Conditions: Pediatric Brain Tumor Diffuse Intrinsic Pontine Glioma
Keywords: DIPG Glioblastoma Anaplastic Astrocytoma High Grade Glioma (HGG) Not Otherwise Specified (NOS) Supratentorial Tumor NOS
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 6
Healthy volunteers: no

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 in the pediatric population.

Detailed description:
Eligible patients will be stratified to one of two arms, according to clinical indication for tumor resection. Pediatric patients who are scheduled for 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. This arm has been completed and is currently closed to enrollment.

Pediatric patients with diffuse intrinsic pontine glioma (DIPG) 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: Intratumoral Ad-RTS-hIL-12 freehand injection after tumor resection and oral veledimex (activator ligand) in pediatric patients with brain tumors. arm 2: Intratumoral Ad-RTS-hIL-12 stereotactic injection and oral veledimex (activator ligand) in pediatric patients with DIPG.

Interventions: intervention 1: Ad-RTS-hIL-12 intervention 2: Oral Veledimex - Arm 1 (Pediatric Brain Tumor) intervention 3: Oral Veledimex - Arm 2 (DIPG)
Intervention descriptions: intervention 1: 2.0 x 10\^11 viral particles (vp) per injection, one intratumoral injection of Ad-RTS-hIL-12 intervention 2: 1 dose level (10mg/day) 15 oral daily doses of veledimex intervention 3: 2 dose levels (10mg/day, 20mg/day) 14 oral daily doses of veledimex

Protocol document:
Prot_000.pdf: 


Ad-RTS-hIL-12 + veledimex 
 
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2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES .................2 
TABLE OF CONTENTS .................................................................................................................2 
LIST OF TABLES ...........................................................................................................................7 
LIST OF FIGURES .........................................................................................................................8 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS...............................9 
4. 
CLINICAL PROTOCOL SUMMARY ......................................................................12 
5. 
INTRODUCTION ......................................................................................................30 
5.1. 
Disease Background ...................................................................................................30 
5.2. 
Interleukin-12 and Cancer Immunotherapy ................................................................30 
5.3. 
Adenoviral Vectors for Gene Therapy .......................................................................31 
5.3.1. 
Adenoviral Safety .......................................................................................................31 
5.3.2. 
Safety of Intratumoral Injection of IL-12 Gene Vectors ............................................32 
 
 
 
 
 
 
5.4.3. 
Veledimex ...................................................................................................................34 
 
 
5.6. 
Study Rationale ...........................................................................................................35 
 
 
6. 
STUDY OBJECTIVES ..............................................................................................37 
6.1. 
Primary Objective .......................................................................................................37 
6.2. 
Secondary Objectives .................................................................................................37 
 
 
7. 
INVESTIGATIONAL PLAN .....................................................................................38 
7.1. 
Overall Study Design ..................................................................................................38 
7.2. 
Study Oversight for Safety Evaluation .......................................................................42 
7.3. 
Dose Escalation, Cohort Expansion, and De-Escalation Decision Rules ...................43 


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7.4. 
Dose-Limiting Toxicity ..............................................................................................45 
7.5. 
Recommended Pediatric Phase II Veledimex Dose and Corticosteroid 
Exposure .....................................................................................................................46 
7.6. 
Dose Modification and Dose Delays ..........................................................................46 
7.7. 
Safety Monitoring and Adverse Effect Management .................................................47 
7.8. 
Severity Grading and Management of Local Reactions .............................................47 
7.9. 
Prophylactic Antipyretic and/or Analgesic Administration .......................................47 
7.10. 
Study Stopping Rules .................................................................................................48 
7.11. 
Principal Investigator ..................................................................................................48 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................49 
8.1. 
Inclusion Criteria ........................................................................................................49 
8.2. 
Exclusion Criteria .......................................................................................................50 
8.3. 
Subject Enrollment .....................................................................................................51 
8.4. 
Subject Withdrawal Criteria .......................................................................................51 
8.5. 
Replacement of Subjects .............................................................................................52 
8.6. 
Premature Termination of Study or Study Site ...........................................................52 
9. 
INVESTIGATIONAL PRODUCT ............................................................................53 
9.1. 
Preparation of Ad-RTS-hIL-12...................................................................................53 
9.2. 
Preparation of Veledimex ...........................................................................................53 
9.3. 
Handling and Storage .................................................................................................53 
9.4. 
Treatment Compliance ................................................................................................53 
9.5. 
Disposition of Unused Drug .......................................................................................53 
9.6. 
Accountability and Dispensation ................................................................................53 
10. 
TREATMENT ADMINISTRATION ........................................................................54 
10.1. 
Ad-RTS-hIL-12 Dosage and Administration Procedures ...........................................54 
10.2. 
Veledimex Administration and Timing ......................................................................54 
11. 
CONCOMITANT THERAPY ...................................................................................56 
11.1. 
Permitted Medications ................................................................................................56 
11.2. 
Prohibited Medications ...............................................................................................56 
12. 
STUDY PROCEDURES ............................................................................................57 
12.1. 
Written Informed Consent ..........................................................................................57 
12.2. 
Subject Registration ....................................................................................................57 


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12.3. 
Schedule of Procedures and Observations ..................................................................57 
12.3.1. 
Study Tests, Exams, and Procedures ..........................................................................57 
12.3.2. 
Screening ....................................................................................................................59 
12.3.3. 
Treatment Period – Day 0-14 .....................................................................................60 
12.3.4. 
Treatment Period Day 0 (Ad-RTS-hIL-12 + Veledimex Administration) .................60 
12.3.5. 
Treatment Period Day 1 ..............................................................................................61 
12.3.6. 
Treatment Period Day 2 ..............................................................................................62 
12.3.7. 
Treatment Period Day 3 ..............................................................................................62 
12.3.8. 
Treatment Period Days 4-6 (to occur Day 4, Day 5, and Day 6) ...............................63 
12.3.9. 
Treatment Period Day 7 ..............................................................................................64 
12.3.10. 
Treatment Period Days 8-13 .......................................................................................64 
12.3.11. 
Treatment Period Day 14 ............................................................................................64 
12.3.12. 
Initial Follow-Up Period Day 15 ................................................................................65 
12.3.13. 
Initial Follow-Up Period Day 28 (± 7 days) ...............................................................66 
12.3.14. 
Initial Follow-Up Period Day 56 (± 7 days) ...............................................................66 
12.3.15. 
Long-Term Follow-Up (every 8 weeks ± 1 week) .....................................................67 
12.3.16. 
Unscheduled Visit Collections ...................................................................................67 
13. 
TUMOR RESPONSE ASSESSMENTS ....................................................................68 
13.1. 
Tumor Response .........................................................................................................68 
13.2. 
Tumor Response Evaluation and Pseudo-Progression ...............................................68 
14. 
ASSESSMENT OF SAFETY .....................................................................................70 
14.1. 
Adverse Events and Definitions .................................................................................70 
14.2. 
Evaluation of Adverse Events ....................................................................................70 
14.3. 
Determination of Seriousness .....................................................................................71 
14.3.1. 
Serious Adverse Event ................................................................................................71 
14.3.2. 
Non-Serious Adverse Event .......................................................................................72 
14.4. 
Determination of Severity ...........................................................................................72 
14.5. 
Determination of Causality .........................................................................................72 
14.6. 
Documenting Adverse Events ....................................................................................73 
14.7. 
Reporting Dose-Limiting Toxicities and Serious Adverse Events .............................74 
14.8. 
Sponsor and Investigator Responsibility for Adverse Events ....................................75 
14.9. 
Follow-Up Information for Adverse Events ...............................................................75 




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17.8.2. 
Subject Informed Consent Form .................................................................................85 
17.9. 
Audits and Inspections ................................................................................................85 
18. 
PROTOCOL APPROVAL .........................................................................................86 
19. 
LIST OF REFERENCES ............................................................................................87 
20. 
APPENDICES ............................................................................................................91 
APPENDIX 1. LANSKY PERFORMANCE STATUS .............................................................92 
APPENDIX 2. KARNOFSKY PERFORMANCE STATUS .....................................................93 
APPENDIX 3. ECOG PERFORMANCE STATUS...................................................................94 
APPENDIX 4. PROHIBITED AND PERMITTED ANTIEPILEPTIC DRUGS.......................95 
APPENDIX 5. RECOMMENDED REGIMEN FOR ANTIPYRETIC AND/OR 
ANALGESIC PROPHYLAXIS .................................................................................96 
APPENDIX 6. IMMUNOTHERAPY RESPONSE ASSESSMENT IN NEURO-
ONCOLOGY:  A REPORT OF THE RANO WORKING GROUP .........................97 
 


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LIST OF TABLES 
Table 1: 
Schedule of Study Procedures ....................................................................................25 
Table 2: 
Arm 1 Schedule of Veledimex Pharmacokinetic Sampling Times ............................29 
Table 3: 
Arm 2 Schedule of Veledimex Pharmacokinetic Sampling Times ............................29 
Table 4a: 
ATI001-103 Cohorts ...................................................................................................41 
Table 4b: Veledimex Dosing Table ............................................................................................42 
Table 5: 
Dose Escalation and De-Escalation Decision Rules ...................................................44 
Table 6: 
Criteria for Dose Delay and Dose Reduction .............................................................47 
 






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Abbreviation or Specialist Term 
Explanation 
GalRE/P 
Gal4 responsive promoter 
GCP 
Good Clinical Practice 
hIL-12 
human interleukin-12 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IFN-γ 
interferon-gamma 
INR 
international normalized ratio 
IP-10 
IFN-γ-induced protein 10 
iRANO 
Immunotherapy Response Assessment for Neuro-Oncology 
IRB 
Institutional Review Board 
IV 
intravenous(ly) 
IRES 
internal ribosome entry site 
LDH 
lactate dehydrogenase 
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 
PTT 
partial thromboplastin time 
PFS 
progression -free survival 
PI 
Principal Investigator 
PK 
pharmacokinetic(s) 
PKP 
Pharmacokinetics Population 
PO 
oral(ly) 
polyA 
polyadenylation signal 
PUbC 
ubiquitin C promoter 


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Abbreviation or Specialist Term 
Explanation 
QD 
once daily 
rAd 
recombinant adenovirus 
RANO 
Response Assessment for Neuro-Oncology 
RBC 
red blood cell 
rhIL-12 
recombinant human IL-12 
RTS 
 
RXR 
retinoid X receptor 
SAE 
serious adverse event 
SRC 
Safety Review Committee 
TEAE 
treatment-emergent adverse event   
Th1 
T helper cell type 1 
ULN 
upper limit of normal 
Vp 
viral particles 
VP16-RXR 
fusion between VP16 transcriptional activation domain and 
a chimeric RXR 
WBC 
white blood cell 
 


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4. 
CLINICAL PROTOCOL SUMMARY 
Title of Study:  
A Phase I/II Study of Ad-RTS-hIL-12, an Inducible Adenoviral Vector Engineered to Express hIL-12 
in the Presence of the Activator Ligand Veledimex in Pediatric Brain Tumor Subjects 
Protocol Number:  
ATI001-103 
Clinical Phase:  
Phase I/II 
Investigational Product:  
Adenovirus-
 (RTS)-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, which is activated in the presence of the orally (PO) 
administered 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 depends on the dose and frequency of veledimex administration, 
the expression of hIL-12 can be modulated and turned on and off by the veledimex dose and schedule. 
Primary Objective: 
• 
Phase I/II: To determine the safety and tolerability of intratumoral Ad-RTS-hIL-12 and 
varying veledimex doses administered PO in pediatric brain tumor subjects 
(supratentorial and/or DIPG) 
Secondary Objectives: 
• 
Phase I: To determine the recommended Phase II veledimex dose in pediatric brain tumor 
subjects when given with intratumoral Ad-RTS-hIL-12 (supratentorial and/or DIPG) 
• 
Phase I/II: To determine the pharmacokinetics (PK) of veledimex in subjects treated with 
Ad-RTS-hIL-12 + veledimex (supratentorial and/or DIPG) 
• 
Phase I: To determine the veledimex concentration ratio between the brain tumor and 
blood in subjects treated with Ad-RTS-hIL-12 + veledimex (Arm 1 only)  
 
 
• 
Phase I/II: To determine investigator assessment of response, including tumor objective 
response rate (ORR) and progression-free survival (PFS) of subjects treated with Ad-
RTS-hIL-12 + veledimex (supratentorial and/or DIPG) 
• 
Phase I/II: To determine overall survival (OS) of subjects treated with Ad-RTS-hIL-12 + 
veledimex (supratentorial and/or DIPG) 
 
 
 
 




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Arm 2: Subjects with DIPG who will NOT undergo tumor resection 
Subjects with DIPG who will not undergo tumor resection will receive Ad-RTS-hIL-12 by standard 
stereotactic surgery on Day 0. At the time of stereotactic surgery, prior to Ad-RTS-hIL-12 injection, 
brain tumor biopsy and blood samples will be collected.  
Ad-RTS-hIL-12 
 will be administered by stereotactic injection into the intratumoral site.  
The day of Ad-RTS-hIL-12 administration is designated as Day 0. The total amount delivered to each 
site will be recorded in the eCRF. If 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 PO QD for 14 days. The first 
veledimex dose is to be given on Day 1, preferably in the morning and within approximately 
30 minutes of completion of a regular meal. Subsequent veledimex doses (Days 2 to 14) are to be 
taken QD and at approximately the same time of day (± 1 hour) as the Day 1 dosing and within 
approximately 30 minutes of completion of a regular meal. There should be a minimum of 10 hours 
between veledimex doses.   
Cohorts: 
Arm 1: This study has been modified to explore one veledimex dose in Arm 1: 10 mg.  
Arm 2: This study is designed to explore two veledimex doses in Arm 2: 10 mg and 20 mg. Subject 
enrollment and veledimex dose escalation will proceed according to a standard 3+3 design. The first 
cohort will receive 10 mg veledimex followed by the second cohort receiving 20 mg veledimex.   
Arm 1 and Arm 2 subjects may exhibit different safety and tolerability profiles. The 3+3 standard 
study design has been modified to independently evaluate the two arms separately. 
The study arms and assigned doses will be divided into three cohorts as shown below: 
Arm 
Cohort 
Procedure 
Veledimex Dosea Assigned   
1 
1 
Craniotomy 
10 mg 
2 
3b 
Stereotactic 
10 mg 
2 
4 
Stereotactic 
20 mg 
a Doses are BSA-adjusted doses 
b Arm 1 Cohort 2 was removed in Protocol Amendment 2. The SRC reviewed the safety profile of Arm 1 
Cohort 1 and determined it was appropriate to move forward with Arm 1, Cohort 2 and Arm 2, Cohort 1, 
however due to issues with enrollment of supratentorial patients, it was determined not to proceed with Cohort 
2. 
Note: After the completion of a phase I dose escalation cohort in Arm 2, the SRC may elect to expand that 
cohort by up to 30 DIPG patients, which will be considered the Phase II component of study.  
Each cohort will consist of subjects ≤ 21 years-of-age who meet eligibility criteria.    
Each subject in each dose escalation cohort will be monitored for 28 days after Ad-RTS-hIL-12 
injection before additional subjects are enrolled in the same cohort. The evaluation period for DLT is 
28 days after Ad-RTS-hIL-12 injection (Day 0 to Day 28). 


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Determination of safety and the recommendation to expand the current dose cohort, dose escalate, or 
discontinue the investigation, will occur after all dosed subjects in a cohort have been evaluated for at 
least 28 days after Ad-RTS-hIL-12 injection, as described in Section 7.3. 
Number of Centers:  
Approximately 3 to 5 centers  
Number of Subjects (planned):  
Approximately 45 subjects may be enrolled. 
Study Population:  
The eligible study population includes pediatric subjects with a) recurrent or refractory supratentorial 
brain tumors, not in direct continuity with the ventricular system, that are unresponsive to 
conventional treatment or for which there is no alternative curative therapy (Arm 1) and b) non-
disseminated DIPG post prior standard focal radiotherapy and for which a biopsy has previously been 
obtained (access to results required; access to tissue preferred) (Arm 2). 
Inclusion Criteria: 
1. Male or female subjects ≤ 21 years-of-age with the demonstrated ability to swallow capsules 
whole and who are willing to provide access to previously obtained biopsy results 
2. Provision of written informed consent and assent, when applicable, for tumor resection, 
stereotactic surgery, tumor biopsy, sample collection, and/or treatment with study drug prior 
to undergoing any study-specific procedures 
3. Arm 1: Evidence of recurrent or progressive supratentorial tumor, which has shown a > 25% 
increase in bi-dimensional measurements by MRI or is refractory with significant 
neuro-deterioration that is not otherwise explained with no known curative therapy, not in 
direct continuity with the ventricular system (e.g., there is physical separation between the 
tumor and ventricle, the tumor does not open directly into the ventricular system). 
Arm 2: Clinical presentation of DIPG and compatible MRI with approximately 2/3 of the 
pons included and without evidence of dissemination. Subjects should be ≥ 2 weeks and ≤ 10 
weeks post standard focal radiotherapy (i.e., dose of 5400 to 5960 cGy and maximum 
dexamethasone of 1 mg/m2/day). 
4. 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. Targeted agents, including small-molecular tyrosine kinase inhibitors: 2 weeks 
b. Other cytotoxic agents: 3 weeks 
c. Nitrosoureas: 6 weeks 
d. Monoclonal antibody immunotherapies (e.g., PD-1, CTLA-4): 6 weeks 
e. Vaccine-based and/or viral therapy: 3 months 
5. On a stable or decreasing dose of dexamethasone for the previous 7 days 
6. Able to undergo standard MRI scans with contrast agent before enrollment and after 
treatment 


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7. Have age-appropriate functional performance: 
a. Lansky score ≥ 40 (Appendix 1) or  
b. Karnofsky score > 50 (Appendix 2) or  
c. Eastern Cooperative Oncology Group (ECOG) score ≤ 2 (Appendix 3) 
8. Have adequate bone marrow reserves and liver and kidney function, as assessed by the 
following laboratory requirements: 
a. Hemoglobin ≥ 8 g/L 
b. Absolute lymphocyte count ≥ 500/mm3 
c. Absolute neutrophil count ≥ 1000/mm3 
d. Platelets ≥ 100,000/mm3 (untransfused [> 5 days] without growth factors) 
e. Serum creatinine ≤ 1.5 x upper limit of normal (ULN) for age 
f. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x ULN for age 
g. Total bilirubin < 1.5 x ULN for age 
h. International normalized ratio (INR) and activated thromboplastin time within normal 
institutional limits 
9. Male and female subjects of childbearing potential must agree to use a highly reliable method 
of birth control (expected failure rate < 1% per year) from the Screening visit through 28 days 
after the last dose of study drug. Women of childbearing potential must have a negative 
pregnancy test at screening. 
Exclusion Criteria: 
1. Radiotherapy treatment prior to the first veledimex dose: 
a. Focal radiation ≤ 4 weeks 
b. Whole-brain radiation ≤ 6 weeks 
c. Cranio-spinal radiation ≤ 12 weeks 
 
Note: Subjects in Arm 2 (i.e., with DIPG) must be ≥ 2 weeks and ≤ 10 weeks post standard 
focal radiotherapy (dose of 5400 to 5960 cGy and maximum dexamethasone of 1 mg/m2/day) 
per Inclusion Criterion 3 above. 
2. Subjects with clinically significant increased intracranial pressure (e.g., impending herniation 
or requirement for immediate palliative treatment) or uncontrolled seizures 
3. Subjects whose body surface area (BSA) would expose them to < 75% or > 125% of the 
target dose per the provided dosing table 
4. Known immunosuppressive disease, autoimmune condition, and/or chronic viral infection 
(e.g., human immunodeficiency virus [HIV], hepatitis) 
5. 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. 
6. Use of enzyme-inducing antiepileptic drugs (EIAEDs) within 7 days prior to the first dose of 
study drug. See Appendix 4 for prohibited and permitted antiepileptic drugs. 
7. Other concurrent clinically active malignant disease, requiring treatment 


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8. Nursing or pregnant females 
9. Prior exposure to veledimex 
10. 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 
11. Use of heparin or acetylsalicylic acid (ASA) without consultation with the Medical Monitor 
a. The use of systemic heparinization, or any ASA containing medications, is prohibited 
during active dosing with veledimex. Prophylactic heparin SC, per institutional protocol, 
or heparin when used for maintaining patency of an access port of a PICC line is 
permitted. 
12. Presence of any contraindication for a neurosurgical procedure 
13. Unstable or clinically significant concurrent medical condition that would, in the opinion of 
the Investigator as agreed to by the Medical Monitor, jeopardize the safety of a subject and/or 
their compliance with the protocol 
Study Oversight for Safety Evaluation:  
The first level of safety oversight will occur through the site Investigator in conjunction with the 
Medical Monitor. The site Investigator will communicate with the Medical Monitor during the active 
dosing period for all subjects on a daily basis regarding clinical status and laboratory values, prior to 
the patient receiving the daily dose of veledimex, and additionally as clinically indicated.  
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 subject 
safety within each cohort. If no significant safety events occur with the first subject of each cohort, 
the second and third subjects will be enrolled and treated. If a significant safety event occurs with the 
first subject, the SRC will convene to evaluate the safety event(s) and to make a recommendation and 
decision on the enrollment of the second and third subjects in the same cohort. 
Upon completion of each cohort, the SRC will meet to review the data collected to determine next 
steps as described in Section 7.3. Enrollment in Cohort 4 (with the 20 mg assigned veledimex dose) 
will not commence until the SRC has determined that dosing at the lower level, Cohort 3, did not 
result in DLTs that would preclude dose escalation. 
In addition to recommending the opening of Arm 2 Cohort 3, or dose escalation to Cohort 4, the SRC 
may also determine if the study should proceed with the Phase II portion (an expansion of an Arm 2 
cohort). In the event that the SRC determines that escalation and/or expansion is not warranted, a 
decision will be made about stopping the investigation. At the discretion of the SRC, the investigation 
may be continued at a lower dose. Dose escalation, cohort expansion, and de-escalation rules will be 
followed as defined in Section 7.3 and study stopping rules will be followed as defined in Section 
7.10. 
 
 


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Study Drug Dose and Mode of Administration:  
Ad-RTS-hIL-12: 
Ad-RTS-hIL-12 will be administered by either 
 injection into residual tumor sites 
immediately after tumor resection (Arm 1) or by stereotactic injection into the intratumoral site (Arm 
2). 
Veledimex: 
Veledimex will be administered PO. There should be a minimum of 10 hours between veledimex 
doses.   
Arm 1 (Cohort 1) will receive veledimex 3 (± 2) hours before the planned craniotomy and will 
continue veledimex dosing after Ad-RTS-hIL-12 administration for an additional 14 days.  
Subsequent veledimex doses (Days 1 to 14) are to be taken QD and at approximately the same time of 
day (± 1 hour) as the Day 1 dosing and within approximately 30 minutes of completion of a regular 
meal. 
Arm 2 (Cohorts 3 and 4) will receive veledimex only after Ad-RTS-hIL-12 administration for 14 
days. The first veledimex dose is to be given on Day 1, preferably in the morning and within 
approximately 30 minutes of completion of a regular meal. Subsequent veledimex doses (Days 2 to 
14) are to be taken QD and at approximately the same time of day (± 1 hour) as the Day 1 dosing and 
within approximately 30 minutes of completion of a regular meal.  
Based on the planned Phase III dose (20 mg [approximately 10.6 mg/m2]) in the adult population, this 
study will explore the following BSA-adjusted veledimex doses given after Ad-RTS-hIL-12 
 
 administration.  The starting dose in Cohort 1 will be 10 mg, which is approximately 5.3 mg/m2. 
The actual administered dose will depend on the subject’s BSA and available capsule sizes. Because 
veledimex is an oral agent and is supplied in fixed capsule sizes (5 mg and 20 mg), the actual 
administered dose is based on a subject’s BSA and is bound by the rounding constraints set by 5 mg. 
The Sponsor developed a BSA-adjusted dosing algorithm designed to enable dosing within 25% of 
the target mg/m2 dose. 
If a subject’s BSA would expose the subject to < 75% or > 125% of the target assigned dose, the 
actual administered dose will be modified to ensure that the target mg/m2 dose is achieved. Minimum 
BSA restrictions for enrollment must be met in order for a subject to be appropriately dosed.  
Potential subjects whose BSAs do not have a correlated administered dose may be enrolled at the 
discretion of the Investigator and the Medical Monitor, but will not be considered in the assessment of 
the recommended Phase II pediatric dose. Dosing of these subjects can only commence once the 
cohort has been reviewed by the SRC and determined that the dosing at the specified level (10 mg or 
20 mg) is appropriate for escalation or as the recommended Phase II pediatric dose. These subjects 
will be analyzed separately. 
The dosing table illustrates this algorithm and captures the BSA-adjusted actual administered dose 
that subjects would receive at assigned dose levels based on a minimum capsule size of 5 mg. 
 
 
 






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• 
Any Grade 3 or higher non-hematologic adverse event that is at least possibly related to 
study drug and lasts ≥ 3 days 
• 
Nausea and vomiting will not be considered a DLT unless at least Grade 3 and refractory 
to antiemetics 
• 
Grade 3 or higher thrombocytopenia (< 50,000/mm3) at least possibly related to study 
drug 
• 
Any Grade 4 hematologic toxicity (except thrombocytopenia) that is at least possibly 
related to study drug and lasts ≥ 5 days 
Dose escalation may be stopped by the Medical Monitor before a DLT is observed, but where the 
observed toxicities indicate the strong likelihood of unacceptable toxicity at higher doses. 
Note: Diagnostic brain tumor biopsy is not considered a DLT. Seizures, headaches, fatigue and 
cerebral or pontine edema are commonly observed in this population and will be recorded according 
to the grade of toxicity but will not be considered a DLT unless a relationship to study drug is deemed 
to be the main contributory factor.  Transient neurological changes are expected in Arm 2 and will not 
be considered a DLT unless they last > 10 days.   
Expansion cohorts will be allowed in Arm 2 if deemed appropriate by the SRC. 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, using the definition 
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 must be 
reported to the Sponsor within 24 hours of Investigator/site awareness. 
Definition of Recommended Phase II Pediatric Dose:  
The recommended Phase II pediatric veledimex dose will be determined from the Evaluable Safety 
Population (ESP), as defined below. The recommended Phase II pediatric dose is defined as the dose 
level below the dose in which ≥ 33% of subjects in the same cohort experience DLTs. If two DLTs 
occur in the same cohort, subject dosing will stop in the cohort experiencing the DLTs. 
Safety Evaluation:  
Safety will be evaluated in the Overall Safety Population (OSP) and the Evaluable Safety Population 
(ESP), as defined below, using National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) v5.0. 
In the DLT evaluation period (Day 0 to Day 28), if any subject experiences a local reaction that 
requires operative intervention and is felt to be attributable to study drug(s); any local reaction that 
has life-threatening consequences requiring urgent intervention or results in death and is felt to be 
attributable to study drug; or any Grade 4 hematologic toxicity, except thrombocytopenia, that is at 
least possibly related to study drug and lasts ≥ 5 days, enrollment of new subjects will be paused 
pending review by the SRC. 
Safety assessments will be based on medical review of adverse event reports and the results of vital 
signs, physical and neurologic examinations, electrocardiograms (ECGs), clinical laboratory tests, and 


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monitoring of the frequency and severity of adverse events. The incidence of adverse events will be 
tabulated and reviewed for potential significance and clinical importance. 
Urine, fecal, saliva, buccal, and blood samples will be collected and tested for viral replication. 
The reporting period for safety data will be from the date of ICF or assent signature through the Initial 
Follow-Up Period (Day 56). 
Evaluation at the Recommended Phase II Pediatric Veledimex Dose:  
A decision to enroll additional subjects as part of an expansion cohort will be made by the SRC. 
Criteria for Evaluation: 
Tumor Response Assessments and Overall Survival: 
The ESP will be evaluated for Investigator assessment of ORR, PFS, and OS. Response will be 
assessed using the baseline (Day 2 ± 24 hours) Immunotherapy Response Assessment for Neuro-
Oncology (iRANO) criteria used to characterize tumor response assessments. In the absence of a 
pediatric RANO criteria, adult response criteria will be used.  
 
 
 
 
 
Pharmacokinetic Evaluations: 
Veledimex PK parameters will be evaluated at each dose level in the dose escalation cohorts and in 
any expansion cohort(s). 
Statistical Methods: 
Analysis Populations: 
This is an amendment to an ongoing study that has been previously described. For all practical 
purposes the connotation of the safety population for the planned safety analysis are subjects being 
denoted in defining the overall safety population (OSP) defined below to distinguish this group from 
the subgroup of subjects denoted as the evaluable safety population (ESP) who must receive Ad-RTS-
hIL-12 and at least one dose of veledimex after injection.  
This distinction provides for inclusion of both drug components (Ad-RTS-hIL-12 + veledimex) in 
order to evaluate dose escalation via the rule-based criteria fundamental to the 3+3 method. This 
means that during dose escalation if at least one of three Ad-RTS-hIL-12 treated subjects does not 
receive at least one dose of veledimex after injection, additional eligible subjects will be enrolled as 
applicable in order to achieve the samples size of three evaluable subjects to assist the SRC’s 
evaluation when making a dose escalation or a dose de-escalation decision. Specifically,  


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• 
The OSP includes all subjects who received at least one dose of veledimex or 
Ad-RTS-hIL-12 
• 
The ESP includes all subjects who received Ad-RTS-hIL-12 and at least one dose of 
veledimex after Ad-RTS-hIL-12 administration, and are BSA conformant 
• 
The Pharmacokinetics Population (PKP) includes all subjects who received veledimex 
with sufficient timepoints 
Safety Analysis: 
The OSP will be used to perform safety evaluations for all safety variables. 
The ESP will be used to make decisions regarding escalation to higher veledimex doses for Arm 2, 
the rule-based criteria of a 3 + 3 design, as previously described. 
For the first (10 mg) veledimex dose cohorts in Arms 1 and 2 (i.e., Cohorts 1 and 3, respectively), a 
minimum of three ESP subjects must be eligible for evaluation of safety. In addition, evaluation of 
any DLTs will be performed according to protocol-defined criteria.  
Safety variables will be tabulated and presented by arm and by dose cohort. Exposure to study drug(s) 
and reasons for discontinuation of study treatment will be tabulated. All treatment-emergent adverse 
events (TEAEs) will be coded according to the System Organ Class and Preferred Term using the 
Medical Dictionary for Regulatory Activities (MedDRA). The TEAEs will be tabulated by the 
number and percent of subjects according to relationship to study drug(s), severity, and seriousness.  
Laboratory parameters will be summarized by visit. Vital signs and physical examination data will be 
listed by visit.  
Tumor Response and Overall Survival Analyses 
If an SRC committee decision results in enrolling subjects into an expansion cohort, the primary 
analysis for tumor response variables and OS will be performed on the ESP population. Secondary 
analyses will include all treated subjects as defined by the safety population denoted the OSP. The 
Investigator assessment of ORR and PFS will be determined for each cohort. The 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 after first dose of study drug, subjects will be censored at the last follow-up contact 
date. A 2-sided confidence interval will be computed for the ORR. The PFS and OS will be analyzed 
using Kaplan-Meier methods. If an expansion cohort to treat up to 30 subjects is not performed, 
instead of a statistical analysis of data from very small sample sizes, listings of the investigator 
assessment of ORR and PFS by subjects will constructed on the subjects treated during the dose 
escalation phase. 
 PK, 
 
Veledimex PK parameters will be determined based on blood (plasma) levels of veledimex using 
WinNonLin Phoenix 64.
 
   
Sample Size Determination 
The choice of the number of subjects was based on the standard 3 + 3 design, modified for 
independent evaluation of two subject arms that may exhibit different safety and tolerability profiles. 


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Up to 45 subjects may be enrolled into this study, including 3 to 6 subjects per cohort, and the 
expansion cohort, if recommended by the SRC. Subjects who withdraw from the study during the 
DLT evaluation period (Day 0 to Day 28) for reasons other than toxicity or disease progression may 
be replaced. 
Study Duration 
The duration of this study from the time of initiating subject screening until completion of survival 
follow-up is anticipated to be approximately 48 months, including 24 months for enrollment and 
24 months for follow-up. 
The study start is defined as the date when the first subject is consented into the study; the study stop 
date is the date when all subjects in the survival follow-up portion of the study have died or reached 
the 24 month follow-up assessment for which the data captured indicate that the subject is still living.  










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Table 2: 
Arm 1 Schedule of Veledimex Pharmacokinetic Sampling Times 
Sample 
Number 
Day 0 
Day 1 
Day 2 
Day 14 
Day 15 
1 
pre-dosea 
pre-dosea 
pre-dosea 
pre-dosea 
24 hours post 
Day 14 doseb 
2 
During resection 
2 hours post-
doseb  
- 
2 hours post-
doseb 
- 
3 
- 
4 hours post-
doseb 
- 
4 hours post-
doseb 
- 
4 
- 
6 hours post-
doseb 
- 
6 hours post-
doseb 
- 
a ≤ 30 minutes prior to veledimex dose 
b PK Collections: post-dose PK collections will have a ± 30-minute draw window 
 
Table 3: 
Arm 2 Schedule of Veledimex Pharmacokinetic Sampling Times 
Sample Number 
Day 0 
Day 1 
Day 2 
Day 14 
Day 15 
1 
- 
pre-dosea 
pre-dosea 
pre-dosea 
24 hours post Day 
14 doseb 
2 
- 
2 hours post-
doseb 
- 
2 hours post-
doseb 
- 
3 
- 
4 hours post-
doseb 
- 
4 hours post-
doseb 
- 
4 
- 
6 hours post-
doseb 
- 
6 hours post-
doseb 
- 
a ≤ 30 minutes prior to veledimex dose 
b PK Collections: post-dose PK collections will have a ± 30-minute draw window 
 


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5.
INTRODUCTION
5.1. 
Disease Background
Pediatric central nervous system tumors are a heterogeneous group of tumors, with subtypes that 
possess distinctly different clinical courses (Johnson, Cullen et al. 2014).  Pediatric glioblastoma 
is characterized by its aggressive clinical course and accounts for a significant amount of 
morbidity and mortality among children with brain tumors.  According to the Central Brain 
Tumor Registry of the United States (CBTRUS), glioblastoma comprises approximately 2.9% of 
brain and central nervous system tumors in children 0 to 19 years old (Ostrom, Gittleman et al. 
2016).  Their 2-year survival rate is approximately 33%.  Although the prognosis of glioblastoma 
is better in children than in adults, there are fewer therapies available for use in children.  
Currently only lomustine and temozolomide are labeled for pediatric use.  Lomustine use in 
pediatrics is not based on adequate and well-controlled clinical studies (NextSource 
Biotechnology 2014).  The safety and effectiveness of temozolomide in pediatric patients have 
not been established (Merck & Co. 2015).  Nonetheless, the current standard-of-care is 
considered to be temozolomide and radiation therapy (Al-Saffar, Marshall et al. 2014). 
The most common form of pediatric brainstem gliomas is diffuse intrinsic pontine glioma 
(DIPG), representing 75% to 85% of these tumors (Warrren 2012).  The prognosis of children 
with DIPG is poor, with a 1-year overall survival (OS) of less than 45% (Cohen, Heideman et al. 
2011).  There are no effective treatments available for DIPG.  Indeed, an open-label Phase II 
study in children with DIPG found no evidence that chemoradiotherapy with temozolomide 
followed by adjuvant temozolomide resulted in better event-free survival or OS than a historical 
control of radiation therapy (Cohen, Heideman et al. 2011).  Other recent studies of pediatric 
subjects with DIPG generally report 2-year survival rates of < 10% (Warrren 2012).  The current 
standard of care for DIPG is focal radiation therapy. 
5.2. 
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, Gerosa et al. 2000).  
IL-12 is produced by innate immune cells in response to pathogens, leading to the production of 
interferon-gamma (IFN-γ) and tumor necrosis factor-alpha from T and natural killer (NK) cells 
(Micallef, Ohtsuki et al. 1996, Trinchieri 2003).  The discovery that IL-12 can drive naïve T 
helper cell differentiation to the inflammatory T helper cell type 1 (Th1) phenotype (Hsieh, 
Macatonia et al. 1993) established IL-12 as a bridge between innate immune cells and the 
adaptive immune response through polarization of naïve cluster of differentiation (CD) CD4+ 
cells.  IL-12 also directly influences CD8+ T cell differentiation (Kalinski, Hilkens et al. 1999, 
Curtsinger, Lins et al. 2003) and the reactivation and survival of memory CD4+ T cells (Yoo, 
Cho et al. 2002).  This is particularly important in the context of the tumor microenvironment, 
where high levels of IL-12 repolarize antigen-experienced CD4+ T cells back to the functional 
antitumor Th1 phenotype (Wesa, Kalinski et al. 2007). 


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The first human study of IL-12 as an anticancer agent was a Phase I dose escalation of 
intravenously (IV) administered recombinant human IL-12 (rhIL-12) in subjects with either 
melanoma or renal cell carcinoma.  There was 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 2 IL-12-related deaths prompted the Food and Drug Administration (FDA) 
to suspend the trial (Atkins, Robertson et al. 1997, Leonard, Sherman et al. 1997).  Additional 
studies confirmed that systemic administration of recombinant IL-12 resulted in significant 
toxicity, limiting its potential for clinical development (Salem, Gillanders et al. 2006).  These 
results prompted the investigation of local (intratumoral) delivery of IL-12 as a direct anticancer 
therapeutic or as an adjuvant to vaccination. 
5.3. 
Adenoviral Vectors for Gene Therapy 
5.3.1. 
Adenoviral Safety 
Adenoviral vectors have been used extensively to deliver a variety of gene products to human 
subjects, including subjects with cancer.  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 to 1 × 1012 viral particles [vp]) was well 
tolerated, with minimal adverse events (AEs) (Patel, Young 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, Li 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 AEs (Shimada, 
Matsubara et al. 2006).  The most common AEs were fever (all 10 subjects [100%]), pain (30%), 
and hyperglycemia (30%), which was attributed to the use of total parental nutrition.  
Hypocalcemia was reported in 20% of subjects and 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 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 adenoviral 
vectors, including transient, mild to moderate fever, malaise, sweating, and lymphopenia 
(Sangro, Massolini 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), IV 
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, overall survival 
(OS) was not improved relative to the standard-of-care regimen (Westphal, Yla-Herttuala 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. 














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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a multicenter, open-label study, of Ad-RTS-hIL-12 administered by intratumoral 
injection and veledimex administered PO  in pediatric brain tumor subjects, starting with phase I 
dose escalation cohorts. After the completion of a phase I dose escalation cohort in Arm 2, the 
SRC may elect to expand that cohort by up to 30 DIPG patients, which will be considered the 
Phase II component of the study. This study will investigate one fixed intratumoral Ad-RTS-hIL-
12 dose 
 
 and escalating veledimex doses to determine the safe and 
tolerable Phase II pediatric dose based on the safety profiles observed in the presence of variable 
corticosteroid exposure. The study schema is outlined in Figure 4 (Arm 1) and Figure 5 (Arm 2). 
This study is divided into 3 periods: the Screening Period, the Treatment Period, and the Follow-
up Period (Initial and Long Term). After the informed consent form (ICF) or subject assent, as 
applicable, is signed, subjects will enter the Screening Period to assess eligibility. Eligible 
subjects will be stratified into one of two arms, according to diagnosis. Arm 1 is open to 
pediatric brain tumor subjects who are scheduled for a standard-of-care craniotomy and tumor 
resection, with the exclusion of subjects with diffuse intrinsic pontine glioma (DIPG). Arm 2 is 
open to subjects with DIPG who are post prior standard focal radiotherapy (≥ 2 weeks and ≤ 10 
weeks). Arm 1 subjects will receive one veledimex dose before the resection procedure. Samples 
(tumor, blood, and cerebrospinal fluid [CSF] [if available]) will be collected as described below. 
After Ad-RTS-hIL-12 intratumoral injection, Arm 1 subjects will continue administration of 
veledimex PO daily for 14 days for a total of 15 doses of veledimex. Arm 2 subjects will receive 
a single Ad-RTS-hIL-12 
 
 dose by stereotactic injection and will receive veledimex 
PO daily for 14 days. 




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Arm 1:  Pediatric brain tumor subjects scheduled for craniotomy and tumor resection 
(excluding DIPG) 
Subjects with a clinical indication for tumor resection will receive veledimex 3 (± 2) hours 
before the craniotomy procedure, on an empty stomach (excluding other medications). At the 
time of tumor resection, brain tumor, blood, and CSF (if available) samples will be collected to 
determine the veledimex concentration ratio between brain tumor, blood, and CSF (if available). 
Immediately after tumor resection, Ad-RTS-hIL-12 
 
 will be administered by 
 injection into approximately two sites within the residual tumor for a total volume of 
0.1 mL. The total amount delivered to each site will be recorded in the CRF. If 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. The day of 
Ad-RTS-hIL-12 administration is designated as Day 0.  When available, an intra-operative 
magnetic resonance imaging (MRI) scan should 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 PO QD for 14 days. The 
first postresection veledimex dose is to be given on Day 1, preferably in the morning and within 
approximately 30 minutes of completion of a regular meal. There should be a minimum of 10 
hours between veledimex doses. Subsequent veledimex doses (Days 2 to 14) are to be taken at 
approximately the same time of day (± 1 hour) as the Day 1 dosing and within approximately 
30 minutes of completion of a regular meal. 
Arm 2:  Subjects with DIPG who will NOT undergo tumor resection 
Subjects with DIPG who will not undergo tumor resection will receive Ad-RTS-hIL-12 by 
standard stereotactic surgery on Day 0. At the time of stereotactic surgery, prior to Ad-RTS-hIL-
12 injection, brain tumor biopsy and blood samples will be collected. Ad-RTS-hIL-12 
 
 will be administered by stereotactic injection into the intratumoral site. The day of Ad-RTS-
hIL-12 administration is designated as Day 0. The total amount delivered to each site will be 
recorded in the eCRF. If 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 PO QD for 14 days. The 
first veledimex dose is to be given on Day 1, preferably in the morning and within approximately 
30 minutes of completion of a regular meal. Subsequent veledimex doses (Days 2 to 14) should 
be at approximately the same time of day (± 1 hour) as the Day 1 dosing and within 
approximately 30 minutes of completion of a regular meal. There should be a minimum of 10 
hours between veledimex doses.   
Cohorts 
Arm 1: This study has been modified to explore one veledimex dose in Arm 1: 10 mg.  
Arm 2: This study is designed to explore two veledimex doses in Arm 2: 10 mg and 20 mg. 
Subject enrollment and veledimex dose escalation will proceed according to a standard 3+3 
design. The first cohort will receive 10 mg veledimex followed by the second cohort receiving 
20 mg veledimex.   


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Arm 1 and Arm 2 subjects may exhibit different safety and tolerability profiles. The 3+3 
standard study design has been modified to independently evaluate the two arms separately. 
The study arms and assigned doses will be divided into 3 cohorts as shown below: 
Table 4a: 
ATI001-103 Cohorts 
Arm 
Cohort 
Indication 
Procedure 
Assigned Veledimex 
Dosea  
1 
1 
Resectable pediatric brain 
tumor 
Craniotomy 
10 mg 
2 
3b 
DIPG 
Stereotactic 
10 mg 
2 
4 
DIPG 
Stereotactic 
20 mg 
a Doses are BSA-adjusted doses 
b Arm 1 Cohort 2 was removed in Protocol Amendment 2. The SRC reviewed the safety profile of Arm 1 Cohort 1 
and determined it was appropriate to move forward with Arm 1, Cohort 2 and Arm 2, Cohort 1, however due to 
issues with enrollment of supratentorial patients, it was determined not to proceed with Cohort 2. 
Note: After the completion of a phase I dose escalation cohort in Arm 2, the SRC may elect to expand that cohort by 
up to 30 DIPG patients, which will be considered the Phase II component of study. 
Each cohort will consist of subjects ≤ 21 years-of-age who meet eligibility criteria.   
Each subject in each dose escalation cohort will be monitored for 28 days after Ad-RTS-hIL-12 
injection before additional subjects are enrolled in the same cohort. The evaluation period for 
DLT is 28 days after Ad-RTS-hIL-12 injection (Day 0 to Day 28). 
Determination of safety and the recommendation to expand the current dose cohort, dose 
escalate, or discontinue the investigation, will occur after all dosed subjects in a cohort have been 
evaluated for at least 28 days after Ad-RTS-hIL-12 injection, as described in Section 7.3. 
The starting dose in Cohort 1 will be 10 mg, which is approximately 5.3 mg/m2.  The actual 
administered dose will depend on the subject’s BSA and available capsule sizes (Table 4b).  
Because veledimex is an PO agent and is supplied in a fixed capsule size (5 mg and 20 mg), the 
actual administered dose is based on a subject’s BSA and is bound by the rounding constraints 
set by 5 mg.  The Sponsor developed a BSA-adjusted dosing algorithm designed to enable 
dosing within 25% of the target dose in mg/m2. 
If a subject’s BSA would expose the subject to < 75% or > 125% of the target assigned dose, the 
actual administered dose will be modified to ensure that the target dose in mg/m2 is achieved. 
Minimum BSA restrictions for enrollment must be met in order for a subject to be appropriately 
dosed. Potential subjects whose BSAs do not have a correlated administered dose may be 
enrolled at the discretion of the Investigator and the Medical Monitor but will not be considered 
in the assessment of the recommended Phase II pediatric dose. Dosing of these subjects can only 
commence once the cohort has been reviewed by the SRC and determined that the dosing at the 
specified level (10 mg or 20 mg) is appropriate for escalation or as the recommended Phase II 
pediatric dose.   These subjects will be analyzed separately. 
The dosing table (Table 4b) illustrates this algorithm and captures the BSA adjusted-actual 
administered dose that subjects would receive at assigned dose levels based on a minimum 
capsule size of 5 mg. 




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veledimex dose will not commence until the SRC has determined that dosing at the lower level, 
Cohort 3, did not result in DLTs that would preclude dose escalation. 
In addition to recommending the opening of Arm 2 Cohort 3, or dose escalation to Cohort 4, the 
SRC may also determine if the study should proceed with the Phase II portion (an expansion of 
an Arm 2 cohort). In the event that the SRC determines that escalation and/or expansion is not 
warranted, a decision will be made about stopping the investigation. At the discretion of the 
SRC, the investigation may be continued at a lower dose. 
Dose escalation, cohort expansion, and de-escalation rules will be followed as defined in Section 
7.3 and study stopping rules will be followed as defined in Section 7.10. 
7.3. 
Dose Escalation, Cohort Expansion, and De-Escalation Decision 
Rules 
Expansion cohort(s) are prospectively planned in this study, in Arm 2, at the discretion of the 
SRC.  
Each subject in each dose escalation cohort (3+3 standard design) will be monitored for 28 days 
before subsequent subjects are enrolled. The SRC will convene after the third and/or final subject 
in each cohort completes the 28-day DLT evaluation period and will make a recommendation 
regarding expanding the current cohort by up to 30 additional subjects (phase II component), 
opening of the next cohort/dose escalating, dose de-escalating, or discontinuing the investigation. 
If the SRC recommends expanding the current cohort, a 28-day review period may not be 
required between each patient. Based on the safety profile of the current cohort, the SRC will 
make a determination related to the waiting period.  
The SRC will determine if/when the MTD is met and may recommend cohort expansion at that 
dose. 
Study stopping rules will be followed as defined in Section 7.10.  
 
Dose Escalation/Cohort Expansion 
Each subject in each dose escalation cohort (3+3 standard design) will be monitored for 28 days 
before subsequent subjects are enrolled. The SRC will convene after the final subject in Cohort 1 
completes the 28-day DLT evaluation period. The SRC will make a recommendation regarding: 
• Opening enrollment of Cohort 3  
• Discontinuing the investigation 
If the SRC recommends opening enrollment in Cohort 3, each subject will be monitored for 28 
days before subsequent subjects are enrolled in the same cohort. The SRC will convene once the 
third and/or final subjects (i.e.. subject 3 of 3 or 6 of 6) in Cohort 3 complete the 28-day DLT 
evaluation period. The SRC will make a recommendation regarding: 
• Expansion of Cohort 3 (Phase II portion) 
• Opening enrollment of Cohort 4 
• Discontinuing the investigation 


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If the SRC recommends enrollment of Cohort 4, each subject will be monitored for 28 days 
before subsequent subjects are enrolled in the same cohort. The SRC will convene once the third 
and/or final subject (i.e., subject 3 of 3 or 6 of 6) in Cohort 4 complete the 28-day DLT 
evaluation period. The SRC will make a recommendation regarding: 
•
Expansion of Cohort 4 (Phase II portion)
•
Discontinuing the investigation
In addition to recommending dose escalation, cohort expansion, or discontinuation of treatment, 
as noted above, the SRC may recommend dose de-escalation at any point based on safety review. 
Dose De-Escalation 
If it is determined that dose escalation or cohort expansion should not proceed, dose de-
escalation may be undertaken and the SRC will consider de-escalating the veledimex dose as 
follows: 
•
De-escalation by increments of 5 mg from the cohort in which 2 or more DLTs were
observed (e.g., 15 mg, de-escalated from 20 mg)
•
If there are 2 or more DLTs in the dose de-escalation cohort, the SRC will consider
stopping enrollment at that dose and de-escalating the veledimex dose by an
additional increment of 5 mg (e.g., 5 mg down from 10 mg) or declaring a previously
studied dose level the recommended Phase II pediatric dose
If no DLTs occur among the three subjects in Cohort 1, dosing may proceed to the next cohort, 
Cohort 3, after the SRC provides their recommendation to proceed (Table 5).  In any cohort, if 
one DLT occurs among the three subjects, three additional subjects will be enrolled. If one or 
more of the three additional subjects experience a DLT, dosing will stop. The SRC will then 
convene to evaluate safety, determine if the recommended Phase II dose has been reached per 
Section 7.5 , and will decide whether to stop treatment or de-escalate veledimex dosing. The 
SRC may also seek an ad hoc safety evaluation and recommendation by external experts as 
needed. 
Table 5: 
Dose Escalation and De-Escalation Decision Rules 
Subjects with DLTs 
(Any Dose Level) 
Decision Rule 
Subject 
Count 
None of the first 3 
subjects OR ≤ 1 subject 
(in the case of a 6-patient 
cohort) experiences a 
DLT  
Expand current dose level cohort or enroll the next higher dose level 
cohort (after SRC recommendation). 
3 or 6 
1 of the first 3 subjects 
experiences a DLT 
Enroll at least 3 more subjects in this dose level cohort. 
If none of the 3 additional subjects experiences a DLT, expand current 
dose level cohort or proceed to the next planned dose level cohort (after 
SRC recommendation). 
6 


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Table 5: 
Dose Escalation and De-Escalation Decision Rules (Continued) 
Subjects with DLTs 
(Any Dose Level) 
Decision Rule 
Subject 
Count 
2 or more subjects in a 
cohort experience a 
DLT 
If 2 subjects experience a DLT, 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 2 DLTs has met the definition of the recommended 
Phase II pediatric veledimex dose (Section 7.5).  Based 
upon this review, the SRC will make a 
recommendation that the cohort either continue at the 
existing dose, at a lower dose level, or other measures 
to be undertaken including discontinuation of 
treatment.  If it has been determined that escalation or 
cohort expansion should not proceed, dose 
de-escalation may be undertaken and the SRC will 
consider de-escalating the veledimex dose as follows: 
o 
De-escalation by increments of 5 mg from the 
cohort in which 2 or more DLTs were 
observed (e.g., 15 mg down from 20 mg). 
• 
If there are 2 of more DLTs in the dose de-escalation 
cohort, the SRC will consider de-escalating the 
veledimex dose by additional increments of 5 mg (e.g., 
5 mg down from 10 mg) or declaring a previously 
studied dose level the recommended  Phase II pediatric 
dose. 
2 to 6 
After completion of a cohort, if it has been determined that the recommended Phase II pediatric 
dose has not been reached, escalation to the next cohort will proceed once recommended and 
authorized by the SRC.   
7.4. 
Dose-Limiting Toxicity 
An event, occurring within the first 28 days (i.e., Day 0 to Day 28) that meets at least one of the 
following conditions:   
• Any local reaction that requires operative intervention and is felt to be attributable to 
study drug 
• Any local reaction that has life-threatening consequences requiring urgent 
intervention or results in death and is felt to be attributable to study drug 
• Any Grade 3 or higher non-hematologic adverse event that is at least possibly related 
to study drug and lasts ≥ 3 days 
• Nausea and vomiting will not be considered a DLT unless at least Grade 3 or 4 and 
refractory to antiemetics (i.e, defined as symptoms unrelieved by maximal medical 
support as directed by the PI (per institutional guidelines) in consultation with the 
medical monitor).  
• Grade 3 or higher thrombocytopenia (< 50,000/mm3) at least possibly related to study 
drug 


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•
Any Grade 4 or higher hematologic toxicity (except thrombocytopenia) that is at least
possibly related to study drug and lasts ≥ 5 days
Dose escalation may be stopped by the Medical Monitor before a DLT is observed, but where the 
observed toxicities indicate the strong likelihood of unacceptable toxicity at higher doses. 
Note: Diagnostic brain tumor biopsy is not considered a DLT. Seizures, headaches, and cerebral 
or pontine edema are commonly observed in this population and will be recorded according to 
the grade of toxicity but will not be considered a DLT unless a relationship to study drug is 
deemed to be the main contributory factor. Transient neurological changes are expected in Arm 2 
and will not be considered a DLT unless they last > 10 days. 
Expansion cohorts will be allowed in Arm 2 if deemed appropriate by the SRC. 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, using the 
definition 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. 
7.5. 
Recommended Phase II Pediatric Veledimex Dose and 
Corticosteroid Exposure 
The recommended Phase II pediatric veledimex dose will be determined using the Evaluable 
Safety Population (ESP). The recommended pediatric Phase II dose is defined as the dose level 
below the dose in which ≥ 33% of subjects in the same cohort experience DLTs. If 2 DLTs occur 
in the same cohort, dose escalation will stop in the cohort experiencing the DLTs. A decision to 
enroll additional subjects in an expansion cohort will be made by the SRC. 
The recommended pediatric Phase II dose in this study will be determined in the context of 
variable corticosteroid exposure and will be reported as such. Investigational treatment requires 
that steroid use be allowed to manage brain tumor related symptoms or edema, especially after 
tumor resection. 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 should consider the minimum starting steroid dose for study 
subjects, if determined that it is safe and appropriate for that individual subject. 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. 
7.6. 
Dose Modification and Dose Delays 
Treatment dose delays and dose reductions for individual subjects will be allowed in the event of 
toxicities, according to the criteria shown in Table 6. If a drug-related Grade 3 or higher AE 
occurs (excluding nausea and/or vomiting in subjects who did not receive optimal treatment with 
anti-emetics), the Investigator in conjunction with the Sponsor’s Medical Monitor will decide 
whether the subject will remain on the study. The withheld doses will not be made up; the 
subject may be allowed to complete dosing according to the remaining schedule. 
As mentioned in Section 7.4, fatigue, seizures, headaches, and cerebral or pontine edema are 
commonly observed in this population and will be recorded according to grade of toxicity, but 


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will not be considered a DLT unless a relationship to study drug is deemed to be the main 
contributory factor. If ≥ 33% of subjects experience DLTs, 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 deemed clinically indicated. 
Table 6: 
Criteria for Dose Delay and Dose Reduction 
Event 
Course of Action 
Any local injection reaction that requires 
operative intervention 
Hold study drug and contact the Medical Monitor 
for instructions on resuming dosing 
Any local injection reaction that has life-
threatening consequences requiring urgent 
intervention or results in death 
Hold study drug and contact the Medical Monitor 
for instruction on resuming dosing 
Any drug-related Grade 3 or higher AEa 
Hold study drug and contact the Medical Monitor 
for instruction on resuming dosing 
a Excluding nausea and/or vomiting in subjects who did not receive optimal treatment with anti-emetics 
7.7. 
Safety Monitoring and Adverse Effect Management 
Safety will be evaluated in the Overall Safety Population (OSP) and the Evaluable Safety 
Population (ESP) using National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) v5.0. Safety assessments will be based on medical review of adverse 
event reports and the results of vital signs, physical and neurologic examinations, 
electrocardiograms (ECGs), clinical laboratory tests, and monitoring of the frequency and 
severity of adverse events. In addition, urine, fecal, saliva, buccal, and blood samples will be 
collected and tested for viral replication. 
7.8. 
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 v5.0 criteria. Study stopping rules will not apply to a specific 
event if it is clearly unrelated to study drug administration. 
7.9. 
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 subject safety and must be recorded as concomitant medications. Please refer to 
exclusion criteria for acute clinically significant and/or chronic infections. 
Note: Because flu-like symptoms (e.g., fever, headache, chills, dehydration, etc.) are commonly 
experienced following adenoviral vector administration, it is strongly 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. 
Please refer to Appendix 5 for the recommended regimen for the prophylactic administration 
of antipyretics and/or analgesics. 


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7.10. 
Study Stopping Rules 
In the DLT evaluation period (Day 0 to Day 28), if any subject experiences a local reaction that 
requires operative intervention and is felt to be attributable to study drug; any local reaction that 
has life-threatening consequences requiring urgent intervention or results in death and is felt to 
be attributable to study drug; or any Grade 4 hematologic toxicity, except thrombocytopenia, that 
is at least possibly related to study drug and lasts ≥ 5 days, enrollment of new subjects will be 
paused pending review by the SRC. 
In the event that there are other subjects actively being dosed in the cohort, the treating site’s 
Principal Investigator (PI) and the Medical Monitor will discuss the relationship to study drug 
and determine whether or not to convene an urgent SRC meeting to make a decision to continue 
active dosing in ongoing subjects. 
The SRC will make a decision to the enrollment of additional subjects at the relevant veledimex 
dose level, to expand the current dose level cohort, to de-escalate veledimex dosing at the 
relevant dose level, or to amend the protocol prior to enrollment of additional subjects, or to 
discontinue enrollment in the study.  In the event that a decision is made to de-escalate dosing, 
the SRC will evaluate the appropriateness of dosing at a previously evaluated lower dose or 
exploring an intermediate dose level. 
For any subject death within 30 days of study therapy, enrollment will be held pending review of 
the event by the SRC. Active dosing in ongoing subjects will continue at the discretion of the 
treating site’s PI and the Medical Monitor pending the SRC review. 
7.11. 
Principal Investigator 
The Principal Investigator (PI) for study reporting purposes will be determined by the time of 
database lock.  The PI will be chosen based on his or her contributions to the study design and/or 
analysis. 


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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Inclusion Criteria 
The eligible study population includes pediatric subjects with a) recurrent or refractory 
supratentorial brain tumors, not in direct continuity with the ventricular system, that are 
unresponsive to conventional treatment or for which there is no alternative curative therapy (Arm 
1) and b) non-disseminated DIPG post prior standard focal radiotherapy and for which a biopsy 
has previously been obtained (access to results required; access to tissue preferred) (Arm 2). 
Inclusion Criteria: 
1. Male or female subjects ≤ 21 years-of-age with the demonstrated ability to swallow 
capsules whole and who are willing to provide access to previously obtained biopsy 
results 
2. Provision of written informed consent and assent, when applicable, for tumor resection, 
stereotactic surgery, tumor biopsy, sample collection, and/or treatment with study drug 
prior to undergoing any study-specific procedures 
3. Arm 1:  Evidence of recurrent or progressive supratentorial tumor, which has shown a 
> 25% increase in bi-dimensional measurements by MRI or is refractory with significant 
neuro-deterioration that is not otherwise explained with no known curative therapy, not in 
direct continuity with the ventricular system (e.g., there is physical separation between 
the tumor and ventricle, the tumor does not open directly into the ventricular system). 
Arm 2: Clinical presentation of DIPG and compatible MRI with approximately 2/3 of the 
pons included and without evidence of dissemination. Subjects should be ≥ 2 weeks and 
≤ 10 weeks post standard focal radiotherapy (i.e., dose of 5400 to 5960 cGy and 
maximum dexamethasone of 1 mg/m2/day). 
4. 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. Targeted agents, including small-molecular tyrosine kinase inhibitors:  2 weeks 
b. Other cytotoxic agents:  3 weeks 
c. Nitrosoureas:  6 weeks 
d. Monoclonal antibody immunotherapies (e.g., PD-1, CTLA-4):  6 weeks 
e. Vaccine-based and/or viral therapy:  3 months 
5. On a stable or decreasing dose of dexamethasone for the previous 7 days 
6. Able to undergo standard MRI scans with contrast agent before enrollment and after 
treatment 
7. Have age-appropriate functional performance: 
a. Lansky score ≥ 40 (Appendix 1) or  
b. Karnofsky score > 50 (Appendix 2) or  
c. Eastern Cooperative Oncology Group (ECOG) score ≤ 2 (Appendix 3) 


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8. Have adequate bone marrow reserves and liver and kidney function, as assessed by the 
following laboratory requirements: 
a. Hemoglobin ≥ 8 g/L 
b. Absolute lymphocyte count ≥ 500/mm3 
c. Absolute neutrophil count ≥ 1000/mm3 
d. Platelets ≥ 100,000/mm3 (untransfused [> 5 days] without growth factors) 
e. Serum creatinine ≤ 1.5 x upper limit of normal (ULN) for age 
f. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x ULN for age 
g. Total bilirubin < 1.5 x ULN for age 
h. International normalized ratio (INR) and activated thromboplastin time within normal 
institutional limits 
9. Male and female subjects of childbearing potential must agree to use a highly reliable 
method of birth control (expected failure rate < 1% per year) from the Screening Visit 
through 28 days after the last dose of study drug.  Women of childbearing potential must 
have a negative pregnancy test at screening. 
8.2. 
Exclusion Criteria 
1. Radiotherapy treatment prior to the first veledimex dose: 
a. Focal radiation ≤ 4 weeks 
b. Whole-brain radiation ≤ 6 weeks 
c. Cranio-spinal radiation ≤ 12 weeks 
 
Note: Subjects in Arm 2 (i.e., with DIPG) must be ≥ 2 weeks and ≤ 10 weeks post 
standard focal radiotherapy (dose of 5400 to 5960 cGy and maximum dexamethasone of 
1 mg/m2/day) per Inclusion Criterion 3 above.  
2. Subjects with clinically significant increased intracranial pressure (e.g., impending 
herniation or requirement for immediate palliative treatment) or uncontrolled seizures 
3. Subjects whose body surface area (BSA) would expose them to < 75% or > 125% of the 
target dose per the provided dosing table 
4. Known immunosuppressive disease, autoimmune condition, and/or chronic viral 
infection (e.g., human immunodeficiency virus [HIV], hepatitis) 
5. 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. 
6. Use of enzyme-inducing antiepileptic drugs (EIAEDs) within 7 days prior to the first 
dose of study drug. See Appendix 4 for prohibited and permitted antiepileptic drugs. 
7. Other concurrent clinically active malignant disease, requiring treatment 
8. Nursing or pregnant females 
9. Prior exposure to veledimex 


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10. 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 
11. Use of heparin or acetylsalicylic acid (ASA) without consultation with the Medical 
Monitor 
a. The use of systemic heparinization, or any ASA containing medications, is prohibited 
during active dosing with veledimex. Prophylactic s.c. heparin, per institutional 
protocol, or heparin used for maintaining patency of an access port of PICC line is 
permitted. 
12. Presence of any contraindication for a neurosurgical procedure 
13. Unstable or clinically significant concurrent medical condition that would, in the opinion 
of the Investigator in conjunction with the Medical Monitor, jeopardize the safety of a 
subject and/or their compliance with the protocol 
8.3. 
Subject Enrollment 
Approximately 45 subjects may be enrolled into the study. 
8.4. 
Subject Withdrawal Criteria 
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.   
A subject may discontinue study treatment prematurely for any of the following reasons: 
• The Investigator 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 discontinue study treatment in the event of any of the following: 
• Subject request to end study treatment 
• Any treatment-related AE(s) that meet withdrawal criteria 
• Substantial noncompliance with study requirements 
• 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 
A subject MUST be withdrawn from the study in the event of any of the following: 
• Withdrawal of informed consent for the study 
• Ad-RTS-hIL-12 injection was not injected 


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Every effort should be made to follow subjects who withdraw from study treatment for ongoing 
treatment-related AEs until resolved, no resolution is expected, or the study has ended. 
8.5. 
Replacement of Subjects 
Subjects who withdraw from the study during the DLT evaluation period (Day 0 to Day 28) for 
reasons other than toxicity or disease progression may be replaced. 
8.6. 
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 
CRFs, 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; a center’s decision to 
re-challenge subject 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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9. 
INVESTIGATIONAL PRODUCT 
9.1. 
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. 
9.2. 
Preparation of Veledimex 
The Sponsor will provide veledimex capsules to be dispensed by the study site pharmacy to 
subjects for PO administration. 
9.3. 
Handling and Storage 
Study drug must be stored in a restricted access area under the storage conditions indicated in the 
Investigator’s Brochure, Pharmacy Manual, or Package Insert. All necessary precautions while 
handling potentially toxic compounds must be strictly followed. 
9.4. 
Treatment Compliance 
The first veledimex dose is expected to be administered when the subject is at the clinical site, 
under careful 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 
veledimex 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 they 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 of the daily dose, the time the subject ate breakfast, the number of capsules 
taken, whether the 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 or before Day 15, so that staff can properly assess dose compliance. 
9.5. 
Disposition of Unused Drug 
All unused Ad-RTS-hIL-12 and veledimex should be destroyed at the study site in accordance 
with standard institutional practice and in accordance with the United States Occupational Safety 
and Health Administration procedures, after full accountability has been documented. Any study 
drug destruction at the study site must be documented and records maintained in the 
Investigator’s study file. 
9.6. 
Accountability and Dispensation 
The Investigator must maintain accurate records accounting for the receipt and dispensation of 
study drug. 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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In Arm 2, the first veledimex dose will be taken the day after administration of Ad-RTS-hIL-12 
(i.e., on Day 1). After the initial dose of veledimex, subjects will continue QD veledimex for an 
additional 13 days. Subjects in Arm 2 will receive up to a total of 14 veledimex doses. 
In both study Arms, veledimex doses (Days 2 to 14) are to be taken QD and at approximately the 
same time of day (± 1 hour) as the Day 1 dosing and within approximately 30 minutes of 
completion of a regular meal. There should be a minimum of 10 hours between veledimex doses.   
All veledimex doses will be recorded and safety monitored. If Ad-RTS-hIL-12 injection is not 
performed, subjects will not receive subsequent veledimex dosing. 


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11. 
CONCOMITANT THERAPY 
Information on concomitant medications, including all medications, blood products, vitamins, 
and other supplements, will be collected from Screening through the Initial Follow-Up Period 
(Day 56). Subjects will be followed to document other anticancer therapies for two years 
following administration of Ad-RTS-hIL-12 (Day 0). 
11.1. 
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 the individual subject. For study subjects who 
require a higher steroid dose, efforts should be made to taper steroids to the lowest 
amount that controls the subject’s symptoms, as determined to be safe and 
appropriate by the treating physician. 
• Antidiarrheal therapy is permitted 
• Anti-emetics are permitted for nausea and vomiting 
11.2. 
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 antiepileptic drugs (EIAEDs) are listed in Appendix 4 and are NOT 
permitted.   
• CYP450 3A4 inducers, inhibitors, or substrates (including vitamins and/or herbal 
supplements) are prohibited prior to the first dose of veledimex until after the last 
dose of veledimex. Consultation with the Medical Monitor is required. 
• Vitamins and/or herbal supplements are not recommended prior to the first dose of 
veledimex and until after the last dose of veledimex due to potential drug-drug 
interactions. Consultation with the Medical Monitor is required. 


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12.
STUDY PROCEDURES
12.1. 
Written Informed Consent 
The written ICF or assent form, as applicable, must be signed before any protocol-specific 
procedures and assessments can be performed. A copy of the signed ICF or assent form, as 
applicable, will be given to the subject and a copy should be filed in the medical record. The 
original ICF or assent form 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 or assent 
form can be used if they were conducted within the timeframe of the Screening Period. Refer to 
Section 17.8 for further information. 
12.2. 
Subject Registration 
Centralized registration of subjects will be completed according to a process defined by the 
Sponsor.  Eligible subjects will 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. 
12.3. 
Schedule of Procedures and Observations 
Screening assessments must be performed within 28 days prior to Ad-RTS-hIL-12 injection. All 
study visits must be completed as described in the protocol while subjects are taking veledimex 
capsules. Initial follow-up period and long-term follow-up period assessments are allowed a 
window of ± 7 days. 
12.3.1. 
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 (Day 56). Subjects will be followed to document other anticancer 
therapies for two years following administration of Ad-RTS-hIL-12 (Day 0). 
Physical Examinations 
A complete physical examination, which includes a neurological examination will be completed 
and documented per the Schedule of Study Procedures (Table 1). 
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 the Schedule of Study Procedures (Table 1). 


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Lansky, Karnofsky, and ECOG Performance Status 
The Lansky Performance Status measures the ability of subjects < 16 years-of-age with cancer to 
perform ordinary tasks; the Karnofsky scale is applicable to subjects ≥ 16 years-of-age. Scores 
for both assessments range from 0 to 100, with a higher score meaning that the subject is better 
able to carry out daily activities. The ECOG score is also used to describe a subject’s functional 
status or decide if a subject can be enrolled in the clinical trial. The ECOG scale ranges from 0 to 
5, with 0 indicating that a subject is fully active and a score of 5 indicating death.   
These scales are used to determine prognosis, measure changes in a subject’s ability to function, 
or decide if a subject can be enrolled in the clinical trial. Subjects must have a Lansky 
Performance Status score of ≥ 40 (Appendix 1), a Karnofsky Performance Status score of > 50 
(Appendix 2), or an ECOG score of ≤ 2 to be included in the study (Appendix 3). Lansky, 
Karnofsky, or ECOG Performance testing will be conducted according to the Schedule of Study 
Procedures (Table 1). 
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 after signing of the ICF or assent and 
through the Initial Follow-up Period (Day 56) must be recorded on the AE CRF. AEs that are 
ongoing at the end of the Initial Follow-up Period and are considered drug related should be 
followed until resolution or no resolution is expected.  
Definitions, documentation, and reporting of AEs and SAEs are described in Section 14. 
Maintaining adequate hydration is crucial. It is important that subjects be instructed repeatedly to 
maintain adequate oral hydration throughout the active veledimex dosing period; study sites must 
closely monitor the subject’s hydration status.  Blood pressure should be monitored regularly. 
Administration of prophylactic antipyretics is strongly recommended during the first week 
following Ad-RTS-hIL-12 injection. 
Clinical Laboratory Assessments 
All laboratory assessments should be collected prior to study drug administration, as applicable, 
unless otherwise stated. 
In the event that the blood volume to be drawn on a given study day would exceed the allowable 
amount, the Principal Investigator and the Medical Monitor will discuss and determine the 
priority of testing to be completed to ensure patient safety. 
The hematology panel comprises a complete blood count (CBC), including white blood cell 
(WBC) count with differential, red blood cell (RBC) count, hematocrit, hemoglobin, erythrocyte 
sedimentation rate (ESR), and platelet count. 
The coagulation panel includes: aPTT/PTT and INR. 
The serum chemistry panel comprises the following parameters: AST, ALT, lactate 
dehydrogenase (LDH), alkaline phosphatase (ALP), lipase, amylase, creatinine, total bilirubin, 
total protein, albumin, blood urea nitrogen (BUN), glucose, sodium, potassium, chloride, 
calcium, phosphorus, C-reactive protein (CRP), and bicarbonate. 


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The urinalysis panel (dipstick) includes: appearance, pH, specific gravity, glucose, 
protein/albumin, blood, ketones, bilirubin, nitrates, and leukocyte esterase. In addition, a 
microscopic exam for casts, crystals, and cells may be done if clinically indicated. 
Pregnancy Testing 
Females of childbearing potential will have a serum pregnancy test at Screening and a urine or 
serum pregnancy test on Day -1 or Day 0, with a negative test result required prior to the first 
dose of study drug (either veledimex [Arm 1] or injection of Ad-RTS-hIL-12 [Arm 2]). 
Pregnancy tests will be repeated on Day 28. 
MRI 
Subjects should be able to undergo MRI scans with a contrast agent at Screening and during 
study participation. MRI scans should be sent to the Sponsor per the Sponsor’s defined process.  
Electrocardiogram 
A single-measurement standard 12-lead electrocardiogram (ECG) will be performed for 
evaluation of the QT/QTc interval and cardiac safety. 
12.3.2. 
Screening 
The screening exams, tests, and procedures that must be done within 28 days of Ad-RTS-hIL-12 
injection are: 
• Signed ICF and assent form, as applicable 
• Medical/cancer history, including prior treatments 
• Physical examination (including targeted neurological examination) 
• Lansky Performance Status, Karnofsky Performance Status, or ECOG status 
• Height and weight 
• Vital signs 
• AEs 
• Concomitant medications, including medications taken within 28 days of 
Ad-RTS-hIL-12 injection 
• Serum pregnancy test for females of childbearing potential 
• Hematology Panel including: CBC, including WBC count with differential, RBC 
count, hematocrit, hemoglobin, ESR, and platelet count 
• Coagulation Panel including: aPTT/PTT and INR  
• Serum Chemistry Panel including: AST, ALT, LDH, ALP, lipase, amylase, 
creatinine, total bilirubin, total protein, albumin, BUN, glucose, sodium, potassium, 
chloride, calcium, phosphorus, CRP, and bicarbonate 
• Urinalysis Panel (dipstick) including: appearance, pH, specific gravity, glucose, 
protein/albumin, presence of blood, ketones, bilirubin, nitrates, and leukocyte 


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esterase.  In addition, a microscopic exam for casts, crystals, and cells may be done if 
clinically indicated 
• ECG 
• Eligibility review 
• Subject registration 
 
 
• MRI scan for surgical planning 
 
 
 
 
12.3.3. 
Treatment Period – Days 0-14 
• All assessments should be performed pre-dose, as applicable, unless otherwise stated. 
• The site Investigator will communicate with the Medical Monitor during the active 
dosing period for all subjects on a daily basis regarding clinical status and laboratory 
values, prior to the patient receiving their daily dose of veledimex, and additionally as 
clinically indicated. 
• Patient contact required daily to discuss clinical status and updates on current/new 
adverse events. If the patient is discharged prior to Day 14, follow-up may occur via 
telephone. Successful contact and contact attempts will be documented in EDC. 
• Subjects should be instructed to remain in close proximity to the clinical site from 
Day 0-14. 
12.3.4. 
Treatment Period Day 0 (Ad-RTS-hIL-12 + Veledimex Administration) 
• Physical examination (including targeted neurological examination) 
• Lansky Performance Status, Karnofsky Performance Status, or ECOG status 
• Weight 
• Vital signs 
• AEs 
• Concomitant medications, including medications taken within 28 days of 
Ad-RTS-hIL-12 injection 
• Survival status 
• Urine or serum pregnancy test for females of childbearing potential (may be replaced 
with testing on Day -1) 
• Hematology Panel including: CBC, including WBC count with differential, RBC 
count, hematocrit, hemoglobin and platelet count, and ESR, (may be replaced with 
testing on Day -1) 


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• Coagulation Panel including:  aPTT/PTT and INR, (may be replaced with testing on 
Day -1) 
• Serum Chemistry Panel including: AST, ALT, LDH, ALP, lipase, amylase, 
creatinine, total bilirubin, total protein, albumin, BUN, glucose, sodium, potassium, 
chloride, calcium, phosphorus, CRP, and bicarbonate (may be replaced with testing 
on Day -1) 
• 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 (may be replaced with testing on Day -1) 
• ECG (may be replaced with testing on Day -1) 
• Confirm eligibility 
• Arm 1: blood samples for veledimex PK pre-dose and at time of resection (see 
Table 2) 
 
 
 
 
• Arm 1:  a cohort-specific-veledimex dose 3 (± 2) hours prior to resection, on an 
empty stomach (excluding other medications) 
• Arm 1: intratumoral Ad-RTS-hIL-12 administered by 
 injection 
• Arm 1: tumor sample and CSF (if available) will be collected at time of resection 
• Arm 2: intratumoral Ad-RTS-hIL-12 administered by stereotactic injection into the 
intratumoral site 
 
 
• Patient contact to discuss clinical status and updates on current/new adverse events 
• PI/MM contact regarding clinical status and laboratory values, prior to veledimex 
administration 
12.3.5. 
Treatment Period Day 1 
• Physical examination (including targeted neurological examination) 
• Vital signs 
• AEs 
• Concomitant medications 
• Survival status 
• Hematology Panel including: CBC, including WBC count with differential, RBC 
count, hematocrit, hemoglobin, ESR, and platelet count 




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• Vital signs 
• AEs 
• Concomitant medications 
• Survival status 
• Hematology Panel including:  CBC, including WBC count with differential, RBC 
count, hematocrit, hemoglobin, and platelet count, and ESR. 
• Coagulation Panel including: aPTT/PTT and INR,  
• Serum Chemistry Panel including: AST, ALT, LDH, ALP, lipase, amylase, 
creatinine, total bilirubin, total protein, albumin, BUN, glucose, sodium, potassium, 
chloride, calcium, phosphorus, CRP, and bicarbonate 
• ECG 
• For all subjects, a cohort-specific veledimex dose 
• Complete veledimex dose diary 
 
 
 
• Patient contact to discuss clinical status and updates on current/new adverse events.  
• PI/MM contact regarding clinical status and laboratory values, prior to veledimex 
administration 
12.3.8. 
Treatment Period Days 4-6 (to occur Day 4, Day 5, and Day 6) 
• AEs 
• Concomitant medications 
• Survival status 
• For all subjects, a cohort-specific veledimex dose 
• Complete veledimex dose diary 
• Hematology Panel including:  CBC, including WBC count with differential, RBC 
count, hematocrit, hemoglobin, and platelet count, and ESR. 
• Serum Chemistry Panel including: AST, ALT, LDH, ALP, lipase, amylase, 
creatinine, total bilirubin, total protein, albumin, BUN, glucose, sodium, potassium, 
chloride, calcium, phosphorus, CRP, and bicarbonate 
 
 
• Patient contact to discuss clinical status and updates on current/new adverse events.  
• PI/MM contact regarding clinical status and laboratory values, prior to veledimex 
administration 


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12.3.9. 
Treatment Period Day 7 
• Physical examination (including targeted neurological examination) 
• Weight 
• Vital signs 
• AEs 
• Concomitant medications 
• Survival status 
• Hematology Panel including: CBC, including WBC count with differential, RBC 
count, hematocrit, hemoglobin and platelet count, ESR 
• Coagulation Panel including: aPTT/PTT and INR,   
• Serum Chemistry Panel including: AST, ALT, LDH, ALP, lipase, amylase, 
creatinine, total bilirubin, total protein, albumin, BUN, glucose, sodium, potassium, 
chloride, calcium, phosphorus, CRP, and bicarbonate 
• For all subjects, a cohort-specific veledimex dose 
• Complete veledimex dose diary 
 
 
 
 
• Patient contact to discuss clinical status and updates on current/new adverse events. 
• PI/MM contact regarding clinical status and laboratory values, prior to veledimex 
administration 
12.3.10. 
Treatment Period Days 8-13  
• AEs 
• Concomitant medications 
• Survival status 
• For all subjects, a cohort-specific veledimex dose 
• Complete veledimex dose diary 
• Patient contact to discuss clinical status and updates on current/new adverse events. 
• PI/MM contact regarding clinical status and laboratory values, prior to veledimex 
administration 
12.3.11. 
Treatment Period Day 14 
• Physical examination (including targeted neurological examination) 
• Lansky Performance Status, Karnofsky Performance Status, or ECOG status 


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• Weight 
• Vital signs 
• AEs 
• Concomitant medications 
• Survival status 
• Hematology Panel including: CBC, including WBC count with differential, RBC 
count, hematocrit, hemoglobin and platelet count, and ESR 
• Coagulation Panel including: aPTT/PTT and INR   
• Serum Chemistry Panel including: AST, ALT, LDH, ALP, lipase, amylase, 
creatinine, total bilirubin, total protein, albumin, BUN, glucose, sodium, potassium, 
chloride, calcium, phosphorus, CRP, and bicarbonate 
• 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 
• ECG 
• For all subjects, a cohort-specific veledimex doseComplete veledimex dose diary 
•
 
• Blood sample for veledimex PK (Arm 1: Table 2; Arm 2: Table 3) 
 
 
 
 
• MRI scan. CSF may be collected at time of MRI via Ommaya reservoir. Collection is 
optional. 
• Patient contact to discuss clinical status and updates on current/new adverse events. 
• PI/MM contact regarding clinical status and laboratory values, prior to veledimex 
administration 
 
 
12.3.12. 
Initial Follow-Up Period Day 15 
• AEs 
• Concomitant medications 
• Survival status 
• Blood sample for veledimex PK (Arm 1: Table 2; Arm 2: Table 3) 


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12.3.13. 
Initial Follow-Up Period Day 28 (± 7 days) 
• Physical examination (including targeted neurological examination) 
• Lansky Performance Status, Karnofsky Performance Status, or ECOG status 
• Weight 
• Vital signs 
• AEs 
• Concomitant medications 
• Survival status 
• Hematology Panel including:  CBC, including WBC count with differential, RBC 
count, hematocrit, hemoglobin and platelet count, and ESR 
• Serum Chemistry Panel including:  AST, ALT, LDH, ALP, lipase, amylase, 
creatinine, total bilirubin, total protein, albumin, BUN, glucose, sodium, potassium, 
chloride, calcium, phosphorus, and bicarbonate 
• Urine or serum pregnancy test for females of childbearing potential  
 
 
 
 
 
 
• MRI scan. CSF may be collected at time of MRI via Ommaya reservoir. Collection is 
optional. 
 
 
12.3.14. 
Initial Follow-Up Period Day 56 (± 7 days) 
• AEs 
• Concomitant medications 
• Survival status 
• MRI scan. CSF may be collected at time of MRI via Ommaya reservoir. Collection is 
optional. 
• Arm 2: A tumor sample should be collected once there is a concern of pseudo-
progression. The biopsy at Day 56 is strongly recommended. Patients should remain 
on-study for continued follow-up until confirmed progression per iRANO or the 
patient meets other withdrawal criteria.    
 
 


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12.3.15. 
Long-Term Follow-Up (every 8 weeks ± 1 week) 
• Concomitant medications (subjects will be followed to document start of new 
anticancer treatments and survival status for two years following administration of 
Ad-RTS-hIL-12, [Day 0]) 
• MRI scan. CSF may be collected at time of MRI via Ommaya reservoir. Collection is 
optional. 
 
 
12.3.16. 
Unscheduled Visit Collections 
In the event of subject termination or an unscheduled visit for a drug-related AE, an unscheduled 
visit kit should be obtained 
 for CSF evaluation, if applicable. 
 
 
• A tumor sample should be collected if there is a concern of pseudo-progression. The 
biopsy at Day 56 is strongly recommended. Patients should remain on-study for 
continued follow-up until confirmed progression per iRANO or the patient meets 
other withdrawal criteria.    
• CSF may be collected at time of the time of MRI scans such as if sedation is 
clinically indicated or if an Ommaya reservoir is implanted. Collection is optional. 


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13. 
TUMOR RESPONSE ASSESSMENTS 
13.1. 
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 on Day 2 (a window of ± 24 hours is allowed). The Ad-RTS-hIL-12-injected lesion 
and/or other measurable brain lesions will be measured according to the iRANO criteria 
guidelines for adults, pending issuance of pediatric criteria (Okada, Weller et al. 2015) (see 
Appendix 6). MRI scans will be collected and stored at the study site and each subject will be 
evaluated for response by the study Investigator. MRI scans and reports should be sent to the 
Sponsor per the Sponsor’s defined process. 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 tumor sample should be collected if there is a concern of 
pseudo-progression. The biopsy at Day 56 is strongly recommended. Repeat scans to confirm 
progression should be completed at 4 weeks and preferably again at 12 weeks (per iRANO) after 
first documentation of progression, if within 6 months of starting investigational therapy. 
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 iRANO criteria. In addition, changes in neurologic function and 
steroid use will be considered to determine stable disease. 
Tumor response assessments will occur at Day 14, at 4 weeks (Day 28 ± 7 days), at 8 weeks 
(Day 56 ± 7 days), and every 8 weeks (± 7 days) 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 two years following administration of Ad-RTS-
hIL-12 (Day 0), whichever occurs first. 
13.2. 
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 Ad-RTS-hIL-12 + veledimex therapy 
since the veledimex treatment period lasts 14 (Arm 2) to 15 (Arm 1) days. Imaging assessments 


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will be performed using iRANO criteria. A tumor sample should be collected once there is a 
concern for pseudo-progression as noted above. The biopsy at Day 56 is strongly recommended. 
Patients should remain on-study for continued follow-up until confirmed progression per iRANO 
or the patient meets other withdrawal criteria.    


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14. 
ASSESSMENT OF SAFETY 
Safety will be evaluated in the Overall Safety Population (OSP) and the Evaluable Safety 
Population (ESP) using CTCAE v5.0. 
The OSP includes all subjects who received at least 1 dose of veledimex or Ad-RTS-hIL-12. 
The ESP includes all subjects who received Ad-RTS-hIL-12 and at least one dose of veledimex 
after Ad-RTS-hIL-12 administration, and are BSA conformant. 
14.1. 
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 as an adverse drug reaction 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. 
14.2. 
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. 
• 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. 


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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” should be reported as an SAE if, by medical opinion, the 
term best describes the cause of death. 
Adverse events will be recorded from the time of consent and followed through the initial 
follow-up period (Day 56). AEs that are ongoing at Day 56 and considered drug related should 
be followed until resolved or no resolution is expected. 
14.3. 
Determination of Seriousness 
14.3.1. 
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 birth. 


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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. 
Important medical events also include: 
 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. 
14.3.2. 
Non-Serious Adverse Event 
An AE that does not fulfill the criteria for a SAE is classified as a non-serious AE. 
14.4. 
Determination of Severity 
The severity of AEs will be assessed according to the NCI CTCAE, v.5.0. If the AE is not 
defined in the NCI CTCAE, v.5.0, 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. 
14.5. 
Determination of Causality 
The Investigator will use medical consideration to determine the potential relationship of the AE 
to the study drug 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, 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 study drug: 
• Unrelated: The event is related to an etiology other than the study drug (the 
alternative etiology must be documented in the study subject’s medical record and/or 
SAE form). 
• Unlikely related: The event is unlikely to be related to the study drug and likely to be 
related to factors other than study drug. 
Relationship assessments that indicate “Related” to study drug: 
• Possibly related: There is an association between the event and the administration of 
the study drug and there is a plausible mechanism for the event to be related to study 
drug; but there may also be alternative etiology, such as characteristics of the 
subject’s clinical status or underlying disease. 
• Probably related: There is an association between the event and the administration 
of study drug, a plausible mechanism for the event to be related to the study drug and 
the event could not be reasonably explained by known characteristics of the subject’s 
clinical status or an alternative etiology is not apparent. 
• Related: There is an association between the event and the administration of study 
drug, a plausible mechanism for the event to be related to the study drug and causes 
other than the study drug have been ruled out and/or the event re-appeared on re-
exposure to the study drug. 
For any untoward medical occurrence that starts before administration of study drug, only those 
that are assessed by the Investigator as protocol related should be reported to the Sponsor as an 
adverse event. If deemed unrelated to a study-specific procedure, the event should be added to 
the Medical History eCRF.  
The following guidelines should be used by Investigators to assess the relationship of an 
untoward medical occurrence 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). 
14.6. 
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 ICF or assent form through the 
initial follow-up period (Day 56). AEs that are ongoing at the end of the Initial Follow-up Period 
and are considered drug related should be followed until resolution or no resolution is expected. 




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• Information regarding study drug administration (e.g., start/stop date, dose, and 
frequency) 
• Day of SAE or DLT occurrence documentation on SAE or DLT report forms 
• Description of event 
• Action taken with the study drug 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) 
14.8. 
Sponsor and Investigator Responsibility for 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, including but not limited to CFR 
312.32. 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. 
14.9. 
Follow-Up Information for Adverse Events 
Safety data will be reported from the time of consent, as applicable, through the initial follow-up 
period (Day 56). Ongoing drug-related AEs should be followed until resolution unless none is 
expected.   
14.10. 
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. 
14.11. 
Overdose 
Study drug overdose of a subject, with or without associated AEs/SAEs, should be reported 
within 24 hours of awareness to the Sponsor (Ziopharm Oncology, Drug Safety and 
Pharmacovigilance, 
. All AEs or SAEs as a result of 
overdose should be reported as described previously in Section 14.6 and Section 14.7. 






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16. 
STATISTICAL METHODS 
This study is designed as a multicenter Phase I/II dose escalation study in pediatric subjects with 
brain tumors. Enrollment in Arm 1 Cohort 1 is open to subjects except those with DIPG; 
enrollment in Arm 2 (i.e., Cohorts 3 and 4) is open to subjects with DIPG only. Cohorts will be 
enrolled according to a standard 3 + 3 design (see Section 7.1).   
The primary analysis will be performed after all subjects complete the Initial Follow-up Period 
(Day 56). Additional analyses will be performed to determine ORR, PFS, and OS. The final 
analysis will be performed when the last subject completes two years of follow-up. 
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. 
16.1. 
Populations for Analysis 
This is an amendment to an ongoing study that has been previously described. For all practical 
purposes the connotation of the safety population for the planned safety analysis are subjects 
being denoted in defining the overall safety population (OSP) defined below to distinguish this 
group from the subgroup of subjects denoted as the evaluable safety population (ESP) who must 
receive Ad-RTS-hIL-12 and at least one dose of veledimex after injection.  
This distinction provides for inclusion of both drug components (Ad-RTS-hIL-12+ veledimex) in 
order to evaluate dose escalation via the rule-based criteria fundamental to the 3+3 method. This 
means that during dose escalation if at least one of three Ad-RTS-hIL-12 treated subjects does 
not receive at least one dose of veledimex, additional eligible subjects will be enrolled as 
applicable in order to achieve the samples size of three evaluable subjects to assist the SRC’s 
evaluation when making a dose escalation or a dose de-escalation decision. Specifically,  
• The OSP will be used to perform safety evaluations for all subjects who have received at 
least one dose of veledimex or Ad-RTS-hIL-12. 
• The ESP will include subjects who received Ad-RTS-hIL-12 and at least one dose of 
their cohort specific-dose of veledimex after Ad-RTS-hIL-12 administration and are BSA 
conformant. The ESP will be used to make decisions regarding escalation to higher 
veledimex doses for Arms 1 and 2 separately, based on a standard 3 + 3 design, as 
described in Section 7.3. 
• The Pharmacokinetics Population (PKP) for veledimex includes all subjects who receive 
veledimex with sufficient PK timepoints. 
Up to 30 evaluable subjects in the Phase II expansion cohort may be enrolled to provide time to 
OS estimation. This subgroup will include subjects treated with both Ad-RTS-hIL-12 and at least 
one dose of veledimex as defined by the ESP and other evaluability criteria described in the 
Statistical Analysis Plan. 
16.2. 
Sample Size and Power Calculations 
• The sample size chosen was based on clinical considerations.  




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16.4. 
Analyses 
16.4.1. 
Baseline Demographics and 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 according to the defined 
populations for analysis. 
16.4.2. 
Safety Analyses 
For the first veledimex dose cohorts in Arms 1 and 2 (i.e., Cohorts 1 and 3, respectively), a 
minimum of three ESP subjects must be eligible for evaluation of safety. In addition, evaluation 
of any DLTs will be performed according to protocol-defined criteria. Safety variables will be 
tabulated and presented by arm and by dose cohort. 
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, 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 subject signs the ICF or assent form, as 
applicable, through the Initial Follow-up Period (Day 56), unless the subject discontinues from 
active follow-up due to one of the following reasons: 
• Symptomatic deterioration also denoted symptomatic progression 
• Loss to follow up 
• Noncompliance with the protocol 
• Other reason not listed above 
Exposure to study drug(s) and reasons for discontinuation of study treatment will be tabulated.  
All treatment emergent- AEs (TEAEs) will be coded according to the System Organ Class and 
Preferred Term using the Medical Dictionary for Regulatory Activities (MedDRA). The TEAEs 
will be tabulated by number and percent of subjects according to relationship to the study 
drug(s), severity, and seriousness. A TEAE 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. 
After the conclusion of the safety evaluation period is triggered by a discontinuation event, the 
subject continues to be followed only for OS. 
Laboratory parameters will be summarized by visit. Listings of vital signs and physical 
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17. 
STUDY MANAGEMENT 
17.1. 
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 and sufficient training on the electronic data capture (EDC) application to permit site 
personnel to enter and/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 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 eCRFs. 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 
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. 
The 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. 
17.2. 
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. 
17.3. 
Study 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 and instruction for eCRF 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, which will include telephone and/or onsite visits. During these visits, eCRFs will be 
reviewed for completeness and adherence to protocol. As part of the data audit, it is expected that 


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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 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 17.5.  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 regulatory authorities. 
17.4. 
Duration of the Study 
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 for follow-up. 
The overall duration is expected to be up to 2 years and 28 days for an individual subject, 
including the following: 
•
Screening period of up 28 days
•
Study treatment period of up to 15 days
•
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 per 
iRANO has been documented. Subjects will be followed for survival status for two years after 
Ad-RTS-hIL-12 injection. The active study period refers to the study period from informed 
consent through the Survival Follow-up Period. 
17.5. 
Records Retention 
Records of drug disposition, eCRFs, and reports of the clinical trial must be maintained by the 
Investigator for a period of at least two 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. 
17.6. 
Institutional Review Board / Independent Ethics Committee 
This protocol and the study ICF and assent form 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. As part of the review of the study, the 
IRB/IEC will be provided the protocol, the Investigator Brochure, and informed consent 
documents, including age appropriate assent forms per each institution’s standards in order to 
determine that the study meets the requirements of 21 CFR 312.50, Subpart D. During the course 
of the study, the Investigator shall make timely and accurate reports to the IRB/IEC on study 


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progress at intervals not exceeding one 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 three months of the completion or 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. 
17.7. 
Confidentiality and HIPPAA 
The ICF and assent form 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 ICF and assent form will also explain that, for data verification purposes, authorized 
representatives of Ziopharm, a regulatory authority (e.g., 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 ICF and assent form 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. 
17.8. 
Informed Consent 
17.8.1. 
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 and assent form 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.  If the prospective subject voluntarily agrees to 
and signs the informed consent statement, he/she may enroll into the study. A copy of his/her 
signed and dated informed consent will be provided to each prospective subject. The signed ICF 
and assent form are to remain in the Investigator’s file. 


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The ICF, assent form, 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 confirm continuation of his/her participation in the study by 
his/her signature on the revised ICF or assent form, if applicable. Any written ICF, assent form, 
and written information must receive IRB/IEC approval/favorable opinion in advance of use. 
17.8.2. 
Subject Informed Consent Form 
Ziopharm will provide a sample subject ICF and assent form for modification, as appropriate, by 
the Investigator. 
17.9. 
Audits and Inspections 
Authorized representatives of Ziopharm, a regulatory authority, an IEC, or an IRB may visit the 
site to perform audits or inspections, including source data verification. The purpose of a 
Ziopharm audit or inspection is to systematically and independently examine all study-related 
activities and documents to determine whether these activities were conducted, and data were 
recorded, analyzed, and accurately reported according to the protocol, GCP guidelines of the 
ICH, and any applicable regulatory requirements. The investigator should contact Ziopharm 
immediately if contacted by a regulatory agency about an inspection. 


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18. 
PROTOCOL APPROVAL 
A Phase I/II Study of Ad-RTS-hIL-12, an Inducible Adenoviral Vector Engineered to 
Express hIL-12 in the Presence of the Activator Ligand Veledimex in Pediatric Brain 
Tumor Subjects 
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 approved 
protocol will be documented.  Any significant deviation or deviation related to dosing or safety 
evaluation will be reported to Ziopharm. 
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   
 
Institution Name:   ____________________________________ 
 
Principal Investigator 
Print Name:  _____________________________________ 
 
Signature: _____________________________________ 
 
 










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20. 
APPENDICES 


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APPENDIX 1. LANSKY PERFORMANCE STATUS 
 
Lansky Performance Status Scale 
Definitions Rating Criteria 
100 
Fully active, normal 
90 
Minor restrictions in physically strenuous activity 
80 
Active, but tires more quickly 
70 
Both greater restriction of, and less time spent in, active play 
60 
Up and around, but minimal active play; keeps busy with quieter 
activities 
50 
Gets dressed, but lies around much of the day; no active play; able to 
participate in all quiet play and activities 
 
40 
Mostly in bed; participates in quiet activities 
30 
In bed; needs assistance even for quiet play 
20 
Often sleeping; play entirely limited to very passive activities 
10 
No play; does not get out of bed 
0 
Unresponsive 
Lansky et al, 1987 
 


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APPENDIX 2. 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 ≥ 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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APPENDIX 3. ECOG PERFORMANCE STATUS 
 
ECOG Performance Status Scale 
Definitions Rating Criteria 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities.  Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled.  Cannot carry on any selfcare.  Totally confined to 
bed or chair 
5 
Dead 
Oken et al, 1982 


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APPENDIX 4. PROHIBITED AND PERMITTED ANTIEPILEPTIC 
DRUGS 
 
Prohibited Enzyme-Inducing Antiepileptic Drugs 
Permitted Antiepileptic Drugs 
Dilantin® (phenytoin) 
Depakote®, Depakene® (valproic acid) 
Felbatol® (felbamate) 
Gabitril® (tigabine) 
Mysoline® (primidone) 
Keppra® (levetircetam) 
Solfoton®, Luminal® (phenobarbital) 
Lamictal® (lamotrigine) 
Tegretol® (carbamazepine) 
Neurontin® (gabapentin) 
Trileptal (oxcarbazepine) 
Topamax® (topiramate) 
 


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APPENDIX 5. 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 recombinant adenovirus vector administration and 
temperatures up to 40°C or 104° F with chills and generalized malaise have been observed with 
treatment.  Because low grade fever is very likely to occur during study treatment, anti-pyretic 
medication is recommended at the situation. 
Acetaminophen and ibuprofen are commonly used anti-pyretic medication for pediatric patients. 
Both are available without a prescription. Current evidence suggests that there is no substantial 
difference in the safety and effectiveness of acetaminophen and ibuprofen in the care of a 
generally healthy child with fever. Severe side-effects of acetaminophen and ibuprofen are rare, 
over doses of acetaminophen may cause liver failure.  Patients with liver disease should avoid 
using acetaminophen. Nephrotoxicity of ibuprofen were reported in children with dehydration. 
Therefore, precaution should be taken for using ibuprofen in patients with dehydration or kidney 
diseases. Some people may be allergic to the medications.  
Alternating doses of ibuprofen and acetaminophen will also effectively control fever and prevent 
accidental overdose.  Although some reports indicated that combination of both may result in a 
lower body temperature for a greater period of time, However, there is a lack of proven efficacy 
and safety evidence of the combination ibuprofen and/or acetaminophen should be taken in 
accordance with the package label.  


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APPENDIX 6. IMMUNOTHERAPY RESPONSE ASSESSMENT IN 
NEURO-ONCOLOGY:  A REPORT OF THE RANO 
WORKING GROUP 
Immunotherapy Response Assessment in Neuro-Oncology: A Report of the RANO Working 
Group  


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Protocol ATI001-103                                                                                                    Amendment 1 – 25Sep2017 
 
 
 
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 Pediatric Brain Tumor Subjects 
Protocol Number: 
ATI001-103 
Study Drug: 
Adenovirus-RheoSwitch Therapeutic System®-human 
interleukin-12 (Ad-RTS-hIL-12) and veledimex (RTS 
activator ligand) 
 
Date of Protocol: 
Amendment 1: 25September2017 
Original: 04April2017 
 
 
 
 
 
 
NOTE TO INVESTIGATORS 
Amendment 1 dated 25 September 2017 will be used to conduct the study in place of any 
preceding version of this protocol. ZIOPHARM Oncology will implement this version as of 25 
September 2017.  This protocol should be submitted to your IRB promptly.  
 
 
CONFIDENTIAL 
 


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Protocol ATI001-103                                                                                                    Amendment 1 – 25Sep2017 
 
 
AMENDMENT 1 
ATI001-103 
1. Summary and Rationale for Changes 
ZIOPHARM is amending the clinical protocol for the ATI001-103 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 Pediatric Brain Tumor Subjects” to provide updated guidance to the investigator 
based on discussions with FDA, and updated SAE reporting process and to administrative edits for 
internal consistency purposes.  
 
2. Tabular Summary of Revisions Implemented in the Amended Protocol 
Updates due to FDA request: 
 
Section in 
Amended 
Protocol 
Revised or Deleted Text/Section 
Rationale for 
Change 
Study Design  
The first subject Each subject in each cohort will be monitored for 218 
days after Ad-RTS-hIL-12 injection before additional subjects are 
enrolled in the same cohort.  The evaluation period for DLT is 28 days 
after Ad-RTS-hIL-12 injection (Day 0 to Day 28). 
 
 
Inclusion 
Criteria 3 
Arm 1:  Evidence of recurrent or progressive supratentorial tumor, 
which has shown a > 25% increase in bi-dimensional measurements by 
MRI or is refractory with significant neuro-deterioration that is not 
otherwise explained with no known curative therapy, not in direct 
continuity with the ventricular system  (e.g., there is physical separation 
between the tumor and ventricule, the tumor does not open directly into 
the ventricular system). 
 
 
Inclusion 
Criteria 8 
Have adequate bone marrow reserves and liver and kidney function, as 
assessed by the following laboratory requirements: 
a. Hemoglobin ≥ 8 g/L 
b. Absolute lymphocyte count ≥ 500/mm3 
c. Absolute neutrophil count ≥ 1000/mm3 
d. Platelets ≥ 100,000/mm3 (untransfused [> 5 days] without growth 
factors) 
e. Serum creatinine ≤ 1.5 x upper limit of normal (ULN) for age 
f. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤5 
2.5 x ULN for age 
g. Total bilirubin < 1.5 x ULN for age 
 
 


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Protocol ATI001-103                                                                                                    Amendment 1 – 25Sep2017 
 
 
Section in 
Amended 
Protocol 
Revised or Deleted Text/Section 
Rationale for 
Change 
h. International normalized ratio (INR) and activated thromboplastin 
time within normal institutional limits 
Study Drug Dose 
and Mode of 
Administration 
 
If a subject’s BSA would expose the subject to < 75% or > 125% of the 
target assigned dose, the actual administered dose will be modified to 
ensure that the target mg/m2 dose is achieved.  Minimum BSA 
restrictions for enrollment must be met in order for a subject to be 
appropriately dosed.  Potential subjects whose BSAs do not have a 
correlated administered dose may be enrolled at the discretion of the 
Investigator and the Medical Monitor, but will not be considered in the 
assessment of the recommended pediatric Phase II dose. Dosing of 
these subjects can only commence once the cohort has been reviewed 
by the SRC and determined that the dosing at the specified level (10 mg 
or 20 mg) is appropriate for escalation or as the recommended Phase 2 
pediatric dose.  These subjects will be analyzed separately. 
 
 
 
Definition of 
DLT 
• 
Any Grade 3 or higher non-hematologic adverse event that is at 
least possibly related to study drug and lasts ≥ 35 days 
• 
If judged appropriate by the SRC, certain DLTs that would 
otherwise preclude dose escalation (eg, observed in the presence of 
a prohibited CYP450 3A4 medication) may not limit the ability to 
escalate to the next dose. 
 
 
7.1 Overall Study 
Design 
Table 4 was updated to Table 4a and re-named ATI1-001 103 Cohorts. 
The following footnote was added: Doses are BSA-adjusted doses.  
Table 7 was updated and moved to become Table 4b (Veledimex 
Dosing Table). 
 
Moved from Section 10.2.1, BSA-Adjusted Dosing  
Table 4: ATI1-001 Study Design The starting dose in Cohort 1 will be 
10 mg, which is approximately 5.3 mg/m2.  The actual administered 
dose will depend on the subject’s BSA and available capsule sizes 
(Table 4b).  Because veledimex is an PO agent and is supplied in a 
fixed capsule size (5 mg and 20 mg), the actual administered dose is 
based on a subject’s BSA and is bound by the rounding constraints set 
by 5 mg.  The Sponsor developed a BSA-adjusted dosing algorithm 
designed to enable dosing within 25% of the target mg/m2 dose. 
If a subject’s BSA would expose the subject to < 75% or > 125% of the 
target assigned dose, the actual administered dose will be modified to 
ensure that the target mg/m2 dose is achieved.  Minimum BSA 
restrictions for enrollment must be met in order for a subject to be 
appropriately dosed.  Potential subjects whose BSAs do not have a 
 
 
 
 




Ad-RTS-hIL-12 + veledimex 
 
ZIOPHARM Oncology, Inc. 
Protocol ATI001-103                                                                                                    Amendment 1 – 25Sep2017 
 
 
Updates due to new SAE reporting process: 
Section in 
Amended 
Protocol 
Revised or Deleted Text/Section 
Rationale for 
Change 
14. 7. Reporting 
Dose-Limiting 
Toxicities and 
Serious Adverse 
Events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Updates for internal consistency: 
 
 
 
Section in 
Amended 
Protocol 
Revised or Deleted Text/Section 
Rationale for 
Change 
Synopsis (Study 
Design) 
 
Each cohort will consist of subjects ≤ 21 years-of-age who meet 
eligibility criteria.  Once the last subject in Cohort 1 completes the 
dose-limiting toxicity (DLT) evaluation period and the SRC has 
approved, enrollment may be opened for Cohort 2 and Cohort 3.  Once 
the last subjects in Cohorts 2 and Cohort 3 completes the DLT 
evaluation period and the SRC has approved, enrollment may be 
opened for Cohort 4. 
 
Updated for internal 
consistency with 
section 7.2.  
Tables 2 and 3 
b   PK Collections: post-dose PK collections will have a ± 30-minute draw 
window 
 
Added for clarity 
Table 5 
Moved from the body of the table to after the table:  
After completion of a cohort, if it has been determined that the recommended 
pediatric Phase 2 dose has not been reached, escalation to the next cohort will 
proceed once recommended and authorized by the SRC.   
Subject Count column added 
Administrative 
change for clarity 
7.4 Dose-
Limiting Toxicity • 
Nausea and vomiting will not be considered a DLT unless at least 
Grade 3 or 4 and refractory to antiemetics (i.e, defined as symptoms 
Updated for clarity      


Ad-RTS-hIL-12 + veledimex 
 
ZIOPHARM Oncology, Inc. 
Protocol ATI001-103                                                                                                    Amendment 1 – 25Sep2017 
 
 
unrelieved by maximal medical support as directed by the PI (per 
institutional guidelines) in consultation with the medical monitor).  
• 
Any Grade 4 or higher hematologic toxicity (except 
thrombocytopenia) that is at least possibly related to study drug and 
lasts ≥ 5 days 
14.3.1. Serious 
Adverse Event 
• 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. Important medical events also 
include: 
Updated formatting for the following (now sub-bullets) to the 
above: 
• 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. 
Administrative 
change for accuracy 
Document 
Minor wording updates and typographical/clerical updates were 
made throughout 
Updated for clarity 
 
 


Ad-RTS-hIL-12 + veledimex 
 
Ziopharm Oncology, Inc. 
Protocol ATI001-103 
 
  
 
Amendment 2 
 
 
PROTOCOL AMENDMENT  
Summary of Changes 
 
Protocol Title: 
A Phase I/II Study of Ad-RTS-hIL-12, an Inducible 
Adenoviral Vector Engineered to Express hIL-12 in the 
Presence of the Activator Ligand Veledimex in Pediatric Brain 
Tumor Subjects 
Protocol Number: 
ATI001-103 
Study Drug: 
Adenovirus-RheoSwitch Therapeutic System®-human 
interleukin-12 (Ad-RTS-hIL-12) and veledimex (RTS 
activator ligand) 
 
Date of Protocol: 
Amendment 2: 30Oct2019 
Amendment 1: 25Sep2017 
Original: 04Apr2017 
 
 
 
 
 
 
NOTE TO INVESTIGATORS 
Amendment 2 dated 30 October 2019 will be used to conduct the study in place of any 
preceding version of this protocol. Ziopharm Oncology, Inc. will implement this version as 
of 30 October 2019. This protocol should be submitted to your IRB promptly.  
 
 
CONFIDENTIAL 
 


Ad-RTS-hIL-12 + veledimex 
 
Ziopharm Oncology, Inc. 
Protocol ATI001-103 
 
  
 
Amendment 2 
 
ATI001-103 Amendment 2 
1. Summary and Rationale for Changes 
Ziopharm is amending the clinical protocol for the ATI001-103 study, “A Phase I/II Study of Ad-
RTS-hIL-12, an Inducible Adenoviral Vector Engineered to Express hIL-12 in the Presence of the 
Activator Ligand Veledimex in Pediatric Brain Tumor Subjects” based on meetings with the Safety 
Review Committee (SRC) to further explore Arm 2, which is in line with Ziopharm’s long-term 
goal of impacting DIPG patients.    
 
2. Tabular Summary of Revisions Implemented in the Amended Protocol 
Section in 
Clinical Protocol 
Summary 
(Section 4) 
Section in 
Amended 
Protocol 
Revised or Deleted Text/Section 
Rationale for 
Change 
 
Title of Study 
 
 
Section 1. 
Title Page 
 
Section 18. 
Protocol 
Approval 
 
A Phase I/II Study of Ad-RTS-hIL-12, an 
Inducible Adenoviral Vector Engineered to 
Express hIL-12 in the Presence of the Activator 
Ligand Veledimex in Pediatric Brain Tumor 
Subjects 
Addition of 
Phase II 
expansion 
cohort in Arm 
2 to provide a 
better estimate 
of  overall 
survival. 
Primary, 
Secondary, and 
Exploratory 
Objectives 
 
 
Section 6. 
Study 
Objectives 
Primary Objective: 
• 
Phase I/II: To determine the safety 
and tolerability of intratumoral Ad-
RTS-hIL-12 and varying PO 
veledimex doses administered PO 
in pediatric brain tumor subjects 
(supratentorial and/or DIPG) 
Secondary Objectives: 
• 
Phase I: To determine the 
recommended Phase II veledimex 
dose in pediatric brain tumor 
subjects when given with 
intratumoral Ad-RTS-hIL-12 
(supratentorial and/or DIPG) 
• 
Phase I/II: To determine the 
pharmacokinetics (PK) of 
veledimex in subjects treated with 
To align with 
addition of 
Phase II 
expansion 
cohort in Arm 
2.  




Ad-RTS-hIL-12 + veledimex 
 
Ziopharm Oncology, Inc. 
Protocol ATI001-103 
 
  
 
Amendment 2 
 
Section in 
Clinical Protocol 
Summary 
(Section 4) 
Section in 
Amended 
Protocol 
Revised or Deleted Text/Section 
Rationale for 
Change 
Cohorts 
 
 
Section 7.1 
Overall Study 
Design 
Arm 1: This study has been modified to 
explore one veledimex dose in Arm 1: 10 mg.  
Arm 2: This study is designed to explore 2two 
veledimex doses in Arm 2: 10 mg and 20 mg. 
Subject enrollment and veledimex dose 
escalation will proceed according to a standard 
3+3 design, modified to independently 
evaluate 2 groups (ie, arms) of subjects that 
may exhibit different safety and tolerability 
profiles, with the . The first cohort of each 
arm receivingwill receive 10 mg veledimex 
followed by the second cohort of each arm 
receiving 20 mg veledimex.   
 
Arm 1 and Arm 2 subjects may exhibit 
different safety and tolerability profiles. The 
3+3 standard study design has been modified 
to independently evaluate the two arms 
separately. 
 
The study arms and assigned doses will be 
divided into 4three cohorts as shown below: 
Cohort 
Arm 
Cohort 
Arm 
Procedure 
Assigned 
Veledimex 
Dosea 
Assigned 
1 
1 
Craniotomy 
10 mg 
32 
23b 
Stereotactic 
10 mg 
42 
24 
Stereotactic 
20 mg 
a Doses are BSA-adjusted doses 
b Arm 1 Cohort 2 was removed in Protocol 
Amendment 2. The SRC reviewed the safety 
profile of Arm 1 Cohort 1 and determined it 
was appropriate to move forward with Arm 
1, Cohort 2 and Arm 2, Cohort 1, however 
due to issues with enrollment of 
supratentorial patients, it was determined 
not to proceed with Cohort 2. 
Removed Arm 
1 Cohort 2. 
The SRC 
reviewed the 
safety profile 
of Arm 1 
Cohort 1 and 
determined it 
was 
appropriate to 
move forward 
with Arm 1, 
Cohort 2 and 
Arm 2, Cohort 
1, however due 
to issues with 
enrollment of 
supratentorial 
patients, it was 
determined not 
to proceed with 
Cohort 2. 
 
Clarification 
that enrollment 
of an 
expansion 
cohort is 
considered the 
Phase II 
portion of the 
study. 


Ad-RTS-hIL-12 + veledimex 
 
Ziopharm Oncology, Inc. 
Protocol ATI001-103 
 
  
 
Amendment 2 
 
Section in 
Clinical Protocol 
Summary 
(Section 4) 
Section in 
Amended 
Protocol 
Revised or Deleted Text/Section 
Rationale for 
Change 
Note: After the completion of a phase I dose 
escalation cohort in Arm 2, the SRC may 
elect to expand that cohort by up to 30 DIPG 
patients, which will be considered the Phase 
II component of the study. 
Safety Oversight 
for Safety 
Evaluation 
 
 
Section 7.2 
Study 
Oversight for 
Safety 
Evaluation 
 
Table 1: 
Schedule of 
Study 
Procedures 
 
Section 12.3.3 
Treatment 
Period – Days 
0-14 
The first level of safety oversight will occur 
through the site Investigator and Medical 
Monitor.  in conjunction with the Medical 
Monitor. The site Investigator will 
communicate with the Medical Monitor 
during the active dosing period for all 
subjects on a daily basis regarding clinical 
status and laboratory values, prior to the 
patient receiving the daily dose of veledimex, 
and additionally as clinically indicated.  
 
 
Based on SRC 
discussions 
regarding 
DIPG 
population, 
ongoing 
communication 
with the patient 
and the 
Sponsor is 
useful to the 
Medical 
Monitor in 
providing 
ongoing 
guidance. 
 
Dose 
Escalation/Cohort 
Expansion 
 
Dose De-
Escalation 
Section 7.3 
Dose 
Escalation, 
Cohort 
Expansion, 
and De-
Escalation 
Decision 
Rules 
Dose Escalation/Cohort Expansion:  
Each subject in each dose escalation cohort 
(3+3 standard design) will be monitored for 
28 days before subsequent subjects are 
enrolled. The SRC will convene after the 
final subject in Cohort 1 completes the 28-
day DLT evaluation period. The SRC will 
make a recommendation regarding:  
• Opening enrollment of Cohort 3  
• Discontinuing the investigation  
 
The SRC will convene once the third and/or 
final subject in Cohort 3 completes the 28-
day DLT evaluation period. The SRC will 
make a recommendation regarding:  
• Expansion of Cohort 3 (Phase II portion)  
• Opening enrollment of Cohort 4  
• Discontinuing the investigation  
 
The SRC will convene once the third and/or 
final subject in Cohort 4 completes the 28-
day DLT evaluation period. Cohorts 1 and 3 
will be reviewed independently by the SRC. 
Removal of 
Arm 1 Cohort 
2, as above, 
and addition of 
Phase II 
expansion 
cohort by up to 
30 patients in 
Arm 2 to 
provide a 
better estimate 
of overall 
survival. 


Ad-RTS-hIL-12 + veledimex 
 
Ziopharm Oncology, Inc. 
Protocol ATI001-103 
 
  
 
Amendment 2 
 
Section in 
Clinical Protocol 
Summary 
(Section 4) 
Section in 
Amended 
Protocol 
Revised or Deleted Text/Section 
Rationale for 
Change 
The SRC will make a recommendation 
regarding:  
• Expansion of Cohort 4 (Phase II portion)  
• Discontinuing the investigation  
 
In addition to recommending dose escalation, 
cohort expansion, or discontinuation of 
treatment, as noted above, the SRC may 
recommend dose de-escalation at any point 
based on safety review. 
 
Dose De-Escalation:  
Based on their review, the SRC will 
recommend either that the cohort continue 
at the existing veledimex dose, begin dosing 
at a lower dose level, or that other measures 
be undertaken, including discontinuation of 
treatment. If it is determined that 
escalationIf it is determined that dose 
escalation or cohort expansion should not 
proceed, dose de-escalation may be undertaken 
and the SRC will consider de-escalating the 
veledimex dose as follows:  
• De-escalation by increments of 5 mg from the 
cohort in which 2two or more DLTs were 
observed (eg,e.g., 15 mg, de-escalated from 20 
mg)  
• If there are 2two or more DLTs in the dose 
de-escalation cohort, the SRC will consider de-
escalating the veledimex dose by an additional 
increment of 5 mg (eg,e.g., 5 mg down from 10 
mg) or declaring a previously studied dose level 
the recommended Phase II pediatric Phase II 
dose.  
Number of 
Subjects 
(planned) 
 
 
 
Section 8.3 
Subject 
Enrollment 
 
Approximately 24Up to 45 subjects may be 
enrolled into this study, including 3 to 6 
subjects per cohort, and the expansion cohort, 
if recommended by the SRC. 
Removal of 
Arm 1 Cohort 
2, as above, 
and addition of 
Phase II 
expansion 
cohort by up to 
30 patients in 
Arm 2 to 
provide a 
better estimate 


Ad-RTS-hIL-12 + veledimex 
 
Ziopharm Oncology, Inc. 
Protocol ATI001-103 
 
  
 
Amendment 2 
 
Section in 
Clinical Protocol 
Summary 
(Section 4) 
Section in 
Amended 
Protocol 
Revised or Deleted Text/Section 
Rationale for 
Change 
of overall 
survival. 
Inclusion Criteria 
 
 
Section 8.1 
Inclusion 
Criteria 
Arm 2: Clinical presentation of DIPG and 
compatible MRI with approximately 2/3 of 
the pons included and without evidence of 
dissemination. Subjects should be ≥ 2 
weeks and ≤ 10 weeks post standard focal 
radiotherapy (i.e., dose of 5400 to 5960 
cGy and maximum dexamethasone of 1 
mg/m2/day). 
To provide 
clarification on 
inclusion 
requirement. 
Inclusion Criteria 
 
 
Section 8.1 
Inclusion 
Criteria 
Have age-appropriate functional performance: 
a. Lansky score ≥ 5040 (Appendix 1) 
or  
b. Karnofsky score > 50 (Appendix 2) 
or  
c. Eastern Cooperative Oncology 
Group (ECOG) score ≤ 2 
(Appendix 3) 
To ensure that 
eligible 
subjects are 
consistent 
across the 
different 
performance 
metrics.  
Exclusion 
Criteria 
 
 
Section 8.2 
Exclusion 
Criteria 
Use of heparin or acetylsalicylic acid (ASA) 
without consultation with the Medical 
Monitor 
a. The use of systemic heparinization, 
or any ASA containing medications, 
is prohibited during active dosing 
with veledimex. Prophylactic heparin 
SC, per institutional protocol, or 
heparin when used for maintaining 
patency of an access port of a PICC 
line is permitted. 
Administrative 
Memo #1 
N/A 
Figure 4: 
Study 
ATI001-103 
Schema: Arm 
1 (Cohort 1) 
 
Figure 5: 
Study 
ATI001-103 
Schema: Arm 
2 (Cohorts 3 
and 4) 
Figure updated to correctly reflect,  
• 
Study ATI001-103 Schema: Arm 1 
(Cohort 1) 
• 
Study ATI001-103 Schema: Arm 2 
(Cohorts 3 and 4) 
Administrative 
Memo #1 
 
Removal of 
Cohort 2 as 
above. 


Ad-RTS-hIL-12 + veledimex 
 
Ziopharm Oncology, Inc. 
Protocol ATI001-103 
 
  
 
Amendment 2 
 
Section in 
Clinical Protocol 
Summary 
(Section 4) 
Section in 
Amended 
Protocol 
Revised or Deleted Text/Section 
Rationale for 
Change 
N/A 
Table 1: 
Schedule of 
Study 
Procedures 
 
Section 12.3.3 
Treatment 
Period – Days 
0-14 
The patient should be contacted every day 
during the treatment period to discuss 
clinical status and updates on current/new 
adverse events. If the patient is discharged 
prior to Day 14, follow-up may occur via 
telephone. Successful contact and contact 
attempts will be documented in EDC. 
Based on SRC 
discussions 
regarding 
DIPG 
population, 
ongoing 
communication 
with the patient 
and the 
Sponsor is 
useful to the 
Medical 
Monitor in 
providing 
ongoing 
guidance. 
 
N/A 
Section 12.3.3 
Treatment 
Period – Days 
0-14 
Subjects should be instructed to remain in 
close proximity to the clinical site from Day 
0-14. 
Due to the 
vulnerability of 
this population, 
advising the 
patient to 
remain local to 
the site would 
be beneficial to 
provide 
additional care 
by the PI, as 
needed. 
N/A 
Table 1: 
Schedule of 
Study 
Procedures 
 
Section 12.3.6 
Treatment 
Period Day 2 
The MRI scan designated on Day 2 should be 
taken within 72 has an allowable window of 
± 24 hours of Ad RTS hIL 12 administration 
and will be considered the baseline scan for 
tumor response assessments.   
Based on SRC 
discussion and 
clinical effect 
that has been 
seen on Day 2 
in previous 
patients. 
Statistical 
Methods- 
Analysis 
Populations 
 
 
Section 16.1 
Populations 
for Analysis 
This is an amendment to an ongoing study 
that has been previously described. For all 
practical purposes the connotation of the 
safety population for the planned safety 
analysis are subjects being denoted in 
defining the overall safety population (OSP) 
defined below to distinguish this group from 
the subgroup of subjects denoted as the 
To provide 
additional 
clarification 
regarding the 
analysis 
populations. 


Ad-RTS-hIL-12 + veledimex 
 
Ziopharm Oncology, Inc. 
Protocol ATI001-103 
 
  
 
Amendment 2 
 
Section in 
Clinical Protocol 
Summary 
(Section 4) 
Section in 
Amended 
Protocol 
Revised or Deleted Text/Section 
Rationale for 
Change 
evaluable safety population (ESP) who must 
receive Ad-RTS-hIL-12 and at least one dose 
of veledimex after injection.  
This distinction provides for inclusion of 
both drug components (Ad-RTS-hIL-12 + 
veledimex) in order to evaluate dose 
escalation via the rule-based criteria 
fundamental to the 3+3 method. This means 
that during dose escalation if at least one of 
three Ad-RTS-hIL-12 treated subjects does 
not receive at least one dose of veledimex 
after injection, additional eligible subjects 
will be enrolled as applicable in order to 
achieve the samples size of three evaluable 
subjects to assist the SRC’s evaluation when 
making a dose escalation or a dose de-
escalation decision. Specifically,  
• 
The OSP includes all subjects who 
received at least 1one dose of 
veledimex (pre tumor resection 
and/or post stereotactic 
procedure) and/or all subjects 
who received Ad-RTS-hIL-12 
• 
The ESP includes all subjects who 
received Ad-RTS-hIL-12 and at 
least 1one dose of veledimex after 
Ad-RTS-hIL-12 administration., 
and are BSA conformant 
• 
The Pharmacokinetics Population 
(PKP) includes all subjects who 
received veledimex with sufficient 
time points.timepoints 
Statistical 
Methods-Tumor 
Response and 
Overall Survival 
Analyses 
 
N/A 
TumorIf an SRC committee decision results 
in enrolling subjects into an expansion 
cohort, the primary analysis for tumor 
response analysis variables and OS will be 
performed on the ESP population. Secondary 
analyses will include all treated subjects as 
defined by the safety population denoted the 
OSP. The Investigator assessment of ORR and 
PFS will be determined for each cohort. The OS 
To provide 
additional 
clarification 
regarding the 
analysis of 
tumor response 
and overall 
survival 


Ad-RTS-hIL-12 + veledimex 
 
Ziopharm Oncology, Inc. 
Protocol ATI001-103 
 
  
 
Amendment 2 
 
Section in 
Clinical Protocol 
Summary 
(Section 4) 
Section in 
Amended 
Protocol 
Revised or Deleted Text/Section 
Rationale for 
Change 
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 2two years after first 
dose of study drug, subjects will be censored at 
the last follow-up contact date. A 2-sided 
confidence interval will be computed for the 
ORR. The PFS and OS will be analyzed using 
Kaplan-Meier methods. If an expansion cohort 
to treat up to 30 subjects is not performed, 
instead of a statistical analysis of data from 
very small sample sizes, listings of the 
investigator assessment of ORR and PFS by 
subjects will constructed on the subjects 
treated during the dose escalation phase. 
N/A 
Section 16.2 
Sample Size 
and Power 
Calculations 
• 
The sample size chosen was based on 
clinical consideration for a standard 
3+3 study considerations.  
• 
For Cohorts 1 and 3, treated at 10 
mg, the 3+3 rule-based dose escalation 
design, modified for criteria will be 
applied to provide an independent 
evaluation of 2 subject arms that may 
exhibit differentalgorithmic safety 
and tolerability profiles.  Power 
calculation for comparison of AE 
rates are simply too inexact to be 
clinically meaningful because the AE 
rates are unknown and cannot even 
by approximately 
projected.assessment to either dose 
escalate from 10 to 20 mg or to 
consider de-escalation, as applicable. 
The SRC will incorporate the 
findings in combination with other 
clinical factors to make the final 
recommendation pertaining to dose 
escalation from 10 mg to 20 mg or 
de-escalation from 10 mg to 5 mg.  
Approximately 24 subjects may be enrolled 
into this study, including 3 to 6 subjects per 
cohort.  Subjects who withdraw from the 
To provide 
statistical 
clarification 
regarding 
sample size 
and power 
calculations. 






Ad-RTS-hIL-12 + veledimex 
 
Ziopharm Oncology, Inc. 
Protocol ATI001-103 
 
  
 
Amendment 2 
 
Section in 
Clinical Protocol 
Summary 
(Section 4) 
Section in 
Amended 
Protocol 
Revised or Deleted Text/Section 
Rationale for 
Change 
N/A 
Table 1: 
Schedule of 
Study 
Procedures 
 
Section 12.3.5 
Treatment 
Period Day 1 
Addition: CT Scan, as clinically indicated 
Based on SRC 
discussions to 
enhance 
reliability of 
patient 
outcome. 
N/A 
Table 1: 
Schedule of 
Study 
Procedures 
 
Section 12.3.1 
Study Tests, 
Exams, and 
Procedures 
*All assessments should be performed prior 
to study drug administration, as applicable, 
unless otherwise stated. 
 
 
Clarification 
N/A 
Table 1: 
Schedule of 
Study 
Procedures 
cc Every 8 weeks from Day 56. 
Clarification 
N/A 
Table 1: 
Schedule of 
Study 
Procedures 
 
Section 12.3.8 
Treatment 
Period Days 
4-6 (to occur 
Day 4, Day 5, 
and Day 6) 
gg Assessments to be performed on Day 4, 
Day 5, and Day 6. 
Clarification 
N/A 
Table 1: 
Schedule of 
Study 
Procedures 
 
Section 
Section 12.3.1 
Study Tests, 
Exams, and 
Procedures 
 
14.2 
Evaluation of 
Adverse events will be recorded from the time 
of consent and followed through 30 days after 
each subject’s last dose of any study drug. 
the initial follow-up period (Day 56). AEs that 
are ongoing at Day 56 and considered drug 
related should be followed until resolved or no 
resolution is expected. 
 
 
Clarification of 
safety 
reporting 
period. 
Inconsistent in 
Amendment 1. 
More 
conservative 
reporting 
period ICF 
through Day 
56 vs. through 
30 days last 


Ad-RTS-hIL-12 + veledimex 
 
Ziopharm Oncology, Inc. 
Protocol ATI001-103 
 
  
 
Amendment 2 
 
Section in 
Clinical Protocol 
Summary 
(Section 4) 
Section in 
Amended 
Protocol 
Revised or Deleted Text/Section 
Rationale for 
Change 
Adverse 
Events 
 
Section 14.6 
Documenting 
Adverse 
Events 
 
Section 14.9 
Follow-Up 
Information 
for Adverse 
Events 
dose of any 
study drug 
(Day 44). 
 
 
N/A 
 
Section 14.5 
Determination 
of Causality 
For any untoward medical occurrence that 
starts before administration of study drug, 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 as an AEadverse event. If 
deemed unrelated to a protocol 
requiredstudy-specific procedure, the event 
should be added to the Medical History 
eCRF. 
Clarification 
that before 
study drug 
administration 
determination 
of relatedness 
to protocol 
assessments is 
required to be 
determined an 
adverse event. 
N/A 
Section 11.2 
Prohibited 
Medications 
• 
NOTE:  Care should be given 
when prescribing medications 
that are classified as CYP450 3A4 
inducers, inhibitors, or substrates 
(including vitamins and/or herbal 
supplements) are prohibited 
prior to the first dose of 
veledimex until after the last dose 
of veledimex. Consultation with 
the Medical Monitor is required. 
• 
Vitamins and/or herbal 
supplements are not 
recommended prior to the first 
dose of veledimex and until after 
the last dose of veledimex due to 
Clarification 
that CYP450 
3A4 
interacting 
drugs are 
prohibited 
during the 
treatment 
period and 
Medical 
Monitor 
consultation is 
required to 
ensure patient 
safety if 
administering.  
 


Ad-RTS-hIL-12 + veledimex 
 
Ziopharm Oncology, Inc. 
Protocol ATI001-103 
 
  
 
Amendment 2 
 
Section in 
Clinical Protocol 
Summary 
(Section 4) 
Section in 
Amended 
Protocol 
Revised or Deleted Text/Section 
Rationale for 
Change 
potential drug-drug interactions 
with the study drug.  In the event 
that one is prescribed, 
consultation. Consultation with 
the Medical Monitor is advised.  
All medications should be 
recorded in the CRF as indicated 
in the completion guidelines. 
required. 
Due to the lack 
of research on 
certain 
vitamins/herbal 
supplements, 
as a 
precautionary 
measure these 
are not 
recommended 
without 
Medical 
Monitor 
consultation to 
ensure patient 
safety if 
administering. 
Safety Evaluation 
Section 7.7 
Safety 
Monitoring 
and Adverse 
Effect 
Management 
 
Section 7.8 
Severity 
Grading and 
Management 
of Local 
Reactions 
 
Section 14. 
Assessment 
of Safety 
 
Section 14.4 
Determination 
of Severity 
Safety will be evaluated in the Overall Safety 
Population (OSP) and the Evaluable Safety 
Population (ESP), as defined below, using 
National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events 
(CTCAE) v4.03 5.0  
Administrative 
Memo #2 


Ad-RTS-hIL-12 + veledimex 
 
Ziopharm Oncology, Inc. 
Protocol ATI001-103 
 
  
 
Amendment 2 
 
Section in 
Clinical Protocol 
Summary 
(Section 4) 
Section in 
Amended 
Protocol 
Revised or Deleted Text/Section 
Rationale for 
Change 
N/A 
Section 16.4.2 
Safety 
Analyses 
The safety evaluation period extends from the 
date the subject signs the ICF or assent form, as 
applicable, until approximately 2 years after 
receiving study drug from through the Initial 
Follow-up Period (Day 1 dosing,56), unless 
the subject discontinues the trial from active 
follow-up due to 1one 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 
Clarification 
on reasons for 
subject 
disconuation 
during the 
safety 
reporting 
period as these 
do not apply 
during this 
time period. 
  
 

SAP_001.pdf: 
 
STATISTICAL ANALYSIS PLAN 
 
A Phase I/II Study of Ad-RTS-hIL-12, an Inducible Adenoviral Vector  
Engineered to Express hIL-12 in the Presence of the Activator  
Ligand Veledimex in Pediatric Brain Tumor Subjects 
 
Protocol Number: 
ATI001-103 
Phase: 
Phase I/II 
Protocol Version and Date:  
Amendment 2: 30OCT2019  
Amendment 1: 25Sep2017 
Original: 04April2017 
Study Drug Name: 
Ad-RTS-hIL-12 and Veledimex 
Sponsor: 
ZIOPHARM Oncology, Inc. 
 
Author:  
 
Analysis Plan Date: 
06May2021 
Analysis Plan Version: 
Version 1.0 
 
 
 
Confidentiality Statement 
All information contained in this document is privileged and confidential to 
ZIOPHARM. Any distribution, copying, or disclosure is strictly prohibited  
without prior written approval by ZIOPHARM. 


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VERSION CONTROL  
Version 
Date 
Draft 1 
22Dec2020 
Draft 2 
06May2021 
 




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TABLE OF CONTENTS 
VERSION CONTROL ....................................................................................................................2 
LIST OF TABLES ...........................................................................................................................7 
LIST OF FIGURES .........................................................................................................................7 
LIST OF ABBREVIATIONS ..........................................................................................................8 
1. 
INTRODUCTION ......................................................................................................10 
2. 
STUDY DESIGN OVERVIEW .................................................................................11 
2.1. 
Overall Study Design before Amendment 2 ...............................................................11 
2.1.1. 
Safety Review Committee (SRC) Recommendations After Review of Arm 1 
Cohort 1 ......................................................................................................................13 
2.2. 
Amendment 2 Study Design Modifications ...............................................................13 
2.2.1. 
Amendment II overview .............................................................................................13 
2.2.2. 
Study Design ...............................................................................................................13 
2.2.3. 
Projection of Study Duration ......................................................................................14 
2.2.4. 
Sample Size ................................................................................................................15 
2.2.5. 
Randomization ............................................................................................................15 
3. 
STUDY OBJECTIVES ..............................................................................................15 
3.1. 
Amendment 2 Revision of Objectives. .......................................................................15 
3.1.1. 
Primary Objectives (before and revised) for Amendment 2: ......................................15 
3.1.2. 
Secondary Objectives (before and revised) for Amendment 2: ..................................16 
 
 
 
 
4. 
STUDY ENDPOINTS AND EVALUATIONS FOR PHASE I COHORTS ............17 
4.1. 
Study Endpoints ..........................................................................................................17 
4.1.1. 
Primary Endpoint ........................................................................................................17 
4.1.2. 
Secondary Endpoints ..................................................................................................17 
 
 
4.2. 
Baseline and Demographic Characteristic Evaluations ..............................................18 
4.3. 
Dose Limiting Toxicity (DLT) ...................................................................................18 
4.4. 
Recommended Pediatric Phase II Veledimex Dose ...................................................19 
4.5. 
Safety Evaluations ......................................................................................................19 
4.6. 
Efficacy Evaluations ...................................................................................................19 


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4.7. 
Pharmacokinetic Assessment ......................................................................................20 
 
 
5. 
ANALYSIS POPULATIONS AND APPLICATIONS .............................................20 
5.1. 
Enrolled Population (EP) including Screen Failures ..................................................20 
5.2. 
Full Analysis Set (FAS) or the Overall Safety Population (OSP) ..............................21 
5.3. 
Per Protocol (PP) Population or the Evaluable Safety Population (ESP) ...................21 
5.4. 
Pharmacokinetics Population (PKP) ...........................................................................21 
 
 
6. 
PLANNED ANALYSES ............................................................................................22 
6.1. 
Changes from Planned Analysis .................................................................................22 
7. 
GENERAL STATISTICAL ANALYSIS CONSIDERATIONS ...............................22 
7.1. 
General Statistical Procedure ......................................................................................23 
7.1.1. 
Baseline Definition .....................................................................................................23 
7.1.2. 
Analysis Visit Window ...............................................................................................23 
7.2. 
Data Handing ..............................................................................................................24 
7.2.1. 
Age ..............................................................................................................................24 
7.2.2. 
Safety Data Handing ...................................................................................................24 
7.2.3. 
Handling of Repeated Clinical Laboratory Tests .......................................................24 
7.2.4. 
Handling of Partial Dates for AEs ..............................................................................24 
7.2.5. 
Handling of Partial Dates for Medications .................................................................25 
8. 
PROTOCOL DEVIATIONS ......................................................................................25 
9. 
SUBJECT DISPOSITION ..........................................................................................26 
10. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................................26 
10.1. 
Demographic and Baseline Characteristics ................................................................26 
10.2. 
Medical History ..........................................................................................................27 
10.3. 
Prior Therapies/Surgeries ...........................................................................................27 
10.4. 
Prior and Concomitant Medications/Procedures ........................................................28 
11. 
DOSE LIMITING TOXICITIES (DLT) ....................................................................28 
12. 
RECOMMENDED PEDIATRIC PHASE II VELEDIMEX DOSE ..........................29 
13. 
SAFETY ANALYSIS ................................................................................................29 
13.1. 
Adverse Events (AEs) .................................................................................................29 
13.2. 
Extent of Study Drugs Exposure ................................................................................30 
13.2.1. 
Ad-RTS-hIL-12 Injections ..........................................................................................30 


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13.2.2. 
Veledimex Exposure ...................................................................................................30 
13.3. 
Treatment Compliance and Modification ...................................................................31 
13.4. 
Clinical Laboratory Assessments ...............................................................................31 
13.5. 
Vital Signs including Weight ......................................................................................32 
13.6. 
Physical Exams ...........................................................................................................32 
13.7. 
Electrocardiogram (ECG) ...........................................................................................32 
13.8. 
Lansky, Karnofsky and ECOG Performance Status ...................................................32 
13.9. 
Pregnancy Test ............................................................................................................32 
14. 
EFFICACY ANALYSIS ............................................................................................33 
14.1. 
Tumor Response by iRANO .......................................................................................33 
14.2. 
Objective Response Rate (ORR) ................................................................................33 
14.3. 
Progression Free Survival (PFS) ................................................................................33 
14.4. 
Overall Survival (OS) .................................................................................................33 
15. 
PHARMACOKINETIC ANALYSIS .........................................................................34 
15.1. 
Plasma PK Concentration Listings by Subject ...........................................................34 
15.2. 
PK Concentrations in Brain Tumor (Arm 1 Only) .....................................................34 
 
 
17. 
REFERENCES ...........................................................................................................35 
APPENDIX 1. SCHEDULE OF EVENTS .................................................................................36 
 
 
 


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LIST OF TABLES 
Table 1: 
ATI001-103 Study Design ..........................................................................................12 
Table 2: 
ATI001-103 Amendment 2 Breakdown of Arm 1 Completed Cohort and 
Arm 2 Cohorts 3 and 4 for Phase I Dose Escalation ..................................................13 
Table 3: 
Arm 1 Schedule of Veledimex Pharmacokinetic Sampling Times ............................14 
Table 4: 
Arm 2 Schedule of Veledimex Pharmacokinetic Sampling Times ............................14 
 
 
LIST OF FIGURES 
 
 
 
 
 
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation  
Definition 
SAP 
Statistical Analysis Plan 
Ad-RTS-hIL-12 
 
AE 
Adverse Event 
aPTT 
Activated Partial Thromboplastin Time 
ATC 
Anatomical Therapeutic Chemical  
BEP 
Biomarker Evaluation Population 
BMI 
Body Mass Index 
BPM  
Respiratory Rate 
BSA 
Body Surface Area 
CD 
Cluster of Differentiation 
CI  
Confidence Interval 
CRF 
Case Report Form 
CSF 
Cerebrospinal Fluid 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of Variation  
DD 
Drug Dictionary  
DIPG 
Diffuse Intrinsic Pontine Glioma 
DLT 
Dose-Limiting Toxicity 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EP 
Enrolled Population 
ESP 
Evaluable Safety Population 
hIL-12 
Human Interleukin-12 
ICF 
Informed Consent Form 
ID 
Identity 
IFN-γ 
Interferon-Gamma 
IP-10 
IFN-Γ-Induced Protein 10 
iRANO 
Immunotherapy Response Assessment for Neuro-Oncology 
KM 
Kaplan-Meier  
LDH 
Lactate Dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGMT 
Methylguanine-DNA Methyltransferase 
MRI 
Magnetic Resonance Imaging 
NCI 
National Cancer Institute 
ORR 
Objective Response Rate 
OS 
Overall Survival 
OSP 
Overall Safety Population 
PD 
Pharmacodynamics 


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Abbreviation  
Definition 
PFS 
Progression -Free Survival 
PK 
Pharmacokinetic(s) 
PKP 
Pharmacokinetics Population 
PO 
Oral(Ly) 
PT 
Preferred Term 
QD 
Once Daily 
SAE 
Serious Adverse Event 
SAS 
Statistical Analysis System 
SD 
Standard Deviation 
SOC 
System Organ Class 
SRC 
Safety Review Committee 
TEAE 
Treatment-Emergent Adverse Event 
Vp 
Viral Particles 
WHODrug 
World Health Organization Drug Dictionary 
 
 
 


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1. 
INTRODUCTION  
This Statistical Analysis Plan (SAP) describes the proposed statistical analyses in concert with 
Ziopharm Protocol ATI001-103 Amendment 2 entitled: A Phase I/II Study of Ad-RTS-hIL-12, 
an Inducible Adenoviral Vector Engineered to Express hIL-12 in the Presence of the Activator 
Ligand Veledimex in Pediatric Brain Tumor Subjects 
This (SAP) will describe the statistical methods used for all analyses and data presentation for 
reporting safety, efficacy, pharmacodynamics (PD) and immunology of Ad-RTS-hIL-12, 
administered by intratumoral injection plus veledimex administered PO for Ziopharm study 
protocol ATI001-103 Amendment 2. The Pharmacokinetics (PK) and exploratory analysis for 
PD endpoints will be summarized in a separate analysis plan.  
Importantly, and where applicable, this SAP contains a more detailed explanation of the 
statistical analyses described in the protocol. It includes additional and sometimes technical 
discussion for implementing statistical procedures along with the assumptions and data handling 
rules of how an analysis is performed. Details describing the data listings, summary tables and 
figures will be presented in a corresponding Tables, Listings and Figures excel spreadsheet.  
Background 
Pediatric central nervous system tumors are a heterogeneous group of tumors, with subtypes that 
possess distinctly different clinical courses (Johnson, Cullen et al. 2014).  Pediatric glioblastoma 
is characterized by its aggressive clinical course and accounts for a significant amount of 
morbidity and mortality among children with brain tumors.  According to the Central Brain 
Tumor Registry of the United States (CBTRUS), glioblastoma comprises approximately 2.9% of 
brain and central nervous system tumors in children 0 to 19 years old (Ostrom, Gittleman et al. 
2016).  Their 2-year survival rate is approximately 33%.  Although the prognosis of glioblastoma 
is better in children than in adults, there are fewer therapies available for use in 
children.  Currently only lomustine and temozolomide are labeled for pediatric use.  Lomustine 
use in pediatrics is not based on adequate and well-controlled clinical studies (NextSource 
Biotechnology 2014).  The safety and effectiveness of temozolomide in pediatric patients have 
not been established (Merck 2015).  Nonetheless, the current standard-of-care is considered to be 
temozolomide and radiation therapy (Al-Saffar, Marshall et al. 2014). 
The most common form of pediatric brainstem gliomas is diffuse intrinsic pontine glioma 
(DIPG), representing 75% to 85% of these tumors (Warren 2012).  The prognosis of children 
with DIPG is poor, with a 1-year overall survival (OS) of less than 45% (Cohen, Heideman et al. 
2011).  There are no effective treatments available for DIPG.  Indeed, an open-label Phase II 
study in children with DIPG found no evidence that chemoradiotherapy with temozolomide 
followed by adjuvant temozolomide resulted in better event-free survival or OS than a historical 
control of radiation therapy (Cohen, Heideman et al. 2011).  Other recent studies of pediatric 
subjects with DIPG generally report 2-year survival rates of < 10% (Warrren 2012).  The current 
standard of care for DIPG is focal radiation therapy. 
Systemic recombinant IL-12 in clinical trials has been effective in the treatment of cancer but has 
limited utility due to systemic toxicity (Atkins, Robertson et al. 1997, Leonard, Sherman et al. 
1997, Rodolfo and Colombo 1999). 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 


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treatment of patients with solid tumors. 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 for the production of the active moiety, human 
interleukin-12 (hIL-12). 
2. 
STUDY DESIGN OVERVIEW 
2.1. 
Overall Study Design before Amendment 2 
As originally designed, this was a multicenter Phase I/II open-label study, of Ad-RTS-hIL-12 
administered by intratumoral and varying oral (PO) veledimex doses in pediatric brain tumor 
subjects. This study will investigate one fixed intratumoral Ad-RTS-hIL-12 dose 
 
and escalating veledimex doses (10 mg and 20 mg) to determine the safe and tolerable Phase II 
pediatric dose based on the safety profiles observed in the presence of variable corticosteroid 
exposure.  
Eligible subjects were to be stratified into one of two arms, according to diagnosis.  
Arm 1: Pediatric brain tumor subjects scheduled for craniotomy and tumor resection (excluding 
DIPG)  
Arm 1 was open to pediatric brain tumor subjects who are scheduled for a standard-of-care 
craniotomy and tumor resection, with the exclusion of subjects with diffuse intrinsic pontine 
glioma (DIPG).  
• Subjects in Arm 1 will receive one veledimex dose before the resection procedure.  
• Samples (tumor, blood, and CSF, if available) will be collected during the resection 
procedure to determine the veledimex concentration ratio between the tumor, blood, 
and CSF if available.  
• Subjects will receive Ad-RTS-hIL-12 
 by freehand injection. After Ad-
RTS-hIL-12 injection, subjects will continue PO veledimex for 14 days for a total of 
15 doses of veledimex.  The study schema for Arm 1 is outlined in Figure 1.  
 


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Arm 2: Subjects with DIPG who will NOT undergo tumor resection  
Subjects in Arm 2 will receive a single Ad-RTS-hIL-12 
 dose by stereotactic 
injection into the intratumoral site and will receive PO veledimex for 14 days for a total of 14 
doses of veledimex.  The study schema for Arm 2 is outlined in Figure 2. 
• Arm 2 was open only to subjects with DIPG who are post prior standard focal 
radiotherapy (≥ 2 weeks and ≤ 10 weeks).  
• Arm 2 subjects will receive a single Ad-RTS-hIL-12 (2 x 1011 vp) dose by 
stereotactic injection and will receive veledimex PO daily for 14 days. 
Cohorts 
Study arms and assigned doses will be divided into 4 cohorts (Table 1). 
Table 1: 
ATI001-103 Study Design 
Arm 
Cohort 
Indication 
Procedure 
Assigned Veledimex Dosea 
1 
1 
Resectable pediatric brain tumor 
Craniotomy 
10 mg 
1 
2 
Resectable pediatric brain tumor 
Craniotomy 
20 mg 
2 
3 
DIPG 
Stereotactic 
10 mg 
2 
4 
DIPG 
Stereotactic 
20 mg 
a Doses are BSA-adjusted doses  
Subject enrollment and veledimex dose escalation were to proceed according to a standard 3+3 
design, modified to independently evaluate 2 groups (arms) of subjects that may exhibit different 
safety and tolerability profiles, with the first cohort of each arm receiving 10 mg veledimex, 
followed by the second cohort receiving 20 mg veledimex.  
Each cohort will consist of subjects ≤ 21 years-of-age who meet eligibility criteria. Once the last 
subject in Cohort 1 completes the dose-limiting toxicity (DLT) evaluation period, enrollment 
may be opened for Cohort 2 and Cohort 3. Once the last subjects in both Cohort 2 and Cohort 3 
complete the DLT evaluation period, enrollment may be opened for Cohort 4.  
The first subject in each cohort will be monitored for 28 days after Ad-RTS-hIL-12 injection 
before additional subjects are enrolled in the same cohort. The evaluation period for DLT is 28 
days after Ad-RTS-hIL-12 injection (Day 0 to Day 28).  


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2.1.1. 
Safety Review Committee (SRC) Recommendations After Review of Arm 1 
Cohort 1 
When the Safety Review Committee (SRC) reviewed the safety profile of the subjects treated in 
Arm 1 Cohort 1, (n=3), the SRC indicated that it was appropriate to dose escalate moving 
forward with:  
• Arm 1, Cohort 2 and  
• Arm 2, Cohort 1.  
However due to issues with enrollment of supratentorial subjects, it was determined not to 
proceed with enrollment of Arm 1, Cohort 2 as originally planned. Therefore, the Arm 1 portion 
of the study was deemed concluded.  
Ziopharm performed database lock upon the completion of Arm 1 Cohort 1, under Protocol 
Amendment 1.0 dated 25-Sep-2017. Arm 1 used the Medidata RAVE database, which was 
locked on 08-Nov-2019.  
2.2. 
Amendment 2 Study Design Modifications 
2.2.1. 
Amendment II overview  
Protocol Amendment 2.0 was finalized 30-Oct-2019, and Arm 2 enrollment was opened, using 
the nowEDC database for data collection.  
Table 2 summarizes the overall study status reflecting:  
• Completion of Arm 1 Cohort 1 as described above.  
• Removal of Arm 1 Cohort 2.  
• DIPG subject enrollment beginning with Arm 2, cohort 3, at 10mg veledimex and,  
Arm 2, cohort 4 at 20mg veledimex PO daily dosing for 14 days. 
Table 2: 
ATI001-103 Amendment 2 Breakdown of Arm 1 Completed Cohort and Arm 
2 Cohorts 3 and 4 for Phase I Dose Escalation 
Arm 
Cohort 
Procedure 
Veledimex Dosea Assigned 
Status 
1 
1 
Craniotomy 
10 mg 
Complete 
2 
3b 
Stereotactic 
10 mg 
Enrolling 
2 
4 
Stereotactic 
20 mg 
Future 
a Doses are BSA-adjusted doses 
b Arm 1 Cohort 2 was removed in Protocol Amendment 2.  
2.2.2. 
Study Design 
This was to be a multicenter, open-label study of Ad-RTS-hIL-12 administered by intratumoral 
injection and veledimex PO doses in pediatric brain tumor subjects.  This study was planned to 
investigate one fixed intratumoral Ad-RTS-hIL-12 dose 
 and 
escalating veledimex doses to determine the safe and tolerable Phase II pediatric dose based on 
the safety profiles observed in the presence of variable corticosteroid exposure. After completion 
of the phase I dose escalation cohort(s) in DIPG subjects enrolled in Arm 2, the SRC may 


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recommend expanding treatment based on its review of the data to a new cohort for up to 30 to 
35 DIPG subjects. Such an expansion was to be considered the Phase II component of the study. 
• The schedule of study procedures is presented in Appendix 1 ,  
• The veledimex PK sampling schedule is presented in Table 3 and Table 4. 
Table 3: 
Arm 1 Schedule of Veledimex Pharmacokinetic Sampling Times 
Sample 
Number 
Day 0 
Day 1 
Day 2 
Day 14 
Day 15 
1 
Pre-dosea 
Pre-dosea 
Pre-dosea 
Pre-dosea 
24 hours post 
Day 14 doseb 
2 
During 
resection 
2 hours post-
doseb 
 
2 hours post-
doseb 
 
3 
 
4 hours post-
doseb 
 
4 hours post-
doseb 
 
4 
 
6 hours post-
doseb 
 
6 hours post-
doseb 
 
a ≤ 30 minutes prior to veledimex dose 
b PK Collections: post-dose PK collections will have a ± 30-minute draw window 
 
Table 4: 
Arm 2 Schedule of Veledimex Pharmacokinetic Sampling Times 
Sample Number 
Day 0 
Day 1 
Day 2 
Day 14 
Day 15 
1 
 
Pre-dosea 
Predosea 
Predosea 
24 hours post Day 
14 doseb 
2 
 
2 hours post-doseb 
 
2 hours post-doseb 
 
3 
 
4 hours post-doseb 
 
4 hours post-doseb 
 
4 
 
6 hours post-doseb 
 
6 hours post-doseb 
 
a ≤ 30 minutes prior to veledimex dose 
b PK Collections: post-dose PK collections will have a ± 30-minute draw window 
2.2.3. 
Projection of Study Duration  
The study duration is projected to be approximately 48 months. This assumes that after the 
enrollment and evaluation of cohort 4 for safety, that the SRC recommends expansion of 
enrollment into the phase 2 single arm cohort of up to 30 to 35 eligible subjects to obtain at least 
30 subjects deemed evaluable for OS. The breakdown of timing suggests:  
• Arm 2 enrollment of phase I cohorts is approximately 12 months  
• 30 to 35 evaluable DIPG subject enrollment begins one month after the SRC 
recommends expanding enrollment into a phase 2 component. 
• Enrollment to accrue Phase II DIPG subjects is projected to be 12 months. 
• Then at least 24 months of follow-up of the last subject enrolled and treated as part of 
the phase 2 projection. 


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The overall duration is expected to be up to 2 years and 28 days for an individual subject, 
assuming: 
• Screening period of up 28 days 
• Study treatment period of up to 15 days  
• Survival status through 24 months from the first dosing date. 
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. The active 
study period refers to the study period from informed consent through the Survival Follow-up 
Period. 
2.2.4. 
Sample Size  
Originally, the choice of the number of subjects was based on the standard 3 + 3 design, 
modified for independent evaluation of 2 subject arms that may exhibit different safety and 
tolerability profiles.  
• Without the phase II component, it was projected that approximately 24 subjects may 
have been enrolled including 3 to 6 subjects per cohort.  
• Subjects who withdraw from the study during the DLT evaluation period (Day 0 to 
Day 28) for reasons other than toxicity or disease progression may be replaced. 
2.2.5. 
Randomization 
This is an open-label study, and subjects will not be randomized.  
3. 
STUDY OBJECTIVES 
3.1. 
Amendment 2 Revision of Objectives. 
Revisions to the objectives of ATI001-103 Amendment 2 are described in a “before, after” 
presentation depicting changes to the primary, secondary and exploratory objectives in the 
following three subsections. Most revisions are in underlined red font indicating additions to the 
original wording to capture the potential of expanding the current trial to a Phase II trial in DIPG eligible 
subjects.  
3.1.1. 
Primary Objectives (before and revised) for Amendment 2: 
Primary Objective Before Amendment 2: 
• To determine the safety and tolerability of intratumoral Ad-RTS-hIL-12 and varying 
PO veledimex doses in pediatric brain tumor subjects. 
 
 
 








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− The grade of toxicity will be recorded.  
− However, unless a relationship to study drug is documented to be the main 
contributory factor, the AE will not be considered a DLT.  
• Transient neurological changes are expected in Arm 2 and will not be considered a 
DLT unless they last > 10 days. 
4.4. 
Recommended Pediatric Phase II Veledimex Dose 
The recommended pediatric Phase II veledimex dose will be determined using the Evaluable 
Safety Population (ESP) which is defined in Section 5 .  
• The recommended pediatric Phase II dose is defined as the dose level below the dose 
in which ≥ 33% of subjects in the same cohort experience DLTs. If 2 DLTs occur in 
the same cohort, dose escalation will stop in the cohort experiencing the DLTs.  
The recommended pediatric Phase II dose will also be determined in the context of variable 
corticosteroid exposure and will be reported as such. 
4.5. 
Safety Evaluations 
The safety evaluations include: 
• Adverse Events (AEs) 
• Extent of study drugs exposure  
• Treatment compliance and modification 
• Clinical laboratory assessments including hematology, coagulation, serum chemistry 
and urinalysis 
• Vital signs including weight 
• Physical exams including targeted neurological exam 
• Electrocardiogram (ECG) 
• Lansky, Karnofsky, and ECOG performance Status 
• Pregnancy test 
4.6. 
Efficacy Evaluations  
The secondary efficacy endpoints include Investigator assessment of ORR, PFS and OS. The 
Investigator assessment of ORR and PFS will be determined for each cohort according to the 
baseline (Day 2) iRANO assessment, with tumor response characterized by iRANO criteria for 
adults, pending issuance of pediatric criteria. 
The following variables will be used for the determination of tumor response variables and OS 
by subject ID: 
• Tumor response by iRANO for 
− Target, non-target and non-enhancing lesions. 






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6. 
PLANNED ANALYSES  
6.1. 
Changes from Planned Analysis 
The major change to the original planned analyses is that for all practical purposes, statistical 
summaries of very small sample sizes will be avoided. Instead, relevant data listings by subject 
for the OSP and ESP will be presented along with descriptions of subject characteristics as 
applicable. 
When Amendment 2 was implemented,  
• Arm 2 enrollment was opened, using the nowEDC database.  
• The data for Arm 1, Cohort 1, consisting of 3 subjects for whom the data were 
captured in Rave eCRF will be summarized separately from the data captured based 
on DIPG eligibility, beginning with Arm 2, cohort 3.  
• After completion of enrollment of DIPG subjects in cohort 3 and cohort 4, the data 
from the Arm 1, cohort 1, may be combined for reporting purposes in which case 
remapping the data on the three subjects for whom the data are complete will be 
applied to creating derived variables like those to be chosen when data extractions 
from the nowEDC are implemented 
• Therefore, this current version of the SAP for ATI001-103 based on amendment 2 
will not include tables shell entries for Arm 1, Cohort 1.  
Interim Analyses 
There is no formal interim analysis planned for this study.   
• There will be SRC meetings to evaluate the subjects’ safety data.  
• The SRC will determine whether the dosing at the specified level (10 mg or 20 mg) is 
appropriate for escalation or as the recommended Phase 2 pediatric dose.  
• After the completion of phase I dose escalation of Arm 2, the SRC may recommend 
expanding the current study for one of the doses evaluated in either cohort 3 or 4 in 
which case a cohort expansion of up to 30 to 35 evaluable DIPG subjects will be 
enrolled.  
• This new cohort of subjects will be defined and referenced as the Phase II component 
of the study.  
Final Analyses and Reporting 
All final planned analyses per protocol and this SAP will be performed only after database lock. 
7. 
GENERAL STATISTICAL ANALYSIS CONSIDERATIONS 
All analyses described in this plan are considered priori analyses in that they have been defined 
prior to locking the database.  All other analyses, if any, designed subsequently to locking the 
database, will be considered post hoc analyses and will be described as exploratory analyses in 
the Clinical Study Report.  


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For this study,  
• Multiplicity adjustment will NOT be performed for analysis.   
• Possible covariate effects will NOT be adjusted for analysis.   
• No imputations for missing or partial data will be made.  
• Data across multiple study sites will be pooled for an integrated summary.  
• SAS version 9.4 or higher will be utilized for all listings and tables. 
7.1. 
General Statistical Procedure 
The descriptive statistics for continuous variables (e.g., age) will be the number of subjects with 
a non-missing value of the variable (n), mean, standard deviation (SD), median, quartiles (Q1, 
Q3), minimum and maximum.  Mean, median, Q1, and Q3 will be reported to 1 more decimal 
place than the raw data. The SD will be reported to 2 more decimal places than the raw data.  
Minimum and maximum will be reported the same as the original data.  
In addition to the above descriptive statistics, coefficient of variation (CV%), geometric mean 
and geometric CV% will also be used to summarize the drug veledimex concentration where 
applicable.  
Coefficient of variation CV% is calculated as 100×(SD/mean). Geometric CV% is calculated as 
follows: CV% = 100 X ඥexp(𝜎𝜎ො2) −1, where 𝜎𝜎ො2denotes the estimated variance of the log-
transformed values.  
Categorical variables will be summarized by frequency table which includes the number of 
subjects with a response in the category and the percentage of the total number of subjects in that 
particular column.  Unless otherwise stated, missing responses will NOT be included in the 
analysis.  Percentages will be rounded to one decimal place. 
Unless otherwise stated, data will be tabulated by arm and dose cohort, and overall according to 
the defined population. If dose escalation is stopped before reaching higher veledimex doses, 
those columns will be omitted from the summaries. 
All listings will be ordered by arm and dose cohort, and subject ID for available data.  
7.1.1. 
Baseline Definition 
The day of Ad-RTS-hIL-12 administration is designated as Day 0.  Baseline value for safety and 
demographic data is defined as the last non-missing value closest, but prior to, the first dose of 
study drug veledimex or Ad-RTS-hIL-12.  For tumor assessment, a baseline MRI will be 
performed within 72 hours of Ad-RTS-hIL-12 administration (Day 2). 
7.1.2. 
Analysis Visit Window 
For safety parameters excluding clinical laboratory data, measurements collected from 
unscheduled visits will NOT be included in the by-visit summary tables but will be included in 
the listings. Early termination visits for safety measurements will not be mapped to any 
scheduled post-baseline visit but will be used as the last assessment during the treatment period.  


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7.2. 
Data Handing  
7.2.1. 
Age 
For partial dates of birth with both the month and day missing, the month and day will be set to 
June 30. Completely missing dates of birth will remain as missing, with no imputation applied. 
Consequently, the age of the subject will not be calculated and will remain missing. In listings of 
demographic data, the partial dates of birth as entered will be displayed. 
7.2.2. 
Safety Data Handing  
For all safety data, only observed data will be used for analyses, and missing data will not be 
imputed. 
7.2.3. 
Handling of Repeated Clinical Laboratory Tests 
For laboratories results at unscheduled visits, it will be treated as repeated laboratory results for 
the closest previous visit. The last repeat of laboratory results will be used in the summary tables 
for that visit. All the laboratory test results (original test results and repeated results) will be 
included in the data listings. 
7.2.4. 
Handling of Partial Dates for AEs   
When determining the AE, partial start dates of AEs will be assumed to be the closest possible 
date to date of first dose and are consistent with the partial date. Imputation of partial dates is 
used only to determine whether an event is treatment-emergent; data listings will present the 
partial date as recorded in the eCRF. 
• A completely missing onset date will be coded as the date of first dose. If the 
resulting onset date is after a reported date of resolution, the onset date will be set 
equal to the date of resolution.   
• If year is present, but both month and day are missing, or month is present, and day is 
missing, 
− if year < year of first dose date, then set missing month to December and missing 
day to last day of the month. 
− if year > year of first dose date, then set missing month to January and missing 
day to 1st day of the month. 
− if year = year of first dose date, then set missing month to the month of first dose 
and missing day to the day of first dose. 
• If year and month are present, but day is missing, 
− if date of year and month < date of year and month of first dose, then set missing 
day to last day of the month.  
− if date of year and month > date of year and month of first dose, then set missing 
day to 1st day of the month.  


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− if date of year and month = date of year and month of first dose, then set missing 
day to the day of first dosing. 
• For all other cases, set the date to date for first dose. 
7.2.5. 
Handling of Partial Dates for Medications  
When determining prior or concomitant medications, partial start dates of prior and concomitant 
medications will be assumed to be the earliest possible date consistent with the partial date. 
Partial stop dates of prior and concomitant medications will be assumed to be the latest possible 
date consistent with the partial date.  
• For Start Date, 
− If the start date is completely missing, then the start date will not be imputed. 
Medication will be assumed to be prior medication. 
− If the year is present and month or day are missing, then set missing month to 
January and missing day to 1st of the month. 
• For End Date, 
− If the end date is completely missing, then the end date will not be imputed. 
Medication will be assumed to be ongoing. 
− If the year is present and the month or day are missing, then set missing month to 
December and missing day to last day of the month. 
8. 
PROTOCOL DEVIATIONS   
A protocol deviation is any change, divergence, or departure from the study design or procedures 
defined in the protocol.  
• Important protocol deviations are a subset of protocol deviations that may 
significantly impact the completeness, accuracy, and/or reliability of the study data or 
that may significantly affect a subject's rights, safety, or well-being.  
• Where applicable, important protocol deviations will be categorized as major protocol 
deviations.  
− Protocol deviations that are not deemed important protocol deviations are 
classified as minor protocol deviations 
• The list of protocol deviations along with whether the deviation is classified as major 
or minor will be finalized prior to database lock. 
No subject will be removed from any analysis population because of a protocol deviation. 
In accordance with ICH E3, subject eligibility violations and important post- treatment protocol 
deviations will be identified and listed by subject ID and study center. Major deviations that are 
considered to potentially impact the efficacy or safety analyses will be tabulated. Important 
protocol deviations will be identified prior to database lock. Protocol deviations will be listed 
and summarized by type. 


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• Deviation from inclusion/exclusion criteria  
• Withdrawal criteria met during the study but subject ID was not withdrawn  
• Prohibited concomitant medications  
• Treatment deviation 
• Other protocol deviation 
9. 
SUBJECT DISPOSITION 
Subject Disposition 
The completion status of subjects treated by any experimental treatments will be summarized 
overall and by treatment arm and dose cohort based on the OSP.  The primary reasons for 
treatment and study discontinuation will be summarized by treatment arm and dose cohort based 
on the OSP.   
Subjects who are screen failures are not subjects that are treated on any study treatment and are 
only counted as the part of the subject disposition denoted as screened and not treated.   
10. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS  
10.1. 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be listed and described by subject ID (instead of 
being tabulated using descriptive statistics by treatment arm and dose cohort) for the OSP.  
• Demographic variables include:  
− Age (years) 
− Sex 
− Race 
− Ethnicity  
• Baseline characteristics include:  
− Height (cm) 
− Weight (kg) 
− BMI (body mass index, kg/m2, calculated as Weight (kg) / Height (m)2) 
− ECOG performance status, KPS, lansky  
Conversions for Height and Weight are as follows: 
Height (cm) = Height (inches) x 2.54 
Weight (kg) = Weight (lb) x 0.4536 


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10.2. 
Medical History 
The medical history will be coded using the current version of the Medical Dictionary for 
Regulatory Activates (MedDRA). Originally, the frequency count and percentage of subjects 
who experience any medical conditions were to be tabulated by system organ class (SOC) and 
preferred term (PT) of MedDRA for all subjects and by treatment arm and dose cohort for the 
OSP. Instead, medical history, will be listed and described by subject ID. 
If the same PT or SOC is reported more than once for a subject ID, the subject ID will only count 
once in the corresponding incidence of PT or SOC.    
Listings will be presented by treatment arm, dose cohort, and subject ID for the EP. 
10.3. 
Prior Therapies/Surgeries 
Listings will be presented by treatment arm and dose cohort, by subject ID for the EP. Listings 
will summarize prior therapies, surgeries, and/or concomitant disease by treatment arm and dose 
cohort for the OSP  
• (instead of Frequency counts and percentages for the summary of prior therapies, 
surgeries or concomitant disease by treatment arm and dose cohort for OSP).  
• The therapies/surgeries with the same sequence/regimen number are counted as one 
prior therapy/surgery. 
Where applicable, the following variables may be included as part of the subject listing: 
• Relevant Disease under study 
− Any relevant past or concomitant disease 
− Most severity/CTCAE grade 
• Surgery History 
− Any relevant past surgeries 
− Most severity/CTCAE grade 
• Brain tumor diagnosis 
− Initial grade  
− Initial MGMT gene promoter status  
− Initial IDH status  
− Current disease status 
− Current grade  
− Current MGMT gene promoter status 
− Current IDH status  
• Prior cancer treatment 
− Any cancer related therapy  


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− Treatment type 
− Best response 
− Disease under study 
If the subject experienced multiple surgeries, the most severe grade will be used for the 
summary.   
10.4. 
Prior and Concomitant Medications/Procedures  
All medications as documented by Investigator will be coded using the World Health 
Organization Drug Dictionary (WHODrug, Sept 2016).   
Prior medications are defined as medications that were started before the start of the study 
treatment and either ended before the start of the study treatment or continued after study 
treatment.   
 
Concomitant medications are defined as non-study medications that were either initiated before 
study treatment and continued during the study treatment or initiated on/after study treatment but 
within the initial follow-up period (through Day 56).  
In general, listings by treatment arm and dose cohort, and subject ID for concomitant 
medications and concurrent Medical Procedures will be provided for the OSP (instead of using 
frequency tables). 
The prior and concomitant medications will be tabulated by subject ID, along with the treatment 
arm and dose cohort, ATC term 2 and the Preferred term for OSP.  
• If the start and stop dates of the concomitant medications do not clearly define the 
period(s) during which a medication was taken, it will be assumed to have been a 
concomitant medication. 
• For summary listings, if a subject has taken a medication more than once, the subject 
will be only counted once for the medication.  
• Medications initiated prior to the start of first dose of study drug and are continued 
after the first dose of study drug will be counted as both prior and concomitant 
medications. 
11. 
DOSE LIMITING TOXICITIES (DLT) 
In general, listings by subject ID for DLT data by treatment arm and dose cohort, will be 
provided for the ESP. 
The number of DLTs and the proportion of subjects with any DLT and each type of DLT will be 
summarized by treatment arm and dose cohort for the ESP if applicable.  


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12. 
RECOMMENDED PEDIATRIC PHASE II VELEDIMEX DOSE 
The recommended pediatric Phase II dose in the study will be determined in the context of 
variable corticosteroid exposure and other factors.   
Where applicable, listings along with descriptive statistics will be used to tabulate the total 
corticosteroid daily dose (mg) by arm and dose cohort, and visit for the ESP.  
As originally planned, listings including demographics could be provided for the total 
corticosteroid daily dose by arm and dose cohort, visit and subject ID for the OSP. 
13. 
SAFETY ANALYSIS 
13.1. 
Adverse Events (AEs) 
AEs will be coded using MedDRA and will be classified by SOC and PT of MedDRA. All AEs 
will be captured up through day 56.  
Severity: The severity of AEs will be assessed according to the NCI CTCAE v. 4.03 ranging 
from Grade 1 to Grade 5.  
TEAE: A treatment emergent AE (TEAE) is defined as any AE that begins, or any preexisting 
condition that worsen in severity during the treatment period.  For determination of TEAEs 
during the treatment period, AEs with the greatest severity before baseline will be used as a 
benchmark for comparison of AEs occurring captured up through day 56.  
Relationship (Causality): AEs that have possibly, probably or related relationship to the study 
drug are defined to be Related to the study drug. Otherwise, the AE will be defined as Not 
Related. AEs for which the relationship to the study drug is missing will be considered as related 
to the study drug. AEs with the closest relationship to the study drug will be used for the 
summary.  
TEAEs will be tabulated by subject ID in listings by treatment arm and dose cohort, SOC and PT 
according to the relationship to study drug(s), the severity and seriousness for the OSP.  The 
following types of TEAEs will be provided:  
• Overview of TEAEs 
• TEAEs by SOC and PT 
• TEAEs by SOC, PT, and Maximum CTCAE toxicity grade 
• TEAEs by SOC, PT, and Maximum CTCAE toxicity grade ≥ 3 
• TEAEs by PT in decreasing frequency 
• 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 
• TEAEs leading to treatment discontinuation by SOC and PT 


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• TEAEs leading to dose interruption by SOC and PT  
• TEAEs leading to dose reduction by SOC and PT 
If the same PT or SOC is reported more than once for a subject, the subject will only be counted 
once in the corresponding incidence of PT or the SOC.    
To avoid overcounting events for a given PT or SOC, only the most severe and the most closely 
related PT and/or SOC term will be included for each subject ID in tabulations by severity (i.e., 
CTCAE toxicity grade) and relationship,  
For all subjects in the OSP, AEs, serious AEs and AEs leading to treatment discontinuation will 
be listed by the subject ID, by the treatment arm and the dose cohort.  
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 included for each subject.  
13.2. 
Extent of Study Drugs Exposure  
Listings of exposure of study drugs (veledimex and Ad-RTS-hIL-12) will be provided by 
treatment arm, dose cohort and subject ID for the OSP. 
13.2.1. 
Ad-RTS-hIL-12 Injections 
The total volume received, the number of sites and whether the dose was modified will be 
tabulated by subject ID. 
13.2.2. 
Veledimex Exposure  
The number and percentage of subjects exposed to the veledimex study drug will be provided by 
treatment arm and the dose cohort, for the OSP.  
Listings of treatment compliance and modification of study drug veledimex will be provided by 
the treatment arm, dose cohort, and subject ID for the OSP. 
Veledimex study drug exposure will be summarized by subject ID for: 
• Duration of exposure 
− In days, defined as last dose date – first dose date + 1 
• Cumulative dose 
− Actual cumulative dose (mg), defined as the sum of all doses taken during the 
treatment period. 
− Expected cumulative dose (mg), defined as sum of all doses assigned during the 
treatment period. 
• Dose intensity 
− Actual dose intensity (mg/day), defined as the actual cumulative dose (mg) 
divided by the duration of exposure (days).  
− Expected dose intensity (mg/day), defined as the expected cumulative dose (mg) 
divided by the duration of exposure (days). 


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• BSA-adjusted dosing 
− defined as the actual administered dose divided by body surface area (BSA).   
− BSA-adjusted dosing <75%, 75%-125%, and >125% will be categorized for 
summary. 
13.3. 
Treatment Compliance and Modification 
Veledimex study drug treatment compliance and any modifications to the dose and schedule of 
treatment will be summarized by subject ID for the following variables:  
• Relative dose intensity (%) 
− defined as the actual dose intensity (mg/day) divided by the expected dose 
intensity (mg/day), expressed as a percentage. 
• Dose interruptions by subject ID 
− The number of subjects with any dose interruptions  
− Time in days from first dose date to date of first dose interruptions for any reason:  
− Time in days from first dose date to date of first dose interruption due to AEs 
− Total days of dose interruptions due to AEs 
• Dose reduction 
− Number of subjects who were classified as receiving a dose reduction 
− Time in days from first dose date to the date of first dose reduction due to AEs 
− Total days of dose reduction due to AEs for subjects experiencing a dose 
reduction 
13.4. 
Clinical Laboratory Assessments  
Clinical laboratory assessments include hematology, coagulation, serum chemistry and 
urinalysis. Laboratory tests will be performed in a central laboratory. Laboratory values will be 
converted to standardized units. Only numerical values will be used for summary of continuous 
parameters.    
For hematology, coagulation and serum chemistry laboratory parameters, subject listings will be 
provided for values at baseline and changes from baseline instead of descriptive summary tables 
by treatment arm, dose cohort and visit for the OSP.  
In addition, laboratory test results will be categorized by CTCAE toxicity grades according to the 
normal ranges of the central laboratory.  Subject listings will provide the shift from baseline to 
worst post-baseline extreme values denoting the visit for which the worst post-baseline shift 
occurred. Laboratory results with toxicity grades missing at either baseline or at post-baseline 
will not be used for summarizing the worst post-baseline shift by subject ID. The number of 
subjects who have both baseline and post-baseline laboratory values will be summarized where 
applicable. 


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Urinalysis laboratory parameters are summarized by subject ID (instead of Frequency tables used 
to summarize the urinalysis laboratory parameters by treatment arm and dose cohort, and visit.).  
Separate listings by subject ID for each subject ID visit will be summarized for all laboratory 
tests where applicable for the OSP. Both laboratory parameters’ values in the original unit 
collected and standardized units will be listed.  
13.5. 
Vital Signs including Weight 
The vital signs’ parameters include systolic and diastolic blood pressure (mmHg), heart rate 
(bmp), respiratory rate (breaths/minute), temperature (0C) and weight.  
Observed vital signs will be summarized in listings by subject ID for the OSP (instead of using 
descriptive statistics by treatment arm, dose cohort and visit for the OSP). 
Conversion of temperature from Celsius to Fahrenheit is defined: 
Temperature (ºC) = (Temperature (ºF) – 32) x 5/9 
Listings of vital signs, height and weight will be provided by subject ID for the OSP.  
13.6. 
Physical Exams 
Physical exams including general physical exam and targeted neurological exam will be 
tabulated by subject ID for the OSP. 
13.7. 
Electrocardiogram (ECG) 
Where applicable, a summary of actual values and changes from baseline will be provided by 
Subject ID for the OSP. This is in lieu of presenting the overall interpretation of ECG results be 
summarized using frequency tables by treatment arm, dose cohort, and visit for the OSP. 
13.8. 
Lansky, Karnofsky and ECOG Performance Status 
Where applicable, a summary of actual values and changes from baseline will be provided by 
Subject ID for the OSP. 
Scores and changes from baseline for Lansky, Karnofsky and ECOG Performance Status will be 
tabulated by subject ID for the OSP. 
Listings will be presented by subject ID based on EP for Lansky, Karnofsky and ECOG 
Performance Status.  
13.9. 
Pregnancy Test 
Pregnancy test results will be listed by arm and dose cohort, visits, and subject ID for the OSP.  
 
 


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14. 
EFFICACY ANALYSIS  
Tumor response will be assessed using iRANO criteria at Day 14, 4 weeks (Day 28 ± 7 days), 8 
weeks (Day 56 ± 7 days), and every 8 weeks (± 7 days) thereafter for all subjects. The analysis 
will be performed by arm and dose cohort for ESP.  
Tumor assessments after the initiation of further anticancer therapy are excluded for the 
assessment of best overall response. 
Listing will have presented for tumor response for OSP.  Listing will be presented for all efficacy 
data by arm and dose cohort, and visit for ESP. 
14.1. 
Tumor Response by iRANO 
Frequency tables will be used to summarize response of tumor assessment for target, non-target 
and non-enhancing lesions, and overall response by arm and dose cohort, and visit using ESP.   
14.2. 
Objective Response Rate (ORR) 
ORR is the proportion of subjects meeting iRANO response criteria which is defined as sum of 
partial responses plus complete responses.  ORR will be summarized using frequency tables by 
arm and dose cohort, and visit with 2-sided 95% exact binomial confidence interval (CI).   
A figure similarly to a forest plot will be provided to display the response rates of each arm and 
dose cohort systematically along with a 2-sided 95% exact binomial confidence CI. 
14.3. 
Progression Free Survival (PFS) 
Progression-Free Survival (PFS) will be calculated as the time from baseline (Day 2) to date of 
disease progression or death, whichever occurs first. A subject who has neither progressed nor 
die will be censored on the date of last tumor response assessment.  Subjects without valid 
baseline will not use for analysis.  Subjects without post-baseline disease progression assessment 
will be censored at date of last non-progression disease response assessment or withdrawal.  
The Kaplan-Meier (KM) method will be used to estimate the distribution of PFS for each arm 
and dose cohorts.  Survival time will be summarized using descriptive statistics including 95% 
exact CI for median survival. Progression free survival rate at end of visit will also be included 
with 95% exact CI.   
KM plots of PFS will be provided to graphically present the survival risk for each arm and dose 
cohort.  
14.4. 
Overall Survival (OS) 
OS is defined as the duration of time from first dose of the study drug to the date of death. 
Subjects who are still alive 2 years after first does of study drug will be censored at the last 
follow up contact date.  
Details of death and survival time will be listed. 






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APPENDIX 1. SCHEDULE OF EVENTS 
Schedule of Study Procedure 
Screening 
Period 
Treatment Period 
Initial Follow-up 
Period 
Long 
Term 
Follow
- up 
Activity 
Day 
-28 to -1 
Day 
0 
Day 
1 
Day 
2 
Day 
3 
Day 
4-6 
Day 
7 
Day 
8-
13 
Day 
14 
Day 
15 
Day 
28± 
7 
Day 
56±
7 
Every 
8 
weeks 
(± 1 
week) 
Clinical Assessments 
Informed Consent 
X 
Medical/Cancer 
Historya,b 
X 
Physical Examc, 
including targeted 
neurological exam 
X 
X 
X 
X 
X 
X 
X 
X 
Lansky PSd, 
Karnofsky, or 
ECOG 
X 
X 
X 
X 
Height (only at 
Screen) and 
Weight 
X 
X 
X 
X 
X 
Vital Signse 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Eventsf 
X 
Concomitant 
Medicationsb,f 
X 
Xg 
Survival Statusg 
X 
Clinical Laboratoryu 
Pregnancy Testh 
X 
X 
X 
Hematology Paneli 
X 
X 
X 
X 
Xi 
X 
Xi 
X 
X 
Coagulation Panelj 
X 
X 
X 
X 
X 
Serum Chemistry 
Panelk 
X 
X 
X 
X 
Xk 
X 
Xk 
X 
X 
Urinalysis Panell 
X 
X 
X 
ECGm 
X 
X 
X 
X 
Eligibility Review 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Registrationn 
X 
Study Drug Administration 
Ad-RTS-hIL-12 
Xo,p 
Veledimex Dose 
Arm 1 
X 
Xp,q 
X 
Xi,k 
X 
X 
X 
Xr 
Veledimex Dose 
Arm 2 
Xp,q 
X 
Xi,k 
X 
X 
X 
Xr 
Veledimex Dose 
Compliance/ 
Subject Diaryr 
X 
X 
X 
X 
X 
X 
X