  In each cohort, the first subject will be 
monitored for the 14 days of treatment and will be observed an additional 7 days post the last 
veledimex dose before the second and third subjects are enrolled in that same cohort.  At the end of 
each cohort, the SRC will convene to review the safety data after the final patient in a cohort, within a 
group, has completed veledimex dosing and has been monitored for 28 days after the Ad-RTS-hIL-12 
injection.   
Each dose cohort will enroll three subjects.  If no DLTs occur among the first three subjects in a 
cohort, within the same group, dosing may proceed to the next higher dose cohort after the SRC and 
DSMB have provided their recommendation to proceed.  In any cohort, if one DLT occurs among the 
first three subjects within the same group, three additional subjects of the same group will be enrolled.  
If one or more of the three additional subjects experience a DLT (i.e., two DLTs in Group 1 or two 
DLTs in Group 2), the dose escalation in the group with the two DLTs will stop. The SRC will then 
convene to evaluate safety, determine if the MTD has been reached per Section 6.6, and decide 
whether to stop treatment or de-escalate veledimex dosing in that group.  The SRC may also seek an ad 
hoc safety evaluation and recommendation by external experts and/or the DSMB as needed.  
Enrollment in the group that did not experience DLTs (zero or one DLT per corhort), will continue to a 
total of three or six evaluable subjects, respectively, to assess the dose escalation separately. 
The MTD is defined as the dose level below the dose in which more than 33% of subjects of the same 
cohort and group experience DLTs, with an independent assessment of Group 1 and Group 2 subjects.  
If two DLTs occur in the same cohort in a group   the dose escalation will stop in the group 
experiencing the DLTs.  The MTD will then be explored in six subjects of the same group at the next 
lower dose level and will be declared to be the dose in which less than 33% of subjects experience 
DLTs.  Intra-subject dose escalation is not permitted.  An intermediate dose cohort may be explored 
during the dose escalation phase, as deemed necessary and as recommended by the SRC. 
During the dose escalation phase, the DSMB will recommend proceeding with the next dose cohort, 
de-escalating to a lower dose or stopping the study.  If an expansion cohort is implemented, the SRC 
may recommend a dose reduction for any individual subject who experiences a DLT.  If DLTs are 
observed in ≥ 33% of the subjects treated in the expansion phase, the SRC and/or DSMB may 
recommend enrolling additional subjects at a dose below the MTD defined in the escalation phase, 
thereby establishing a new MTD, or may stop the study. A decision to enroll additional subjects, as 
part of an expansion cohort, at the determined veledimex MTD and the Ad-RTS-hIL-12 dose will be 
made by the SRC after the MTD has been identified for one or both groups and safety evaluated.  If an 
expansion cohort is implemented, the veledimex dose may be delayed or reduced for individual 
subjects in the event of toxicity.  If ≥ 33% of subjects in the expansion cohort experience DLTs 
(according to the definition used in the dose escalation phase), additional subjects may be enrolled at 
the next lower dose tested in the dose escalation phase, or at an intermediate dose, as recommended by 
the SRC. 
 
 


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TABLE 6  DOSE ESCALATION DECISION RULES 
Subjects with DLTs 
(Any Dose Level) 
Escalation Decision Rule 
No subject experience a 
DLT 
Enroll the next higher dose level cohort (after DSMB recommendation). 
1 subject experiences a 
DLT 
Enroll at least three more subjects in the same group at this dose level cohort. 
If zero or one of the three additional subjects experience a DLT, proceed to the next planned 
dose level cohort (after DSMB recommendation). 
2 or more subjects 
experience a DLT 
If two subjects experience a DLT (two DLTs in Group 1 or two DLTs in Group 2), then 
STOP dose escalation in the cohort experiencing the DLTs and do the following: 
• 
The SRC will conduct a safety review to evaluate safety and determine whether 
the cohort experiencing the two DLTs has met the definition of the MTD 
(Section 6.6) Based upon this review, the SRC will make a recommendation that 
the cohort experiencing the ≥ two DLTs either continue at the existing dose, at a 
lower dose level or other measures to be undertaken including discontinuation of 
treatment. After completion of a cohort, if it has been determined that the MTD 
has not been reached, escalation to the next cohort will proceed once 
recommended by the SRC and authorized by the DSMB. If it has been 
determined that escalation should not proceed, dose de-escalation will be 
undertaken. 
. 
 
6.4 
Modification of Dose Escalation Schedule 
This trial implements a design that is aimed to identify the veledimex pharmacokinetic profile in 
human subjects so that a more accurate determination can be made of the veledimex distribution ratio 
between the tumor, CSF (if available), and blood.  A single cohort-specific veledimex dose will be 
administered to subjects undergoing standard of care tumor resection 3 (± 2) hours prior to the 
craniotomy and Ad-RTS-hIL-12 injection.  At the time of the tumor resection, samples of the tumor, 
CSF (if available), and blood will be collected to determine the level of veledimex in these 
compartments. 
A period of at least 1 week will be required to analyze the veledimex concentration ratio in brain 
tumor, CSF, and blood from subjects in Group 1.  Interpretable data from at least three subjects should 
be sufficient to provide an initial estimate of the veledimex concentration in human brain tissue and the 
ratio of veledimex in the tumor, CSF (if available), and blood.  Based on this initial estimate and data 
from subsequent cohorts, dosage level may be modified after review by the SRC and DSMB. 
Three interpretable and properly analyzed samples are required before the planned dose escalation 
schedule can be modified.  An assessment and evaluation of the veledimex ratio and the safety profile 
will be conducted after the first three evaluable patient tumor samples are available.  If there is a 
significant change in the veledimex ratio (greater or less than 50%), the question to modify the dose 
escalation schedule will be proposed to the SRC and the DSMB.  The dose escalation schedule will be 
modified accordingly after consultation with the SRC and DSMB.  If a determination can be made on 
three interpretable and properly analyzed samples, then the veledimex dose before the Ad-RTS-hIL-12 
injection in subjects who are scheduled for standard of care resection may be discontinued. 


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6.5 
Dose Limiting Toxicity 
• Dose Limiting Toxicities are defined as events that occur during the first 28 days (Day 0 – Day 
28) that meets one of the following criteria: 
o Any local reaction that requires operative intervention and felt to be attributable to Ad-
RTS-hIL-12 and/or veledimex  
o Any local reaction that has life-threatening consequences requiring urgent intervention 
or results in death and felt to be attributable to Ad-RTS-hIL-12 and/or veledimex. 
• 
Any Grade 3 or greater non-hematological adverse event that is at least possibly related to the study 
drug 
• 
Any Grade 4 hematologic toxicity that is at least possibly related to the study drug and lasts at least 5 
days  
• 
Grade 3 or higher thrombocytopenia at least possibly related to the study drug 
 Note: Diagnostic brain or tumor biopsy is not considered a DLT.  Seizures, headaches, and 
cerebral edema are commonly observed in this patient population and will be recorded 
according to grade of toxicity, but will not be considered a DLT unless they are deemed as 
most likely to be drug related as the main contributing factor. 
• Safety and tolerability will be assessed by the incidence and severity of AEs, with severity 
assigned according to the National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) v4.03.  Details provided in Section 10. 
• If multiple toxicities are seen, the DLT should be defined as the most severe toxicity 
experienced. 
• All DLTs should be reported to the sponsor within 24 hours of investigator or site awareness. 
6.6 
Maximum Tolerated Dose 
The veledimex MTD given in combination with either Ad-RTS-hIL-12 2 x 1011 vp or 1 x 1012 vp dose 
will be that dose at which fewer than 33 % of subjects experience a DLT.  
The MTD in this study will be determined in the context of variable corticosteroid exposure and will 
be reported as such.  Investigational treatment of the high-grade glioma patient population requires that 
steroid use be allowed to manage brain tumor-related symptoms or edema, especially after tumor 
resection (Section 7).  It is expected that the use and dose of corticosteroids will vary among trial sites 
and among subjects, and therefore, the extent and dose of steroids is not specified in this protocol.  The 
treating physician will make this determination as it is safe and appropriate for the individual subject 
and should consider the minimum steroid dose or the lowest amount that controls the subject’s 
symptoms. 
6.7 
Dose Modifications and Dose Delays 
Treatment dose delays and dose reductions for individual subjects will be allowed in the event of a 
DLT, according to the criteria shown in Table 7. 


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If ≥ 33% of subjects experience DLTs in a cohort within a group, the SRC will convene to determine 
the course of action.  The medical monitor or investigators may request a meeting of the SRC at other 
times, as appropriate. 
TABLE 7  CRITERIA FOR DOSE DELAY AND DOSE REDUCTION 
Event 
Course of Action 
Any local injection reaction that requires 
operative intervention 
Hold veledimex and contact the medical monitor for 
instruction on resuming dosing 
Any local injection reaction that has 
life-threatening consequences requiring 
urgent intervention or results in death 
Hold veledimex and contact the medical monitor for 
instruction on resuming dosing 
Any drug-related Grade 3 or higher AEa  
Hold veledimex and contact medical monitor for instruction 
on resuming dosing 
AE = adverse event 
a:  Excluding nausea and/or vomiting in subjects who did not receive optimal treatment with anti-emetics 
6.8 
Safety Monitoring and Adverse Effect Management 
Each subject receiving Ad-RTS-hIL-12 and/or at least one dose of veledimex will be included in the 
Overall Safety Population (OSP).  The MTD will be determined from the Evaluable Safety Population 
(ESP).  Parameters used in the safety analysis of all populations will include all laboratory tests, 
physical examination, imaging scans, and spontaneous reports of AEs reported by subjects.  Each 
patient will be assessed according to the scheduled study procedures and any additional visits as a 
result of AEs.  Adverse events will be assessed according to the NCI CTCAE v4.03 criteria. 
6.9 
Severity Grading and Management of Local Reactions 
Injection of agents into tissue carries a potential risk of local reactions that may be characterized as 
intense immunologic reaction at or near the injection site.  Local reactions will be graded according to 
the NCI CTCAE v4.03 criteria. 
As with all signs and symptoms, events should be recorded and graded as AEs according to NCI 
CTCAE v.4.03 criteria.  Study stopping rules will not apply to a specific event if it is clearly unrelated 
to the Ad-RTS-hIL-12 injection. 
6.10 Prophylactic Antipyretic and/or Analgesic Administration 
The use of antipyretics and/or analgesics is allowed as a prophylactic measure perioperatively.  
Antipyretics and/or analgesics can be used anytime during study treatment, as indicated and required 
for patient safety and must be recorded as concomitant medications.  Please refer to exclusion criteria 
for acute clinically significant and/or chronic infections. 
NOTE:  Since fever and flu-like symptoms (e.g., fever, headache, chills, dehydration, etc.) are 
commonly experienced following adenoviral vector administration, it is highly recommended that 
subjects be treated with prophylactic antipyretic and/or analgesic medication prior to Ad-RTS-hIL-12 
injection and during the first week after injection. 


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Please refer to Appendix 16.2 for the recommended regimen for the prophylactic administration of 
antipyretics and/or analgesics. 
 


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7 CONCOMITANT THERAPY 
Information on concomitant medications, including all medications, blood products, vitamins, and 
other supplements, will be collected through the Screening, Treatment, and the Initial Follow-up 
Period of this study.  
Subjects experiencing brain tumor-related symptoms or edema should be treated with corticosteroids 
as per standard practice. The treating physician should consider the minimum starting steroid dose for 
study subjects, if determined that it is safe and appropriate for that individual patient.  For study 
subjects who require a higher starting steroid dose, efforts should be made to taper steroids to the 
lowest amount that controls the subjects’ symptoms, as determined to be safe and appropriate by the 
treating physician 
7.1 
Permitted Medications 
Subjects may receive standard treatments, including palliative and supportive care for any illness or 
symptom management during study treatment, including: 
 Corticosteroids are permitted for brain tumor-related symptoms.  The treating physician should 
consider the minimum steroid dose for study subjects, if determined that it is safe and 
appropriate for that individual patient.  For study subjects who require a higher steroid dose, 
efforts should be made to taper steroids to the lowest amount that controls the subjects 
symptoms, as determined to be safe and appropriate by the treating physician. 
 Antidiarrheal therapy is permitted for study drug-induced diarrhea 
 Anti-emetics are permitted for study drug-induced nausea and vomiting 
NOTE: Care should be given when prescribing medications that are classified as CYP450 3A4 
inducers, inhibitors, or substrates due to potential interactions with the study drug. In the event that 
one is prescribed, consultation with the Medical Monitor is advised. All medications should be 
recorded in the case report form as indicated in the completion guidelines.  
 
7.2 
Prohibited Medications 
The following medications are prohibited during the study: 
 Any other investigational agent or anticancer therapy (chemotherapy, radiotherapy, etc.) while 
receiving study treatment 
 Palliative radiotherapy is not permitted while on study 
 Enzyme inducing anti-epileptic drugs (EIAED) are listed in Appendix 16.2 and are NOT 
permitted.   
NOTE: Care should be given when prescribing medications that are classified as CYP450 3A4 
inducers, inhibitors, or substrates due to potential interactions with the study drug. In the event 
that one is prescribed, consultation with the Medical Monitor is advised. All medications 
should be recorded in the case report form as indicated in the completion guidelines.  


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8 STUDY PROCEDURES 
8.1 
Written Informed Consent 
The provided written ICF must be signed before any protocol specific procedures and assessments can 
be performed.  A copy of the signed ICF will be given to the subject and a copy should be filed in the 
medical record.  The original ICF should be kept on file with the study reports.  Standard of care 
evaluations performed as part of the subject’s routine treatment prior to signing the ICF can be used if 
they were conducted within the timeframe of the screening period.  Refer to Section 13.8 for further 
information. 
8.2 
Subject Registration 
Centralized registration of subjects will be completed according to a process defined by the sponsor.  
Eligible subjects are to be enrolled and assigned a unique study identification number before the 
planned intratumoral Ad-RTS-hIL-12 injection.  Once assigned, a subject’s identification number will 
not be reused. 
8.3 
Schedule of Procedures and Observations 
Screening assessments must be performed within 28 days prior to the Ad-RTS-hIL-12 injection.  Any 
screening tests, exams, or procedures outside of this range may be repeated at the investigator’s 
discretion.  All study visits must be completed as described in the protocol while subjects are taking 
veledimex capsules.  Follow-up assessments are allowed a window of ± 7 days. 
8.3.1 Study Tests, Exams, and Procedures 
Demographics, Medical and Cancer History, and Concomitant Medications 
Each subject’s complete medical history will be documented during screening, including demographic 
information, relevant medical history, current primary cancer diagnosis, and prior cancer treatments 
(chemo- and immunotherapies, radiation therapy, surgeries, and any associated residual toxicities).  In 
addition, concomitant medications, including blood products, vitamins, and other supplements received 
during the screening period (28 days) prior to initiating study treatment will be recorded. Concomitant 
medications will continue to be collected through the Initial Follow-Up period (e.g. Day 56). 
Physical Examinations 
A complete physical examination will also include a neurological examination. 
Vital Signs, Height, and Weight 
Vital signs will include blood pressure, pulse rate, temperature, and respiration rate. Subject’s blood 
pressure is to be monitored closely, with hydration as needed to prevent hypotension for 72 hours after 
administration of Ad-RTS-hIL-12.  Assessment of vital signs is required prior to injection of 
Ad-RTS-hIL-12, and prior to veledimex dosing.  Height and weight will be measured and recorded 
according to Schedule of Study Procedures. 


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Karnofsky Performance Status 
The Karnofsky Performance Status measures the ability of cancer subjects to perform ordinary tasks. 
Scores range from 0 to 100 with a higher score meaning that the patient is better able to carry out daily 
activities. The Karnofsky Performance Status is used to determine a patient's prognosis, to measure 
changes in a patient’s ability to function, or to decide if a patient could be included in a clinical trial. 
Subjects must have a Karnofsky Performance Status score of ≥ 70 at the Screening Visit to be included 
in the study (Appendix 16.1). 
Pregnancy Testing 
Females of childbearing potential will have a serum pregnancy test at the Screening Visit and a urine 
or serum pregnancy test on Day 0, with a negative pregnancy outcome prior to study drug initiation. 
Monitoring of Adverse Events 
Monitoring and recording of AEs and serious adverse events (SAEs) will be conducted throughout the 
study. Adverse events and SAEs that occur following the signing of the ICF through the Initial 
Follow-up Period (e.g. Day 56) must be recorded on the AE CRF. 
Definitions, documentation, and reporting of AEs and SAEs are described in Section 10. 
Proper hydration is critical.  It is important that subjects are instructed repeatedly to maintain 
adequate oral hydration on and between veledimex doses; study sites must closely monitor 
subjects’ hydration status.  Blood pressure should be monitored regularly. 
Administration of prophylactic antipyretics is strongly recommended during the first week after 
Ad-RTS-hIL-12 injection. 
Clinical Laboratory Assessments 
The hematology panel comprises a complete blood count (CBC), including white blood cell (WBC) 
count with differential, red blood cell (RBC) count, hematocrit, hemoglobin, red blood cell indices, 
mean corpuscular volume (MCV), and platelet count. 
The serum chemistry panel comprises the following parameters:  AST, ALT, lactate dehydrogenase 
(LDH), alkaline phosphatase (ALP), creatinine, total bilirubin, total protein, albumin, amylase, blood 
urea nitrogen (BUN), glucose, sodium, potassium, chloride, calcium, phosphorus, and bicarbonate. 
The coagulation panel includes activated partial thromboplastin time (aPTT) and INR. 
The urinalysis panel (dipstick) includes appearance, pH, specific gravity, glucose, protein/albumin, 
presence of blood, ketones, bilirubin, nitrates, and leukocyte esterase.  In addition, a microscopic exam 
for casts, crystals, and cells may be done if clinically indicated. 
MRI 
Subjects should be able to undergo MRI scans with contrast agent at screening and during study 
participation.  MRI scans should be available for collection upon sponsor request. 


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Electrocardiogram 
A standard, single, 12-lead electrocardiogram (ECG) for evaluation of the QT/QTc interval will be 
performed. 
8.3.2 Screening Period:  Assessments 
The screening exams, tests, and procedures that must be done within 28 days of Ad-RTS-hIL-12 
injection are: 
• Signed informed consent form 
• Medical/cancer history 
• Physical examination (including neurological examination) 
• Height and weight 
• Vital signs 
• ECG 
• Karnofsky Performance Status 
• History of prior treatments and any associated residual toxicity  
• Medications taken within 28 days of Ad-RTS-hIL-12 injection 
• Adverse Events 
• Concomitant medications  
• Serum pregnancy test 
• Hematology Panel including: complete blood count (CBC), white blood cell (WBC) count 
with differential, red blood cell (RBC) count, hematocrit, hemoglobin, red blood cell indices,  
mean corpuscular volume (MCV), and platelet count 
• Serum Chemistry Panel including:  aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), creatinine, 
total bilirubin, total protein, albumin, blood urea nitrogen (BUN), glucose, sodium, potassium, 
chloride, calcium, phosphorus, and bicarbonate. 
• Coagulation Panel including:  partial thromboplastin time (PTT), international normalized 
ratio (INR) ESR – erythrocyte sedimentation rate and CRP - C - reactive protein.  
• Urinalysis Panel (dipstick) including:  appearance, pH, specific gravity, glucose, 
protein/albumin, presence of blood, ketones, bilirubin, nitrates, and leukocyte esterase.  In 
addition, a microscopic exam for casts, crystals, and cells may be done if clinically indicated 
• 
 
• Subject Registration 


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• MRI scan for surgical planning and/or stereotactic procedures 
8.3.3 Treatment Period:  Day 0 (Ad-RTS-hIL-12 injection) 
• Physical Examination (including neurological examination) 
• Karnofsky Performance Status 
• Vital Signs 
• Adverse Events Evaluation 
• Concomitant medications  
• Urine or Serum Pregnancy Test 
• Hematology Panel 
• Coagulation Panel 
• Serum Chemistry Panel  
• Urinalysis Panel 
• ECG 
• Group 1 subjects undergoing a tumor resection will take a cohort specific dose of veledimex 
3 (± 2) hours prior to resection, on an empty stomach (excluding other medications).  Tumor, 
CSF (if available), and blood samples will be collected at time of resection.  Intratumoral 
Ad-RTS-hIL-12 will be administered by 
 injection. 
• Group 2 subjects who will not undergo tumor resection will receive Ad-RTS-hIL-12 by 
stereotactic injection 
• Group 1 only: Blood Sample for Veledimex PK 
• Blood Sample for Evaluation of Serum Cytokine Profile 
• 
 
• Tumor and CSF (if available) for Group 1 subjects only 
8.3.4 Treatment Period:  Day 1 
• Once Daily Veledimex (in the morning with food) AND compliance diary 
• Physical Examination (including targeted neurological evaluation) 
• Vital Signs 
• Adverse Events Evaluation 
• Concomitant Medications 
• Blood Sample for Veledimex PK  
8.3.5 Treatment Period:  Day 2 
• Once Daily Veledimex Dose (in the morning with food) AND compliance diary 


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• Physical Examination (including targeted neurological evaluation) 
• Vital Signs 
• Adverse Events Evaluation 
• Concomitant Medications 
• Hematology Panel  
• Serum Chemistry Panel 
• Blood Sample for Veledimex PK 
• MRI scan (to be done within 72 hours of Ad-RTS-hIL-12 administration and to be used as the 
baseline MRI for tumor response assessment) 
8.3.6 Treatment Period:  Day 3 
• Once Daily Veledimex Dose (in the morning with food) AND compliance diary 
• Physical Examination (including targeted neurological evaluation) 
• Vital Signs 
• Adverse Events Evaluation 
• Concomitant Medications 
• Hematology Panel  
• Serum Chemistry Panel  
• Coagulation Panel 
• 
 
• Blood Sample for Veledimex PK  
• Blood Sample for evaluation of Serum Cytokine Profile 
• ECG 
8.3.7 Treatment Period:  Days 4 through 6 
• Once Daily Veledimex Dose (in the morning with food) AND compliance diary 
• Adverse Events evaluation 
• Concomitant Medications 
8.3.8 Treatment Period: Day 7 
• Once Daily Veledimex Dose (in the morning with food) AND compliance diary 
• Physical Examination (including targeted neurological evaluation) 
• Vital Signs 
• Weight 


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• Adverse Events Evaluation 
• Concomitant Medications 
• Hematology Panel 
• Serum Chemistry Panel  
• Coagulation Panel 
• Blood Sample for Veledimex PK  
• Blood Sample for evaluation of Serum Cytokine Profile 
• 
 
8.3.9 Treatment Period:  Days 8 through 13 
• Once Daily Veledimex Dose (in the morning with food) AND compliance diary 
• Adverse Events Evaluation 
• Concomitant Medications 
8.3.10 Treatment Period:  Day 14 
• Once Daily Veledimex Dose (in the morning with food) AND compliance diary 
• Physical Examination (including targeted neurological evaluation) 
• Karnofsky Performance Status  
• Weight 
• Vital Signs 
• ECG 
• Adverse Events Evaluation 
• Concomitant Medications 
• Hematology Panel  
• Serum Chemistry Panel 
• Coagulation Panel 
• Urinalysis Panel 
• Veledimex Dose Compliance  
• Blood Sample for Veledimex PK  
• 
 
• Blood Sample for evaluation of Serum Cytokine Profile 
• MRI 


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8.3.11 Follow-up Period:  Day 15 
• AE evaluation 
• Concomitant medications 
• Blood sample for veledimex PK 
8.3.12 Follow-up Period:  Day 28 (± 7 days) 
• Physical Examination (including targeted neurological examination) 
• Karnofsky Performance Status  
• Weight 
• Vital Signs 
• Adverse Events Evaluation 
• Concomitant Medications (including any new anti-cancer therapies) 
• Hematology Panel  
• Serum Chemistry Panel  
• Blood Sample for evaluation of Serum Cytokine Profile 
• 
 
• MRI scan  
8.3.13 Follow-up Period:  Day 56 (± 7 days) and every 8 weeks (± 7 days) thereafter 
• AE evaluation (Day 56 only) 
• Documentation of any anti-cancer therapies 
• MRI Scan 
o Subjects should continue to be followed until confirmed disease progression has been 
documented 
o Documentation of total daily dose of steroids taken for the two weeks prior to the MRI 
scan 
• Survival Follow-up 
o Subjects should continue to be followed for 2 years after enrollment. 
8.3.14 Unscheduled Visits Collections 
In the event of subject termination or an unscheduled visit for a drug-related AE, an unscheduled visit 
kit should be obtained for cytokines 
 for CSF evaluation, if applicable. 


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9.0 
TUMOR RESPONSE ASSESSMENTS 
9.1   Tumor Response 
The secondary time-to event endpoints of this study include Investigator assessment of ORR, PFS and 
OS. 
Tumor response will be evaluated radiographically using MRI scans to determine tumor response and 
to assess the time of objective disease progression (estimate of PFS).  A baseline MRI will be 
performed within 72 hours of Ad-RTS-hIL-12 administration (Day 2).  The Ad-RTS-hIL-12 injected 
lesion and/or other measureable brain lesions will be measured according to the RANO/iRANO 
criteria guidelines attached in Appendix 16.3 and Appendix 16.5.  MRI scans will be collected and 
stored at the study site and each subject will be evaluated for response by the study investigator.  
Subjects should be imaged throughout the study using the same method(s) as were used for the 
screening and baseline MRIs.  Independent tumor response assessments, as well as posttreatment 
tumor biopsies, may occur as available and at the discretion of the investigator.  A repeat scan to 
confirm progression should be completed at 4 weeks (per RANO) and preferably again at 12 weeks 
(per iRANO) after first documentation of progression. Consideration should be given to performing a 
diagnostic brain biopsy, which should be performed in accordance with the current iRANO guidelines. 
Response is defined by radiographic and clinical criteria.  Complete response (CR) or partial response 
(PR) will be first assessed by radiographic changes that indicate a reduction of bidimensional tumor 
size as per RANO/iRANO criteria.  In addition, changes in neurologic function and steroid use will be 
considered to determine stable disease (SD). 
Tumor response assessments will occur at 4 weeks (Day 28 ± 7 days), 8 weeks (Day 56 ± 7 days), and 
every 8 weeks thereafter for all subjects, including those who may have experienced a dose delay or 
missed a dose, until the occurrence of confirmed tumor progression, initiation of alternative therapy, or 
one year, whichever occurs first. 
9.2   Tumor Response Evaluation and Pseudo-Progression 
The interpretation of MRI findings in subjects with treated brain tumors has an inherent uncertainty 
that stems from the pseudo-progression phenomena.  Pseudo-progression is a term used to describe the 
appearance of radiographic disease progression due to increase contrast enhancement on MRI without 
true tumor progression.  The increase in contrast enhancement can be influenced by several parameters 
including differences in radiologic technique, the amount of contrast agent used, the timing of the 
contrast agent administration relative to the imaging, postsurgical changes, infarction, treated related 
inflammation, seizure activity, sub-acute radiation effects, radiation necrosis, and corticosteroid use.  
Consideration of these factors by experts and clinical experience is likely to identify these subjects.  In 
this study, pseudo-progression is unlikely to impact the duration of therapy since the veledimex 
treatment period lasts 14 days and the first tumor assessment MRI will be done on Day 28 (± 7 days).  
Imaging assessments will be performed using RANO/iRANO criteria. 
 


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10 SAFETY ASSESSMENTS 
Safety evaluation will include all subjects enrolled in the study using NCI CTCAE v.4.03 criteria for 
reporting AEs. 
The OSP will include all subjects who have received at least one dose of veledimex (pretumor 
resection and/or post-stereotactic procedure) and/or all subjects who have received Ad-RTS-hIL-12. 
The ESP will include subjects who have received both Ad-RTS-hIL-12 and at least one dose of 
veledimex after Ad-RTS-hIL-12 administration. 
10.1 Adverse Events and Definitions 
Adverse Event 
Any untoward medical occurrence associated with the use of a drug in humans, whether or not 
considered drug-related.  An AE can be any unfavorable and unintended sign including an abnormal 
laboratory finding, symptom, disease temporarily associated with the use of a medical treatment or 
procedure, and any worsening of a pre-existing condition regardless of causality to study drug. An AE 
is also known as an adverse experience. 
Suspected Adverse Reaction 
Any AE for which there is evidence to suggest a causal relationship (reasonable possibility) between 
the drug and the AE.  A suspected adverse reaction implies a lesser degree of certainty about causality 
than an adverse reaction. 
Adverse Reaction 
Any AE caused by the use of a drug.  Adverse reactions are a subset of all suspected adverse reactions 
for which there is reason to conclude that the drug caused the event. 
Unexpected Adverse Reaction 
Any AE that is (a) not listed in the Investigator’s Brochure, (b) not listed with the specificity and 
severity that is being observed, (c) not consistent with the risk information described in the general 
investigational plan or elsewhere in the current application (in the absence of an investigator brochure), 
and (d) listed as occurring with a class of drugs, but not specifically mentioned as occurring with the 
particular drug under investigation. 
10.2 Evaluation of Adverse Events 
Adverse events include: 
• Suspected adverse drug reactions 
• Reactions from study drug overdose, abuse, withdrawal, sensitivity, or toxicity 
• Significant changes or abnormalities when compared to baseline, in signs, symptoms, clinical 
laboratory results, or physiological testing. This includes any worsening of a pre-existing 
condition temporally associated with the use of study drug. 


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• Other untoward medical events, regardless of their relationship to the study drug, such as 
injury, events that require surgery, accidents, extensions of symptoms, or apparently unrelated 
illnesses 
The following considerations apply when identifying an AE: 
• Anticipated day-to-day 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. 
• In the event that a constellation of symptoms results in a confirmed diagnosis, the diagnosis 
(not the symptoms) should be recorded as the AE term. 
• If a diagnosis cannot be established, the symptoms should be recorded as the AEs. 
• If an ongoing symptom has been included in the medical history, an associated severity grade 
and frequency should also be documented so that a worsening in severity or frequency of a 
symptom can be readily identified as an AE. 
• Progression of disease is not itself an AE; however, the presenting sign or symptom of the 
disease progression should be documented as an AE (e.g., increase in pain).  However, if a 
subject experiences progression of disease that results in death, “progression of disease” may 
be reported as an SAE if, by medical opinion, the term best describes the cause of death. 
Adverse events will be followed through the Day 56 Visit.  AEs that are drug-related should be 
followed until resolved or no resolution is expected. 
10.3 Determination of Seriousness 
10.3.1 Serious Adverse Event 
An AE is considered an SAE if at least one of the following conditions applies: 
• Death:  An AE that results in death during the active study period or within 30 days following 
study drug administration.  In addition, a reported death at any time post-study that is thought 
to be related to study drug administration. 
• Life-threatening AE:  An AE that places the subject, in the view of the investigator, at 
immediate risk of death from the event as it occurred (i.e., this does not include a reaction that, 
had it occurred in a more severe form, might have caused death). 
• Permanent, persistent, or significant disability:  A disability is defined as any substantial 
disruption of a person’s ability to conduct normal life functions. 
• Inpatient hospitalization or prolongation of existing hospitalization:  In general, hospitalization 
refers to admission of a subject into a hospital for at least a 24-hour stay.  Hospitalizations for 
routine blood transfusions, hospitalization for an elective or diagnostic procedure, or surgery 
for a pre-existing condition that has not worsened, are not considered SAEs.  Emergency room 
visits that do not result with admission are not considered as SAEs. 
• A congenital anomaly/birth defect:  A fixed, permanent impairment established at or before 
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• Important medical event:  Events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical judgment, they 
jeopardize the subject and require medical or surgical intervention to prevent a life-threatening 
situation, hospitalization or death. 
• New cancer: Occurrence or diagnosis of a new cancer during the trial is considered an SAE. 
(This does not pertain to metastasis of current disease); 
• Any AE associated with an overdose of the study drug:  An overdose of study drug is defined 
as an occurrence of administered dose exceeding that which is prescribed by the investigator 
per protocol. 
10.3.2 Non-Serious Adverse Event 
An AE that does not fulfill the criteria for a SAE is classified as a non-serious AE. 
10.4 Determination of Severity 
The severity of AEs will be assessed according to the NCI CTCAE, v. 4.03.  If the AE is not defined in 
the NCI CTCAE, v. 4.03, the investigator will determine the severity of an AE based on the following 
definitions: 
• Mild (Grade 1):  The AE is noticeable to the subject, but does not interfere with routine 
activity.  The AE does not require discontinuing administration or reducing the dose of the 
study drug. 
• Moderate (Grade 2):  The AE interferes with routine activity, but responds to symptomatic 
therapy or rest.  The AE may require reducing the dose, but not discontinuation of 
administration of the study drug. 
• Severe (Grade 3):  The AE significantly limits the subject’s ability to perform routine activities 
despite symptomatic therapy.  In addition, the AE leads to discontinuation of administration or 
reducing the dose of the study drug. 
• Life-threatening (Grade 4):  The AE requires discontinuing administration of the study drug.  
The subject is at immediate risk of death. 
• Death (Grade 5):  The subject dies as a direct result of the complication or condition. 
 
10.5 Determination of Causality 
The investigator will use medical consideration to determine the potential relationship of the AE to the 
study drugs based on his/her clinical judgment.  Assessment of causality will be based upon the 
following: 
• Alternative possible causes of the AE, including the subject’s underlying disease or comorbid 
conditions, other drugs, other host, and environmental factors 
• The temporal sequence between the exposure to study drug and the AE 
• Whether the clinical or laboratory manifestations of the AE are consistent with known actions 
or previously reported toxicity of the study drug or similar drugs 


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• Whether the AE resolved or improved with decreasing the dose or stopping the study drug (i.e., 
dechallenge); or recurred or worsened with re-exposure to the drug (i.e., rechallenge). 
Relationship assessments that indicate “Not Related” to investigational product: 
• None:  The event is related to an etiology other than the investigational product (the alternative 
etiology must be documented in the study subject’s medical record and/or SAE form). 
• Unlikely or Remote:  The event is unlikely to be related to the investigational product and 
likely to be related to factors other than investigational product. 
Relationship assessments that indicate “Related” to investigational product: 
• Possible:  There is an association between the event and the administration of the 
investigational product and there is a plausible mechanism for the event to be related to 
investigational product; but there may also be alternative etiology, such as characteristics of the 
subject’s clinical status or underlying disease. 
• Probable:  There is an association between the event and the administration of investigational 
product, a plausible mechanism for the event to be related to the investigational product and the 
event could not be reasonably explained by known characteristics of the subject’s clinical status 
or an alternative etiology is not apparent. 
• Definite:  There is an association between the event and the administration of investigational 
product, a plausible mechanism for the event to be related to the investigational product and 
causes other than the investigational product have been ruled out and/or the event re-appeared 
on re-exposure to the investigational product. 
For AEs that occur prior to the administration of investigational product, an assessment of protocol 
relatedness must be made.  AEs may occur as a result of procedures required during the screening 
process (e.g., blood collection, washout of an existing medication) prior to the initial administration of 
investigational product.  For AEs that occur before administration of investigational product, only 
those that are assessed by the investigator as protocol-related should be reported to the sponsor.  The 
following guidelines should be used by investigators to assess the relationship of an AE to a 
protocol-required procedure: 
• Protocol-related:  The event occurred due to a procedure or intervention that was described in 
the protocol for which there is no alternative etiology present in the subject’s medical record. 
• Not protocol-related:  The event is related to an etiology other than the study procedure (the 
alternative etiology must be documented in the study subject’s medical record). 
10.6 Documenting Adverse Events 
All AEs, including SAEs, are to be accurately recorded on the Adverse Event page of the subject’s 
electronic CRF from the time the subject signs the informed consent through the Follow-up Period.  
Each event will be assessed for serious criteria, severity, and causality (Section 10.5). The date of 
onset, as well as the duration of the event will be recorded.  In addition, treatments provided to the 
subject, actions taken with the study drugs, and the outcome of the AE will also be noted. 


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10.7 Reporting Dose-Limiting Toxicities and Serious Adverse Events 
Time Frame for Reporting 
All DLTs and SAEs must be reported to the sponsor or sponsor designee within 24 hours of awareness, 
regardless of initiation of new anticancer therapy including the following: 
• Any death or SAE experienced by the subject from the signing of informed consent to 30 days 
after the last dose of study drug, regardless of relationship to study drug. 
• Any death or SAE that the investigator becomes aware of, and believes to be study 
drug-related, that occurs more than 30 days after the subject last received study drug. 
 
All DLTs and SAEs must be reported to the following fax line within 24 hours of awareness: 
 
 
Questions or assistance with completing forms can be directed to ZIOPHARM Oncology, 
 
 
Additional data concerning the SAE (e.g., diagnostic test reports, hospital summaries, etc.) must be 
promptly reported (within 24 hours of receipt) to the sponsor or sponsor’s designee, until resolution of 
the SAE.  Should the FDA or National Regulatory Authorities require that the sponsor submit 
additional data on the event, the investigator will be asked to provide those data to the sponsor in a 
timely fashion. 
Information to be Provided by the Investigator 
Within 24 hours of becoming aware of the SAE or subject death, the investigator must notify the 
sponsor or designee and transmit information to the sponsor or designee.  Information (initial and 
follow-up) should be provided on an electronic and/or paper SAE Report form signed and dated by the 
investigator.  The SAE Report form and copies of source documents with subject identifiers redacted 
will be transmitted by fax.  A hospital discharge summary should be provided if the subject was 
hospitalized.  An SAE report will be considered final once all relevant information has been received 
and reviewed by the sponsor. 
The SAE report form is provided in the investigator study files.  A DLT specific form will be used to 
report DLTs and is also provided in the investigator files.  Please refer to the investigator study files 
for instructions on how to complete these forms.  The investigator will provide all of the following 
information related to the event: 
 
• Investigator identification 
• Subject identification (e.g., subject number, initials, sex, age or date of birth) 
• Information regarding study drug administration (e.g. start/stop date, dose, and frequency) 
• Cycle and Day of SAE or DLT occurrence documentation on SAE or DLT report forms 
• Description of event 


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• Action taken with the study drugs in relation to the SAE or DLT 
• Outcome of the SAE or DLT 
In addition to the above information, the investigator must provide, for each event term, an assessment 
of: 
• Severity/intensity 
• Relationship to the study drug (causality assessment) 
10.8 Sponsor and Investigator Responsibility for Reporting Adverse Events 
All AEs and SAEs will be reported to regulatory authorities, IRBs/IECs, and investigators in 
accordance with all applicable global laws and regulations.  The investigator must submit all Safety 
Letters received from the sponsor to his/her IRB/IEC per agreements and local requirements.  The 
investigator must keep copies of all safety reports/letters, including correspondence with ZIOPHARM 
and the IRB/IEC, in the study file. 
10.9 Follow-up Information for Adverse Events 
Appropriate diagnostic tests should be performed and therapeutic measures, as medically indicated, 
should be instituted.  Appropriate consultation and follow-up evaluations should be carried out until 
the event has resolved, stabilized, returned to baseline, or is otherwise explained by the investigator. 
Required Follow-up for Adverse Events 
All treatment-related AEs and SAEs will be collected through the Follow-up Period (i.e., 42 days after 
the end of veledimex treatment) or until: 
• The event resolves 
• The event returns to baseline, if a baseline value is available 
• The event stabilizes (following consultation and agreement by the ZIOPHARM medical 
monitor) 
• The event can be attributed to factors other than the study drug or other than study procedure 
10.10 Pregnancies 
Subjects who become pregnant during the study should immediately discontinue participation in the 
study.  The sponsor should be immediately notified. 
An initial Pregnancy Report form and a Pregnancy Outcome Form are to be completed by the 
investigator or designee.  The Pregnancy Report form and the completion guidelines will be provided 
in the investigator study files.  Please refer to the investigator study files for details on how to complete 
these forms. 
10.11 Overdose 
Investigational product overdose of study subject, with or without associated AEs/SAEs, should be 
reported within 24 hours of awareness to sponsor (ZIOPHARM Oncology, 
 


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  All AEs or SAEs as a result of overdose 
should be reported as described previously in Sections 10.6 and 10.7. 
 
 






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12 STATISTICAL METHODS 
This study is designed as a Phase I dose escalation according to a standard 3 + 3 design to determine if 
the MTD will be reached in up to four veledimex dose cohorts; 20 mg, 40 mg, 80 mg and 120 mg.  It is 
modified to independently evaluate the safety of two groups of recurrent HGG subjects previously 
described: 
• Group 1:  Subjects scheduled for craniotomy and tumor resection 
• Group 2:  Subjects who will not undergo tumor resection 
The statistical difference between the groups is that Group 1 subjects will receive a cohort-specific 
dose of veledimex 3 (± 2) hours before the craniotomy procedure on Day 0 on an empty stomach 
(excluding other medications).  At the time of tumor resection, tumor CSF (if available), and blood 
samples will be collected to determine the veledimex concentration in these samples.  This will not 
occur for Group 2 subjects because they will not undergo a standard of care tumor resection. 
In each cohort, starting on Day 1 the first subject will be monitored for the 14 days of treatment and 
will be observed an additional 7 days post the last veledimex dose before the second and third subjects 
are enrolled in that same cohort.  Evaluation for the determination to dose escalate will occur after all 
dosed subjects in a cohort have participated on-study for at least 28 days postdose from Day 1, unless 
the subject discontinued due to a DLT. 
12.1 Populations for Analysis 
The following subject populations will be evaluated and used for presentation and analysis of the data:  
• The OSP includes all subjects who have received at least one dose of veledimex (pretumor 
resection and/or post-stereotactic procedure) and/or all subjects who received Ad-RTS-hIL-12. 
• The ESP includes subjects who have received Ad-RTS-hIL-12 and at least one dose of 
veledimex after Ad-RTS-hIL-12 administration. 
• The PKP includes all subjects who receive veledimex. 
12.2 Sample Size and Power Calculations 
The sample sizes chosen were based on clinical consideration for a standard 3 + 3 dose escalation 
design to determine the MTD for two separate groups of subjects independently evaluable for safety 
and dose escalation.  Power calculations for comparison of AE rates are simply too inexact to be 
clinically meaningful because the AE rates are unknown and cannot even be approximately projected.  
If an AE occurs at a rate of 1% or 10%, then the chance for observing such an AE among six subjects 
receiving that dose will be 6% and 47% respectively.  If no AE is observed in any of the six subjects, 
then the true incidence is at most 24% with 80% confidence and 32% with 90% confidence. 


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12.3 Endpoints 
12.3.1 Primary Endpoint 
The primary endpoint is the assessment of safety of Ad-RTS-hIL-12, administered by intratumoral 
injection plus veledimex administered orally, as determined by the AE rate and the occurrence of 
DLTs analyzed specifically for each group. 
12.3.2 Secondary Endpoints 
Secondary endpoints are as follows: 
• Investigator assessment of ORR and PFS 
• OS 
• Veledimex concentration ratio between brain tumor, CSF, and blood (Group 1, Day 0) 
• Veledimex PK estimates starting Day 1, as previously described 
• Correlative measures of immune response including serum cytokine levels 
 
 
12.4 Analyses 
12.4.1 Baseline Characteristics 
Demographic and baseline disease characteristic data will be summarized.  Data to be tabulated will 
include at least demographic features such as sex, age, and race, as well as disease-specific status and 
medical history. 
Categorical data will be summarized using counts and percentages based on non-missing values.  For 
continuous variables, the mean, median, standard deviation, minimum, and maximum values will be 
presented.  Data will be summarized by dose cohort and by group (Group 1 or Group 2) and according 
to the defined populations for analysis. 
12.4.2 Safety Analyses 
The ESP will be used to make determinations for dose escalation to subsequent higher veledimex 
doses for each group (Group 1 or Group 2) separately based on a standard 3 + 3 design, as previously 
described. 
For the first veledimex dose cohort, a minimum of three ESP subjects must be eligible and have 
received veledimex dosing.  In addition, DLT evaluation must also be performed on these subjects 
according to the rules of the protocol in both Group 1 and Group 2, respectively.  As previously 
described, all subjects (Group 1 and Group 2) must have a minimum of 28 days of postdose 
observation experience or discontinued the trial due to a DLT before the data will be summarized 
based on a safety template to be created for an SRC review.  The SRC during or after its review may 
request additional data before it makes a recommendation to the DSMB.  The sponsor will coordinate 
the logistics of all SRC and DSMB interactions in order to expedite obtaining a dose escalation 
recommendation from the DSMB according to the rules of the SRC and DSMB charter. 


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The OSP will be used to perform safety evaluations for all safety variables of all subjects who received 
at least one dose of veledimex and/or all subjects who received Ad-RTS-hIL-12. 
Safety evaluations will be based on the incidence, intensity, and type of AEs and SAEs.  Clinically 
significant changes in the subjects’ physical examinations, vital signs, and ECG evaluations, and 
abnormal laboratory values will be captured as AEs.  Safety will also be assessed based on medical 
history and prior/concomitant medications. 
The safety evaluation period extends from the date the patient signs the ICF until approximately 1 year 
after receiving study drug from Day 1 dosing, unless the patient discontinues the trial due to one of the 
following reasons: 
• Documented progression 
• Symptomatic deterioration also denoted symptomatic progression 
• AEs that the investigator feels will subsequently make the subject noncompliant with the 
protocol planned Schedule of Study Procedures 
• Loss to follow-up 
• Noncompliance with the protocol 
• Other reason not listed above 
All treatment-emergent AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) and will be tabulated by number and percent of subjects, and according to relationship to 
the study drugs, severity, and seriousness.  Treatment-emergent is defined as any AE that occurs 
during or after administration of the first dose of study drug through the evaluation period for safety 
defined above, regardless of relationship to study drug; or any event that is present at baseline that 
worsens in intensity or is subsequently considered to be drug related by the investigator.  Deaths, 
SAEs, and AEs resulting in study discontinuation will be listed. 
Subjects who discontinue the trial as defined above will be followed for safety up to 30 days after 
discontinuation and until all safety events that have started during the safety evaluation period are 
classified as resolved or the end of the study is reached.  After the conclusion of the safety evaluation 
period is triggered by a discontinuation event, the subject continues to be followed only for OS. 
Listings of vital signs and physical examination data will be presented by visit. 
12.4.3 Tumor Response Analyses 
Tumor response analysis will be performed on the ESP.  Investigator assessment of ORR and PFS will 
be determined for each dose cohort according to RANO/iRANO criteria.  OS is defined as either the 
duration of time from the first dose of study drug to the date of death or to the last follow-up contact 
date if the subject has not died, in which case the subject is censored if still alive up to 2 year from the 
first dose of study drug received.  A two-sided confidence interval will be computed for the ORR.  PFS 
and OS will be estimated using the Kaplan-Meier method for appropriately-sized subject groups. 
Following completion of the study, best response will be determined for each subject in accordance 
with RANO/iRANO guidelines and the ORR will be presented for all ESP subjects and for each group 
of subjects.  Where applicable, summary data of PFS, OS, and durability of response will be 


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determined using Kaplan-Meier methodology; otherwise, a listing by-subject of each dosing cohort for 
Group 1 and Group 2 will display the data obtained.  Two-sided confidence intervals will be computed 
for the ORR.  Descriptive statistics will be performed on all of the cohorts combined and by Group 1 
and Group 2. 
12.4.4 Multi-Center Study 
Tumor response and safety data will be presented for each dose cohort by specific group pooled over 
all study centers. 
12.4.5 Adjustments for Covariates 
No adjustments for covariates will be made. 
12.4.6 Procedures for Handling Missing, Unused, and Spurious Data 
No imputation of values for missing data will be performed.  Standard clinical monitoring and data 
management practices will be used to ensure the integrity of data. 
12.5 Procedures for Reporting Deviations to Original Statistical Analysis Plan 
A formal statistical plan for the analysis and presentation of data from this study will be prepared prior 
to database lock.  Deviations from the statistical analyses outlined in this protocol will be indicated in 
this plan; any further modifications will be noted in the final clinical study report. 
 
 


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13 STUDY MANAGEMENT 
13.1 Electronic Case Report Forms and Source Documentation 
For each subject, electronic case report forms (eCRFs) and corresponding source records will be 
maintained at each clinical site.  The sponsor or designee will provide the study sites with secure 
access to and sufficient training on the electronic data capture (EDC) application, to permit site 
personnel to enter or correct information in the eCRFs for the subjects for whom they are responsible. 
The eCRFs should be completed in a timely manner, and every effort should be made to have forms 
completed and up-to-date in anticipation of a visit by the sponsor’s monitor.  Specific instructions will 
be provided to the site.  All requested information must be entered on the eCRF in the spaces provided.  
If an item is not available or is not applicable, it should be documented as such; do not leave a space 
blank. 
It is the investigator’s responsibility to ensure the accuracy, completeness, clarity, and timeliness of the 
data reported in the subject’s eCRF.  Through the EDC application, the investigator must provide 
formal approval of all subject information in the eCRFs and changes to the eCRFs to endorse the final 
submitted data for the subjects for whom he/she is responsible.  The audit trail entry will show the 
user’s identification information and the date and time of any corrections. 
eCRF completion may be delegated to other study personnel; however, such delegation must be 
documented in writing.  If, for any reason, certain data are lacking to complete an individual report 
form, the investigator will provide a written statement explaining the reasons for the lack of data. 
Sponsor or designee will retain the eCRF data and corresponding audit trails.  A copy of the final 
archival eCRF in the form of a compact disk or other electronic media will be placed in the 
investigator’s study file. 
13.2 Good Clinical Practice 
The study will be conducted in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Conference on Harmonization (ICH) 
Good Clinical Practice (GCP) guidelines, applicable regulatory requirements, and ZIOPHARM 
policies. 
13.3 Sponsor Monitoring 
After satisfactory receipt of all necessary regulatory paperwork, the sponsor’s monitor will arrange that 
all study material be delivered to the study site at a mutually convenient time.  An initiation visit by 
ZIOPHARM and its monitoring personnel will be made.  At this meeting, all personnel expected to be 
involved in the conduct of the study will undergo an orientation to include review of study protocol, 
instruction for CRF completion and overall responsibilities, including those for drug accountability and 
study file maintenance. 
Throughout the course of the study, the sponsor’s monitor will make frequent contact with the 
investigator, and this will include telephone and/or onsite visits.  During these visits, CRFs will be 
reviewed for completeness and adherence to protocol.  As part of the data audit, it is expected that 
source documents (e.g., hospital records, office records) will be made available for review by the 
monitor.  The monitor also will perform drug accountability checks, and may periodically request 


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review of the investigator’s study file to assure completeness of documentation in all respects of study 
conduct. 
Upon study completion, the monitor will arrange for a final review of the study files, after which the 
file should be secured by storage for the appropriate period as specified in Section 13.5.  The 
investigator or appointed delegate will receive the sponsor’s representative during these onsite visits 
and will cooperate in providing the documents for inspection and responding to inquiries that may 
arise as part of this review.  The investigator will also permit inspection of the study files by authorized 
representatives of the FDA. 
13.4 Duration of the Study 
The duration of this study from the time of initiating subject enrollment until the completion of 
survival follow-up is anticipated to be approximately 48 months, including 24 months for enrollment 
and 2 years of further follow-up. 
The overall duration is expected to be up to 2 years for an individual subject, including the following: 
• Screening period of up to 28 days 
• Study treatment period of 2 weeks (Days 0 through 14) 
• Assessment of safety through the Follow-up Period 
• Assessment of tumor response at Day 28 (± 7 days), Day 56 (± 7 days), and every 2 months 
thereafter until the occurrence of confirmed tumor progression 
• Survival status through 2 years 
In addition, subjects who discontinue or complete study treatment without objective evidence of 
disease progression should continue to be followed until confirmed disease progression has been 
documented. Subjects will be followed for survival status for 2 years after enrollment, whichever 
occurs first.  The active study period refers to the study period from informed consent through the 
Initial Follow-up Period. 
13.5 Records Retention 
Records of drug disposition, CRFs, and reports of the clinical trial must be maintained by the 
investigator for a period of at least 2 years following the date on which the test article is approved by 
FDA for marketing for the purposes that were investigated in the study.  If no application is to be filed 
or if the application is not approved for such indication, the records must be stored for two additional 
years and then returned to ZIOPHARM.  No records will be destroyed, but will be indefinitely stored. 
13.6 Institutional Review Board/ Independent Ethics Committee 
This protocol and the study ICF must be reviewed and approved by the Institutional Biosafety 
Committee, where applicable, and IRB/IEC prior to the start of the study, and a copy of the approval 
letter supplied to ZIOPHARM.  During the course of the study, the investigator shall make timely and 
accurate reports to the IRB/IEC on study progress at intervals not exceeding 1 year, as well as 
satisfying any other local IRB/IEC reporting regulations.  Copies of all reports to, and correspondence 
with, the IRB/IEC must be provided to ZIOPHARM.  Further, within 3 months of the completion or 


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early termination of the study, a final report should be made to the IRB/IEC and ZIOPHARM by the 
investigator. 
All protocol revisions must originate with and be documented by ZIOPHARM.  If the requested 
revision is an amendment, the investigator must sign it.  The FDA will be notified of all revisions by 
ZIOPHARM.  The investigator must submit the amendment to his/her IRB/IEC for review and 
approval prior to implementation.  Documentation of approval signed by the chairperson or designee 
of the IRB/IEC must be sent to ZIOPHARM. 
It is the investigator’s obligation to maintain an IRB/IEC correspondence file and to make this 
available for review to ZIOPHARM representatives as part of the routine study monitoring process. 
13.7 Confidentiality and HIPAA 
The written ICF will explain that study data will be stored in a database, maintaining confidentiality in 
accordance with national data legislation.  All data processed by ZIOPHARM, or its representatives, 
will be identified by subject number and study code. 
The written ICF will also explain that, for data verification purposes, authorized representatives of 
ZIOPHARM, a regulatory authority (FDA), and/or the IRB/IEC may require direct access to parts of 
the hospital or clinic records relevant to the study that include the subject’s medical history. 
The written ICF will be accompanied by or include a separate document incorporating United States 
Health Insurance Portability and Accountability Act (HIPAA)-compliant wording by which the 
subjects authorize the use and disclosure of their Protected Health Information. 
13.8 Informed Consent 
13.8.1 FDA Informed Consent Requirements 
The investigator or his/her staff will explain the nature of the study, its purpose and associated 
procedures, the expected duration, and the potential risks involved to the prospective subject prior to 
enrollment.  The ICF should also indicate that, by signature, the prospective subject or, where 
appropriate, a legal guardian, permits access to relevant medical records by the sponsor and by 
representatives of the FDA.  If a prospective subject does not understand English, an appropriate 
translation into his or her primary language must be made available.  The investigator or designee will 
obtain written, informed, and witnessed consent.  The prospective subject will have ample time and 
opportunity to ask questions.  The prospective subject will be informed about the right to withdraw 
from the study at any time without any disadvantage and without having to provide a reason for this 
decision.  Following the discussion regarding the study, the prospective subject will be asked if he/she 
is willing to sign and personally date a statement of informed consent.  Only if the prospective subject 
voluntarily agrees to sign the informed consent statement and has done so, may he/she enroll into the 
study.  A copy of his/her signed and dated informed consent will be provided to each prospective 
subject.  The signed ICF is to remain in the investigator’s file. 
The ICF and any other written information provided to the subjects will be revised whenever important 
new information becomes available that may be relevant to the subject’s consent, or if there is an 
amendment to the protocol that necessitates a change to the content of the subject’s informed consent.  
The investigator will inform the subject of changes in a timely manner and will ask the subject to 


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confirm continuation of his/her participation in the study by his/her signature on the revised ICF, if 
applicable.  Any written ICF and written information must receive IRB/IEC approval/favorable 
opinion in advance of use. 
13.8.2 Subject Informed Consent Form 
ZIOPHARM will provide a sample subject ICF for modification, as appropriate, by the investigator. 
 
 


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14 PROTOCOL APPROVAL PAGE 
A Phase I Study of Ad-RTS-hIL-12, an Inducible Adenoviral Vector Engineered to Express hIL-12 
in the Presence of the Activator Ligand Veledimex in Subjects with Recurrent or Progressive 
Glioblastoma or Grade III Malignant Glioma 
With the exception of a change intended to eliminate an immediate hazard to subjects, the study shall 
be conducted as described in the approved protocol.  All deviations from the protocol will be 
documented in the CRF.  Any significant deviation or deviation related to dosing or safety evaluation 
will be reported to ZIOPHARM and documented in the CRF. 
I agree to the terms of this study protocol.  I will conduct the study according to the procedures 
specified herein, and according to principles of Good Clinical Practice and local regulations and 
requirements. 
 
Study Site   
 
Center Name:   ____________________________________ 
 
Principal Investigator 
Print Name:  _____________________________________ 
 
Signature: 
_____________________________________ 
 
Date:   
_____________________________________ 
 








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16 APPENDICES 
16.1 Karnofsky Performance Status 
Karnofsky Performance Status Scale 
Definitions Rating (%) Criteria 
Able to carry on normal activity and 
work; no special care needed. 
100 
Normal no complaints; no evidence of disease 
90 
Able to carry on normal activity; minor signs of 
symptoms of disease 
80 
Normal activity with efforts; some signs of 
symptoms of disease 
Unable to work; able to live at home 
and care for most personal needs; 
varying amount of assistance needed. 
70 
Cares for self; unable to carry on normal activity 
or to do active work 
60 
Requires occasional assistance, but is able to care 
for most of his personal needs 
50 
Requires considerable assistance and frequent 
medical care 
Unable to care for self; requires 
equivalent of institutional or hospital 
care; diseases may be progressing 
rapidly. 
40 
Disabled; requires special care and assistance 
30 
Severely disabled; hospital admission is indicated 
although death not imminent 
20 
Very sick; hospital admission necessary; active 
support treatment necessary 
10 
Moribund; fatal processes progressing rapidly 
0 
Dead 
Oxford Textbook of Palliative Medicine, Oxford University Press.  1993, 109. 
 


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16.2 Prohibited Enzyme-Inducing Antiepileptic Drugs and Enzyme-Inhibiting Antiepileptic 
Drugs 
Enzyme-inducing Antiepileptic Drugs 
Enzyme-inhibiting Antiepileptic Drugs 
Dilantin® (phenytoin) 
Depakene®, Depacon®, Depakote®, Stavzor®, Valproic® 
(divalproex sodium or valproate) 
Lamictal® (lamotrigine)a 
Mysoline® (primidone) 
Sabril® (vigabatrin) 
Solfoton®, Luminal® (phenobarbital) 
Tegretol® (carbamazepine) 
Topamax® (topiramate)b 
Trileptal® (oxacarbazepine) 
a:  Barely induces uridine diphosphate-glucuronosyltransferase enzymes, rarely has clinical impact 
b:  Effect is only significant at higher doses 
16.3 Recommended Regimen for Antipyretic and/or Analgesic Prophylaxis 
Recombinant adenoviral vectors have the potential to elicit potent cellular and humoral immune 
responses. While the mechanism responsible for these effects is poorly understood, transient low-grade 
fevers are common after systemic rAD vector administration and temperatures up to 104° F with chills 
and generalized malaise have been observed with treatment.  Because low-grade fever is very likely to 
occur, prophylaxis with acetaminophen is strongly recommended. 
While meta-analyses suggest that ibuprofen is a better anti-pyretic medication than acetaminophen, 
acetaminophen also prevents and/or reduces a fever.  Acetaminophen is available without a 
prescription in 325 mg or 500 mg tablets.  Each site should follow the institutional protocol for the 
administration of acetaminophen. 
Adverse events are rare, but some people are allergic to the medication.  Overdoses may cause liver 
failure.  Therefore, people with liver disease and chronic alcohol users should avoid this medication. 
Common brand names of acetaminophen include Aspirin Free Anacin®, Feverall®, Genapap®, 
Panadol®, Tempra®, and Tylenol®. 
In general, a fever can be treated with acetaminophen.  Alternating doses of ibuprofen with 
acetaminophen will also effectively control fever and prevent accidental overdose.  If a fever occurs in 
spite of prophylactic medication or does not respond to usual doses of acetaminophen, then a 
combination of both acetaminophen and ibuprofen may be needed to stop the fever. 
16.4 Updated Response Criteria for High-grade Glioma:  Response Assessment in 
Neuro-oncology Working Group (Attached) 
16.5 Immunotherapy Response Assessment in Neuro-Oncology: a Report of the RANO 
Working Group (Attached) 
 
























e
 
 














 


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Protocol Amendment for Ad-RTS-IL-12 + Veledimex (Amendment 1) 
Effective Date:  14 April 2015 
Summary of Changes 
Section in 
Amended 
Protocol 
Revised or Deleted Text/Section 
Rationale for Change 
Title Page, 
Page Headings 
and Footers 
 
Title change for Medical Monitor to Executive Vice President and Chief 
Medical Monitor 
 
Date change made to the protocol date and to the header on each page. 
Updated Protocol 
Amendment 
Global 
 
Schedule of Assessment and Section 8 in the protocol were corrected for 
consistency between the two. 
 
Wherever the collection of CSF is mentioned, if available has been added. 
 
After all edits were made, numbering of tables and sections were updated 
in the document. 
Updated Protocol 
Amendment 
Primary 
Objective  
To determine the safety and tolerability of varying dose levels of Ad-RTS-hIL-12a 
single intra tumor Ad-RTS-hIL-12 dose (1.0 × 1012 vp) plus escalating  and  oral 
veledimex doses in subjects with recurrent or progressive glioblastoma or Grade III 
malignant glioma 
Addition of lower IL-12 
dose due to new 
nonclinical information 
Secondary 
Objective 
To determine the veledimex maximum tolerated dose (MTD) when given with 
varying doses of a single intra tumor  Ad-RTS-hIL-12. dose (1.0 × 1012 vp) 
Addition of lower IL-12 
dose due to new 
nonclinical information 
Protocol 
Synopsis 
Study Design 
This is a Phase I study of varying dose levels of Ad-RTS-hIL-12, administered 
by intra tumor injection, and varying escalating veledimex doses, administered 
orally, in subjects with recurrent or progressive glioblastoma or Grade III 
malignant glioma. This study will investigate  a single two intra tumor Ad-RTS-
hIL-12 doses (2 x 1011 and 1.0× 1012 vp) and escalating veledimex doses to 
determine the safe and tolerable  veledimex dose based on the safety profiles 
observed. 
 
This study is divided into three periods: the Screening Period, the Treatment 
Period and the Follow-up Period. After the 
Informed Consent is signed, subjects will enter the Screening Period to assess 
eligibility. Eligible patients will be stratified to one of two groups, according to 
clinical indication for tumor resection.  Patients who are scheduled for a standard 
of care craniotomy and tumor resection (Group 1) will receive one veledimex dose 
before the resection procedure. Samples (tumor, cerebrospinal fluid (CSF)  (if 
available)  and blood) will be collected during the resection procedure to determine 
the veledimex concentration ratio between the tumor, the CSF and the blood.  
Approximately 1.0 × 1012 Ad-RTS-hIL-12 by dose cohort (either 2 x 1011 or 1 x 
1012 vp) viral particles (vp) will be administered by 
 injection. After Ad- 
RTS-hIL-12 injection, patients will continue on oral veledimex for 14 days.  
Patients not scheduled for tumor resection (Group 2) will receive approximately 
1.01 × 1012 Ad-RTS-hIL-12 viral particles by stereotactic injection and then will 
continue on oral veledimex for 14 days. 
 
Note:  Subjects in Group 1 will receive up to a total of 15 veledimex doses:  one 
veledimex dose 3 ± 2 hours before the craniotomy procedure (first dose prior to 
craniotomy will be a dose specific to the assigned cohort) and tumor resection 
(prior to Ad-RTS-hIL-12 administration), and up to 14 veledimex doses after Ad-
RTS-hIL-12 administration. Subjects in Group 2 will receive up to a total of 14 
veledimex doses after Ad-RTS-hIL-12 administration. 
 
Addition of lower IL-12 
dose due to new 
nonclinical information 


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Section in 
Amended 
Protocol 
Revised or Deleted Text/Section 
Rationale for Change 
Group 1: Patients 
scheduled for craniotomy 
and tumor resection. 
 
Patients with a clinical indication for tumor resection will receive veledimex 
dose specific to the assigned cohort 3 ± 2 hours before the craniotomy 
procedure, on an empty stomach (excluding other medications). At the time of 
tumor resection, brain tumor, CSF (if available) and blood samples will be 
collected to determine the veledimex concentration 
  ratio between brain tumor, CSF and blood. 
 
Immediately after tumor resection, subjects in Cohorts 1 & 2 will receive 
approximately Ad-RTS-hIL-12 2 x 1011 vp. 
This will be administered by free-hand injection into approximately two sites within 
the residual tumor for a total volume of 0.1 mL. The day of Ad-RTS-hIL-12 
administration is designated as Day 0. 
Immediately after tumor resection, approximately 1.0 × 1012 Ad RTS hIL 12 viral 
particles will be administered by 
 injection into multiple sites 
(approximately five selected sites) within the residual tumor (day of Ad RTS hIL
12 administration is designated as Day 0). The planned total injection volume is up 
to 0.5 mL given in approximate aliquots of 0.1 mL at each injection site.  For 
Cohorts 3, 4, 5 and 6, immediately after tumor resection, Ad-RTS-hIL-12 1 x 1012 
vp will be administered by 
 injection into multiple sites (approximately 
five selected sites) within the residual tumor (day of Ad-RTS-hIL-12 administration 
is designated as Day 0). The planned total injected volume for these cohorts is 0.5 
mL given in approximate aliquots of 0.1 mL at each injection site.  When available 
an intra-operative MRI can be performed to guide the Ad-RTS-hIL-12 injection to 
areas of contrast enhancing tumor tissue. 
 
After the Ad-RTS-hIL-12 injection, veledimex will be administered orally for 14 
days. The first post resection veledimex dose is to be given on the day immediately 
following Ad-RTS-hIL-12 administration designated as Day 1, preferably with 
food. Subsequent veledimex doses are to be taken once daily, in the morning and 
within 30 minutes of a regular meal. 
 
Group 2: Patients who will not undergo tumor resection 
Patients who will not undergo tumor resection will receive Ad-RTS-hIL-12 by 
standard stereotactic surgery on Day 0. 
Approximately Ad-RTS-hIL-12 1.01 × 1012  Ad RTS hIL 12 vp viral particles will 
be administered by stereotactic injection into approximately five intra tumor sites 
to deliver up to 0.5 mL volume in approximate aliquots of 0.1 mL at each site. 
Care should be taken to avoid 
intraventricular or basal cisternal 
injection. 
 
After the Ad-RTS-hIL-12 injection, veledimex will be administered orally for 14 
days.  The first veledimex dose is to be given on the day immediately following 
Ad-RTS-hIL-12 administration designated as Day 1, preferably with food. 
Subsequent veledimex doses are to be taken once daily, in the morning and within 
30 minutes of a regular meal. 
 
This Group 2 will start dosing patients only after two patients have completed 28 
days in Group 1, Cohort 3. 
 


Ad-RTS-hIL-12 
 
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Section in 
Amended 
Protocol 
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Rationale for Change 
Dose-limiting toxicity (DLT) is defined as: one was added
Diagnostic brain tumor biopsy is not considered a DLT
 
Expansion cohorts are not prospectively planned in this study.  A decision to 
enroll additional subjects, as part of an expansion cohort, at the determined 
veledimex MTD and the  fixed  Ad-RTS-hIL-12 dose (1.0 × 1012 vp) will be made 
by the SRC only after the MTD has been identified for one or both groups and 
safety evaluated. 
 
Study 
Synopsis 
Number of 
subjects: 
Up to 48 72  subjects may be enrolled.
 
Addition of 2 cohorts 
Protocol 
Synopsis 
Investigational 
Products,  
Dose and Mode 
of 
Administration 
Ad-RTS-hIL-12 Dose 
This study will explore one varying dose levels of Ad-RTS-hIL-12 dose. 
Approximately 1.0 × 1012 Ad-RTS-hIL-12 viral particles (0.5 mL) . The Ad-
RTS-hIL-12 will be administered by either 
 injection into residual 
tumor sites immediately after tumor resection (Group 1) or by stereotactic 
injection at intra tumor sites (Group 2). 
 
 
 
 
Cohort 
Ad‐RTS‐hIL‐12a
(Day 0) 
Veledimexb 
(Days 1‐14) 
Dose(vp) 
Total Daily Dose 
(mg) 
1 
2 x 1011 
20 
2 
2 x 1011 
40 
3 
1 × 1012 
20 
4 
1 × 1012 
40 
5 
1 × 1012 
80 
6 
1 × 1012 
120 
 a Intra Tumor Injection
 b Oral Administration Post Ad‐RTS‐hIL‐12 on Days 
1‐14. Dose  
   levels may be modified based on additional 
clinical and    
   nonclinical PK data (Section 6.4) 
 
 
 
 
 
 
Addition of lower IL-12 
dose due to new 
nonclinical information 












Ad-RTS-hIL-12 
 
ZIOPHARM Oncology, Inc. 
Protocol ATI001-102  
Summary of Changes Amendment 1 - 14 April 2015 
 
Amendment 1 
 
 
 
Confidential 
 
 
 
 
 
Page 9 of 12 
 
Section in 
Amended 
Protocol 
Revised or Deleted Text/Section 
Rationale for Change 
After the Ad-RTS-hIL-12 injection, veledimex will be administered   
orally for 14 days. The first post 
resection  veledimex  dose  is  to  be  given  on  the  day  
immediately  following  Ad-RTS-hIL-12administration designated 
as Day 1, preferably with food.  Subsequent veledimex doses are to 
be taken once daily, in the morning and within 30 minutes of a 
regular meal. 
 
Patients with a clinical indication for tumor resection will receive 
veledimex dose specific to the assigned cohort 3 ± 2 hours before the 
craniotomy procedure, on an empty stomach (excluding other 
medications). At the time of tumor resection, brain tumor, CSF and 
blood samples will be collected to determine the veledimex 
concentration ratio between brain tumor, CSF and blood. 
Immediately after tumor resection, subjects in cohorts 1 & 2 will 
receive approximately 2 x 1011 Ad RTS hIL 12 viral particles 
administered by 
 injection into multiple sites 
(approximately two selected sites) within the residual tumor (day of 
Ad RTS hIL 12 administration is designated as Day 0). The planned 
total injection volume For cohorts 1 & 2 is up to 0.1 mL given in 
divided dose at each injection site.  For cohorts 3, 4, 5 and 6, 
immediately after tumor resection, approximately 1 x 1012  Ad
RTS hIL 12 viral particles will be administered by 
 
injection into multiple sites (approximately five selected sites) 
within the residual tumor (day of Ad RTS hIL 12 administration is 
designated as Day 0). The planned total injected volume for these 
cohorts is 0.5 mL given in approximate aliquots of 0.1 mL at each 
injection site. When available an intra-operative MRI can be 
performed to guide the Ad RTS hIL 12 injection to areas of contrast 
enhancing tumor tissue. 
 
Patients with a clinical indication for tumor resection will 
receive  a cohort specific oral dose of veledimex 3 ± 2 hours 
before the craniotomy procedure, on an empty stomach 
(excluding other medications).   At the time of tumor resection, 
tumor, CSF and blood samples will be collected to determine the 
veledimex PK. Neuropathology can reconfirm malignant glioma 
diagnosis from frozen tissue; surgeon will proceed with Ad-RTS-
hIL 12 injection in case sample is insufficient for diagnosis. 
Immediately after tumor resection, Cohort 1 and 2 subjects will 
receive approximately 2 x 1011 Ad RTS  hIL 12 and Cohorts 3 6 
will receive approximately 1.0 × 1012 Ad-RTS-hIL-12 viral 
particles. These doses will be administered by 
 injection 
into multiple sites (approximately five selected sites) within the 
residual tumor. The planned total injection volume will be up to 0.5 


Ad-RTS-hIL-12 
 
ZIOPHARM Oncology, Inc. 
Protocol ATI001-102  
Summary of Changes Amendment 1 - 14 April 2015 
 
Amendment 1 
 
 
 
Confidential 
 
 
 
 
 
Page 10 of 12 
 
Section in 
Amended 
Protocol 
Revised or Deleted Text/Section 
Rationale for Change 
mL given in approximate aliquots of 0.1 mL at each injection site.  
When available an intra operative MRI can be performed to guide 
the Ad RTS hIL 12 injection to areas of contrast enhancing tumor 
tissue. 
 
After the Ad-RTS-hIL-12 injection, veledimex will be administered 
orally for 14 days.  The first post resection veledimex dose is to be 
given on the day immediately following Ad RTS hIL 12 injection 
designated as Day 1, preferably with food.  Subsequent veledimex 
doses are to be taken once daily, in 
the morning and within 30 minutes of a regular meal. 
 
Group 2: Patients who will NOTnot undergo tumor resection 
Patients who will not undergo tumor resection will receive Ad-
RTS-hIL-12 by standard stereotactic surgery. Neuropathology 
Tumor biopsy is recommended to can reconfirm malignant glioma. 
from frozen tissue.   Approximately  Ad-RTS-hIL-12  1.01 × 1012  Ad-
RTS hIL 12  viral particles will be administered by stereotactic 
injection into approximately five intra tumor sites to deliver up to 
0.5 mL volume in approximate aliquots of 0.1 mL at each site.  
Extreme care should be taken to avoid intraventricular or basal 
cisternal injection or other critical locations. 
 
Section 6  
Treatment 
Plan and 
Table 5 
Patients Undergoing Tumor Resection (Group 1)
1.   3 ± 2 hours before craniotomy, patients will be given a cohort 
specific dose of veledimex by mouth, on an empty stomach 
(excluding other medications).   The actual time of veledimex 
administration should be noted and recorded. 
 
2.   Surgical planning will be performed on a diagnostic MRI 
acquired prior to the surgery as per standard of care. 
 
3.   At the time of tumor resection tumor, CSF (if available) and blood 
samples will be collected. 
 
4.    Immediately after tumor resection, when available, an 
intraoperative MRI can be performed to identify contrast enhancing 
or T2/FLAIR hyper intense residual tumor.  If intraoperative MRI is 
not available, the neurosurgeon will select sites for injection. 
 
5.   Patients in Cohorts 1 & 2 will receive Ad-RTS-hIL-12 2 x 1011 
vp. This will be administered 
by free-hand injection into approximately two sites within the 
residual tumor for a total volume of 0.1 mL selected by the 
neurosurgeon. When available an intra-operative MRI can be 
Addition of lower IL-12 
dose due to new 
nonclinical information 


Ad-RTS-hIL-12 
 
ZIOPHARM Oncology, Inc. 
Protocol ATI001-102  
Summary of Changes Amendment 1 - 14 April 2015 
 
Amendment 1 
 
 
 
Confidential 
 
 
 
 
 
Page 11 of 12 
 
Section in 
Amended 
Protocol 
Revised or Deleted Text/Section 
Rationale for Change 
performed to guide the Ad-RTS-hIL-12 injection to areas of contrast 
enhancing tumor tissue. 
 
6.   For Cohorts 3, 4, 5 and 6, immediately after tumor resection, Ad-
RTS-hIL-12 1 x 1012 vp will be administered by 
 injection 
into multiple sites (approximately five selected sites) within the 
residual tumor at sites selected by the neurosurgeon. The planned 
total injected volume for these cohorts is 0.5 mL given in 
approximate aliquots of 0.1 mL at each injection site. When available 
an intra-operative MRI can be performed to guide the Ad-RTS-hIL-
12injection to areas of contrast enhancing tumor tissue. 
4.7. Approximately 1.0 × 1012 Ad RTS hIL 12 viral particles will 
be administered by 
injection into multiple sites 
(approximately five intra tumor sites) selected by the neurosurgeon. 
When available, an intraoperative MRI can be used to guide the 
injections to contrast enhancing tumor sites.   The planned total 
injection volume will be up to 0.5 mL given in approximate 
aliquots of 0.1 mL at each injection site.  The day of Ad-RTS-hIL-12 
administration is designated 
as Day 0. 
 
Two additional cohorts have been added at a lower starting dose for Ad-RTS-hIL-12:  
Cohort 
Ad‐RTS‐hIL‐12a
(Day 0) 
Veledimexb 
(Days 1‐14) 
Dose(vp) 
Total Daily Dose 
(mg) 
1 
2 x 1011 
20 
2 
2 x 1011 
40 
3 
1 × 1012 
20 
4 
1 × 1012 
40 
5 
1 × 1012 
80 
6 
1 × 1012 
120 
 a Intra Tumor Injection
 b Oral Administration Post Ad‐RTS‐hIL‐12 on Days 
1‐14. Dose  
   levels may be modified based on additional 
clinical and    
   nonclinical PK data (Section 6.4) 
 
 


Ad-RTS-hIL-12 
 
ZIOPHARM Oncology, Inc. 
Protocol ATI001-102  
Summary of Changes Amendment 1 - 14 April 2015 
 
Amendment 1 
 
 
 
Confidential 
 
 
 
 
 
Page 12 of 12 
 
Section in 
Amended 
Protocol 
Revised or Deleted Text/Section 
Rationale for Change 
Section 6.4 
Modification 
of dose 
escalation 
schedule 
A period of at least one week will be required to analyze the 
veledimex concentration ratio in brain tumor, CSF and blood from 
patients in Group 1. This study adopts a starting veledimex dose for 
Cohort 1 of 20 mg total daily veledimex and a planned dose 
escalation schedule for Cohort 2 at 40 mg, Cohort 3 at 80 mg, and 
Cohort 4 at 120 mg, given once daily.   Interpretable data from at 
least three subjects should be sufficient to provide an initial estimate 
of the veledimex concentration in human brain tissue and the ratio of 
veledimex in the tumor, CSF (if available) and blood. Based on this 
initial estimate and data from subsequent cohorts, dosage level may 
be modified after review by the SRC and DSMB. 
 
Addition of lower IL-12 
dose due to new 
nonclinical information 
Section 6.6 
Maximum 
Tolerated 
Dose 
The veledimex MTD given in combination with either Ad-RTS-hIL-
12 2 x 1011 or 1 x 1012 vp a constant Ad RTS hIL 12 dose will be that 
dose at which fewer than 33 % of subjects experience a DLT. 
 
Addition of lower IL-12 
dose due to new 
nonclinical information 
Section 10.4  
Determination 
of Severity 
The following was deleted:
 
Adverse events should be reported using the maximum intensity of 
the event (e.g. if a subject reported 
nausea lasting 3 days, 1 start date and stop date should be recorded 
along with the maximum intensity 
experienced for that event over that 3-day timeframe). 
 
Information regarding the 
capture of adverse events 
is included in the eCRF 
Completion Guidelines. 
 


Protocol: ATI001-102                                                         Confidential                                                              29 JANUARY 2016 
 
 
 
Page 1 of 8 
 
 
PROTOCOL AMENDMENT SUMMARY 
 
Protocol Title: 
A Phase I Study of Ad-RTS-hIL-12, an Inducible 
Adenoviral Vector Engineered to Express hIL-12 in the 
Presence of the Activator Ligand Veledimex in Subjects 
with Recurrent or Progressive Glioblastoma or Grade III 
Malignant Glioma 
 
Protocol Number: 
ATI001-102 
Study Drugs: 
Adenovirus-
-human 
interleukin-12 (Ad-RTS-hIL-12) and veledimex (RTS 
activator ligand) 
 
Date of Protocol: 
 
Amendment 2:  29 January2016                              
 
Amendment 1:  14 April 2015 
Original:   12 February 2014 
 
 
 
 
 
NOTE TO INVESTIGATORS 
Amendment 2 dated 29 January 2016 will be used to conduct the study in place of any 
preceding version of this protocol. ZIOPHARM Oncology will implement this version 
as of 01 February 2016.  This protocol should be submitted to your IRB promptly.  
 
 
 
CONFIDENTIAL 


Protocol: ATI001-102                                                         Confidential                                                              29 JANUARY 2016 
 
 
 
Page 2 of 8 
 
 
AMENDMENT 2 
ATI001-102 
1. Summary and Rationale for Changes 
ZIOPHARM is amending the clinical protocol for the ATI001-102 study, “A Phase I Study of 
Ad-RTS-hIL-12, an Inducible Adenoviral Vector Engineered to Express hIL-12 in the 
Presence of the Activator Ligand Veledimex in Subjects with Recurrent or Progressive 
Glioblastoma or Grade III Malignant Glioma” to provide updated guidance to the investigator 
based on review of DLTs with the SRC and DSMB; to incorporate currently approved iRANO 
guidelines, correct inconsistencies between the synopsis and the body of the protocol and to 
clarify the use of CYP450 3A4 medications. Additionally updates including correction of 
typos, administrative edits and formatting errors were made.  
 
These updates included:  
• addition of the word “intratumoral” preceding Ad-RTS-hIL-12 throughout as 
well as the change from “intra tumor” to “intratumoral” 
• the clear designation of the day of Ad RTS hIL 12 administration as “Day 0” 
(as indicated in the Schedule of Study Procedures) throughout the protocol 
• the follow-up period was divided into two portions – Initial Follow up Period 
and Long Term Follow up as certain procedures only took place up to Day 56 
• the addition of abbreviations after the first instance of a phrase and replacement 
of the words with the abbreviations in later sections of the protocol 
• grammatical corrections 
• formatting of tables and figures, including alphabetizing the legends and 
addition of abbreviations under the majority of tables. 
 
2. Tabular Summary of Key Revisions Implemented in the Amended Protocol 
Section in 
Amended 
Protocol 
Revision 
Rationale for Change 
Title Page 
and Footers 
 
FROM: 
Amendment 1: 14 April 2015 
TO: 
Amendment 2: 29 January 2016 
Update to current protocol 
version and date of 
amendment. 
Synopsis 
Study Design 
Addition of text: “in the presence of variable corticosteroid 
exposure.” 
FROM: 
This study will investigate two intra tumor Ad RTS hIL 12 
doses [2 x 1011 viral particles (vp) and 1 × 1012 vp] and 
Updated to align with Section 
3.1 of the protocol.  


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Page 3 of 8 
 
Section in 
Amended 
Protocol 
Revision 
Rationale for Change 
escalating veledimex doses to determine the safe and 
tolerable dose based on the safety profiles observed.   
TO: 
This study will investigate two intratumoral Ad RTS hIL 12 
doses [2 x 1011 viral particles (vp) and 1 × 1012 vp] and 
escalating veledimex doses to determine the safe and 
tolerable dose based on the safety profiles observed in the 
presence of variable corticosteroid exposure. 
Synopsis 
Study Design 
FROM: 
“This Group 2 will start dosing patients only after two 
patients have completed 28 days in Group 1, Cohort 3.” 
TO: 
“Subject enrollment into Group 2 will start no earlier than 
after two subjects have completed 28 days in Group 1, 
Cohort 1.  Enrollment into Group 2 cohorts is otherwise 
independent of enrollment into Group 1 cohorts.” 
Text regarding Cohort 3 was 
an administrative error when 
the new dosing cohorts were 
added in Amendment 1. The 
change clarifies the 
enrollment timing.   
This new language was add 
in Section 3.1 as well.  
Synopsis  
and  
Section 13.4 
ADDITION OF: 
Study Duration 
The duration of this study from the time of initiating subject 
screening until the completion of survival follow up is 
anticipated to be approximately 48 months, including 24 
months for enrollment and 24 months of follow up. 
The start of study is defined as the date when the first subject 
is consented into the study and the study stop date is the date 
of database lock. 
Updated to align with the 
body of the protocol. 
Synoposis 
Study 
Objectives 
and  
Section 2.2  
REMOVAL OF: 
CSF from secondary objectives. 
CSF is not available for all 
subjects. 
Synopsis, 
Study Design  
and  
Section 3.1 
ADDITION OF: 
The total amount delivered to each site will be recorded in 
the CRF. In the event that less than the planned total injected 
volume is administered, the reason will be provided. 
As the protocol indicated that 
up to a specific amount of 
drug would be delivered, 
language was added to ensure 
that the data being collected 
would reflect actual volume 
delivered. 
Synopsis, 
Section 3.1, 
3.2, 4.5 
FROM: 
28 days (Day 0-14, plus 14 days) of DLT evaluation period  
TO: 
14 days (Day 0-14) of DLT evaluation period 
The initial period that is 
being reviewed to make the 
determination from dosing 
subject 1 to allowing 
enrollment of 2 and 3 is an 
additional 7 over the 14 day 
evaluation period, therefore, 


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Page 4 of 8 
 
Section in 
Amended 
Protocol 
Revision 
Rationale for Change 
the DLT evaluation period 
was updated to reflect the 
intention of the 14 day 
review for subsequent 
subjects as opposed to a 
longer time of review for 
subsequent subjects.  
Synopsis, 
Section 3.3 
FROM:  
If a significant safety event occurs with the first patient in 
each cohort, the SRC will convene to evaluate the safety 
event(s) and make a recommendation and decision on the 
enrollment of the second and third subjects in that same 
cohort. If any cohort requires the enrolment of 6 subjects, the 
SRC will evaluate safety and make a recommendation and 
decision between the stratification groups.  The SRC may 
also seek an ad hoc safety evaluation and recommendation 
by external experts and/or the DSMB as needed.   
At the end of each cohort, the SRC will convene to review 
the safety data after the third patient in a cohort, within a 
group, has completed veledimex dosing and has been 
monitored for 28 days after the Ad-RTS-hIL-12 injection.  
TO: 
If a significant safety event occurs with the first patient in 
each cohort, the SRC will convene to evaluate the safety 
event(s) and make a recommendation and decision on the 
enrollment of the second and third subjects in that same 
cohort.  
At the end of each cohort (Group 1 and 2 separately), the 
SRC will convene to review the safety data after the final 
patient in a cohort, within a group, has completed veledimex 
dosing and has been monitored for 28 days after the Ad RTS 
hIL 12 injection. 
Removal of additional 
sentences that represented 
potential conflict about 
timing of meetings. Clarified 
to represent that the SRC will 
meet at the end of a cohort, 
regardless of how many 
subjects are enrolled.  
Sentence that the SRC can 
get expert advice not 
necessary for the protocol.  
Synopsis, 
Section 4.1 
The following text was added regarding the washout 
period: 
windows other than what is listed below should be allowed 
only after consultation with the Medical Monitor 
The washout periods in the 
inclusion criteria are a 
guideline and the specific 
drug and its relative half-life 
should be reviewed to make 
eligibility determination – the 
new language allows for 
updated guidance in relation 
to washout period to be 
considered as new therapies 
become available.  
Synopsis, 
Section 4.2 
FROM: 
Use of medications that induce, inhibit or are substrates of 
CYP450 3A4 within seven days prior to veledimex dosing. 
The new language allows the 
Medical Monitor and 
Investigator to discuss 
appropriate washout periods 


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Page 5 of 8 
 
Section in 
Amended 
Protocol 
Revision 
Rationale for Change 
TO: 
Use of medications that induce, inhibit, or are substrates of 
cytochrome p450 (CYP450) 3A4 within 7 days prior to 
veledimex dosing without consultation with the Medical 
Monitor 
for CYP450 3A4 medications 
or alternate 
therapies/schedules to be 
discussed.  
Section 7.2 
Added Text: 
NOTE: Care should be given when prescribing medications 
that are classified as CYP450 3A4 inducers, inhibitors, or 
substrates due to potential interactions with the study drug. 
In the event that one is prescribed, consultation with the 
Medical Monitor is advised. All medications should be 
recorded in the case report form as indicated in the 
completion guidelines.   
Update necessary to allow for 
Institutions to treat subjects 
according to their standard 
practice, with consultation 
with the Medical Monitor. 
Synopsis, 
Section 6.1 
The following text was added to the veledimex column of 
the dose cohort table:  
Group 1 (Days 0 through 14) 
Group 2 (Days 1 through 14)  
Clarification. 
Synopsis 
Study Design  
and 
Section 6.5 
FROM: 
Dose-limiting toxicity (DLT) is defined as: 
• Any local reaction that requires operative intervention and 
felt to be attributable to Ad-RTS-hIL-12 and/or veledimex  
• Any local reaction that has life-threatening consequences 
requiring urgent intervention or results in death and felt to be 
attributable to Ad RTS hIL 12 and/or veledimex 
• Any study drug related Grade 3 adverse event (AE) 
• Diagnostic brain tumor biopsy is not considered a DLT 
Note: Seizures, intracranial venous thrombosis, and cerebral 
edema are commonly observed in this patient population and 
will be recorded according to grade of toxicity, but will not 
be considered a DLT unless they are deemed drug related 
 
TO:  
Dose-limiting toxicity (DLT) is defined as: 
An event, occurring within the treatment period (Day 0 - 
Day 14) that meets one of the following conditions: 
• Any local reaction that requires operative intervention and 
felt to be attributable to Ad RTS hIL 12 and/or veledimex 
• Any local reaction that has life threatening consequences 
requiring urgent intervention or results in death and felt to be 
attributable to Ad RTS hIL 12 and/or veledimex 
• Any study drug-related Grade 3 or higher adverse event 
(AE) persisting for more than 5 days (i.e. not resolving to 
Grade 2 or lower) despite optimal medical support  
Language was updated to 
clarify that a one-time lab 
value or otherwise transient 
grade 3 or higher event 
would not be a DLT. 
Additionally, headache was 
added as a known 
observation in this population 
and intracranial venous 
thrombosis was removed at 
the request of the DSMB.  
 
Language about the SRC 
being involved in the 
evaluation of DLTs in order 
to make a determination of 
the MTD was added in 
alignment with Section 6.6 of 
the protocol.  


Protocol: ATI001-102                                                         Confidential                                                              29 JANUARY 2016 
 
 
 
Page 6 of 8 
 
Section in 
Amended 
Protocol 
Revision 
Rationale for Change 
• 
Optimal medical support will include the timely 
temporary or permanent discontinuation of 
veledimex in conjunction with changes in 
administration of steroids (or other supportive care) 
as applicable. In the event that the medical support 
provided does not meet these conditions, the SRC 
will review the event to make a DLT determination. 
Note: Diagnostic brain tumor biopsy is not considered a 
DLT.  Seizures, intracranial venous thrombosis, headache 
and cerebral edema are commonly observed in this 
population and will be recorded according to grade of 
toxicity, but will not be considered a DLT unless they are 
deemed as most likely to be drug related as the main 
contributory factor. 
Section 9.1 
 
FROM: 
Tumor Response, Pharmacodynamic and PK Analyses: 
Tumor response analysis will be performed on the ESP.  
Investigator assessment of ORR and PFS will be determined 
for each dose cohort according to RANO criteria (Appendix 
16.5) from the date of ICF signature through the Follow-up 
Period. A two sided confidence interval will be computed for 
the ORR.  PFS and OS will be analyzed using the Kaplan 
Meier method. 
TO: 
Tumor Response, Overall Survival, Pharmacodynamic and 
PK Analyses: 
Tumor response analysis will be performed on the ESP.  
Investigator assessment of ORR and PFS will be determined 
for each dose cohort according to RANO/iRANO criteria 
(Appendix 16.5 and Appendix 16.6).  Overall survival (OS) 
is defined as the duration of time from the first dose of study 
drug to the date of death, or, for subjects who are still alive 
two years post first dose of study drug, they will be censored 
at the last follow-up contact date. A two sided confidence 
interval will be computed for the ORR.  PFS and OS will be 
analyzed using the Kaplan Meier method. 
Updated to include current 
guidelines (iRANO). 
 
Please note: Use of iRANO 
was added to the RANO 
guidelines throughout the 
protocol (represented as 
RANO/iRANO) with the 
exception of the inclusion 
criteria which specifies 
RANO alone.  
Similar language was 
updated in the Synopsis. 
Section 9.1  
and 
Schedule of 
Study 
Assessments 
The following text was added: 
A repeat scan to confirm progression should be completed at 
4 weeks (per RANO) and preferably again at 12 weeks (per 
iRANO) after first documentation of progression. 
Consideration should be given to performing a diagnostic 
brain biopsy, which should be performed in accordance with 
the current iRANO guidelines. 
Updated to align with current 
guidelines (iRANO). 
Section 13.4, 
Schedule of 
FROM: 
In addition, subjects who discontinue or complete study 
treatment without objective evidence of disease progression 
Clarification of the overall 
survival data collection. The 
protocol inadvertently linked 


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Page 7 of 8 
 
Section in 
Amended 
Protocol 
Revision 
Rationale for Change 
Study 
Procedures 
should continue to be followed until confirmed disease 
progression has been documented, or an alternate anticancer 
therapy has been initiated, or one year after enrollment, 
whichever occurs first.  The active study period refers to the 
study period from informed consent through the Follow-up 
Period.  
TO: 
In addition, subjects who discontinue or complete study 
treatment without objective evidence of disease progression 
should continue to be followed until confirmed disease 
progression has been documented. Subjects will be followed 
for survival status for 2 years after enrollment, whichever 
occurs first.  The active study period refers to the study 
period from informed consent through the Initial Follow up 
Period. 
survival to progression or 
new anti-cancer therapy.  The 
language was updated to 
clarify that data will be 
requested during alternate 
anticancer therapy and  for 2 
years.  
Similar language was 
updated in the Synopsis.  
Schedule of 
Study 
Procedures 
The footnotes of Schedule of Study Procedures were updated 
to align with the body of the protocol (see track changes 
attached) 
Clarification to align with 
protocol changes.  
Synopsis, 
Section 3.1, 
Section 6.1 
FROM: 
For Cohorts 3, 4, 5 and 6, immediately after tumor resection, 
Ad-RTS-hIL-12 1 x 1012 viral particles will be administered 
by 
 injection into multiple sites (approximately five 
selected sites) within the residual tumor…The planned total 
injected volume for these cohorts is 0.5 mL given in 
approximate aliquots of 0.1 mL at each injection site.  
TO:  
For Cohorts 3, 4, 5 and 6, immediately after tumor resection, 
Ad RTS hIL 12 1 x 1012 vp will be administered by 
 
injection into multiple sites in a divided dose within the 
residual tumor …The planned total injected volume for these 
cohorts is 0.5 mL given in approximate aliquots of 0.1 mL at 
each injection site.  
Clarification.  
Throughout 
FROM: 
Within 30 minutes of a regular meal. 
TO: 
Within approximately 30 minutes of a regular meal.  
Update to allow for expected 
normal variation.  
Section 10.2 
ADDED Text:  
Adverse events will be followed through the Day 56 
Visit.  AEs that are drug-related should be followed 
until resolved or no resolution is expected. 
To align with Section 10.7 
which requires reporting of 
SAEs through 30 days post 
last dose of study drug (i.e. 
Day 44). Following AEs 
through Day 56 fulfills the 
SAE reporting requirements 
conservatively. 


Protocol: ATI001-102                                                         Confidential                                                              29 JANUARY 2016 
 
 
 
Page 8 of 8 
 
Section in 
Amended 
Protocol 
Revision 
Rationale for Change 
Appendix 
16.2 
Appendix was removed  
Updated to be in line with 
revised guidance with 
relation to CYP450 3A4 
medications. 
Appendix 
16.5 and 16.6 
Appendix 16.5 was replaced with the RANO guidelines 
and Appendix 16.6 (iRANO guidelines) was added 
Included to align with 
protocol revisions. 
 




Protocol: ATI001-102                                                         Confidential                                                              14 MARCH 2016   
 
Page 2 of 3 
 
AMENDMENT 2 
ATI001-102 
1. Summary and Rationale for Changes 
ZIOPHARM is amending the clinical protocol for the ATI001-102 study, “A Phase I Study of 
Ad-RTS-hIL-12, an Inducible Adenoviral Vector Engineered to Express hIL-12 in the 
Presence of the Activator Ligand Veledimex in Subjects with Recurrent or Progressive 
Glioblastoma or Grade III Malignant Glioma” to provide updated guidance to the investigator 
on the DLT evaluation period and the definition of DLT. Additionally updates including 
correction of typos, administrative edits and formatting errors were made.  
 
These updates included:  
 grammatical corrections 
 renumbering of Appendices to correct administrative error (Appendices 
inadvertently skipped from 16.1 to 16.3 in Protocol Amendment 2) 
 
2. Tabular Summary of Key Revisions Implemented in the Amended Protocol 
Section in 
Amended 
Protocol 
Revision 
Rationale for Change 
Title Page 
and Footers 
 
FROM: 
Amendment 2: 29 January 2016 
TO: 
Amendment 3: 14 March 2016 
Updated to reflect current 
protocol version and date of 
amendment. 
Synopsis, 
Section 3.1, 
3.2, 4.5 
FROM: 
14 days (Day 0-14) of DLT evaluation period  
TO: 
28 days (Day 0-14, plus 14 days) of DLT evaluation period  
The DLT evaluation period 
was updated to allow for a 
longer time of review for 
subjects.  
Synopsis 
Study Design  
and 
Section 6.5 
FROM: 
Dose-limiting toxicity (DLT) is defined as: 
An event, occurring within the treatment period (Day 0 - 
Day 14) that meets one of the following conditions: 
• Any local reaction that requires operative intervention and 
felt to be attributable to Ad RTS hIL 12 and/or veledimex 
• Any local reaction that has life threatening consequences 
requiring urgent intervention or results in death and felt to be 
attributable to Ad RTS hIL 12 and/or veledimex 
• Any study drug-related Grade 3 or higher adverse event 
(AE) persisting for more than 5 days (i.e. not resolving to 
Grade 2 or lower) despite optimal medical support  
Language was updated t  
  


Protocol: ATI001-102                                                         Confidential                                                              14 MARCH 2016   
 
Page 3 of 3 
 
Section in 
Amended 
Protocol 
Revision 
Rationale for Change 
 
Optimal medical support will include the timely 
temporary or permanent discontinuation of 
veledimex in conjunction with changes in 
administration of steroids (or other supportive care) 
as applicable. In the event that the medical support 
provided does not meet these conditions, the SRC 
will review the event to make a DLT determination. 
TO:  
An event, occurring within the first 28 days (Day 0 - Day 28) 
that meets one of the following conditions: 
• Any local reaction that requires operative intervention and 
felt to be attributable to Ad RTS hIL-12 and/or veledimex 
• Any local reaction that has life threatening consequences 
requiring urgent intervention or results in death and felt to be 
attributable to Ad RTS hIL-12 and/or veledimex 
• Any Grade 3 or greater non-hematological adverse event 
that is at least possibly related to the study drug 
• Any Grade 4 hematologic toxicity that is at least possibly 
related to the study drug and lasts at least 5 days  
• Grade 3 or higher thrombocytopenia at least possibly 
related to the study drug 
Section 4.4 
The following text was added: 
Subjects who withdraw during the treatment period should 
continue to have study assessments as clinically indicated. 
Updated to clarify how a 
subject should be followed if 
he/she discontinues treatment 
but remains on study. 
Section 6.3 
FROM: 
An intermediate dose cohort may be explored during the 
dose escalation phase, as deemed necessary and as 
recommended by the DSMB and the SRC. 
TO: 
An intermediate dose cohort may be explored during the 
dose escalation phase, as deemed necessary and as 
recommended by the SRC. 
Correcting administrative 
error; updated to align with 
the rest of the protocol.  
Schedule of 
Study 
Procedures 
The following clarification was added: 
MRI Scans are collected during long term follow-up.  
Administrative error 
corrected, footnote text was 
correct, however, the X was 
missing in the table.  
Schedule of 
Study 
Procedures 
FROM: 
Tumor Sampleu   
TO:  
Tumor Sampleu  (Group 1 only) 
Correction; “Group 1 only” 
specification was 
inadvertently removed in 
Protocol Amendment 2.  
 

SAP_001.pdf: 
 
STATISTICAL ANALYSIS PLAN (SAP) 
This is a combined Statistical Analysis Plan (SAP) for the two studies named below: 
Study Title:  
A Phase I Study of Ad-RTS-hIL-12, an Inducible Adenoviral 
Vector Engineered to Express hIL-12 in the Presence of the 
Activator Ligand veledimex in Subjects with Recurrent or 
Progressive Glioblastoma or Grade III Malignant Glioma 
Study Number: 
 
ATI001-102  
Protocol Versions:   
Amendment 3:  
14March2016 
Amendment 2:  
29January2016 
Amendment 1:   
14April2015 
Original: 
 
14February2014 
 
Study Title:  
Protocol ATI001-102 Expansion Substudy 2.0: Evaluation of Ad-
RTS-hIL-12 + veledimex in Subjects with Recurrent or 
Progressive Glioblastoma 
Study Number: 
 
ATI001-102 EXP Substudy 2.0 
Protocol Versions:   
Amendment 1:   
14May2018 
Original: 
 
16March2016 
 
Sponsor:  
 
 
Ziopharm Oncology, Inc. 
Version and Date:   
Version 2.0, 13APR2021 
 
 
 
This study is being conducted in compliance with good clinical practice, 
including the archiving of essential documents. 


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ATI001-102 Main and EXP Substudy 2.0 
 
Ziopharm Oncology 
Statistical Analysis Plan 
 
Version 2.0 
 
3 
 
TABLE OF CONTENTS 
APPROVAL PAGE .........................................................................................................................2 
LIST OF ABBREVIATIONS ..........................................................................................................6 
1. 
INTRODUCTION ......................................................................................................10 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................11 
2.1. 
Study Objectives .........................................................................................................11 
2.2. 
Study Endpoints ..........................................................................................................12 
3. 
PHARMACOKINETIC (PK) AND PHARMACODYNAMIC (PD) ........................12 
4. 
STUDY DESIGN .......................................................................................................12 
4.1. 
ATI001-102 Main .......................................................................................................12 
4.2. 
EXP Substudy .............................................................................................................13 
5. 
INCLUSION AND EXCLUSION CRITERIA ..........................................................14 
5.1. 
Inclusion Criteria ........................................................................................................14 
5.2. 
Exclusion Criteria .......................................................................................................15 
6. 
DOSE ESCALATION DECISION RULES FOR ATI001-102 MAIN .....................16 
7. 
SAMPLE SIZE ...........................................................................................................18 
7.1. 
ATI001-102 Main .......................................................................................................18 
7.2. 
EXP Substudy .............................................................................................................18 
8. 
ANALYSIS POPULATIONS ....................................................................................19 
9. 
GENERAL ANALYSIS CONSIDERATIONS .........................................................20 
9.1. 
Data Presentation ........................................................................................................20 
9.2. 
Populations Used in the Presentation of Statistical Summaries .................................22 
9.3. 
Protocol Deviations ....................................................................................................22 
9.4. 
Multicenter Studies .....................................................................................................23 
9.5. 
Other Strata and Covariates ........................................................................................23 
9.6. 
Examination of Subgroups .........................................................................................23 
9.7. 
Multiple Comparisons and Multiplicity ......................................................................23 
9.8. 
Interim Analysis ..........................................................................................................23 
10. 
DATA HANDLING CONVENTIONS ......................................................................23 
10.1. 
Missing Data ...............................................................................................................23 
10.2. 
Baseline Data ..............................................................................................................24 
10.3. 
Measurements Collected from Subjects Excluded from Predefined Analysis ...........25 


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10.4. 
Derived and Computed Variables ...............................................................................25 
10.5. 
Reference Section 11.1: Derived Data from Overview Book for derived 
study variables were created based on clinical interpretation of the eCRF 
data for the 20mg cohorts in ATI001-102 Main and the EXP Substudy. 
Continuous Variables ..................................................................................................26 
10.6. 
Categorical Variables ..................................................................................................26 
10.7. 
Visit Windows ............................................................................................................26 
11. 
CONVENTIONS ........................................................................................................27 
11.1. 
Derived Data from Overview Book ............................................................................29 
11.2. 
Subject Disposition ...................................................................................................30 
12. 
SUBJECT CHARACTERISTICS AND SUBGROUPS ............................................32 
12.1. 
Subject Characteristics Subgroups ...........................................................................33 
12.1.1. 
Subgroup Analysis for Subjects Receiving Anti-Cancer Therapies Post 
Ad+V ..........................................................................................................................34 
12.2. 
Previous and Concomitant Medications ..................................................................34 
13. 
SAFETY ANALYSIS ................................................................................................35 
13.1. 
Maximum Tolerated Dose/ Dose Limiting Toxicities Study Drug Exposure 
for ATI001-102 Main .................................................................................................35 
13.2. 
Adverse Events ...........................................................................................................36 
13.2.1. 
Adverse Events Number of events .............................................................................37 
13.2.2. 
Summaries of Adverse Event Incidence Rates for FAS .............................................37 
13.2.3. 
Summaries of Adverse Events of Special Interest ......................................................38 
13.3. 
Laboratory Evaluations ...............................................................................................38 
13.4. 
Vital signs ...................................................................................................................39 
13.5. 
ECGs ...........................................................................................................................39 
13.6. 
Physical and Neurological Exam ................................................................................40 
13.7. 
Karnofsky Performance Status ...................................................................................40 
13.8. 
Deaths .........................................................................................................................40 
14. 
EFFICACY ANALYSIS ............................................................................................40 
14.1. 
Tumor Response .........................................................................................................40 
14.1.1. 
Objective Response Rate ............................................................................................41 
14.1.2. 
Best Overall Response (BOR) ....................................................................................41 
14.1.3. 
Progression Free Survival (PFS) ................................................................................42 
14.2. 
Overall Survival ..........................................................................................................42 


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14.2.1. 
Estimation of Overall Survival for the Monotherapy ESP .........................................43 
14.2.2. 
Exploratory Analysis of Subject Characteristics that may Potentially Extend 
OS ...............................................................................................................................43 
15. 
FOREST PLOT FOR 20MG COHORTS ...................................................................44 
16. 
APPENDICES ............................................................................................................46 
Appendix 1: Schedule of Study Procedures ...................................................................................46 
 
LIST OF TABLES 
Table 1: 
Example Summary Table Shell ..................................................................................21 
Table 2: 
Vendors for Data Collection Outside of eCRF ...........................................................28 
 
LIST OF FIGURES 
Figure 1: 
Patient Populations .....................................................................................................31 
 
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
mmol or mmol 
Micromole 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ANOVA 
Analysis of Variance 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate Aminotransferase  
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area Under the Concentration-Time Curve 
AUC(0-¥) 
AUC from Time Zero (pre-dose) Extrapolated to Infinite Time 
AUC(0-t) 
AUC from Time Zero (pre-dose) to Time of Last observed Quantifiable 
Concentration Within a Subject Across all Treatments 
BLQ 
Below Limit of Quantification 
BMI 
Body Mass Index 
b.i.d. 
Twice Daily 
BP 
Blood Pressure 
bpm 
Beats per Minute 
BUN 
Blood Urea Nitrogen 
C 
Center 
°C 
Degrees Celsius 
Ca 
Calcium 
Cl 
Chloride 
CLr 
Renal Clearance 
Cmax 
Maximum Observed Concentration 
CMH 
Cochran Mantel-Haenszel 
COSTART 
Coding Symbols for Thesaurus of Adverse Reaction Terms 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
Ct 
Last Observed Quantifiable Concentration 
DBF 
Database Freeze 
DBP 
Diastolic Blood Pressure 


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DL 
Deciliter 
DOB 
Date of Birth 
dy 
Days 
ECG 
Electrocardiogram 
oF 
Degrees Fahrenheit 
g 
Grams 
GCP 
Good Clinical Practices 
GGT 
Gamma-Glutamyl Transferase 
HGB 
Hemoglobin 
ICD-9 
International Classification of Diseases – 9th Edition 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
In 
Inches 
IP 
Investigational Product 
IR 
Immediate Release 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat Population 
IU 
International Units 
K 
Potassium 
Kg 
Kilogram 
λz 
Terminal Phase Rate Constant 
L 
Liter 
Lb 
Pounds 
LDH 
Lactate Dehydrogenase 
LFTs 
Liver Function Fests 
LLN 
Lower Limit of Normal 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities Terminology 
MAP 
Mean Arterial Pressure 
meq 
Milliequivalent 
mg 
Milligrams 
mL 
Milliliter 
mmHg 
Millimeters of Mercury 


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Mo 
Months 
msec 
Milliseconds 
N 
Total Sample Size 
Na 
Sodium 
ng 
Nanograms 
NIMH 
National Institute of Mental Health 
OC 
Observed Cases 
OTC 
Over the Counter Medication 
PCI 
Potential Clinical Importance 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PP 
Per-Protocol Population 
PT 
Preferred term 
RBC 
Red Blood Cell Count 
S 
Sex 
s.d. 
Standard Deviation 
SAE 
Serious Adverse Event 
SAS 
Statistical Analysis System  
SBP 
Systolic Blood Pressure 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SOC 
System Organ Class 
SR 
Sustained Release 
t 
Time of Last Observed Quantifiable Concentration 
t1/2 
Terminal Phase Half-Life 
tmax 
Time of Occurrence of Cmax 
TG 
Treatment Group 
TIBC 
Total Iron Binding Capacity 
TS 
Transdermal Delivery System-Placebo 
UIBC 
Unsaturated Iron-Binding Capacity 
ULN 
Upper Limit of Normal 
VAS 
Visual Analogue Scale 
WBC 
White Blood Cell Count 


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WHO 
World Health Organization  
yr 
Years 


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1. 
INTRODUCTION 
Glioblastoma Multiforme (GBM) is the most common type of brain tumor and it is uniformly 
fatal. The community standard of treatment for this disease is gross or subtotal resection of the 
tumor, followed by radiation and temozolomide. Many challenges are encountered while trying 
to devise new drugs to treat GBM, such as the presence of the blood brain barrier which is 
impermeable to most drugs. Therefore, in the past few years attention was turned to 
immunological means for the treatment of this devastating disease. IL-12 mediates immuno-
regulatory activities, including activating anti-tumor NK cells, memory T-cells, and cytotoxic   
T-cells, increasing local IFN-γ secretion, and reducing local immunoregulatory cells.  These 
immuno-modulatory changes may result in tumor lysis, restoration of local immune function, 
and induction of immune response memory.  
Systemic recombinant IL-12 in clinical trials has been effective in the treatment of cancer but has 
limited utility due to systemic toxicity. To circumvent these challenges and improve the 
therapeutic index, Ziopharm developed a gene therapy that permits well controlled local 
expression of IL-12 within the tumor microenvironment. Ziopharm is developing                    
Ad-RTS-hIL-12 + veledimex for treatment of patients with GBM. The investigational product, 
Ad-RTS-hIL-12 + veledimex, is comprised of 2 components:  Ad RTS-hIL-12 (Component 1) 
and veledimex (Component 2).  Both components are necessary to produce the active moiety, 
human interleukin-12 (hIL-12). 
This Statistical Analysis Plan will support the planned analyses for two clinical studies of       
Ad-RTS-hIL-12 + veledimex as monotherapy:  
• Protocol ATI001-102 (will be herein referred to as ATI001-102 Main)  
• Protocol ATI001-102 Expansion Substudy 2.0 (will be herein referred to as EXP 
Substudy) 
Previously the SAP (Version 1.0, dated 05Apr2016) only described ATI001-102 Main.  
The purpose of both studies was to evaluate the safety and tolerability of Ad-RTS-hIL-12 + 
veledimex as a monotherapy in subjects with recurrent or progressive. For additional details 
please refer to the current protocol, as indicated on the title page.   
 


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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Study Objectives 
ATI001-102 Main 
• Primary Objective 
− To determine the safety and tolerability of varying doses of antitumoral              
Ad-RTS-hIL-12 plus oral veledimex doses in subjects with recurrent or 
progressive glioblastoma or Grade III malignant glioma.  
• Secondary Objectives  
− To determine the MTD of veledimex when administered with varying doses 
of intratumoral Ad-RTS-hIL-12 dose 
− To determine the veledimex pharmacokinetic profile 
− To determine the veledimex concentration ratio between brain tumor and blood 
− To evaluate cellular 
 immune responses elicited by Ad-RTS-hIL-12 
and veledimex 
− To determine investigator assessment of response including the tumor Objective 
Response Rate (ORR) and progression-free survival (PFS) 
− To determine overall survival (OS) 
EXP Substudy 
• Primary Objective 
− To determine the safety and tolerability of Ad-RTS-hIL-12 and veledimex (RTS 
activator ligand) in subjects with recurrent or progressive glioblastoma.  
• Secondary Objectives 
− To determine the overall survival (OS) of Ad-RTS-hIL-12 + veledimex 
− To determine the veledimex pharmacokinetic (PK) profile  
− To determine the veledimex concentration ratio between the brain tumor and blood 
− To determine the Investigator’s assessment of response, including tumor objective 
response rate (ORR), progression free survival (PFS), and rate of pseudo 
progression (PSP) 


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− To evaluate cellular 
 immune responses elicited by the combination 
treatment 
2.2. 
Study Endpoints 
The endpoints for both ATI001-102 Main and EXP Substudy were the same. 
Primary Endpoint  
The primary endpoint was the assessment of safety of Ad-RTS-hIL-12, administered by 
intratumoral injection plus veledimex, administered orally, as determined by the AE rate and 
the occurrence of DLTs analyzed specifically for each group. 
Secondary Endpoints  
The secondary endpoints are summarized as follows: 
• Investigator Assessment of ORR and PFS 
• Overall survival (OS) 
• Veledimex concentration ratio between brain tumor and blood (Group 1, Day 0) 
• Veledimex PK estimates starting at Day 1 
• Correlative measures of immune response including serum cytokine levels 
 
 
3. 
PHARMACOKINETIC (PK) AND PHARMACODYNAMIC (PD) 
Please refer to the separate PK/PD SAP for a summary of the statistical analysis of PK/PD 
endpoints collected during monotherapy treatment of subjects. 
4. 
STUDY DESIGN  
Please refer to Appendix 1: Schedule of Study Procedures for the schedule of events for both 
ATI001-102 Main and EXP Substudy Other than the dose escalation component and the 
additional eligibility criteria, both ATI001-102 Main Group 1 and the EXP Substudy have the 
same schedule of events.  
4.1. 
ATI001-102 Main 
This is a Phase I study of Ad-RTS-hIL-12, administered as an intratumoral injection with 
escalating veledimex doses administered orally, in subjects with recurrent or progressive 
glioblastoma or Grade III malignant glioma. This study investigated the Ad-RTS-hIL-12 dose of 


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2 x 1011 vp and escalating veledimex doses to determine the veledimex maximum therapeutic 
dose based on the observed safety profile and in the presence of variable corticosteroid exposure. 
This study was divided into three periods with an additional follow-up period:  
• The Screening Period (Day -28 to -1): 
− After signing the informed consent, subjects entered the Screening Period to 
assess eligibility 
• The Treatment Period (Day 0-14): 
− Eligible subjects were stratified into two groups according to clinical indication 
for tumor resection. Group 1 subjects underwent tumor resection and Group 2 
subjects did not undergo tumor resection.  
− On Day 0, Group 1 subjects received one veledimex dose 3 ± 2 hours before the 
craniotomy resection procedure and Ad-RTS-hIL-12 administration. After the 
Ad-RTS-hIL-12 injection, veledimex was administered orally for 14 days, starting 
on Day 1 (for a total of up to 15 doses)  
− On Day 0, Group 2 subjects received Ad-RTS-hIL-12 by stereotactic injection 
and then subsequently took oral veledimex for 14 days, starting on Day 1 (for a 
total of 14 doses)  
• The DLT evaluation period (Day 0-28), and  
• The Follow-up Period (Day 28 [± 7 days], Day 56 [± 7 days] and every 8 weeks 
[± 7 days] thereafter).  
• Survival Follow-Up (2 years from Day 0) 
4.2. 
EXP Substudy 
This is a multicenter Phase I study of an intratumoral injection of Ad-RTS-hIL-12 (2 x 1011vp) 
and 20 mg of veledimex administered orally in subjects with recurrent or progressive 
glioblastoma.  
This study was divided into three periods: 
• The Screening Period (Day -28 to -1): 
− After signing the Informed Consent, subjects entered the Screening Period to 
assess eligibility. 
• The Treatment Period (Day 0-14):  


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− On Day 0, Group 1 subjects received one veledimex dose 3 ± 2 hours before the 
craniotomy resection procedure and Ad-RTS-hIL-12 administration. After the 
Ad-RTS-hIL-12 injection, veledimex was administered orally for 14 days, starting 
on Day 1 (for a total of up to 15 doses). The Follow-up Period (Day 28 [± 7 days], 
Day 56 [± 7 days] and every 8 weeks [± 7 days] thereafter).  
• The Follow-up Period (Day 28 [± 7 days], Day 56 [± 7 days] and every 8 weeks 
[± 7 days] thereafter).  
• Survival Follow-Up (2 years from Day 0) 
5. 
INCLUSION AND EXCLUSION CRITERIA 
5.1. 
Inclusion Criteria  
As in the ATI001-102 Main protocol (changes for the EXP Substudy in bold) 
1. Male or female subject ≥ 18 and ≤ 75 years of age 
2. Provision of written informed consent for tumor resection, stereotactic surgery, tumor 
biopsy, samples collection, and treatment with investigational products prior to 
undergoing any study specific procedures 
3. Histologically confirmed supratentorial glioblastoma or other World Health Organization 
(WHO) Grade III or IV malignant glioma from archival tissue (EXP Substudy: 
Histologically confirmed supratentorial glioblastoma)  
4. Evidence of tumor recurrence/progression by MRI according to response assessment in 
neuro oncology (RANO) criteria after standard initial therapy 
5. Previous standard of care antitumor treatment including surgery and/or biopsy and 
chemoradiation.  At the time of registration, subjects must have recovered from the toxic 
effects of previous treatments as determined by the treating physician.  The washout 
periods from prior therapies are intended as follows: (windows other than what is listed 
below should be allowed only after consultation with the Medical Monitor) 
a. Nitrosoureas:  6 weeks 
b. Other cytotoxic agents:  4 weeks 
c. Antiangiogenic agents, including bevacizumab:  4 weeks [NOTE: short use 
(<4 doses) of bevacizumab for controlling edema is allowed] 
d. Targeted agents, including small molecule tyrosine kinase inhibitors:  2 weeks 
e. Vaccine based therapy:  3 months 
6. Able to undergo standard MRI scans with contrast agent before enrollment and after 
treatment 
7. Karnofsky Performance Status ≥ 70 


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8. Adequate bone marrow reserves and liver and kidney function, as assessed by the 
following laboratory requirements: 
a. Hemoglobin ≥ 9 g/L 
b. Lymphocytes > 500/mm3 
c. Absolute neutrophil count ≥ 1500/mm3 
d. Platelets ≥ 100,000/mm3 
e. Serum creatinine ≤ 1.5 x upper limit of normal (ULN) 
f. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x ULN.  For 
subjects with documented liver metastases, ALT and AST ≤ 5 x ULN 
g. Total bilirubin < 1.5 x ULN 
h. International normalized ratio (INR) and activated partial thromboplastin time within 
normal institutional limits 
9. Male and female subjects must agree to use a highly reliable method of birth control 
(expected failure rate less than 5% per year) from the Screening Visit through 28 days 
after the last dose of study drug.  Women of childbearing potential (perimenopausal 
women must be amenorrheic for at least 12 months to be considered of non-childbearing 
potential) must have a negative pregnancy test at screening. 
5.2. 
Exclusion Criteria 
As in the ATI001-102 Main protocol (changes for the EXP Substudy in bold) 
1. Radiotherapy treatment within 4 weeks or less prior to starting first veledimex dose 
2. Subjects with clinically significant increased intracranial pressure (e.g., impending 
herniation or requirement for immediate palliative treatment) or uncontrolled seizures 
3. Known immunosuppressive disease, autoimmune conditions, and/or chronic viral 
infections [e.g., human immunodeficiency virus (HIV), hepatitis] 
4. Use of systemic antibacterial, antifungal, or antiviral medications for the treatment of 
acute clinically significant infection within 2 weeks of first veledimex dose.  
Concomitant therapy for chronic infections is not allowed.  Subjects must be afebrile 
prior to Ad-RTS-hIL-12 injection; only prophylactic antibiotic use is allowed 
perioperatively. 
5. Use of enzyme inducing antiepileptic drugs (EIAED) within 7 days prior to the first dose 
of study drug.  Note:  Levetiracetam (Keppra®) is not an EIAED and is allowed 
6. Other concurrent clinically active malignant disease, requiring treatment, with the 
exception of non-melanoma cancers of the skin or carcinoma in situ of the cervix or 
nonmetastatic prostate cancer. 
7. Nursing or pregnant females 
8. Prior exposure to veledimex 


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9. Use of medications that induce, inhibit, or are substrates of CYP450 3A4 within 7 days 
prior to veledimex dosing without consultation with the Medical Monitor 
10. Presence of any contraindication for a neurosurgical procedure. 
11. Unstable or clinically significant concurrent medical condition that would, in the opinion 
of the investigator or medical monitor, jeopardize the safety of a subject and/or their 
compliance with the protocol.  Examples include, but are not limited to, unstable angina, 
congestive heart failure, myocardial infarction within 2 months of screening, ongoing 
maintenance therapy for life threatening ventricular arrhythmia or uncontrolled asthma. 
Exclusion Criteria specific to the EXP Substudy: 
12. Previous treatment with bevacizumab for their disease [NOTE: short use (< 4 doses) of 
bevacizumab for controlling edema is allowed) 
13. Subjects receiving systemic corticosteroids during the previous 4 weeks. 
6. 
DOSE ESCALATION DECISION RULES FOR ATI001-102 MAIN  
Dose escalation decision rules were based on a standard 3+3 design modified to independently 
evaluate the two stratified subject groups that may exhibit different safety and tolerability 
profiles. The dose escalation rules were applied to subjects who received Ad-RTS-hIL-12 and at 
least one veledimex dose post Ad-RTS­ hIL-12 administration. A formal Safety Review 
Committee (SRC) and Data Safety Monitoring Board (DSMB) along with an SRC/DSMB 
charter was written to facilitate dose escalation decisions.  
• Members of the SRC were comprised of the study Investigators, the Medical Monitor, 
and other appropriate Ziopharm representatives. 
• The DSMB was an independent multidisciplinary group consisting of clinicians with 
experience in management of patients with GBM and in the conduct and monitoring 
of clinical trials. 
In the standard 3+3 design, the MTD is defined as the dose level below at which more than 
33% of subjects of the same cohort and group experience DLTs. If two DLTs occurred in the 
same cohort in a group (two DLTs in Group 1 or two DLTs in Group 2) dose escalation halts 
in the group experiencing the DLTs. The MTD will then be explored in six subjects of the 
same group at the next lower dose level and will be declared to be the dose in which less than 
33% of subjects experience DLTs. Intra-subject dose escalation is not permitted. An 
intermediate dose cohort may be explored during the dose escalation phase, as deemed 
necessary and/or as recommended by the SRC.  
 
 


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Dose escalation proceeded along the lines of the following.  
• In each cohort, the first subject was monitored for the 14 days of treatment and then 
observed for an additional seven days post the last veledimex dose before the second 
and third subjects were enrolled in that same cohort.  
• At the end of each cohort, the SRC convened to review the safety data after the third 
patient in a cohort, within a group, completed veledimex dosing and had been 
monitored for 28 days after the Ad-RTS-hIL-12 injection.  
• Originally, each dose cohort was to enroll three subjects from Group 1 and three 
subjects from Group 2. If no DLTs occurred among the first three subjects in a 
cohort, within the same group, dosing to the next higher dose cohort could proceed 
after the SRC and DSMB provided a recommendation to proceed.  
• In any cohort, if one DLT occurred among the first three subjects within the same 
group, three additional subjects of the same group were to be enrolled.  
• If one or more of the three additional subjects experienced a DLT (e.g. two DLTs in 
Group 1 or two DLTs in Group 2), then dose escalation was halted.  
− The SRC would convene to evaluate safety, determine if the MTD had been 
reached and decided whether to stop treatment or de-escalate veledimex dosing in 
that group.  
• In the event that the SRC determined that a DLT would not be considered to be 
contributory to the MTD, a decision was made about enrolling additional subjects 
prior to determining the MTD. 
Originally, the study was planned to explore four veledimex dose cohorts of 20 mg, 40 mg, 
80 mg and 120 mg once daily, and two doses of Ad-RTS-hIL-12 (2x1011vp and 1x1012vp). The 
actual dose cohorts were treated at 10mg, 20mg, 30mg and 40 mg of veledimex. Only one dose 
of Ad-RTS-hIL-12 was explored (2x1011vp). 
Originally, expansion cohorts were not prospectively planned in this study. If ≥ 33% of subjects 
in the expansion cohort experience DLTs, according to the definition used in the dose-escalation 
phase, additional subjects might have been enrolled at the next lower dose tested in the dose 
escalation phase, or at an intermediate dose, as recommended by the SRC.  Intermediate cohorts 
and an expansion cohort were explored in Group 1 as noted below. 
Group 1 – Following the completion of Cohort 1, the SRC and DSMB approved dose escalation 
to Cohort 2, as per protocol. Three of six subjects in Cohort 2 experienced a DLT and therefore 
this dose was deemed the maximum administered dose (MAD). The SRC and DSMB approved 
opening an intermediate cohort of 30mg to determine the MTD. At the conclusion of this cohort 
the SRC determined due to veledimex compliance rates, that an expansion cohort of 20mg 
should be explored. Following this cohort, further the SRC approved an intermediate cohort of 


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10mg. At the conclusion, based on veledimex compliance and OS rates, 20mg was determined to 
be the optimal dose.  
Group 2 – Following the completion of Cohort 1, there was a Ziopharm decision to not move 
forward with dose escalation. This was not a safety related decision. 
7. 
SAMPLE SIZE 
7.1. 
ATI001-102 Main  
The choice of the number of subjects was based on the standard 3+3 design modified to 
independently evaluate two stratified subject groups that may exhibit different safety and 
tolerability profiles. 
• In general, up to 72 subjects could have been enrolled into this study, including three 
to six subjects per group enrolled in each of the planned dose level cohorts. Subjects 
who withdraw from the study during the dose-limiting toxicity (DLT) evaluation 
period (Days 0-28) for reasons other than toxicity or disease progression could have 
been considered to be replaced.  
• The sample sizes chosen were based on clinical consideration for a standard 3 + 3 
dose escalation design to determine the MTD for two separate groups of subjects 
independently evaluable for safety and dose escalation. Power calculations for 
comparison of AE rates are simply too inexact to be clinically meaningful because the 
AE rates are unknown and cannot even be approximately projected. 
• If an AE occurs at a rate of 1% or 10%, then the chance for observing such an AE 
among six subjects receiving that dose will be 6% and 47% respectively. If no AE is 
observed in any of the six subjects, then the true incidence is at most 24% with 80% 
confidence and 32% with 90% confidence. 
7.2. 
EXP Substudy 
Sample size statistical considerations were provided as similar to those of ATI001-102 Main.  
• A total of 36 treated subjects in the EXP Substudy provided for a total sample size of 
52 treated subjects with combination Ad+V (FAS) at Ad-RTS-hIL-12 (2 x1011 vp) 
and 20mg of veledimex 
• A total of 51 treated subjects received both Ad-RTS-hIL-12 (2 x1011 vp) and 20mg 
veledimex. 
•  If no AE events occur in approximately 50 subjects, then an AE rate as low as 6% could 
be ruled out with 95% confidence.  


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8. 
ANALYSIS POPULATIONS  
Screen Failures 
• Screen Failures are subjects who signed an informed consent and either did not meet 
the eligibility criteria per protocol or subsequently withdrew consent before receiving 
any study treatment.  The number of subjects classified as screen failures will be 
summarized in the subject disposition. 
FAS Population 
• The Full Analysis Set (FAS): Overall Safety Population (OSP) includes all 
subjects who have received at least one dose of veledimex (pretumor resection and) 
and/or all subjects who received Ad-RTS-hIL-12. 
ESP Population 
• The Evaluable Safety Population (ESP) includes subjects who have received          
Ad-RTS-hIL-12 and at least one dose of veledimex after Ad-RTS-hIL-12 
administration. 
ITT Population 
• In general, the ITT population is defined for randomized controlled trials. In this 
uncontrolled setting, the FAS plays the same role as the ITT. 
Per-Protocol (PP) Population 
• The ESP is denoted as the PP population in this uncontrolled setting. 
PK Population 
• All Subjects with available serum-time concentration data are included in the PK 
Population. 
Completers 
• The completers population is defined as all eligible subjects who survived two years 
from Day 0 without any major protocol deviations. In this uncontrolled setting of the 
rGBM almost all subjects died before two-years of follow-up. This population is not 
described for the purpose of statistical analysis. 


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9. 
GENERAL ANALYSIS CONSIDERATIONS 
9.1. 
Data Presentation 
Originally, when the SAP for ATI001-102 Main was finalized, there was no plan to combine 
ATI001-102 Main with the EXP Substudy. However, after further consideration, for practical 
purposes, combining the SAP and analysis helps facilitate performing the long-term OS analysis 
as well as identify any potential patient characteristics which could be important for late-stage 
clinical trial planning. All final analyses will summarize comparisons of subjects treated with 20 
mg veledimex in ATI001-102 Main (n=15 ESP subjects) combined with the subjects treated with 
20 mg veledimex in the EXP Study (n=36 ESP subjects). 
The summary tables will be presented as follows:  
• The Parent Table Header (N=75 FAS subjects enrolled in ATI001-102 Main and 
ATI001-102 Expansion)  
− Group 1 Craniotomy: 68 subjects over 5 veledimex dosing cohorts combining all 
treated subjects from ATI001-102 Main and the EXP Substudy 
− Group 2 Stereotactic: 7 subjects treated at 20mg veledimex 
• Table A Header (N=39 FAS subjects Enrolled in ATI001-102 Main) 
− Group 1 Craniotomy: 32 subjects over 4 veledimex dosing cohorts from    
ATI001-102 Main 
− Group 2 Stereotactic: 7 subjects treated at 20mg veledimex in ATI001-102 Main 
• Table B Header (N=52 FAS subjects dosed at 20mg veledimex enrolled in   
ATI001-102 Main and ATI001-102 Expansion) 
− ATI001-102 Main, Group 1 (craniotomy): 16 subjects  
− ATI001-102 Expansion: 36 subjects 
 
 
 
 


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Table 1: 
Example Summary Table Shell 
Parent Table Header (N=75) 
Group 1: Intracranial 
Group 2: 
Stereotactic 
All 
Combined 
Main Study Veledimex Dose 
Expansion 
Veledimex Dose 
Main 
10mg/
day 
20mg/
day 
30mg/
day 
40mg/
day 
20mg/day 
20mg/day 
Combined 
  
n =6 
n=16 
n =4 
n =6 
n =36 
n =7 
N =75 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table A Header (Main Study N=39) 
Group 1: Intracranial 
Group 2: 
Stereotactic 
 
veledimex Dose 
 
Main 
 
10mg/
day 
20mg/
day 
30mg/
day 
40mg/
day 
20mg/day 
Combined 
  
n =6 
n=16 
n =4 
n =6 
n=7 
N =39 
Table B Header (N=52) 
Group :1 Intracranial (treated at 20 mg veledimex: Main: n=16; EXP: 
n=36; Combined N=16+36=52 
Main veledimex Dose 
Expansion 
 
 
20mg/
day 
 
 
20mg/day 
 
Combined 
  
 
n=16 
 
 
n =36 
 
N=52 
The listing conventions for combining the data for all treated FAS subjects (n=75) are organized 
as follows: 
• All listings will be ordered by ATI001-102 Main to be followed by the EXP Substudy  
− ATI001-102 Main Group 1, veledimex dose (10mg, 20mg, 30mg, 40mg) and 
subject number  
− ATI001-102 Main Group 2, veledimex dose (20mg) and subject number  
− EXP Substudy, veledimex dose (20mg) and subject number 
• Listings will present all available data. 


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9.2. 
Populations Used in the Presentation of Statistical Summaries 
The following subject populations will be evaluated and used for presentation and analysis of the 
data: 
• The FAS will be used for summaries of baseline characteristics and safety. 
Summaries will be presented by group and veledimex dose. 
• The ESP is to be used for analysis of dose limiting toxicities, overall survival and 
progression free survival and finding the maximum tolerated dose. The ESP will also 
used for the PD/biomarker data analysis. 
• The Pharmacokinetic Population (PKP) includes all subjects who received veledimex 
and have PK samples to be measured (please refer to the PK/PD SAP for details) 
• Summaries of dose limiting toxicities are described for ATI001-102 Main Group 1 
and not Group 2  
− Group 2 subjects were only treated at 20mg veledimex and no DLTs were 
observed. 
− DLTs only apply to ATI001-102 Main 
9.3. 
Protocol Deviations 
A protocol deviation is any change, divergence, or departure from the study design or procedures 
defined in the protocol. Major protocol deviations are a divergence from the protocol that could 
materially: (a) impact the integrity or analyzability of the resultant data, (b) contradict the 
Informed Consent Form (ICF), (c) impact a subject’s safety, rights, or welfare. In general, no 
subject was planned to be removed from any analysis population because of a protocol deviation.  
A planned protocol deviation (i.e., waiver), is a deviation from the protocol that has been 
submitted, reviewed, approved, and documented prior to the deviation occurring. 
Deviations will be identified as either Major, Minor, or Exemption (waiver). Deviations will be 
identified as such and listed by patient and study center. Major deviations that are considered to 
potentially impact the efficacy or safety analyses will be tabulated. Protocol deviations will be 
listed and summarized by type. 
• Deviation from inclusion/exclusion criteria (may also be listed under waiver) 
• Withdrawal criteria met during the study, but subject was not withdrawn.  
• Prohibited concomitant medications  
• Treatment deviation 
• Other protocol deviation 


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9.4. 
Multicenter Studies 
Both the ATI001-102 Main Study and Expansion substudy have enrolled subjects from multiple 
investigative sites. There is no plan to present the data by investigative site. Subject listings will 
indicate the investigative site as part of the subject ID (first three digits, i.e., 457-XXX is Site 
457).  
9.5. 
Other Strata and Covariates 
Exploratory analysis of subject characteristics has been previously described where applicable. 
9.6. 
Examination of Subgroups 
Previously described in Exploratory Analysis of OS. See Section 12.1 for more analyses. 
9.7. 
Multiple Comparisons and Multiplicity 
No formal comparisons. 
9.8. 
Interim Analysis  
There were no formal preplanned interim analyses.  
10. 
DATA HANDLING CONVENTIONS 
The data conventions for all treated FAS subjects (n=75) are as follows: 
10.1. 
Missing Data 
• In general, no imputations for missing or partial data will be made. 
• In analyses presented over time by visit, no imputations will be performed on missing 
data. All analyses will be based on the observed data. The effective sample sizes at 
each assessment visit will be based on the total number of subjects with non-missing 
data for the parameter of interest at that visit. 
• Unless otherwise specified, percentages will be calculated based on the number of 
subjects based on non-missing data as the denominator. 
• A missing values category will also be defined to ensure all subjects are accounted for 
in prespecified populations for analyses.  
• In general, other than for partial dates, missing data will not be imputed and will be 
treated as missing.  


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− The algorithms for imputation of partial dates vary depending on the parameter. 
These will be provided in the programming specifications that will be prepared 
for this study.  
• When applicable, unless otherwise specified, the following general imputation rules 
will be used for missing date in the assessment of an event: 
− If all parts of the date are missing, the date will not be imputed.  
− In the case where only the start day of an event is missing, it will be replaced by 
the start day of study treatment if the event occurs in the same month and year. 
Otherwise, it will be replaced by the first of the month.  
− If the stop day is missing, the stop day of the event will be replaced by the stop 
day of study treatment. Otherwise, the last day of the month will be used to 
replace the missing stop day. 
− If both the start day and month of an event are missing, the start day and month 
will be replaced by the start day and month of study treatment if the event and the 
start of the treatment occur in the same year; otherwise, it will be replaced by 1st 
of January.  
− All imputed dates must be prior to the dates of withdrawal of consent, lost to 
follow-up, and death. 
10.2. 
Baseline Data  
• Unless otherwise specified, baseline is the last observation before the first study drug 
administration. The baseline lesion assessment is considered to be the one within 72 
hours following Ad-RTS-hIL-12 administration. 
• If the schedule of events includes a baseline value (i.e., Day 0 lab just before study 
drug administration) that is not collected as planned for any reason, then the data 
collected for the variable known to be the last observation before the first dose of 
study drug will serve as the baseline value (i.e., Screening value). 
• In addition, the relevant section for each endpoint will describe the baseline values of 
subjects recorded as taken before study treatment according to schedule along with 
subjects for whom measurements should have been taken before study treatment but 
for whom those measurements were taken after study dosing was received. 
• Change from baseline is performed for Serum Chemistry, Hematology, Urinalysis, 
Vital Signs, ECG Results and the Karnofsky Performance Status (KPS) Score. 


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10.3. 
Measurements Collected from Subjects Excluded from Predefined 
Analysis  
• Populations or extra measurements that were repeated or obtained based on 
unscheduled visits may not be included in summary tables unless specified. 
• Regardless of data inclusion for any analysis 
− Subject Listings will present all available data received in the electronic CRF 
(eCRF)  
− Where applicable subject listings will also present all final data received from 
data sources for which data external to the eCRF were captured for which data 
transfer agreement specifications were established.  
10.4. 
Derived and Computed Variables 
• Day 0 corresponds to the date of Ad-RTS-hIL-12 administration. 
− Then more generally, Day n represents the elapsed number of days from Day 0, 
inclusive. 
− Day n = Date of assessment – Date of Day 0 
− Unless otherwise specified, the timing of all study-related events, assessments, 
and interventions will be calculated relative to Day 0. Day −1 will be the day 
before Day 0, and in general, negative days will be measured backwards starting 
from Day −1. 
• 1 year = 365.25 days. Year is calculated as (days / 365.25) and will be rounded up to 
1 significant digit for purposes of presentation. 
• 1 month = 30.4375 days. Month is calculated as (days / 30.4375) and will be rounded 
up to 1 significant digit for purposes of presentation. 
• Age will be calculated in years relative to the date of informed consent based on the 
following SAS statement: Age = floor ((intck(‘month’, date of birth, date of informed 
consent) – (day (informed consent) < day (date of birth))) / 12 (Check with LLX and 
Ziopharm Programming) 
• 1 pound = 0.454 kg 
• 1 inch = 2.54 cm 
• Pregnancy test data will be listed only.  


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10.5. 
Reference Section 11.1 for derived study variables were created 
based on clinical interpretation of the eCRF data for the 20mg 
cohorts in ATI001-102 Main and the EXP Substudy. Continuous 
Variables  
• Summary statistics will be provided for continuous variables (e.g., age).  
• Unless otherwise stated, this will consist of the number of subjects with a non-
missing value of the variable (n), mean, standard deviation, median, minimum, and 
maximum. 
• The same number of decimal places as in the raw data will be presented when 
reporting minimum and maximum. 
• One more decimal place than in the raw data will be presented when reporting mean 
and median.  
• Two more decimal places than in the raw data will be presented when reporting 
standard deviation. 
10.6. 
Categorical Variables  
• Frequency counts will be provided for categorical variables (e.g., gender) 
• Unless otherwise stated, this will consist of the number of subjects with a response in 
a particular category and the percentage of the total number of subjects in that 
column. Unless otherwise stated, missing responses will be included in both the 
display and in the calculation of percentages (i.e., they will be included in the 
denominator).   
• Percentages will be rounded to one decimal place. 
• Percentages equal to 100 will be presented as 100% and percentages will not be 
presented for zero frequencies. 
10.7. 
Visit Windows 
The statistical analysis planned for this study will be performed according to the actual visit 
dates and times and do not require the calculation of visit windows. However, for analyses that 
require a particular visit as planned, measurements included in that visit must have occurred 
during the acceptable window defined for the visit in the protocol, unless otherwise specified in 
this plan. As needed, visit windows will also be created for analysis, to include data collected at 
unscheduled visits. Visit windows will apply to all treatment arms. When multiple visits occur 
within the same window, the visit closest to the target visit day will be selected. When two visits 
are equidistant from the target day, the visit occurring latest in the window will be used for 
analysis. 


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11. 
CONVENTIONS 
• SAS version 9.4 or higher will be utilized for all data analyses, summary tables, 
subject listingsand figures. Derived datasets are also created using (SAS®) software.   
• The definition of all derived variables and decodes for coded data must appear in the 
notes.   
− Due to space limitations, tables and listings may require a page of notes as a one-
time preface to the output.  
• In general, summary tables and listings (e.g., post text tables and individual subject 
data listings) include a “footer” providing explanatory notes that indicate at a 
minimum: 
− Date of data extraction 
− Date of output generation 
− SAS complete program name, and path where it is stored. 
− including the path that generates the output. 
− Any other output specific details that require further elaboration (e.g. CRF pages 
from which the data were obtained)  
Post text tables also include reference(s) to the subject data listing(s) that supports the summary 
data. The data extraction date links the output to the archived database that is locked to ensure 
the replication of the results. 
In general, the listings should be sorted and presented by treatment assignment, investigational 
site, and subject number.  Treatment assignment and site can appear in the banner of the listing.   
• From left to right, the subject number, visit number, visit date, and relative day should 
appear.   
• WHO -DD March 2016: 
• MedDRA Version 23.0 or higher Data Management  
• The database consists of data collected for (Ad+V) monotherapy treated subjects in 
ATI001-102 Main (n=39) and in the EXP Substudy (n=36) for a total of N=75 full 
analysis set (FAS) subjects. 
− In addition, data collection outside of the eCRF as part of the totality of the data 
to be finalized is derived from 7 external data sources denoted as “vendors” 
(Table 2) 






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The Overview Book variables used for the purpose of the TLFs and the CRS assessment will be 
internally reviewed and approved by Ziopharm clinical development personnel and this 
documentation will be filed in the TMF. These two documents will clearly differentiate those 
derived variables obtained from the SDTM from those variables derived by Ziopharm Study 
Subjects. 
11.2. 
Subject Disposition 
Subject disposition summaries will include the number of subjects enrolled and treated in each 
dosing cohort for the FAS population. Figure 1, illustrates,  
• The number of subjects screened N=98 
• N= 75 subjects are classified as belonging to the FAS.  
• N =74 PP subjects also denoted as the ESP  
• In order to provide for flexibility of analyses, there are two sub sections denoting:  
o Biostatistics statistical considerations for which data handling rules and 
populations for analyses are determined for PK/PD variables  
o PK/PD Scientist determination of statistical considerations for which data 
handling rules and populations for analyses are determined for PK/PD variables 
 Refer to the PK/PD statistical analysis plan where applicable for potential 
deviations from this SAP.  
 Such departures could be well suited to scientific data influences that may 
not be captured from a Biostatistics perspective. 




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• The number and percent of subjects who discontinue from the study will be 
summarized by reason for discontinuation by dosing cohort, group and overall.   
• The number and percentage of subjects in each analysis population will be 
tabulated.  
− If applicable, major protocol deviations will be summarized and listed. 
• Subjects who are screen failures will be summarized in the combined column 
− ATI001-102 Main study screen failures under Table A Header 
− EXP Substudy screen failures under Table B Header 
− Combined screen failures for both ATI001-102 Main and the EXP Substudy 
summarized under the Parent Header Combined column 
12. 
SUBJECT CHARACTERISTICS AND SUBGROUPS 
Demographics 
Demographic and baseline variables including age, sex, ethnicity and race, will be summarized 
by dose cohort treatment arm in ATI001-102 Main, the EXP Substudy and all subjects combined 
for the FAS. Age will be calculated relative to date of informed consent and will be summarized 
using descriptive statistics as well as by the number and percent of subjects in age categories (< 
65, ≥ 65 years). Similarly, height and weight will be summarized using descriptive statistics. 
Sex, ethnicity and race, will be summarized with the number and percent of subjects in each 
parameter category. 
Age is taken to be the subject's age on the date of the Screening visit. Conversions for height 
and weight are as follows: 
• Height (cm) = Height (inches) x 2.54  
• Weight (kg) = Weight (lb) x 0.454 
Demographics will be listed and tabulated using descriptive statistics. 
Medical History  
Medical history will be summarized for among other things:  
• Prior cancer treatment,  
• Initial diagnosis of high-grade glioma  


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− along with the time in months since initial diagnosis,  
− grading and type at time of initial diagnosis, and at screening will be tabulated. 
• Current disease status.  
• Medical/surgical history will be captured and listed. 
Prior cancer treatment information will be tabulated.  
• This will include whether the subject had any previous treatment, treatment type 
and the best responses from any previous treatments.  
• Other aspects of the patients’ medical history that are unrelated to their underlying 
malignancy, along with any abnormal findings noted during the screening physical 
examination will be presented in data listings. 
12.1. 
Subject Characteristics Subgroups 
Baseline subject characteristics will be summarized for the FAS by dose cohort treatment group 
in ATI001-102 Main, the EXP Substudy and all subjects combined.  
Among the patient factors to be explored for comparability are the following patient 
characteristic subgroup derived variables:  
• Age category: <65 vs. ≥65 
• Gender: female vs. male  
• MGMT: unmethylated vs. methylated 
• Hispanic or Latino: yes =1 vs. no=0 
• Race: white vs. not White 
• IDH: wild type vs. mutated 
• Prior Steroid: yes=1 vs. no=0 
• Enhanced Lesion: unifocal vs. multifocal 
• Prior Number of Lines of Treatment: 1 vs. GT 1 
• Steroid Cumulative Dose Up to 14 days: ≤ 20mg vs.  >20mg 
• Number of Lesions at Entry: 1 vs. > 1 
• KPS Screening, N(%): ≥70 to 90 vs. ≥90 


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• Veledimex Dosing Compliance: ≥80% vs. <80% 
• Number of Recurrences: 1st recurrence vs. ≥ 2 recurrences 
12.1.1. 
Subgroup Analysis for Subjects Receiving Anti-Cancer Therapies Post Ad+V 
Exploratory analysis will define a subgroup of Subjects documented as receiving any Anti-
Cancer Therapies post Ad+V: 
• Subjects documented as having received any anti-cancer therapies post treatment of 
controlled Ad+V will be summarized to supplement the analysis of BOR as a 
potential surrogate endpoint for OS. 
• Determine Proportion of subjects documented as receiving any Anti-Cancer 
Therapies post Ad+V. 
• Estimate OS for this subgroup. 
• Provide listing of this subgroup to include identification of anti-cancer treatment. 
12.2. 
Previous and Concomitant Medications 
All prior and concomitant medications consumed through Day 56 will be recorded and coded 
using the anatomic-therapeutic-class (ATC) coding system. MedHX and WHO-DD V (March 
2016) is used to code CMEDS. Details of concomitant medication will be listed. 
• Medications will be tabulated according to whether they were being taken pre-study 
and/or during the study.   
• Medications received in the period preceding consent (28 days) in addition to 
those ongoing at screening will be captured in the CRF.  
• Concomitant medications are those medications being taken on or after the first 
dose of study medication.   
− If the start and stop dates of the medications do not clearly define the period(s) 
during which a medication was taken, it will be assumed to have been a 
concomitant medication. 
• Previous and concomitant medications will be tabulated by preferred term and ATC 
term 2.  
• Non-pharmacological concomitant measures (e.g., procedures) will be listed. 


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13. 
SAFETY ANALYSIS 
Clinically significant changes in the subject's physical examinations, vital signs, ECG 
evaluations and abnormal laboratory test results, will be captured as AEs. Safety evaluations will 
use calculations to determine estimates of the incidence, intensity, and the type of AE and SAE’s 
based on preferred term coding.  AEs, ECG findings, and vital signs will be tabulated and 
presented for all subjects in the study, presented by dose cohort and group.   
All clinical findings will be further inspected through a clinical review of relevant parameters 
including AEs, serious adverse events (SAEs), laboratory values (hematology, serum chemistry, 
and urinalysis), body weight, vital signs, physical examinations, and ECOG performance status. 
Safety analysis will be carried out for the FAS Safety Population in general. Where applicable 
the Safety will also be summarized using the ESP.  
Exposure to study drug and reasons for discontinuation of study treatment will be tabulated. 
13.1. 
Maximum Tolerated Dose/ Dose Limiting Toxicities Study Drug 
Exposure for ATI001-102 Main 
The protocol defines the MTD as the dose level below at which less than 33% of subjects, of the 
same cohort in a group, experience DLTs, with an independent assessment of Group 1 and 
Group 2 subjects. The EXP Substudy was one fixed dose and therefore MTD does not apply. 
• The number of DLTs and the proportion of subjects with any DLT and each type of 
DLT will be summarized by veledimex dose within each group. 
• The ESP will be used for summaries of DLTs. 
− DLT data will also be listed by veledimex dose and subject within each group. 
Dose-limiting toxicity (DLT) is defined as: 
• An event, occurring within the first 28 days (Day 0 - Day 28) that meets one of the 
following conditions: 
− Any local reaction that requires operative intervention and felt to be attributable to 
Ad-RTS-hIL-12 and/or veledimex. 
− Any local reaction that has life-threatening consequences requiring urgent 
intervention or results in death and felt to be attributable to AdRTShIL12 and/or 
veledimex. 
− Any Grade 3 or greater non-hematological adverse event that is at least possibly 
related to the study drug. 
− Any Grade 4 hematologic toxicity that is at least possibly related to the study drug 
and lasts at least 5 days.  


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− Grade 3 or higher thrombocytopenia at least possibly related to the study drug 
Note: diagnostic brain tumor biopsy is not considered a DLT. Seizures, headache, and cerebral 
edema are commonly observed in this population and will be recorded according to grade of 
toxicity but will not be considered a DLT unless they are deemed as most likely to be 
drug-related as the main contributory factor. 
Details of study drug administration and dose modifications will be listed as follows:  
• Ad-RTS-hIL-12 
− Total volume received, number of sites and whether the dose was modified will 
be tabulated. 
• Veledimex 
− The total dose received (mg) for each study treatment will be calculated based on 
the Drug Accountability CRFs including the oral dosing diaries. Dosing details 
are summarized per subjects for each dosing cohort. Dose and dose modifications 
per subject treated will be listed. The number of doses received will be tabulated.  
− Subject veledimex dosing compliance will be determined for each subject as the 
total number of tablets dispensed minus the total number of tablets reported as not 
taken, divided by the total number of tablets dispensed, multiplied by 100.  
− Subgroups for dosing compliance may be explored (e.g. compare subgroup of 
subjects who are 100% dosing compliant with subgroup of subjects <100% dosing 
compliant)  
13.2. 
Adverse Events 
The primary presentation of AE’s will be prepared without regard to causality or relationship to 
study treatment. In addition, summaries of all TEAEs, treatment related TEAEs and of all SAEs 
will be tabulated by System Organ Class, Preferred Term, CTCAE grade, by group 1 or 2, and 
veledimex dose.  
TEAEs 
• Verbatim terms captured on the eCRF will be mapped to preferred terms (PT) and 
system organ classes (SOC)’s using the Medical Dictionary for Regulatory Activities 
(MedDRA®) Version 23.0 or higher for purposes of treatment emergent adverse 
events (TEAEs) summarization. AEs will be regarded as TEAEs during the treatment 
period regardless of relationship to study drug if: 
• The AE occurred during or after administration of the first dose of study drug (on or 
after Day 0: either veledimex or Ad-RTS-hlL-12),  


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• An already existing AE that is present when the subject is first dosed worsens in 
intensity during the treatment period. 
Severity  
The severity of AEs will be assessed for classification on a grading scale of Grade 1 to Grade 5 
according to the NCI CTCAE. ATI001-102 Main initially graded adverse events per CTCAE 
v4.03. Administrative Memo #3 (dated 12-Nov-18) instructed the Investigators to assess all 
adverse events using CTCAE v5.0. Ziopharm Drug Safety and Pharmacovigilance had 
conducted a review of adverse events entered at that time and determined no significant impact 
to the grading of these adverse events. EXP Substudy used CTCAE v5.0.  
Relationship (Causality)  
AEs that have possibly, probably, or related relationship to the study drug are defined to be 
Related to the study drug. Other classifications for relatedness to study drug will be defined as 
Not Related. Any AEs for which the relationship to study drug is missing will be considered as 
related to study drug. AEs with closest relationship to the study drug will be used for summary. 
Adverse Events Reporting Period 
The reporting period of safety data for both studies will be from the date of ICF signature 
through initial Follow-up Period (day 56). AEs that are drug-related should be followed until 
resolved or no resolution is expected. 
13.2.1. 
Adverse Events Number of events 
Both number of events and number of subjects will be tabulated. AEs with greatest severity 
before baseline will be used as benchmark for comparison of AEs occurring through Day 56.  
• For summaries of events, percentages will be calculated from the total number of 
events per group/dose cohort.  
13.2.2. 
Summaries of Adverse Event Incidence Rates for FAS 
• For summaries of subjects, the incidence percentages will be calculated from the total 
number of distinct subjects per group/dose cohort. If the same PT or SOC is reported 
more than once for a subject, the subject will only count once in the corresponding 
incidence of PT or SOC.   
− Where a subject has multiple adverse events in a System Organ Class I Preferred 
Term, only the most severe will be considered.  
− In tabulation by severity (i.e., CTCAE toxicity grade) and relationship, for a given 
PT or SOC, only the most severe and most closely related PT and SOC will be 
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• TEAE table summaries will be also be sorted in descending order by SOC based on 
the column combining over all subjects. This will also depend on the header 
presentation chosen. (e.g. for Table B header, this is the combined data for 52 FAS 
subjects or 51 ESP subjects for the group 1 veledimex treated at 20mg).  
TEAEs for the following bulleted categories will be tabulated using frequency tables by dose 
cohort and by group, SOC and PT according to relationship to study drug, severity and 
seriousness for FAS OSP.  All frequency tables will be presented sorted in descending order for 
PT for the combined tables summary within the SOC based on convention described above:  
• Overview of TEAEs 
• TEAEs by SOC and PT 
• TEAEs by SOC, PT, and Maximum CTCAE toxicity grade ≥ 3 
• Drug-related TEAEs by SOC and PT 
• Drug-related TEAEs by PT in decreasing frequency 
• Serious TEAEs by SOC and PT 
• TEAEs leading to death by SOC and PT, including drug related TEAE. 
• TEAEs leading to treatment discontinuation by SOC and PT, including drug related 
TEAE. 
• TEAEs leading to dose interruption by SOC and PT  
• TEAEs leading to dose reduction by SOC and PT 
In addition to the full listing of all AEs, separate listings for TEAEs, SAEs, AEs leading to death 
and AEs leading to study discontinuation will be presented. 
13.2.3. 
Summaries of Adverse Events of Special Interest 
• Cytokine Release Syndrome (CRS) – as defined in the Investigator’s Brochure. See 
Section 11.1 for source information. 
13.3. 
Laboratory Evaluations 
Statistical summaries of all laboratory parameters will be converted to conventional, SI units, for 
the purposes of presenting descriptive statistics.  Listings will present the data in the original unit 
collected, as well as the converted value in conventional units. A separate listing will present all 
units used for data collection, along with the corresponding units and conversion factors. 
Absolute values and change from baseline in clinical laboratory parameters will be summarized 
by visit, group and veledimex dose.  The incidence of normal and abnormal (subdivided into 'not 


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clinically significant' and 'clinically significant') laboratory values will be tabulated by visit, 
group and veledimex dose. 
Hematology, serum chemistry, and urinalysis tests measured on a quantitative scale will be 
summarized in a descriptive manner by calculating the mean, standard deviation, median, and 
range by treatment arm as follows: 
• Baseline value 
• Minimum post-baseline value 
• Maximum post-baseline value 
• Average post-baseline value 
• Last post-baseline value 
Whenever available, laboratory values will be assigned toxicity grades based on the NCI CTCAE 
version 5.0, For some laboratory tests, these criteria may include qualifying definitions (e.g., 
clinical adverse event and/or requirement for concomitant medication) in addition to the specific 
laboratory value used for the definition of the toxicity grades. For such tests, the qualifying 
definitions will not be used for the assignment of toxicity grades. Shifts in laboratory values to 
outside and to within the local laboratory normal range will be evaluated for selected laboratory 
tests by assessing, relative to the baseline value, laboratory values measured at selected time 
points. The number and proportion of patients with directional shifts above or below the normal 
range will be summarized for selected laboratory tests.  
13.4. 
Vital signs 
Vital sign parameters include height, weight, systolic and diastolic blood pressure (mmHg), heart 
rate (bpm), respiratory rate (breaths/minute) and temperature (°C). 
The conversion for temperature is as follows: 
• Temperature (°C) = (Temperature (°F) - 32) x (5/9) 
Absolute values and change from baseline for vital sign parameters will be summarized by visit, 
group and veledimex dose. Body weight (kg) will be summarized for absolute values and 
changes from baseline by visit and treatment arm, and overall. 
All data summarized for vital signs will be provided in subject listings. 
13.5. 
ECGs 
Heart Rate (bpm), PR Interval (ms), QRS complex (ms), QT interval (ms), RR interval (ms) and 
QTc interval (ms) will be summarized for absolute values and changes from baseline (Screening 
visit) by visit, group and veledimex dose. 


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Overall ECG finding categories will be summarized by visit, group and veledimex dose. 
Electrocardiogram results will be listed and summarized in terms of the number and percentage 
of patients with abnormal and normal findings, as reported by the investigator, at the time points 
assessed. For this study, 12-lead ECG assessments are planned at the screening visit only. Post-
baseline electrocardiograms are not required unless clinically indicated. 
Cardiac ejection fraction will be assessed by echocardiogram or MUGA scan at the screening 
visit to determine study eligibility. Patients must have an ejection fraction ≥ 40% to enroll in the 
study. The baseline cardiac ejection fractions will be summarized in a descriptive manner for 
each treatment arm. Post-baseline assessments of cardiac ejection fraction are not required unless 
clinically indicated. 
13.6. 
Physical and Neurological Exam 
In general, Physical examination data will be provided in patient listings listed.  
Results of the targeted neurological exam will be listed and summarized by group and veledimex 
dose.  
Clinically significant abnormalities that are identified during physical examinations will be 
reported as adverse events.  
The disposition of each physical examination (whether performed or not) and the date the 
physical examination was performed will be provided in individual patient listings only. 
Summary tabulation of the physical examination data reported for this study is not planned. 
13.7. 
Karnofsky Performance Status 
Results of the Karnofsky Performance Status and will be summarized as a continuous variable by 
descriptive statistics, tabulating absolute values and changes from baseline by visit for each dose 
cohort treatment arm, and for all subjects combined. All subject data will be summarized in 
listings.  
13.8. 
Deaths 
All deaths that occur on study will be reported in a patient listing. The listing will include the 
primary cause of death and the number of days elapsed between Day 0 and death. 
14. 
EFFICACY ANALYSIS  
14.1. 
Tumor Response 
Target lesion response, non-target lesion response, enhancing non-measurable lesion response, 
non­ enhancing lesion response, new lesions, response adjusted for corticosteroid use, clinical 
status and objective response of the subjects according to the RANO/iRANO criteria were to be 


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summarized by group and veledimex dose. In addition, details of lesions including pre-baseline 
lesions were also to be listed. 
Tumor response was to be evaluated radiographically using MRI scans to determine tumor 
response and to assess the time of objective disease progression (estimate of PFS).  The          
Ad-RTS-hIL-12 injected lesion and/or other measurable brain lesions was to be measured 
according to the RANO/iRANO criteria guidelines. 
Originally, the tumor objective response rate (ORR), progression free survival (PFS), and rate of 
pseudo-progression (PSP) were to be explored as surrogate endpoints for OS. In addition, the 
investigator assessment of tumor response was to be verified by an independent review 
committee (IRC) for multiple time points for each subject assessed. Because tumor response 
assessment produced less than the expected number of subjects with confirmed objective 
responses, the evaluation of ORR, has been revised and redefined for the number of times 
summary statistics are to be presented.  
14.1.1. 
Objective Response Rate 
The objective response rate will be summarized by group and veledimex dose on the ESP. 
An exact two-sided 95% confidence interval for the percentage of responders will also be 
presented by visit and overall (based on the best response). 
For this calculation, responders are defined as those experiencing a confirmed complete response 
or confirmed partial response. Non-responders are those either with stable or progressive disease. 
Those subjects that cannot be assessed will be treated as non-responders for the purposes of 
deriving the percentage of responders and confidence intervals. 
The revised final tables for ORR and the 95% CI will be presented for the following. 
• The ORR is reported overall by treatment arm based on the investigator response at 
timepoints 56 days, Week 16, Week 24, and Week 48. This is a revised subset of 
reporting.  
14.1.2. 
Best Overall Response (BOR) 
The best overall response (BOR) is a derived variable that summarizes for each treated subject 
the best tumor response recorded on the eCRF based on the investigator assessment and the IRC 
assessment for all:  
• Tumor response data collected before evidence that the subject received a new 
anticancer treatment.    
• Tumor response data collected regardless of whether a new anticancer treatment is 
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The BOR categories are defined as: 
• Complete Response 
• Partial Response 
• Stable Disease 
• Progressive Disease 
• Not Evaluable (if subject has BOR assessment but is denoted Not Evaluable) 
• No Response (if subject has no BOR assessment) 
The BOR is evaluated for agreement statistics between the responses of the investigator 
assessment and the IRC for each subject. 
• The IRC verification process was put on hold for the verification process planned as 
part of the EXP Substudy and subsequently cancelled. 
• The agreement statistics between the investigator assessment and the IRC are still 
performed for the BOR of the subjects in ATI001-102 Main. 
14.1.3. 
Progression Free Survival (PFS) 
PFS and pseudo-progression are characterized in subject listings where applicable instead of 
tables. 
PFS, and PSP Progression free survival was originally defined for determination of PSP 
requiring confirmation of progression based on RANO/iRANO criteria guidelines. Instead for 
reporting purposes, PFS is the time in months from the first treatment (either veledimex or Ad-
RTS-hIL-12) to the first assessment on which the overall response is reported as disease 
progression. Subjects withdrawing from the study will be censored at their last non progressive 
disease response assessment. If a subject does not have a non-progressive disease response 
assessment, the subject will be censored on the date of the first treatment as described above.  
14.2. 
Overall Survival  
OS is defined as the duration of time from the first dose of study drug (Day 0) to the date of 
death from any cause in days or months. Subjects are censored based on the last date known to 
be alive. For example: 
• Subjects who discontinue the study without documentation of additional follow-up 
will be censored at the date of discontinuation.  
• Subjects who are lost to follow-up will be censored at last follow-up contact date. 


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• Subjects still alive up to 2 years from the first dose of study drug are classified as 
censored and as having completed all follow-up scheduling. 
This could be captured on the survival page of the eCRF or the date of the subject's final 
assessment/ discontinuation. All summaries and analyses for primary efficacy endpoint will be 
based on the ESP. 
14.2.1. 
Estimation of Overall Survival for the Monotherapy ESP 
OS will be estimated and explored for three sets of subjects of the Monotherapy ESP. 
• ATI001-102 Main Group 1: Craniotomy (treated at 20 mg veledimex: n=15)  
• EXP Substudy: Craniotomy (treated at 20 mg veledimex: n=36) 
• Combined N=15+36=51 
OS data will otherwise be presented in listings for other veledimex dosing cohorts and for 
subjects in Group 2. 
Time to OS will be estimated using the Kaplan Meier (KM) Product-Limit estimation method.  
• Median survival time along with the 95% Confidence Interval (CI) will be 
constructed based on a log-log transformed CI for the survivor function S(t) 
• OS rates at fixed timepoints (month: 6, 9, 12, 15, 18, 24) will be derived from the KM 
estimate. 
− The corresponding CI will be derived based on Greenwood’s formula for the 
variance and the log-log transformation applied to the survivor function S(t) 
14.2.2. 
Exploratory Analysis of Subject Characteristics that may Potentially Extend OS 
• The Subject characteristics illustrated below have been divided into grouping 
variables for which the subgroup categories are well defined.  
• A KM analysis for each of the grouping variables is constructed using SAS 
LIFETEST to compare the OS for each subgroup belonging to its respective 
characteristic.  
• Subgroup summary statistics along with the KM plots are examined for comparability 
of OS for subjects treated in ATI001-102 Main with subjects treated in the EXP 
Substudy 
− The impact of the results observed in the combined analysis reveals whether the 
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• To examine the prognostic influence for subgroups treated with Ad+V on OS, a 
separate Cox regression for each of the grouping variables is performed using SAS 
PHREG,  
− Forest plot presentation is then constructed collecting the summary statistics of 
Cox regressions in order to display the hazard ratio estimates with corresponding 
95% CI’s 
15. 
FOREST PLOT FOR 20MG COHORTS 
Among the patient factors to be explored are the following patient derived variables (from the 
Overview Book and EDC), for ATI001-102 Main Group 1 and EXP substudy 2.0 in a forest plot. 
Reference Section 11.1 for clarification on the source for the data.  
Analysis using these variables (and derived variables) is an exploratory review by Ziopharm. 
 
Age category  
•      <65  vs       ≥65 
Gender 
• Female  vs  Male  
MGMT 
• unmethylated  vs   methylated. 
Hispanic or Latino 
•     yes =1 vs no=0 
Race 
• White   vs not White 
IDH 
• wild-type vs mutated 
Prior Steroid 
• yes=1 vs no=0 
Enhanced Lesion 
• unifocal  vs    Multifocal 
Prior Number of Lines of Treatment 
• 1    vs  GT 1 
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• ≤ 20mg  vs >20mg 
 
Number of Lesions at Entry  
•      1  vs     > 1 
KPS Screening, N(%) 
•    ≥70 to <90 vs ≥90 
Veledimex Dosing Compliance 
• ≥ 80%  vs  <80% 
Number of Recurrences 
• 1st recurrence vs  ≥ 2 recurrences