Conditions: Glioblastoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 40
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.

Cemiplimab-rwlc (Libtayo) is an antibody (a kind of human protein) that is being tested to see if it will allow the body's immune system to work against glioblastoma tumors. Libtayo (cemiplimab-rwlc) is currently FDA approved in the United States for metastatic cutaneous cell carcinoma (CSCC), but is not approved in glioblastoma. Cemiplimab-rwlc may help your immune system detect and attack cancer cells. Ad-RTS-hIL-12 and veledimex will be given in combination with cemiplimab-rwlc to enhance the IL-12 mediated effect observed to date.

The main purpose of this study is to evaluate the safety and efficacy of a single tumoral injection of Ad-RTS-hIL-12 given with oral veledimex in combination with cemiplimab-rwlc.

Detailed description:
Eligible patients will receive one dose of cemiplimab-rwlc, via infusion, one week prior to standard of care craniotomy and tumor resection (subtotal or total). On the day of surgery, patients 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. Following veledimex, patients will receive cemiplimab-rwlc via infusion every three weeks.

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 and oral veledimex (activator ligand, 20mg) given in combination with cemiplimab-rwlc via infusion.

Interventions: intervention 1: Ad-RTS-hIL-12 intervention 2: Veledimex intervention 3: Cemiplimab-Rwlc
Intervention descriptions: intervention 1: * intratumoral injection of Ad-RTS-hIL-12
* 2.0 x 10\^11 viral particles (vp) per injection intervention 2: 20mg/day 15 oral daily doses of veledimex intervention 3: Infusion every 3 weeks (350mg)

Protocol document:
Prot_000.pdf: 






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Protocol ATI001-204 
Amendment 2 
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planned, the reason will be provided. Care should be taken to 
avoid intraventricular or basal cisternal injection or other 
critical locations. 
After the Ad-RTS-hIL-12 injection, veledimex will be 
administered orally for 14 days.  The first post-craniotomy 
veledimex dose is to be given on Day 1. Subsequent 
veledimex doses are to be taken once daily, in the morning. 
Dosing on Days 2-14 should be at approximately the same 
time of day (+/- 1 hours) as the Day 1 dosing. 
Subjects will receive a dose of cemiplimab-rwlc (350 mg) on 
Day 15 and every three weeks thereafter (Q3W) until 
confirmed progression by immunotherapy Response 
Assessment for Neuro Oncology (iRANO) criteria, 
unacceptable toxicity, subject withdrawal or completing the 
safety follow-up period. Delays in cemiplimab-rwlc dosing 
due to toxicity are allowed at the discretion of the Principal 
Investigator in consultation with the Medical Monitor, for up 
to 14 days. 
A formal Safety Review Committee (SRC) will be comprised 
of the study Investigators and the Medical Monitor. 
After the first six subjects have been enrolled and 
administered Ad-RTS-hIL-12 and veledimex in combination 
with at least one post Ad-RTS-hIL-12 dose of cemiplimab-
rwlc, enrollment will be paused. The SRC will review safety 
data after the 6th subject has reached Day 28 and decide if 
enrollment should occur at the same dose and schedule of the 
investigational products.   
The primary endpoint for evaluation of safety is: 
• The safety profile 
The primary endpoint for evaluation of efficacy is: 
• Overall survival (OS)  
Secondary endpoints include:  
• Overall Survival rate at 6, 12, 18 and 24 months 
• PFS, and rate of pseudo-progression (PSP) at 6, 12, 18 
and 24 months 
• Objective Response Rate at 6, 12, 18 and 24 months 
• To determine the tumor response rate at 6, 12, 18 and 
24 months 
 
  
 


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Dose & Schedule 
Ad-RTS-hIL-12:  intratumoral 
vp administered on 
Day 0 
Veledimex: 20 mg PO QD on Days 0 to 14 
Cemiplimab-rwlc: 350 mg IV on Day -7, Day 15, and 
approximately every 3 weeks (Q3W) until confirmed 
progression (iRANO), unacceptable toxicity or subject 
withdrawal. 
Therapy Duration 
From administration of the first study drug (cemiplimab-rwlc) 
until the subject has confirmed progressive disease per 
iRANO, unacceptable toxicity, the subject withdraws consent, 
or the end of the follow-up period. 
Eligible Population 
The eligible study population includes adult subjects with 
recurrent or progressive glioblastoma for which there is no 
alternative curative therapy.  
Eligibility Criteria 
Subjects with supratentorial glioblastoma who have not 
previously been treated with inhibitors of immuno-checkpoint 
pathways (e.g., anti-PD-1, anti-PD-L1, anti-PD-L2, 
anti-CD137, or anti-CTLA-4 antibody) or other agents 
specifically targeting T cells. 
Inclusion Criteria 
1. Male or female subject ≥18 and ≤75 years of age 
2. Provision of written informed consent for tumor 
resection (subtotal allowed), tumor biopsy, samples 
collection, and treatment with investigational products 
prior to undergoing any study-specific procedures 
3. Histologically confirmed glioblastoma from archival 
tissue 
4. Evidence of tumor recurrence/progression by magnetic 
resonance imaging (MRI) according to Response 
Assessment in Neuro-Oncology (RANO) criteria after 
standard initial therapy. Multifocal disease is allowed, 
but subjects must not have more than 5 enhancing 
lesions. 
5. Previous standard-of-care antitumor treatment 
including surgery and/or biopsy and chemoradiation.  
At the time of registration, subjects must have 
recovered from the toxic effects of previous treatments 
as determined by the treating physician.  The washout 
periods from prior therapies are intended as follows: 
(windows other than what is listed below should be 


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Protocol ATI001-204 
Amendment 2 
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allowed only after consultation with the Medical 
Monitor) 
a. Nitrosoureas:  6 weeks 
b. Other cytotoxic agents:  4 weeks  
c. Antiangiogenic agents:  4 weeks  
d. Targeted agents, including small molecule tyrosine 
kinase inhibitors:  2 weeks 
e. Vaccine-based or CAR-T therapy:  3 months 
6. Able to undergo standard MRI scans with contrast 
agent before enrollment and after treatment  
7. Karnofsky Performance Status ≥70 
8. Adequate bone marrow reserves and liver and kidney 
function, as assessed by the following laboratory 
requirements: 
a. Hemoglobin ≥9 g/L 
b. Lymphocytes >500/mm3 
c. Absolute neutrophil count ≥1500/mm3 
d. Platelets ≥100,000/mm3 
e. Serum creatinine ≤1.5 x upper limit of normal 
(ULN) 
f. Aspartate transaminase (AST) and alanine 
transaminase (ALT) ≤2.5 x ULN 
g. Total bilirubin <1.5 x ULN 
h. International normalized ratio (INR) and activated 
partial thromboplastin time (aPTT) or partial 
thromboplastin time (PTT) within normal 
institutional limits 
9. Female of child bearing potential* and sexually active 
male subjects must agree to practice highly effective 
contraception prior to the start of the first treatment, 
during the study, and for at least 4 months after the 
last dose. Highly effective contraceptive measures 
include stable use of combined (estrogen and 
progestogen containing) hormonal contraception (oral, 
intravaginal, transdermal) or progestogen-only 
hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation initiated 2 or 
more menstrual cycles prior to screening; intrauterine 




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Amendment 2 
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permitted. For Subjects with controlled HIV 
infection, monitoring will be performed per local 
standards.  
• Subjects with hepatitis B (HBsAg+) who have 
controlled infection (serum hepatitis B virus DNA 
PCR that is below the limit of detection AND 
receiving anti-viral therapy for hepatitis B) are 
permitted. Subjects with controlled infections must 
undergo periodic monitoring of HBV DNA. 
Patients must remain on anti-viral therapy for at 
least 6 months beyond the last dose of 
investigational study drug.  
• Subjects who are hepatitis C virus antibody 
positive (HCV Ab+) who have controlled infection 
(undetectable HCV RNA by PCR either 
spontaneously or in response to a successful prior 
course of anti-HCV therapy) are permitted.  
6. 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. 
7. Use of enzyme-inducing antiepileptic drugs (EIAED) 
within 7 days prior to the first dose of study drug.  
Note:  Levetiracetam (Keppra®) is not an EIAED and 
is allowed. 
8. Other concurrent clinically active malignant disease, 
requiring treatment, except for non-melanoma cancers 
of the skin or carcinoma in situ of the cervix or non-
metastatic prostate cancer 
9. Nursing or pregnant females 
10. Prior exposure to veledimex 
11. Use of an investigational product within prior 30 days.  
12. Prior exposure to inhibitors of immuno-checkpoint 
pathways (e.g., anti-PD-1, anti-PD-L1, anti-PD-L2, 
anti-CD137, or anti-CTLA-4 antibody) or other agents 
specifically targeting T cells 


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13. Use of medications that induce, inhibit, or are 
substrates of CYP450 3A4 prior to veledimex dosing 
without consultation with the Medical Monitor 
14. Presence of any contraindication for a neurosurgical 
procedure 
15. Use of heparin or other anti-coagulation therapy, or 
acetylsalicylic acid (ASA), or anti-platelet drug within 
Day -7 to Day 21 should not be used unless necessary 
to treat a life-threatening illness. Prophylactic 
subcutaneous heparin per institutional protocol for 
prevention of deep vein thrombosis (DVT) may be 
allowed based on discussion with the Medical 
Monitor. Concomitant medications should continue to 
be reviewed in consultation with the Medical Monitor. 
16. Unstable or clinically significant medical condition 
that would, in the opinion of the Investigator or 
Medical Monitor, jeopardize the safety of a subject 
and/or their compliance with the protocol.  Examples 
include, but are not limited to, a history of myocarditis 
or congestive heart failure (as defined by New York 
Heart Association Functional Class III or IV), unstable 
angina, serious uncontrolled cardiac arrythmia, 
myocardial infarction within 6 months of screening, 
active interstitial lung disease (ILD)/pneumonitis or a 
history of ILD/pneumonitis requiring treatment with 
systemic steroids uncontrolled asthma, or colitis. 
Stopping Rules 
From Day -7 to 30 days after completion of Ad-RTS-hIL12 + 
veledimex dosing, if any subject experienced a death (other 
than death related to progressive disease); or if any subject, 
during the initial treatment period (Day -7 to Day 28) 
experiences a related SAE that has immediately life-
threatening consequences requiring urgent intervention or 
results in death; requires major operative intervention; or is a 
related grade 4 hematologic toxicity that persists for 5 days: 
then enrollment of new subjects will be paused, pending 
review of the event by the Safety Review Committee.  The 
SRC will recommend if changes to the enrollment of 
additional subjects are required, including, but not limited to, 
potentially modifying the dose and schedule of veledimex, to 
amend the protocol prior to enrollment of additional subjects, 
or to discontinue enrollment in the study. 
 
 










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Table 1: 
Schedule of Study Procedures 
Activity 
Screening 
Treatment 
Day -30 
to -8* 
Day -7 
**  
Day 0a 
Day 1 
Day 2 
Day 3 
Day 4 to 6 
Day 7 
Day 8 to 
13 
Informed consent 
X 
 
 
 
 
 
 
 
 
Medical/Cancer historyd 
X 
 
 
 
 
 
 
 
 
Physical exame, including targeted 
neurological exam 
X 
X 
X 
X 
X 
X 
 
X 
 
Karnofsky PSf 
X 
X 
X 
 
 
 
 
 
 
Height (screen) and weight 
X 
 
 
 
 
 
 
X 
 
Vital signsg 
X 
X 
X 
X 
X 
X 
 
X 
 
Adverse eventsh 
CONTINUOUS 
Concomitant medicationsh 
CONTINUOUS 
Survival statusi 
CONTINUOUS  
Pregnancy testj 
X 
X 
X 
 
 
 
 
 
 
Hematologyk 
X 
X 
Xa 
X 
X 
X 
 
X 
 
Coagulationl 
X 
 
Xa 
X 
 
X 
 
X 
 
Serum chemistrym 
X 
X 
Xa 
X 
X 
X 
 
X 
 
Urinalysisn 
X 
X 
Xa 
 
 
X 
 
X 
 
Thyroid panelo 
X 
 
 
 
 
 
 
 
 
ECGp 
X 
 
X 
 
 
X 
 
X 
 
Confirm eligibility 
 
Xq 
 
 
 
 
 
 
 
Cemiplimab-rwlc doseq 
 
X 
 
 
 
 
 
 
 
Ad-RTS-hIL-12 
 
 
Xr,s 
 
 
 
 
 
 
Veledimex dose and diaryv 
 
 
Xs, t 
Xs, t 
X 
Xu 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
MRI scansz 
Xz 
 
 
Xz, aa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 1: 
Schedule of Study Procedures (continued) 
Activity 
Treatment 
Long Term Follow-up 
 
Day 14 
Day 15 
Day 22 
Day 28 
Day 36 ±3 
days 
Day 57 
±3 days 
Every 3 weeksb 
±7days 
Every 
8 weeksc  ±7days 
Informed consent 
 
 
 
 
 
 
 
 
Medical/Cancer historyd 
 
 
 
 
 
 
 
 
Physical exame, including targeted 
neurological exam 
X 
 
 
 
X 
 
X 
 
Karnofsky PSf 
X 
 
 
 
X 
 
X 
 
Height (screen) and weight 
X 
 
 
 
X 
 
 
 
Vital signsg 
X 
 
 
 
X 
 
X 
 
Adverse eventsh 
CONTINUOUS 
Concomitant medicationsh 
CONTINUOUS 
Survival statusi 
CONTINUOUS 
Pregnancy testj 
 
 
 
X 
X 
 
X 
 
Hematologyk 
X 
 
X 
 
X 
X 
X 
 
Coagulationl 
X 
 
 
 
X 
 
 
 
Serum chemistrym 
X 
 
X 
 
X 
X 
X 
 
Urinalysisn 
X 
 
X 
 
 
X 
X 
 
Thyroid panelo 
X 
 
 
 
X 
X 
X 
 
ECGp 
X 
 
 
 
X 
 
X 
 
Confirm eligibility 
 
 
 
 
 
 
 
 
Cemiplimab-rwlc doseq 
 
X 
 
 
X 
X 
X 
 
Ad-RTS-hIL-12 
 
 
 
 
 
 
 
 
Veledimex dose and diary 
Xv 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRI scansz 
 
 
 
 
 
Xz 
 
Xz 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Screening assessments must be conducted within 30 days prior to dosing with Ad-RTS-hIL-12 + veledimex.  
** Day -7 dosing with cemiplimab-rwlc may be performed within ± 3 days.  
a  The PI will review all results of laboratory tests drawn within 24 hours prior to surgery. 
b  Every 3 weeks from Day 57 
c  Every 8 weeks from Day 57 in addition to assessments performed every 3 weeks 
d  Medical history includes demographic information, relevant medical and surgical history.  Cancer history includes current cancer diagnosis, prior treatment (regimen[s], doses, start and stop dates, and 




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Figure 1: 
Study Schema 
 
 
 
 
 
 
 
 
 
* Tumor sample to be obtained at repeat resection or via biopsy to confirm progression.  




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8.2. 
Study Oversight for Safety Evaluation .......................................................................40 
9. 
SUBJECT SELECTION .............................................................................................42 
9.1. 
Inclusion Criteria ........................................................................................................42 
9.2. 
Exclusion Criteria .......................................................................................................43 
9.3. 
Subject Enrollment .....................................................................................................44 
9.4. 
Withdrawal of Subjects from Study Treatment and/or Study ....................................45 
9.5. 
Replacement of Subjects .............................................................................................45 
9.6. 
Premature Termination of Study or Study Site ...........................................................45 
10. 
INVESTIGATIONAL PRODUCTS ..........................................................................46 
 
 
10.2. 
Preparation of Veledimex ...........................................................................................46 
10.3. 
Preparation of Cemiplimab-rwlc ................................................................................46 
10.4. 
Handling and Storage .................................................................................................47 
10.5. 
Monitoring of Subject Adherence and Managing Missed Doses ...............................47 
10.5.1. 
Veledimex ...................................................................................................................47 
10.5.2. 
Cemiplimab-rwlc ........................................................................................................47 
10.6. 
Disposition of Unused Drug .......................................................................................47 
10.7. 
Accountability and Dispensation ................................................................................47 
10.8. 
Treatment Plan ............................................................................................................47 
10.8.1. 
Cemiplimab-rwlc ........................................................................................................47 
10.8.2. 
Ad-RTS-hIL-12 + Veledimex.....................................................................................48 
10.9. 
Stopping Rules ............................................................................................................48 
10.10. 
Dose Modifications and Dose Delays .........................................................................49 
10.11. 
Safety Monitoring and Adverse Effect Management .................................................51 
10.12. 
Severity Grading and Management of Local Reactions .............................................51 
10.13. 
Prophylactic Antipyretic and/or Analgesic Administration .......................................51 
11. 
CONCOMITANT THERAPY ...................................................................................52 
11.1. 
Permitted Medications ................................................................................................52 
11.2. 
Prohibited Medications/Therapies ..............................................................................52 
12. 
STUDY PROCEDURES ............................................................................................53 
12.1. 
Written Informed Consent ..........................................................................................53 
12.2. 
Subject Registration ....................................................................................................53 
12.3. 
Schedule of Assessments and Observations ...............................................................53 


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12.3.1. 
Study Tests, Exams, and Procedures ..........................................................................53 
12.3.1.1. 
Demographics, Medical and Cancer History, and Concomitant Medications ............53 
12.3.1.2. 
Physical Examinations ................................................................................................53 
12.3.1.3. 
Vital Signs, Height, and Weight .................................................................................53 
12.3.1.4. 
Karnofsky Performance Status ...................................................................................53 
12.3.1.5. 
Pregnancy Testing ......................................................................................................54 
12.3.1.6. 
Monitoring of Adverse Events ....................................................................................54 
12.3.1.7. 
Clinical Laboratory Assessments ...............................................................................54 
12.3.1.8. 
MRI .............................................................................................................................54 
 
 
12.3.1.10. Electrocardiogram .......................................................................................................55 
12.3.2. 
Schedule of Assessments ............................................................................................55 
12.3.2.1. 
Screening Period:  Assessments .................................................................................55 
12.3.2.2. 
Treatment Period: Day -7 ...........................................................................................56 
12.3.2.3. 
Treatment Period: Day 0 (Ad-RTS-hIL-12 injection) ................................................56 
12.3.2.4. 
Treatment Period: Day 1 .............................................................................................56 
12.3.2.5. 
Treatment Period: Day 2 .............................................................................................57 
12.3.2.6. 
Treatment Period: Day 3 .............................................................................................57 
12.3.2.7. 
Treatment Period: Days 4 through 6 ...........................................................................57 
12.3.2.8. 
Treatment Period: Day 7 .............................................................................................57 
12.3.2.9. 
Treatment Period: Day 8-13 .......................................................................................58 
12.3.2.10. Treatment Period: Day 14 ...........................................................................................58 
12.3.2.11. Treatment Period: Day 15 ...........................................................................................58 
12.3.2.12. Treatment Period: Day 22 ...........................................................................................58 
12.3.2.13. Treatment Period: Day 28 ...........................................................................................58 
12.3.2.14. Treatment Period: Day 36 ...........................................................................................58 
12.3.2.15. Treatment Period: Day 57 ...........................................................................................59 
12.3.2.16. Treatment Period: Every 3 weeks after Day 57 ..........................................................59 
12.3.2.17. Treatment Period: Every 8 weeks after Day 57 ..........................................................59 
12.3.2.18. Unscheduled Visits Collections ..................................................................................59 
13. 
TUMOR RESPONSE ASSESSMENTS ....................................................................61 
13.1. 
Tumor Response .........................................................................................................61 
13.2. 
Tumor Response Evaluation and Pseudo-Progression ...............................................61 


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13.3. 
Central Imaging Reads ...............................................................................................62 
14. 
SAFETY ASSESSMENTS ........................................................................................63 
14.1. 
Adverse Events and Definitions .................................................................................63 
14.1.1. 
Adverse Event .............................................................................................................63 
14.1.2. 
Suspected Adverse Reaction .......................................................................................63 
14.1.3. 
Adverse Reaction ........................................................................................................63 
14.1.4. 
Unexpected Adverse Reaction ....................................................................................63 
14.2. 
Evaluation of Adverse Events ....................................................................................63 
14.3. 
Determination of Seriousness .....................................................................................64 
14.3.1. 
Serious Adverse Event ................................................................................................64 
14.3.2. 
Non-Serious Adverse Event .......................................................................................64 
14.4. 
Determination of Severity ...........................................................................................65 
14.5. 
Determination of Causality .........................................................................................65 
14.6. 
Documenting Adverse Events ....................................................................................66 
14.7. 
Reporting Serious Adverse Events (SAE), and Adverse Events of Special 
interest (AESI) ............................................................................................................66 
14.7.1. 
Time Frame for Reporting ..........................................................................................66 
14.7.2. 
Information to be Provided by the Investigator ..........................................................67 
14.8. 
Sponsor and Investigator Responsibility for Reporting Adverse Events ...................67 
14.9. 
Follow-up Information for Adverse Events ................................................................68 
14.9.1. 
Required Follow-up for Adverse Events ....................................................................68 
14.10. 
Pregnancies .................................................................................................................68 
14.11. 
Overdose .....................................................................................................................68 
 
 ..............................................................................................
 
 
 
 
69 
 
 
 
 
16. 
STATISTICAL METHODS .......................................................................................71 
16.1. 
Populations for Analysis .............................................................................................71 
16.2. 
Sample Size and Power Calculations .........................................................................71 
16.3. 
Endpoints ....................................................................................................................72 
16.3.1. 
Primary Endpoint ........................................................................................................72 
16.3.2. 
Secondary Endpoints ..................................................................................................72 


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16.4. 
Safety Evaluation ........................................................................................................72 
16.5. 
Efficacy Evaluation ....................................................................................................73 
16.6. 
Analyses ......................................................................................................................73 
16.6.1. 
Baseline Characteristics ..............................................................................................73 
16.6.2. 
Safety Analyses ..........................................................................................................74 
16.6.3. 
Overall Survival ..........................................................................................................74 
16.6.4. 
Tumor Response Analyses .........................................................................................74 
16.6.5. 
Multi-Center Study .....................................................................................................75 
16.6.6. 
Adjustments for Covariates ........................................................................................75 
16.6.7. 
Procedures for Handling Missing, Unused, and Spurious Data .................................75 
16.6.8. 
Procedures for Reporting Deviations to Original Statistical Analysis Plan ...............75 
17. 
STUDY MANAGEMENT .........................................................................................76 
17.1. 
Electronic Case Report Forms and Source Documentation .......................................76 
17.2. 
Good Clinical Practice ................................................................................................76 
17.3. 
Sponsor Monitoring ....................................................................................................76 
17.4. 
Duration of the Study ..................................................................................................77 
17.5. 
Records Retention .......................................................................................................77 
17.6. 
Institutional Review Board/ Independent Ethics Committee .....................................77 
17.7. 
Confidentiality and HIPAA ........................................................................................78 
17.8. 
Informed Consent .......................................................................................................78 
17.8.1. 
FDA Informed Consent Requirements .......................................................................78 
17.8.2. 
Subject Informed Consent Form .................................................................................79 
18. 
PROTOCOL APPROVAL PAGE ..............................................................................80 
19. 
REFERENCES ...........................................................................................................81 
20. 
APPENDICES ............................................................................................................86 
APPENDIX 1. ZIOPHARM CYTOKINE RELEASE SYNDROME WORKING 
DEFINITION - AD-RTS-HIL-12 + VELEDIMEX (VERSION 3, 07 
JANUARY 2019) .......................................................................................................87 
APPENDIX 2. RECOMMENDED REGIMEN FOR ANTIPYRETIC AND/OR 
ANALGESIC PROPHYLAXIS .................................................................................88 
APPENDIX 3. PROHIBITED ENZYME-INDUCING AND NON-
ENZYME-INDUCING ANTIEPILEPTIC DRUGS ..................................................89 
APPENDIX 4. IMMUNOTHERAPY RESPONSE ASSESSMENT IN NEURO-
ONCOLOGY: A REPORT OF THE RANO WORKING GROUP ..........................90 
 






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Abbreviation or Specialist Term 
Explanation 
EMCV 
Encephalomyocarditis virus 
ESR 
Erythrocyte sedimentation rate 
FDA 
U.S. Food and Drug Administration 
Gal4-EcR 
Fusion protein between Gal4 DNA binding domain and 
ecdysone receptor ligand binding domain 
GalRE/P 
Gal4 responsive promoter 
GBM 
Glioblastoma (multiforme) 
GCP 
Good Clinical Practice 
HBsAg 
Hepatitis B Surface Antigen 
HCV 
Hepatitis C Virus 
hIL-12 
Human interleukin-12 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
HLA 
Human leukocyte antigen 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IFN-β 
Interferon-beta 
IFN-γ 
Interferon-gamma 
INR 
International normalized ratio 
IL-2 
Interleukin-2 
IL-12 
Interleukin-12 
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 
IUD 
Intrauterine device 
KDa 
kilo (K)- unified atomic mass units (Daltons or Da) 
LDH 
Lactate dehydrogenase 
MCV 
Mean cell volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 


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Amendment 2 
 
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Abbreviation or Specialist Term 
Explanation 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
NK 
Natural killer 
NOS 
Not otherwise specified 
NPO 
Nothing by mouth (literally, nil per os) 
ORR 
Objective response rate 
OS 
Overall survival 
OSP 
Overall Safety Population 
PCR 
Polymerase chain reaction 
PD 
Progressive disease 
PFS 
Progression-free survival 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
PKP 
Pharmacokinetics Population 
PO 
Oral(ly) 
polyA 
polyadenylation signal 
PR 
Partial response 
PSP 
Pseudo-progression 
PUbC 
Ubiquitin C promoter 
Q 
Each/every (quaque), as in Q3W (every 3 weeks) 
QD 
Each day (quaque die) 
rAd 
Recombinant adenovirus 
RANO 
Response Assessment for Neuro-Oncology 
RBC 
Red blood cell 
rhIL-12 
Recombinant human IL-12 
 
 
RXR 
Retinoid X receptor 
SAE 
Serious adverse event 
SD 
Stable disease 
SpO2 
Saturation of peripheral oxygen 
SRC 
Safety Review Committee 
TEAE 
Treatment-emergent adverse event   
Th1 
T-helper cell type 1 


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Abbreviation or Specialist Term 
Explanation 
ULN 
Upper limit of normal 
V 
Veledimex 
v 
Version (followed by number) 
vp 
Viral particles 
VP16-RXR 
Fusion between VP16 transcriptional activation domain and a 
chimeric RXR 
WBC 
White blood cell 
 


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6. 
INTRODUCTION 
6.1. 
Immunotherapy in Glioblastoma 
The revised 2016 World Health Organization Classification of Tumors of the Central Nervous 
System makes use of molecular genetic findings in addition to histology to define tumor entities 
based on combined phenotypic and genotypic features to generate “integrated diagnoses” (Louis 
et al. 2016). It has resulted in substantial restructuring of the diffuse gliomas, as compared with 
the 2007 CNS WHO Classification.  In the revised classification the diffuse gliomas include the 
anaplastic astrocytomas (anaplastic astrocytoma, IDH-wildtype; anaplastic astrocytoma, IDH-
mutant; and anaplastic astrocytoma, NOS [Not Otherwise Specified]) and anaplastic 
oligodendroglioma (with IDH-mutant and 1p/19q-codeleted subtypes) that are classified as 
WHO Grade III and the glioblastomas (glioblastoma, IDH-wildtype including giant cell 
glioblastoma, gliosarcoma, and epithelioid glioblastoma subtypes; glioblastoma, IDH-mutant; 
and glioblastoma, NOS) that are classified as WHO Grade IV.  Of the WHO Grade III and Grade 
IV tumors, glioblastomas make up 60% to 70%, anaplastic astrocytomas 10% to 15%, and 
several other anaplastic subtypes the rest (Central Brain Tumor Registry).  
Glioblastomas are by far the most frequent malignant glioma and are associated with a 
particularly aggressive course and dismal prognosis (Lieberman 2017). Standard of care 
treatment for glioblastomas is based on surgical resection with the intent to remove as much of 
the tumor as is feasible (Fernandes et al. 2017, Paolillo et al. 2018).  Resection is then followed 
by radiotherapy and concomitant adjuvant temozolomide.  However, such aggressive treatment 
is associated with only modest improvements in survival.  Newly diagnosed glioblastoma 
subjects have a median overall survival (OS) of 12 to 15 months (Ahmed et al. 2014) and 2-year 
OS rate of up to 27% (Omuro et al. 2013), while OS in subjects that have failed TMZ and 
bevacizumab, or equivalent salvage chemotherapy, is reported as being as short as 3 to 5 months 
(Omuro et al., 2013; Iwamoto et al., 2009).  To date, no salvage treatment has been validated by 
Phase III data for recurrent or progressive glioblastoma.  For subjects with recurrent 
glioblastoma, the median OS is 6 to 7 months (Omuro et al. 2013), and median progression-free 
survival (PFS) is 2 to 3 months. 
The lack of standard and validated salvage therapies has prompted the use of nitrosoureas, 
temozolomide rechallenge, bevacizumab, and other targeted agents that are unsatisfactory 
treatment options.  This likely reflects the complexities of disease heterogeneity, and the 
treatment limitations of brain tumors given the low activity of antineoplastic agents, de novo or 
acquired drug resistance, the sensitivity of the brain to irreversible damage in response to 
treatment and the presence of the blood brain barrier (BBB), which maintains the brain as a 
privileged compartment.  Surgical resection may be offered for subjects with recurrent disease, 
with the goal of alleviating mass effect, improving symptoms, and achieving cytoreduction.  
Surgical resection, however, is limited by the infiltrative nature of the disease and the lack of 
clear margins delimitating the tumor.  Given the poor overall prognosis and lack of effective 
treatments, new therapeutic approaches for malignant gliomas are needed. 
Immunotherapy for brain tumors is actively being investigated with an array of newer 
therapeutic modalities.  Only about a third of glioblastomas have been reported to demonstrate a 
robust CD8+ cell population present within the tumor microenvironment (Heimberger et al. 
2008), and these cells are anergic (i.e., not secreting interferon gamma [IFN-γ] or incapable of 
cytolytic activity).  The immune infiltration in glioblastomas is highly variable and is likely 


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driven by the genetic composition and mutational load of the tumor (Beier et al. 2012, Doucette 
et al. 2013). The anticipated specificity and efficiency of cytotoxic T-cells (CD8+), activated by 
local production of IL-12, is particularly attractive and may both spare normal brain cells and 
minimize systemic toxicity.  We have shown in an orthotopic mouse model that survival and 
tumor killing was greatly enhanced by combining a checkpoint inhibitor and Ad-RTS-mIL-12 + 
veledimex (Barrett et al. 2016b).  Early clinical trials suggest that combining immunotherapeutic 
approaches with surgery, radiation, and chemotherapy may improve outcomes (Mitchell et al. 
2008).  Preliminary results from the CheckMate 143 (NCT 02017717) randomized clinical trial 
in first recurrence of glioblastoma, announced in a World Federation of Neuro-Oncology 
Societies (WFNOS) 2017 abstract, demonstrated a failure of nivolumab to prolong overall 
survival of patients with recurrent GBM, and this monotherapy arm of the trial was prematurely 
terminated (Filley et al 2017). However, an encouraging example of a combination 
immunotherapy approach to treating glioblastoma is a study of the safety and activity of 
nivolumab (human programmed death receptor-1 [PD-1] blocking antibody) in combination with 
ipilimumab (anti-cytotoxic T lymphocyte associated antigen 4 [CTLA-4] antibody) in patients 
with recurrent disease (Reardon et al. 2016).  In this ongoing dose escalation study, combination 
therapy was tolerable, with 12-month overall survival (OS) ranging from 25% to 40%.  
In Ziopharm’s ongoing Phase I trial of intratumoral viral delivery of Ad-RTS-hIL-12 + 
veledimex to date 31 subjects have been orally dosed in 4 cohorts:  10 mg (n=6), 20 mg (n=7), 
30 mg (n=4), 40 mg (n=6), and an expansion cohort of 20 mg (n=8).  Results show that 
veledimex crossed the blood-brain-barrier, with approximately 40% of plasma levels detected in 
the brain tumor.  Subjects in the 20 mg dose cohort (n=15) have better median OS (12.7 months) 
than in other cohorts. 
Immune checkpoint inhibitors penetration across the blood-brain-barrier to the tumor tissue 
remains controversial, but the goal is to achieve maximum therapeutic effect while limiting 
systemic toxicity, especially when CD8+ cells have been mobilized to the tumor as we have 
documented following treatment with Ad-RTS-hIL-12 + veledimex. 
6.2. 
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-12 p70 molecule (Carra et al. 2000).  The 
expression of the p40 subunit is tightly regulated and requires specific priming and amplification 
signals through complex combinatorial matching of Toll receptor agonists and specific 
cytokines, thus limiting the cell types that can produce native biologically active IL-12 to 
activated antigen-presenting cells, neutrophils, and macrophages (Trinchieri 2003).  On a 
secondary level, IL-12 production can also be negatively regulated through various mechanisms 
including production of IL-10 and transforming growth factor β (TGFβ). 
Initial studies identified that IL-12 was produced by innate immune cells in response to 
pathogens and that it led to the production of interferon gamma (IFN-γ) and tumor necrosis alpha 
(TNFα) by T and natural killer (NK) cells (Micallef et al.1996, Trinchieri 2003).  When it was 
discovered that IL-12 could drive naïve T-helper cell differentiation to the inflammatory 
T-helper cell type 1 (Th1) phenotype (Hsieh et al. 1993), a role for IL-12 was established as a 
bridge between innate immune cells and the adaptive immune response through polarization of 






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OS was not improved for the investigational regimen relative to the standard of care regimen 
(Westphal et al. 2013).  This apparent difference may have been due to the composite primary 
endpoint and/or that while OS is a robust endpoint, there is no discussion of effect size and for 
recently-diagnosed tumors it might be less suitable to capture meaningful treatment effects for 
the initial stages of disease because of uncontrolled therapy at relapse (ibid). Nevertheless, the 
authors concluded that the treatment had an increased hazard ratio for the primary analysis with a 
positive overall benefit-risk ratio, with similar AEs (hemiparesis [often transient], hyponatremia, 
and seizures, but no cerebral hemorrhages nor hematomas), as compared with the standard-of-
care regimen.   
6.4.1.1. 
Safety of Intratumoral Injection of IL-12 Gene Vectors 
In contrast with the systemic toxicity resulting from administration of recombinant IL-12 protein, 
local administration of IL-12 via injection of plasmid or adenoviral vectors containing the hIL-12 
gene has proven to be well tolerated in subjects with various cancers, and therefore appears to 
provide an effective delivery method for this potent immunomodulatory cytokine.  Several 
studies have investigated the safety of intratumoral expression of IL-12 in subjects with 
metastatic melanoma.  A Phase I study investigated intratumoral expression of IL-12 together 
with the co-stimulatory molecule B7.1 via two separate canarypox virus viral vectors (ALVAC) 
in subjects with metastatic melanoma and reported mild to moderate injection site reactions, 
fever, chills, myalgia, and fatigue as AEs (Triozzi et al. 2005).  However, all subjects also 
developed antibodies to ALVAC.  Notably, serum IL-12 and IFN-γ levels were not increased 
after treatment.  Another Phase I trial showed that delivery by electroporation of a plasmid 
containing IL-12 to tumors in subjects with metastatic melanoma resulted in minimal systemic 
toxicity, with transient pain after electroporation being the most common AE (Daud et al. 2008).  
Results from another Phase I study showed that intratumoral injection of DNA encoding hIL-12 
in subjects with metastatic melanoma was well tolerated overall (Heinzerling et al. 2005).  Eight 
of nine subjects experienced a transient response at the intratumoral injection site, and some 
subjects who had tumor responses also showed some increases in systemic in IL-12, interferon 
gamma-induced protein 10 (IP-10), and IFN-γ. 
Localized production of IL-12 also has been reported as well tolerated in subjects with other 
malignancies.  For example, a Phase I study in 17 subjects with metastatic pancreatic, colorectal, 
or primary liver cancer examined intratumoral injection of dendritic cells engineered to secrete 
IL-12 via a rAD vector (Mazzolini et al. 2005).  In that study, the most common AEs were 
lymphopenia, fever, and malaise.  Subjects also developed antibodies to the adenoviral capsid 
proteins.  Intraperitoneal injection of a plasmid containing the hIL-12 gene in women with 
chemotherapy-resistant, recurrent, ovarian cancer also was found to be generally safe and well 
tolerated (Anwer et al. 2010).  Low-grade fever and abdominal pain were the most common AEs.  
Plasmid DNA was not detected in the subjects’ serum samples, and treatment-related increases in 
IFN-γ levels were observed in pleural fluid, but not in serum.  Similar data were reported in a 
study of subjects with advanced pancreatic, colorectal, or primary liver malignancies who 
received intratumoral injections of adenoviral vectors encoding hIL-12 at doses ranging from 
2.5 × 1010 to 3 × 1012 vp (Sangro et al. 2004).  In that study, treatment was well tolerated and a 
maximum tolerated dose (MTD) was not reached.  Transient lymphopenia was observed in 86% 
of subjects, and the severity was increased at higher vector doses.  Transient, mild to moderate 
fever, sometimes accompanied by malaise and sweating, was observed in ~ 60% of subjects 
during the first 2 days after the injection.  Five of the 21 subjects (24%) experienced nausea 


















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external medical and scientific experts may also be invited to participate in the reviews as needed 
and appropriate and as decided by the SRC.  If a significant safety event occurs, the SRC will 
convene to evaluate the safety event(s) and make a recommendation and decision on the 
enrollment and continued treatment of subjects.  


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9. 
SUBJECT SELECTION 
Subjects with supratentorial glioblastoma who have not previously been treated with inhibitors of 
immuno-checkpoint pathways (e.g., anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or 
anti-CTLA-4 antibody) or other agents specifically targeting T cells. 
9.1. 
Inclusion Criteria 
1. Male or female subject ≥18 and ≤75 years of age 
2. Provision of written informed consent for tumor resection (subtotal allowed), tumor 
biopsy, samples collection, and treatment with investigational products prior to 
undergoing any study-specific procedures 
3. Histologically confirmed glioblastoma from archival tissue 
4. Evidence of tumor recurrence/progression by magnetic resonance imaging (MRI) 
according to Response Assessment in Neuro-Oncology (RANO) criteria after standard 
initial therapy. Multifocal disease is allowed, but subjects must not have more than 5 
enhancing lesions. 
5. Previous standard-of-care antitumor treatment including surgery and/or biopsy and 
chemoradiation.  At the time of registration, subjects must have recovered from the toxic 
effects of previous treatments as determined by the treating physician.  The washout 
periods from prior therapies are intended as follows: (windows other than what is listed 
below should be allowed only after consultation with the Medical Monitor) 
a. Nitrosoureas:  6 weeks 
b. Other cytotoxic agents:  4 weeks  
c. Antiangiogenic agents:  4 weeks  
d. Targeted agents, including small molecule tyrosine kinase inhibitors:  2 weeks 
e. Vaccine-based or CAR-T therapy:  3 months 
6. Able to undergo standard MRI scans with contrast agent before enrollment and after 
treatment  
7. Karnofsky Performance Status ≥70 
8. Adequate bone marrow reserves and liver and kidney function, as assessed by the 
following laboratory requirements: 
a. Hemoglobin ≥9 g/L 
b. Lymphocytes >500/mm3 
c. Absolute neutrophil count ≥1500/mm3 
d. Platelets ≥100,000/mm3 
e. Serum creatinine ≤1.5 x upper limit of normal (ULN) 
f. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤2.5 x ULN.   
g. Total bilirubin <1.5 x ULN 


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h. International normalized ratio (INR) and activated partial thromboplastin time (aPTT) 
or partial thromboplastin time (PTT) within normal institutional limits 
9. Female of child bearing potential* and sexually active male subjects must agree to 
practice highly effective contraception prior to the start of the first treatment, during the 
study, and for at least 4 months after the last dose. Highly effective contraceptive 
measures include stable use of combined (estrogen and progestogen containing) 
hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal 
contraception (oral, injectable, implantable) associated with inhibition of ovulation 
initiated 2 or more menstrual cycles prior to screening; intrauterine device (IUD); 
intrauterine hormone-releasing system (IUS); bilateral tubal ligation; vasectomized 
partner; and or sexual abstinence**. 
* Postmenopausal women must be amenorrheic for at least 12 months in order not to be 
considered of childbearing potential. Pregnancy testing and contraception are not required for 
women with documented hysterectomy or tubal ligation. 
** Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
treatments. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient. 
10. Normal cardiac and pulmonary function as evidenced by a normal ECG with QTc ≤450 
msec and peripheral oxygen saturation (SpO2) ≥ 92% on Room air by pulse oximetry   
9.2. 
Exclusion Criteria 
1. Radiotherapy treatment within 4 weeks of starting veledimex  
2. Prior treatment with bevacizumab 
 
3. Subjects receiving systemic corticosteroids for treatment of disease-related symptoms 
during the 4 weeks prior to Day -7 
4. Subjects with clinically significant increased intracranial pressure (e.g., impending 
herniation or requirement for immediate palliative treatment) or uncontrolled seizures 
5. Uncontrolled infection with human immunodeficiency virus, hepatitis B or hepatitis 
C infection; or diagnosis of immunodeficiency.  
NOTE:        
• Subjects with known HIV infection who have controlled infection (undetectable viral 
load (HIV RNA PCR) and CD4 count above 350 either spontaneously or on a stable 
antiviral regimen) are permitted. For subjects with controlled HIV infection, 
monitoring will be performed per local standards.  
• Subjects with hepatitis B (HBsAg+) who have controlled infection (serum hepatitis B 
virus DNA PCR that is below the limit of detection AND receiving anti-viral therapy 
for hepatitis B) are permitted. Subjects with controlled infections must undergo 
periodic monitoring of HBV DNA. Subjects must remain on anti-viral therapy for at 
least 6 months beyond the last dose of investigational study drug.  


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• Subjects who are hepatitis C virus antibody positive (HCV Ab+) who have controlled 
infection (undetectable HCV RNA by PCR either spontaneously or in response to a 
successful prior course of anti-HCV therapy) are permitted.  
6. 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. 
7. Use of enzyme-inducing antiepileptic drugs (EIAED) within 7 days prior to the first dose 
of study drug.  Note:  Levetiracetam (Keppra®) is not an EIAED and is allowed. 
8. Other concurrent clinically active malignant disease, requiring treatment, except for 
non-melanoma cancers of the skin or carcinoma in situ of the cervix or non-metastatic 
prostate cancer 
9. Nursing or pregnant females 
10. Prior exposure to veledimex 
11. Use of an investigational product within prior 30 days.  
12. Prior exposure to inhibitors of immuno-checkpoint pathways (e.g., anti-PD-1, 
anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody) or other agents 
specifically targeting T cells. 
13. Use of medications that induce, inhibit, or are substrates of CYP450 3A4 prior to 
veledimex dosing without consultation with the Medical Monitor 
14. Presence of any contraindication for a neurosurgical procedure 
15. Use of heparin or other anti-coagulation therapy, or acetylsalicylic acid (ASA), or anti-
platelet drug within Day -7 to Day 21 should not be used unless necessary to treat a life-
threatening illness. Prophylactic subcutaneous heparin per institutional protocol for 
prevention of DVT may be allowed based on discussion with the Medical Monitor. 
Concomitant medications should continue to be reviewed in consultation with the 
Medical Monitor. 
16. Unstable or clinically significant medical condition that would, in the opinion of the 
Investigator or Medical Monitor, jeopardize the safety of a subject and/or their 
compliance with the protocol.  Examples include, but are not limited to, history of 
myocarditis or congestive heart failure (as defined by New York Heart Association 
Functional Class III or IV), unstable angina, serious uncontrolled cardiac arrythmia, 
myocardial infarction within 6 months of screening, active interstitial lung disease 
(ILD)/pneumonitis or a history of ILD/pneumonitis requiring treatment with systemic 
steroids uncontrolled asthma, or colitis. 
9.3. 
Subject Enrollment 
Approximately 36 subjects may be enrolled.   


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9.4. 
Withdrawal of Subjects from Study Treatment and/or Study 
The sponsor may terminate this study at any time.  The investigator and/or the subject have the 
right to terminate the subject’s participation in the study at any time.  Efforts should be made to 
ask subjects who discontinue study drug to be available to complete the Follow-up assessments. 
A subject may withdraw or be withdrawn from the study treatment prematurely for any of the 
following reasons: 
• Principal Investigator (PI) determines further participation is not in the subject’s best 
interest (e.g., subject experiences rapid clinical deterioration in the absence of 
confirmed disease progression) 
• Subject has confirmed disease progression 
• A subject must be withdrawn in the event of any of the following: 
• Subject withdraws informed consent. 
• Any treatment-related AEs that meet withdrawal criteria 
• Substantial noncompliance with study requirements 
• Subjects with a confirmed positive pregnancy test 
• Any intercurrent illness that would, in the judgement of the investigator or sponsor’s 
medical monitor, affect assessments of clinical status to a significant degree and 
require discontinuation of protocol therapy 
• Subjects who did not receive any study drugs 
• NOTE:  Any subject who wishes to withdraw from the study treatment may do so at any time 
but will be asked to be available for the safety, tumor response, and survival follow-up 
assessments. 
Every effort should be made to follow subjects who withdraw from study treatment for ongoing 
treatment-related AEs.  Subjects who withdraw during the treatment period should continue to 
have study assessments as clinically indicated.  
9.5. 
Replacement of Subjects 
Subjects who withdraw from the study or do not receive each study drug may be replaced.  All 
dosed subjects will be included in the overall safety assessment. 
9.6. 
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 electronic case report forms (eCRF), study medication, etc.) must be stored or disposed of 
according to the sponsor’s instructions.  Events that may trigger premature termination of the 
study or closure of a center include but are not limited to the following:  new toxicity findings; 
decision to re-challenge patient who has experienced a Grade 4 event; interim analysis results; 
noncompliance with the protocol; changes in the development plans for the study drug; slow 
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10.4. 
Handling and Storage 
Study drugs must be stored in a restricted access area under the storage conditions indicated in 
the Investigator’s Brochure or Pharmacy Manual.  All necessary precautions while handling 
potentially toxic compounds must be strictly followed. 
10.5. 
Monitoring of Subject Adherence and Managing Missed Doses 
10.5.1. 
Veledimex 
The first veledimex dose following Ad-RTS-hIL-12 injection is expected to be administered 
when the subject is at the clinical site, under careful medical supervision by the clinic staff to 
ensure that the subject does not have difficulty swallowing the capsules. Thereafter, subjects may 
be allowed to self-administer the remaining once daily doses as described.  Subjects are to be 
instructed to take the appropriate number of capsules in the same way for each of the remaining 
treatment period days and may be reminded to do so by phone on non-visit days. 
Subjects should NOT make up any missed doses. 
Subjects should be instructed to document veledimex dosing compliance in a subject diary, 
including the time subject took the once daily dose, the time subject ate breakfast, the number of 
capsules taken, whether subject missed any veledimex doses, and the study day and reason for 
any missed doses.  Study drug container(s) with any remaining capsules should be returned to the 
study staff on Day 15, so that staff can properly assess dose compliance. 
10.5.2. 
Cemiplimab-rwlc 
The recommended dose of cemiplimab-rwlc is 350 mg administered as an intravenous infusion 
over 30 minutes every 3 weeks (Q3W) until confirmed disease progression or unacceptable 
toxicity.  
10.6. 
Disposition of Unused Drug 
All unused study drug should be destroyed at the study site in accordance with standard 
institutional practice and in accordance with United States Occupational Safety and Health 
Administration procedures, after full accountability has been documented. Any study drug 
destruction at study site must be documented and the records maintained in the investigator’s 
study file. 
10.7. 
Accountability and Dispensation 
The investigator must maintain accurate records accounting for the receipt and dispensation of 
study drugs.  The investigational materials are to be prescribed only by the investigator or the 
sub-investigators named on FDA Form 1572 and may only be dispensed by authorized personnel 
at the institution(s) listed therein.  Under no circumstances will the PI allow the investigational 
drug(s) to be used for purposes or in subjects other than as directed by the protocol. 
10.8. 
Treatment Plan 
10.8.1. 
Cemiplimab-rwlc 
On Day -7, Day 15, and approximately every 3 weeks thereafter subjects will receive 
cemiplimab-rwlc until confirmed disease progression or unacceptable toxicity.   




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required, including, but not limited to, potentially modifying the dose and schedule of veledimex, 
to amend the protocol prior to enrollment of additional subjects, or to discontinue enrollment in 
the study. 
10.10. 
Dose Modifications and Dose Delays  
Veledimex dose delays and dose reductions for individual subjects will be allowed in the 
event of an adverse event, according to the criteria shown in Table 2. 
Table 2: 
Criteria for Dose Delay and Dose Reduction of veledimex 
Adverse Reaction 
Severity2 
Veledimex Dosage Modifications1 
Immediately life-threatening/ Potentially-Fatal Severe Adverse Reactions 
Any non-hematologic AE3 
Grade 4 non-hematologic adverse event at 
least possibly related to study drug, that is 
considered by the treating physician to be 
immediately life-threatening, and results 
in emergent medical and/or surgical 
intervention 
Discontinue 
Other Severe Adverse Reactions 
Cytokine Release Syndrome 
Grade 3 or higher (per the Ziopharm 
Working Definition of Cytokine Release 
Syndrome) 
Withhold4 
Any non-hematologic AE3, 5 
(except brain edema) 
Grade 3 or higher non-hematologic 
adverse event that is at least possibly 
related to study drug and persists at least 3 
days 
Withhold4 
Cerebral edema5 
Grade 3 or higher 
Withhold4,6 
Thrombocytopenia 
Grade 3 or higher thrombocytopenia  
(< 50,000/mm3) at least possibly related to 
study drug 
Withhold4 
Lymphopenia or other 
hematologic toxicity 
Grade 4 or higher lymphopenia or other 
hematologic toxicity (except 
thrombocytopenia)  
Withhold4 
Increased transaminitis8
Grade 3 or higher increase in ALT or AST 
Potentially Withhold7 
1.
These recommendations are for general guidance only. Treating physicians should manage patients according to their clinical
judgement, as informed by institutional guidelines, best practices and these guideline recommendations.
2.
Toxicity as graded per National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0.
3.
Nausea and vomiting will not be considered in this category unless at least Grade 3 or 4 and refractory to antiemetics (i.e.,
defined as symptoms not mitigated by maximal medical support as directed by the Investigator (per institutional guidelines)
in consultation with the Sponsor Clinical Medical Monitor).
4.
Withhold the next and any successive doses of veledimex while the Grade 3 or 4 toxicity persists. Veledimex dosing may
resume, after discussion with the Sponsor Clinical Medical Monitor, in subjects with rapid and substantial reversal of toxicity,
either spontaneously or following appropriate medical treatment.  The Sponsor Clinical Study Coordinator will be notified in
advance of veledimex dosage modifications.
5.
Seizures, headache, and cerebral edema are commonly observed in this population and will be recorded according to the grade
of toxicity and therefore will not be considered in this category unless unresponsive to maximal medical support as directed
by the Investigator (informed by institutional guidelines) and in consultation with the Sponsor Clinical Medical Monitor.
6.
Cerebral Edema Guideline Recommendations: As a general guideline, mannitol (Osmitrol), corticosteroid treatment (i.e.,
dexamethasone or Decadron) and/or withholding the next dose(s) of veledimex short-term are considered for cerebral edema,
CTCAE v5.0 Grade 3 (or for “moderate” severity descriptively). For Grade 4 cerebral edema, mannitol (Osmitrol), higher
dose corticosteroids and/or longer-term withholding or discontinuation of veledimex are considered, especially if the edema
is not sufficiently mitigated by urgent medical intervention. It is expected that the use of corticosteroids will vary between
sites and among subjects, and therefore, the precise extent and dosage of steroids cannot be specified per protocol.  The treating 
physician will decide as is safe and appropriate for the individual subject according to their clinical judgement as informed by
the label and institutional guidelines and should consider the minimum steroid dose or the lowest amount that adequately and


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rapidly controls the subject’s signs and symptoms (refer to Rationale section below). Consideration also may be given to a 
limited number of doses of bevacizumab (Avastin) if (typically high-dose) corticosteroids are not in the best interests of the 
subject in the treating physician’s clinical judgement and following consultation with the Medical Monitor. In the event of an 
immediately life-threatening event, the treating physician should consider surgical decompression. 
7.
Rationale: Cerebral edema may pre-exist experimental treatment to a variable extent and usually is associated with the
underlying disease and/or increase following surgical procedures.  The study treatment, particularly with combination therapy 
including an immune checkpoint inhibitor, also may possibly cause an increase in the severity of edema.  Patients with
glioblastoma receiving more than 4 mg dexamethasone qd were reported to have decreased overall survival, possibly due to
immunosuppression (British J Cancer 2015:113, 232–241). Preliminary data presented at the Society for Neuro-Oncology
2018 Annual Meeting by Ziopharm Oncology also suggests that overall survival is decreased in 20 mg veledimex craniotomy
cohort subjects (i.e., administered more than a 20 mg cumulative dosage of dexamethasone) during the initial treatment period 
(Days 0-14); the relative contributions of severity of the condition vs immunosuppression to the negative effect observed on
overall survival are presently uncertain.
8.
Withhold the next dose(s) of veledimex if the transaminitis is part of a constellation of findings consistent with Cytokine
Release Syndrome (refer to Ziopharm Working Definition of Cytokine Release Syndrome). The treating physician may elect
to follow the laboratory test trajectory and clinical status if an isolated transaminitis.
Cemiplimab-rwlc dose delays and dose reductions for individual subjects will be allowed in the 
event of an adverse event, according to the criteria shown in Table 3. 
Table 3: 
Criteria for Dose Delay and Dose Reduction of cemiplimab-rwlc 
Adverse Reaction 
Severity 
Cemiplimab-rwlc Dosage 
Modifications 
Severe and Fatal Immune-Mediated Adverse Reactions 
Pneumonitis 
Grade 2 
Withhold* 
Grades 3 or 4 
Permanently discontinue 
Colitis 
Grades 2 or 3 
Withhold* 
Grade 4 
Permanently discontinue 
Hepatitis 
If AST or ALT increases to more than 3 
and up to 10 times the upper limit of 
normal (ULN) or if total bilirubin 
increases up to 3 times the ULN 
Withhold* 
If AST or ALT increases to more than 10 
times the ULN or total bilirubin increases 
to more than 3 times the ULN 
Permanently discontinue 
Endocrinopathies 
Grades 2, 3, 4 
Withhold if clinically necessary* 
Other immune-mediated 
adverse reactions involving a 
major organ 
Grade 3 
Withhold* 
Grade 4 
Permanently discontinue 
Recurrent or persistent 
immune-mediated adverse 
events 
•
Recurrent Grades 3 or 4
•
Grades 2 or 3 persistent for 12 weeks
or longer after last cemiplimab-rwlc
dose in spite of appropriate therapy
•
Requirement for 10 mg per day or
greater prednisone or equivalent
lasting 12 weeks or longer after last
cemiplimab-rwlc dose
Permanently discontinue 
Severe and Fatal Immune-Mediated Adverse Reactions 
Infusion-related reactions 
Grades 1 or 2 
Interrupt or slow the rate of 
infusion 
Grades 3 or 4 
Permanently discontinue 
AE = adverse event 
*: Resume in patients with complete or partial resolution (Grade 0 to 1) after supraphysiologic dose of corticosteroids 
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10.11. 
Safety Monitoring and Adverse Effect Management 
Each subject receiving cemiplimab-rwlc, Ad-RTS-hIL-12 or at least one dose of veledimex will 
be included in the Overall Safety Population (OSP).  Parameters used in the safety analysis of all 
populations will include all laboratory tests, physical examination, imaging scans, and 
spontaneous reports of AEs reported by subjects.  Each patient will be assessed according to the 
scheduled study procedures and any additional visits as a result of AEs. Cytokine release 
syndrome will be assessed per the Ziopharm Working Definition (Appendix 1). Other adverse 
events will be assessed according to the NCI CTCAE v5 criteria. 
10.12. 
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 criteria. 
As with all signs and symptoms, events should be recorded and graded as AEs according to NCI 
CTCAE v.5 criteria.  Study stopping rules will not apply to a specific event if it is clearly 
unrelated to the study treatment. 
10.13. 
Prophylactic Antipyretic and/or Analgesic Administration 
The use of antipyretics and/or analgesics is allowed as a prophylactic measure perioperatively.  
Antipyretics and/or analgesics can be used anytime during study treatment, as indicated and 
required for patient safety and must be recorded as concomitant medications.  Please refer to 
exclusion criteria for acute clinically significant and/or chronic infections. 
NOTE:  Since fever and other flu-like symptoms (e.g., chills, body aches, malaise, loss of 
appetite, etc.) are sometimes experienced following Ad-RTS-hIL-12 + veledimex, it is 
reasonable for subjects to be administered prophylactic antipyretic and/or analgesic medication 
prior to Ad-RTS-hIL-12 injection and during the first week after injection at the discretion of the 
treating physician.  The incidence of pyrexia and flu-like symptoms to date has been lower in 
glioblastoma subjects as compared with breast cancer or melanoma subjects, likely because a 
lower dose of veledimex is used in glioblastoma. 
Please refer to Appendix 2 or the recommended regimen for the prophylactic administration of 
antipyretics and/or analgesics. 


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11. 
CONCOMITANT THERAPY 
Information on concomitant medications, including all medications, blood products, vitamins, 
and other supplements, will be collected through the Screening, Treatment, through 90 days after 
the subject’s last dose of any study drug.  
Subjects experiencing brain tumor-related symptoms or edema should be treated with 
corticosteroids as per standard practice. The treating physician should consider the minimum 
starting steroid dose for study subjects, if determined that it is safe and appropriate for that 
individual patient.  For study subjects who require a higher starting steroid dose, efforts should 
be made to taper steroids to the lowest amount that controls the subjects’ symptoms, as 
determined to be safe and appropriate by the treating physician 
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 that individual patient.  For study subjects who require a higher 
steroid dose, efforts should be made to taper steroids to the lowest amount that controls 
the subject’s symptoms, as determined to be safe and appropriate by the treating 
physician. Physiologic replacement doses of corticosteroids are also permitted (NOTE: 
Intranasal corticosteroids are excluded due to rapid systemic absorption). 
• Antidiarrheal therapy is permitted for study drug induced- diarrhea 
• Antiemetics are permitted for study drug- induced- nausea and vomiting 
NOTE: Care should be given when prescribing medications to avoid the use of drugs that are 
classified as CYP450 3A4 inducers, inhibitors, or substrates due to interactions with the study 
drug, unless needed for urgent intervention. All medications should be recorded in the case 
report form as indicated in the completion guidelines.  
11.2. 
Prohibited Medications/Therapies 
The following medications are prohibited during the study: 
• Any other investigational agent or anticancer therapy (chemotherapy, radiotherapy, etc.) 
while receiving study treatment 
• Palliative radiotherapy is not permitted while on study 
• Enzyme inducing anti-epileptic drugs (EIAED) are listed in Appendix 3 and are NOT 
permitted.   
• Use of heparin or other anti-coagulation therapy, or acetylsalicylic acid (ASA), or anti-
platelet drug within Day -7 to Day 21 should not be used unless necessary to treat a life-
threatening illness 
NOTE: Care should be given when prescribing medications to avoid the use of drugs that 
are classified as CYP450 3A4 inducers, inhibitors, or substrates due to interactions with 
the study drug, unless needed for urgent intervention. All medications should be recorded 
in the case report form as indicated in the completion guidelines.  


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12.
STUDY PROCEDURES
12.1. 
Written Informed Consent 
The provided written ICF must be signed before any protocol specific procedures and 
assessments can be performed.  A copy of the signed ICF will be given to the subject and a copy 
should be filed in the medical record.  The original ICF should be kept on file with the study 
reports.  Standard of care evaluations performed as part of the subject’s routine treatment prior to 
signing the ICF can be used if they were conducted within the timeframe of the screening period.  
Refer to Section 12.3.2.1  and 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 are to be enrolled and assigned a unique study identification number 
before the planned cemiplimab-rwlc dose.  Once assigned, a subject’s identification number will 
not be reused. 
12.3. 
Schedule of Assessments and Observations 
Screening assessments must be performed within 30 days prior to the Ad-RTS-hIL-12 injection.  
Any screening tests, exams, or procedures outside of this range may be repeated at the 
investigator’s discretion.  All study visits must be completed as described in the protocol while 
subjects are taking veledimex capsules.  Follow-up assessments are allowed a window of ± 7 
days. Refer to Table 1 Schedule of Study Procedures for further information. 
12.3.1. 
Study Tests, Exams, and Procedures 
12.3.1.1. 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 90 
days after the subject’s last dose of any study drug.  
12.3.1.2. Physical Examinations 
A complete physical examination will also include a neurological examination. 
12.3.1.3. Vital Signs, Height, and Weight 
Vital signs will include blood pressure, pulse rate, temperature, and respiration rate. Subject’s 
blood pressure should be monitored regularly, with hydration as needed to prevent hypotension 
for 72 hours after administration of Ad-RTS-hIL-12, as previously noted.  Assessment of vital 
signs is required prior to injection of Ad-RTS-hIL-12, and prior to veledimex dosing.  Height 
and weight will be measured and recorded according to Schedule of Study Procedures. 
12.3.1.4. Karnofsky Performance Status 
The Karnofsky Performance Status measures the ability of cancer subjects to perform ordinary 
tasks. Scores range from 0 to 100 with a higher score meaning that the patient is better able to 
carry out daily activities. The Karnofsky Performance Status is used to determine a patient's 


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prognosis, to measure changes in a patient’s ability to function, or to decide if a patient could be 
included in a clinical trial. Subjects must have a Karnofsky Performance Status score of ≥ 70 at 
the Screening Visit to be included in the study. 
12.3.1.5. Pregnancy Testing 
Females of childbearing potential will have a serum pregnancy test at the Screening Visit and a 
urine or serum pregnancy test on Day 0, with a negative pregnancy outcome prior to study drug 
initiation. 
12.3.1.6. Monitoring of Adverse Events 
Monitoring and recording of AEs and serious adverse events (SAEs) will be conducted 
throughout the study. Adverse events and SAEs that occur following the signing of the ICF 
through 90 days after the subject’s last dose of any study drug- must be recorded on the AE 
eCRF. 
Definitions, documentation, and reporting of AEs and SAEs are described in Section 14. 
NOTE: Subjects should be instructed to maintain adequate oral hydration while being 
administered veledimex.  Study sites must should monitor subjects for proper hydration and 
blood pressure should be monitored regularly.  Prophylactic antipyretic medications may also 
be considered. The incidence of adverse events to date has been lower in glioblastoma subjects 
as compared with breast cancer or melanoma subjects, likely because a lower dose of veledimex 
is used in glioblastoma. 
12.3.1.7. Clinical Laboratory Assessments 
The hematology panel comprises a complete blood count (CBC), including white blood cell 
(WBC) count with differential, red blood cell (RBC) count, hematocrit, hemoglobin, red blood 
cell indices, mean corpuscular volume (MCV), and platelet count. 
The serum chemistry panel comprises the following parameters:  AST, ALT, lactate 
dehydrogenase (LDH), alkaline phosphatase (ALP), creatinine, total bilirubin, total protein, 
albumin, amylase, blood urea nitrogen (BUN), glucose, sodium, potassium, chloride, calcium, 
phosphorus, and bicarbonate. 
The coagulation panel includes activated partial thromboplastin time (aPTT) or partial 
prothrombin time (PTT) and prothrombin time (PT) or INR. The acute phase reactants include 
erythrocyte sedimentation rate (ESR) and CRP. 
The urinalysis panel (dipstick) includes appearance, pH, specific gravity, glucose, 
protein/albumin, presence of blood, ketones, bilirubin, nitrates, and leukocyte esterase.  In 
addition, a microscopic exam for casts, crystals, and cells may be done if clinically indicated. 
12.3.1.8. MRI 
Subjects should be able to undergo MRI scans with contrast agent at screening and during study 
participation.  MRI scans should be available for collection upon sponsor request. 
 
 












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received in the period preceding consent (~28 days), in addition to those ongoing at screening, 
will be captured in the eCRF.  Non-serious events from ICF signature until administration of first 
study drug that are not study related will be reported as medical history.  Concomitant 
medications and AEs/SAEs must be recorded in the eCRF through 90 days after the last dose of 
any study drug.  Ongoing drug-related AEs should be followed until resolution unless none is 
expected.  New anti-cancer medications should be captured through completion of survival 
follow-up.  
Refer to Synopsis Table 1 for Schedule of Study Procedures. 


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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 PFS, and 
ORR.  
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 
should be performed within 24 hours (a + 48hr window is allowed) of Ad-RTS-hIL-12 
administration.  The Ad-RTS-hIL-12 injected lesion and/or other measurable brain lesions will 
be measured according to the iRANO criteria guidelines attached in Appendix 4.  MRI scans will 
be collected and stored at the study site and each subject will be evaluated for response by the 
study investigator.  Subjects should be imaged throughout the study using the same method(s) as 
were used for the screening and baseline MRIs.  Independent tumor response assessments, as 
well as posttreatment tumor biopsies, may occur as available and at the discretion of the 
investigator.  A repeat scan to confirm progression should be completed at 12 weeks (per 
iRANO) after first documentation of progression. Consideration should be given to performing a 
diagnostic brain biopsy, which should be performed in accordance with the current iRANO 
guidelines. 
Tumor response will be assessed both locally and at an independent central imaging lab using the 
iRANO criteria. Copies of all scans will be provided to the independent central imaging lab for 
determination of tumor response. Final progression determinations will be made by the 
independent central imaging lab. Every effort should be made to continue study therapy until 
disease progression is confirmed per iRANO criteria. In the instance that a subject is withdrawn 
from study treatment due to investigator determined progression, scans should be obtained and 
provided to the central imaging lab until disease progression is confirmed centrally. 
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 (SD).  
For 2 years, subjects without confirmed disease progression should continue to have tumor 
assessments every 8 weeks as per standard practice until disease progression has been identified 
(first documentation) and confirmed (12 weeks after first documentation). 
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, treatment 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, the first tumor 
assessment MRI will be done on Day 57 (± 3 days).  Imaging assessments will be performed 
using iRANO criteria. 


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13.3. 
Central Imaging Reads 
An independent central imaging lab will review reported responses and progression events using 
iRANO criteria. An Imaging Charter will be developed to provide guidance and consistency. 


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14. 
SAFETY ASSESSMENTS 
The safety population will include all subjects who have received at least one dose of any of the 
investigational agents: cemiplimab-rwlc, Ad-RTS-hIL-12 or veledimex. 
14.1. 
Adverse Events and Definitions 
14.1.1. 
Adverse Event 
Any untoward medical occurrence associated with the use of a drug in humans, whether 
considered drug-related.  An AE can be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or 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. 
14.1.2. 
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 less certainty about causality 
than an adverse reaction. 
14.1.3. 
Adverse Reaction 
Any AE caused by 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. 
14.1.4. 
Unexpected Adverse Reaction 
Any AE that is (a) not listed in the Reference Safety Information (RSI) of 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 
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. 


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• If 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 unless the progression of disease is assessed 
by the investigator as related to the study treatments; however, the presenting sign or 
symptom of the disease progression should be documented as an AE (e.g., increase in 
pain). Death due to “progression of disease” within the SAE reporting period (from 
the signing of the ICF until 90 days after the last dose of any study treatments) should 
be reported as SAE. 
Adverse events will be followed from the next study until resolution or to the end of the follow-
up period.  AEs that are 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 90 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. 
• 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. 
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. 


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14.4. 
Determination of Severity 
The severity of AEs will be assessed according to the NCI CTCAE, Version 5.  If an AE is not 
specifically defined in the NCI CTCAE, v5.0, the investigator will determine the severity of an 
AE based on the following general definitions recommended (National Cancer Institute 2017): 
• 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 drugs based on his/her clinical judgment.  Assessment of causality will be based 
upon the following: 
• Alternative possible causes of the AE, including the subject’s underlying disease or 
comorbid conditions, other drugs, other host, and environmental factors 
• The temporal sequence between the exposure to study drug and the AE 
• Whether the clinical or laboratory manifestations of the AE are consistent with known 
actions or previously reported toxicity of the study drug or similar drugs 
• Whether the AE resolved or improved with decreasing the dose or stopping the study 
drug (i.e., dechallenge); or recurred or worsened with re-exposure to the drug (i.e., 
rechallenge). 
Relationship assessments that indicate “Not Related” to investigational product: 
• None:  The event is related to an etiology other than the investigational product (the 
alternative etiology must be documented in the study subject’s medical record and/or 
SAE form). 
• Unlikely or Remote:  The event is unlikely to be related to the investigational product 
and likely to be related to factors other than investigational product. 
Relationship assessments that indicate “Related” to investigational product: 
• Possible:  There is an association between the event and the administration of the 
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to investigational product; but there may also be alternative etiology, such as 
characteristics of the subject’s clinical status or underlying disease. 
• Probable:  There is an association between the event and the administration of 
investigational product, a plausible mechanism for the event to be related to the 
investigational product and the event could not be reasonably explained by known 
characteristics of the subject’s clinical status or an alternative etiology is not apparent. 
• Definite:  There is an association between the event and the administration of 
investigational product, a plausible mechanism for the event to be related to the 
investigational product and causes other than the investigational product has been 
ruled out and/or the event re-appeared on re-exposure to the investigational product. 
For AEs that occur prior to the administration of investigational product, an assessment of 
protocol relatedness must be made.  AEs may occur due to procedures required during the 
screening process (e.g., blood collection, washout of an existing medication) prior to the initial 
administration of investigational product.  For AEs that occur before administration of 
investigational product, only those that are assessed by the investigator as protocol-related 
should be reported to the sponsor.  The following guidelines should be used by investigators to 
assess the relationship of an AE to a protocol-required procedure: 
• Protocol-related:  The event occurred due to a procedure or intervention that was 
described in the protocol for which there is no alternative etiology present in the 
subject’s medical record. 
• Not protocol-related:  The event is related to an etiology other than the study 
procedure (the alternative etiology must be documented in the study subject’s medical 
record). 
14.6. 
Documenting Adverse Events 
All AEs, including SAEs, are to be accurately recorded on the Adverse Event page of the 
subject’s eCRF from the time the subject signs the informed consent through 90 days after the 
subject’s last dose of any study drug.  Each event will be assessed for serious criteria, severity, 
and causality (Section 14.5). The date of onset, as well as the duration of the event will be 
recorded.  In addition, treatments provided to the subject, actions taken with the study drugs, and 
the outcome of the AE will also be noted. 
14.7. 
Reporting Serious Adverse Events (SAE), and Adverse Events of 
Special interest (AESI) 
14.7.1. 
Time Frame for Reporting 
All SAEs and AESIs must be reported to the sponsor or sponsor designee within 24 hours of 
awareness, regardless of initiation of new anticancer therapy including the following: 
• Any SAE or AESI experienced by the subject from the signing of informed consent to 
90 days after the last dose of any study drug, regardless of relationship to study drug. 
• Any SAE or AESI that the investigator becomes aware of, and believes to be study 
drug-related, that occurs more than 90 days after the subject last received study drug. 
 
















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16.6.2. 
Safety Analyses 
The safety population will be used to perform safety evaluations for all safety variables. 
Safety evaluations will be based on the incidence, intensity, and type of AEs and SAEs.  
Clinically significant changes in the subjects’ physical examinations, vital signs, and ECG 
evaluations, and abnormal laboratory values will be captured as AEs.  Safety will also be 
assessed based on medical history and prior/concomitant medications. 
The safety evaluation period extends from the date the patient signs the ICF until 90 days after 
the last dose of study drug, unless the patient discontinues the trial due to one of the following 
reasons: 
• Documented progression 
• Symptomatic deterioration also denoted as symptomatic progression 
• AEs that the investigator feels will subsequently make the subject noncompliant with 
the protocol planned Schedule of Study Procedures 
• Loss to follow-up 
• Noncompliance with the protocol 
• Other reason not listed above 
All treatment-emergent AEs will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) and will be tabulated by number and percent of subjects, and according to 
relationship to the study drugs, severity, and seriousness.  Treatment-emergent is defined as any 
AE that occurs during or after administration of the first dose of study drug through the 
evaluation period for safety defined above, regardless of relationship to study drug; or any event 
that is present at baseline that worsens in intensity or is subsequently considered to be drug 
related by the investigator.  Deaths, SAEs, and AEs resulting in study discontinuation will be 
listed. 
Subjects who discontinue the trial as defined above will be followed for safety up to 90 days 
after discontinuation and until all safety events that have started during the safety evaluation 
period are classified as resolved or the end of the study is reached.  After the conclusion of the 
safety evaluation period is triggered by a discontinuation event, the subject continues to be 
followed only for OS. 
Listings of vital signs and physical examination data will be presented by visit. 
16.6.3. 
Overall Survival 
OS is defined as the duration of time from the first dose of study drug (Day -7) to the date of 
death or to the last follow-up contact date if the subject has not died, in which case the subject is 
censored if still alive up to 2 years from the first dose of study drug received. 
16.6.4. 
Tumor Response Analyses 
Investigator assessment of ORR and PFS will be determined according to iRANO criteria.  A 
two-sided confidence interval will be computed for the ORR.  PFS and OS will be estimated 
using the Kaplan-Meier method for appropriately-sized subject groups. 


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Following completion of the study, best response will be determined for each subject in 
accordance with iRANO guidelines and the ORR will be presented for all subjects.  Where 
applicable, summary data of PFS, OS, and durability of response will be determined using 
Kaplan-Meier methodology; otherwise, a listing by-subject will display the data obtained.  
Two-sided confidence intervals will be computed for the ORR.  Descriptive statistics will be 
performed for different patient populations. 
16.6.5. 
Multi-Center Study 
Tumor response and safety data will be presented over all study centers. 
16.6.6. 
Adjustments for Covariates 
No adjustments for covariates will be made. 
16.6.7. 
Procedures for Handling Missing, Unused, and Spurious Data 
No imputation of values for missing data will be performed.  Standard clinical monitoring and 
data management practices will be used to ensure the integrity of data. 
16.6.8. 
Procedures for Reporting Deviations to Original Statistical Analysis Plan 
A formal statistical plan for the analysis and presentation of data from this study will be prepared 
prior to database lock.  Deviations from the statistical analyses outlined in this protocol will be 
indicated in this plan; any further modifications will be noted in the final clinical study report. 


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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 to and sufficient training on the electronic data capture (EDC) application, to permit site 
personnel to enter or correct information in the eCRFs for the subjects for whom they are 
responsible. 
The eCRFs should be completed in a timely manner, and every effort should be made to have 
forms completed and up-to-date in anticipation of a visit by the sponsor’s monitor.  Specific 
instructions will be provided to the site.  All requested information must be entered on the eCRF 
in the spaces provided.  If an item is not available or is not applicable, it should be documented 
as such; do not leave a space blank. 
It is the investigator’s responsibility to ensure the accuracy, completeness, clarity, and timeliness 
of the data reported in the subject’s eCRF.  Through the EDC application, the investigator must 
provide formal approval of all subject information in the eCRFs and changes to the eCRFs to 
endorse the final submitted data for the subjects for whom he/she is responsible.  The audit trail 
entry will show the user’s identification information and the date and time of any corrections. 
eCRF completion may be delegated to other study personnel; however, such delegation must be 
documented in writing.  If, for any reason, certain data are lacking to complete an individual 
report form, the investigator will provide a written statement explaining the reasons for the lack 
of data. 
Sponsor or designee will retain the eCRF data and corresponding audit trails.  A copy of the final 
archival eCRF in the form of a compact disk or other electronic media will be placed in the 
investigator’s study file. 
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. 
Sponsor Monitoring 
After satisfactory receipt of all necessary regulatory paperwork, the sponsor’s monitor will 
arrange that all study material be delivered to the study site at a mutually convenient time.  A site 
initiation visit (SIV) by Ziopharm and its monitoring personnel will be made.  At this meeting, 
all personnel expected to be involved in the conduct of the study will undergo an orientation to 
include review of study protocol, instruction for 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, and this 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 source documents (e.g., hospital records, office records) will be made available for review 
by the Medical Monitor.  The monitor also will perform drug accountability checks and may 


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periodically request 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 FDA. 
17.4. 
Duration of the Study 
The duration of this study from the time of initiating subject enrollment until the completion of 
survival follow-up is anticipated to be approximately 48 months, including 24 months for 
enrollment and 2 years of further follow-up. 
The overall duration is expected to be up to 2 years for an individual subject, including the 
following: 
•
Screening period of up to 30 days prior to dosing with Ad-RTS-hIL-12 and
veledimex
•
Initial Study treatment period of 3 weeks (Days -7 through 14)
•
Assessment of safety through the Follow-up Period
•
Assessment of tumor response at Day 57 (± 3 days), and every 2 months thereafter
until the occurrence of confirmed tumor progression
•
Survival status through 2 years
In addition, subjects who discontinue or complete study treatment without objective evidence of 
disease progression should continue to be followed until confirmed disease progression has been 
documented. Subjects will be followed for survival status for 2 years after enrollment, except for 
death or loss to follow-up.  The active study period refers to the study period from informed 
consent through the Initial 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 2 years following the date on which the test article is 
approved by FDA for marketing for the purposes that were investigated in the study.  If no 
application is to be filed or if the application is not approved for such indication, the records 
must be stored for two additional years and then returned to Ziopharm.  No records will be 
destroyed but will be indefinitely stored. 
17.6. 
Institutional Review Board/ Independent Ethics Committee 
This protocol and the study ICF must be reviewed and approved by the Institutional Biosafety 
Committee, where applicable, and IRB/IEC prior to the start of the study, and a copy of the 
approval letter supplied to Ziopharm.  During the study, the investigator shall make timely and 
accurate reports to the IRB/IEC on study progress at intervals not exceeding 1 year, as well as 
satisfying any other local IRB/IEC reporting regulations.  Copies of all reports to, and 
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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 HIPAA 
The written ICF will explain that study data will be stored in a database, maintaining 
confidentiality in accordance with national data legislation.  All data processed by Ziopharm, or 
its representatives, will be identified by subject number and study code. 
The written ICF will also explain that, for data verification purposes, authorized representatives 
of Ziopharm, a regulatory authority (FDA), and/or the IRB/IEC may require direct access to 
parts of the hospital or clinic records relevant to the study that include the subject’s medical 
history. 
The written ICF will be accompanied by or include a separate document incorporating United 
States Health Insurance Portability and Accountability Act (HIPAA)-compliant wording by 
which the subjects authorize the use and disclosure of their Protected Health Information. 
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 should also indicate that, by signature, the prospective subject or, 
where appropriate, a legal guardian, permits access to relevant medical records by the sponsor 
and by representatives of the FDA.  If a prospective subject does not understand English, an 
appropriate translation into his or her primary language must be made available.  The 
investigator or designee will obtain written, informed, and witnessed consent.  The prospective 
subject will have ample time and opportunity to ask questions.  The prospective subject will be 
informed about the right to withdraw from the study at any time without any disadvantage and 
without having to provide a reason for this decision.  Following the discussion regarding the 
study, the prospective subject will be asked if he/she is willing to sign and personally date a 
statement of informed consent.  Only if the prospective subject voluntarily agrees to sign the 
informed consent statement and has done so, may he/she enroll into the study.  A copy of his/her 
signed and dated informed consent will be provided to each prospective subject.  The signed ICF 
is to remain in the investigator’s file. 
The ICF and any other written information provided to the subjects will be revised whenever 
important new information becomes available that may be relevant to the subject’s consent, or if 
there is an amendment to the protocol that necessitates a change to the content of the subject’s 
informed consent.  The investigator will inform the subject of changes in a timely manner and 
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signature on the revised ICF, if applicable.  Any written ICF 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 for modification, as appropriate, by the investigator. 


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18. 
PROTOCOL APPROVAL PAGE 
A Phase II Study of Ad-RTS-hIL-12 + Veledimex in Combination with Cemiplimab-rwlc 
(Libtayo) in Subjects with Recurrent or Progressive Glioblastoma  
Except for a change intended to eliminate an immediate hazard to subjects, the study shall be 
conducted as described in the approved protocol.  All deviations from the protocol will be 
documented in the eCRF.  Any significant deviation or deviation related to dosing or safety 
evaluation will be reported to Ziopharm and documented in the eCRF. 
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: 
_____________________________________ 
 
Date:   
_____________________________________ 
 
 












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20. 
APPENDICES 


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APPENDIX 1. ZIOPHARM CYTOKINE RELEASE SYNDROME 
WORKING DEFINITION - AD-RTS-HIL-12 + 
VELEDIMEX (VERSION 3, 07 JANUARY 2019) 
Cytokine release syndrome (CRS) is a multi-faceted immune disorder presenting clinically as a multi-system disorder. 
Elevated cytokine levels support the diagnosis of CRS in Ad-RTS-hIL-12 gene therapy study along with the grading criteria 
below:  
Grade 1 
Symptoms that are not life threatening and require symptomatic treatment only, e.g. (any of the following): 
 
General 
Influenza-like illness (flu-like symptoms): fever (temperature of 100°F 
[37.8°C] or greater) and fatigue, malaise, or myalgia 
 
 
Neurological 
Grade 1 headache 
 
 
 
Grade 1 decreased level of consciousness (e.g. somnolence, drowsiness, 
lethargy, disorientation) 
 
 
GI 
Grade 1 nausea or vomiting 
Grade 2 
Symptoms that require and respond to moderate interventions and occurrence of any of the following: 
 
1. 
Hypotension responsive to fluids or single, low dose vasopressor 
 
2. 
Oxygen requirement < 40%  
 
3. 
Grade 3 transaminitis (ALT/AST), lymphopenia, or Grade 2 organ toxicities, e.g.:  
 
 
Hematologic  
Grade 2 neutropenia, or platelets decrease/thrombocytopenia  
 
 
Renal 
Grade 2 creatinine increase 
 
4. 
Other symptoms, e.g.: 
 
 
General 
Grade 3 fever  
 
 
Neurological 
Grade 2 decreased level of consciousness (e.g., slow response to stimuli; 
limiting instrumental activities of daily living)  
 
 
 
Grade 2 or 3 headache 
 
 
GI 
Grade 2 nausea or vomiting  
Grade 3 
Symptoms that require and respond to aggressive interventions and occurrence of any of the following: 
 
1. 
Hypotension requiring high dose or multiple vasopressors 
 
2. 
Oxygen requirement ≥ 40% 
 
3. 
Grade 4 transaminitis (ALT/AST), lymphopenia, or Grade 3 organ toxicities, e.g.:  
                     Hematologic              ≥Grade 3 febrile neutropenia, or platelets decrease/thrombocytopenia  
                     Renal                        Grade 3 creatinine increase 
                     Cardiac                     Grade 3 arrhythmia, or acute heart failure 
                     Pulmonary                Grade 3 pulmonary edema, or dyspnea 
4. 
Other symptoms, e.g.: 
 
 
Neurological 
Grade 3 decreased level of consciousness (e.g. difficult to arouse) 
 
 
 
Aseptic meningitis 
 
 
GI 
Grade 3 nausea or vomiting 
Grade 4 
Life-threatening symptoms and occurrence of any of the following: 
 
1. Requirement for ventilator support 
 
2. Grade 4 organ toxicities (excluding lymphopenia and asymptotic elevated transaminitis), e.g.: 
 
 
Renal 
Renal failure and dialysis indicated 
 
 
Cardiac 
Cardiac arrest 
 
 
Pulmonary 
Respiratory failure 
 
 
Neurological 
Coma 
Grade 5 
Death 
 
 


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APPENDIX 2. RECOMMENDED REGIMEN FOR ANTIPYRETIC 
AND/OR ANALGESIC PROPHYLAXIS 
Recombinant adenoviral vectors have the potential to elicit potent cellular and humoral immune 
responses. While the mechanism responsible for these effects is poorly understood, transient 
low-grade 
fevers are common after systemic rAD vector administration* and temperatures up to 104° F 
with chills and generalized malaise have been observed with treatment. Because low-grade fever 
is very likely to occur, prophylaxis with acetaminophen is strongly recommended. 
Each site should follow its institutional protocol for the administration of acetaminophen. 
Acetaminophen is available without a prescription in 325 mg or 500 mg tablets. Common brand 
names of acetaminophen include Aspirin Free Anacin®, FeverAll®, Genapap®, Mapap®, 
NeoPAP®, Panadol®, Tempra®, and Tylenol®. 
In general, fever can be adequately prophylaxed or treated with acetaminophen.  If a fever occurs 
despite prophylactic medication or does not respond to usual doses of acetaminophen, then a 
combination of both acetaminophen and ibuprofen may be considered.  Alternating doses of 
ibuprofen with acetaminophen may effectively control fever while preventing accidental 
overdose of acetaminophen.  Acetaminophen is typically effective for controlling central fevers 
whereas ibuprofen is more potent as a peripheral analgesic/ anti-inflammatory medication.  
Ibuprofen is available without a prescription at a dosage of 200 mg and by prescription in 400, 
600 or 800 mg tablets or capsules. Common brand names of ibuprofen include Advil®, 
ElixSure®, Ibuprom®, Ibutab®, Motrin® and Tab-Profen®. 
Adverse events are uncommon although may be serious as some individuals are allergic to these 
medications.  Additionally, overdoses of acetaminophen may cause liver failure. Therefore, 
subjects with liver disease and chronic alcohol users should avoid acetaminophen.  Ibuprofen is 
excreted by the kidneys so should be avoided in patients with renal insufficiency, though most 
would be excluded from enrollment.  High dose ibuprofen also may increase the risk of blood 
clots, stroke, heart attack, and gastrointestinal bleeding, and being a potent anti-inflammatory 
agent could reduce the efficacy of the investigational controlled IL-12 therapy. 
 
 


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APPENDIX 3. PROHIBITED ENZYME-INDUCING AND NON-
ENZYME-INDUCING ANTIEPILEPTIC DRUGS 
Enzyme-inducing Antiepileptic Drugs 
Non-Enzyme-inducing Antiepileptic Drugs 
Cerebyx® (fosphenytoin) 
Zarontin® (ethosuximide) 
ONFI® (clobazam) 
 
Dilantin® (phenytoin) 
Gabitril® (tiagabine) 
Luminal®, Solfoton® (phenobarbital) 
Nembutal® (pentobarbital) 
Trileptal® (oxacarbazepine) 
Tegretol® (carbamazepine) 
Topamax® (topiramate) 
 
 
 
 


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APPENDIX 4. 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 
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• To determine the Investigator’s assessment of response, 
including tumor objective response rate (ORR) at 6, 12, 18 
and 24 months 
• To determine the tumor response rates at 6, 12, 18 and 24 
months 
 
   
Investigational Product(s) 
Ad-RTS-hIL-12 + veledimex:  
Adenovirus-RheoSwitch Therapeutic System®-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 an RTS inducible 
promoter activated in the presence of the activator ligand, 
veledimex.  Veledimex is a small molecule RTS specific 
transcription factor that stabilizes the RTS promoter components 
and allows transcription of the hIL-12 target gene.  Since target 
gene expression is dependent on the dose and frequency of 
veledimex administration, the expression of hIL-12 can be turned 
on and off by veledimex dose and schedule. 
Cemiplimab-rwlc 
Cemiplimab-rwlc (Libtayo®) is a programmed death receptor-1 
(PD-1) blocking antibody. 
Number of Centers 
Approximately 10 centers 
Number of Subjects 
Approximately 30 subjects  
Study Design 
This is a multicenter Phase II study of an intratumoral injection of 
Ad-RTS-hIL-12 
 and veledimex (20 
mg) administered PO in combination with cemiplimab-rwlc (350 
mg) administered intravenously (IV) in subjects with recurrent or 
progressive glioblastoma.  This study will determine the safety and 
efficacy of Ad-RTS-hIL-12 + veledimex when administered in 
combination with cemiplimab-rwlc, based on the safety profile 
observed and overall survival, respectively, in the presence of 
variable systemic corticosteroid exposure.  
This study includes a Screening Period, Treatment Period, and 
Survival Follow-up. After the informed consent form (ICF) is 
signed, subjects will enter the Screening Period to be assessed for 
eligibility. Subjects will receive cemiplimab-rwlc on Day -7 
(±3days). On Day 0 (day of Ad-RTS-hIL-12 administration) 
subjects will take one dose of veledimex 3±2 hours prior to 
injection of Ad-RTS-hIL-12 and Ad-RTS-hIL-12 
 
will be administered by freehand injection.  Ad-RTS-hIL-12 will 




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• PFS, and rate of pseudo-progression (PSP) at 6, 12, 18 and 
24 months 
• Objective Response Rate at 6, 12, 18 and 24 months 
• To determine the tumor response rate at 6, 12, 18 and 24 
months 
 
  
 
Dose & Schedule 
Ad-RTS-hIL-12:  intratumoral 
 administered on Day 0 
Veledimex: 20 mg PO QD on Days 0 to 14 
 
Cemiplimab-rwlc: 350 mg IV on Day -7, Day 15, and 
approximately every 3 weeks (Q3W) until confirmed progression 
(iRANO), unacceptable toxicity or subject withdrawal. 
Therapy Duration 
From administration of the first study drug (cemiplimab-rwlc) 
until the subject has confirmed progressive disease per iRANO, 
unacceptable toxicity, the subject withdraws consent, or the end of 
the follow-up period. 
Eligible Population 
The eligible study population includes adult subjects with 
recurrent or progressive glioblastoma for which there is no 
alternative curative therapy.  
Eligibility Criteria 
Subjects with supratentorial glioblastoma who have not previously 
been treated with inhibitors of immuno-checkpoint pathways (e.g., 
anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 
antibody) or other agents specifically targeting T cells. 
Inclusion Criteria 
1. Male or female subject ≥18 and ≤75 years of age 
2. Provision of written informed consent for tumor resection 
(subtotal allowed), tumor biopsy, samples collection, and 
treatment with investigational products prior to undergoing 
any study-specific procedures 
3. Histologically confirmed glioblastoma from archival tissue 
4. Evidence of tumor recurrence/progression by magnetic 
resonance imaging (MRI) according to Response 
Assessment in Neuro-Oncology (RANO) criteria after 
standard initial therapy. Multifocal disease is allowed. 
5. Previous standard-of-care antitumor treatment including 
surgery and/or biopsy and chemoradiation.  At the time of 
registration, subjects must have recovered from the toxic 


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effects of previous treatments as determined by the treating 
physician.  The washout periods from prior therapies are 
intended as follows: (windows other than what is listed 
below should be allowed only after consultation with the 
Medical Monitor) 
a. Nitrosoureas:  6 weeks 
b. Other cytotoxic agents:  4 weeks  
c. Antiangiogenic agents:  4 weeks  
d. Targeted agents, including small molecule tyrosine 
kinase inhibitors:  2 weeks 
e. Vaccine-based or CAR-T therapy:  3 months 
6. Able to undergo standard MRI scans with contrast agent 
before enrollment and after treatment  
7. Karnofsky Performance Status ≥70 
8. Adequate bone marrow reserves and liver and kidney 
function, as assessed by the following laboratory 
requirements: 
a. Hemoglobin ≥9 g/L 
b. Lymphocytes >500/mm3 
c. Absolute neutrophil count ≥1500/mm3 
d. Platelets ≥100,000/mm3 
e. Serum creatinine ≤1.5 x upper limit of normal (ULN) 
f. Aspartate transaminase (AST) and alanine 
transaminase (ALT) ≤2.5 x ULN 
g. Total bilirubin <1.5 x ULN 
h. International normalized ratio (INR) and activated 
partial thromboplastin time (aPTT) or partial 
thromboplastin time (PTT) within normal institutional 
limits 
9. Female of child bearing potential* and sexually active 
male subjects must agree to practice highly effective 
contraception prior to the start of the first treatment, during 
the study, and for at least 4 months after the last dose. 
Highly effective contraceptive measures include stable use 
of combined (estrogen and progestogen containing) 
hormonal contraception (oral, intravaginal, transdermal) or 
progestogen-only hormonal contraception (oral, injectable, 
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initiated 2 or more menstrual cycles prior to screening; 
intrauterine device (IUD); intrauterine hormone-releasing 
system (IUS); bilateral tubal ligation; vasectomized 
partner; and or sexual abstinence**. 
 
 
* Postmenopausal women must be amenorrhoeic 
 
 
for at least 12 months in order not to be  
 
 
considered of childbearing potential. Pregnancy 
 
 
testing and contraception are not required for 
 
 
women with documented hysterectomy or tubal 
 
 
ligation. 
 
 
** Sexual abstinence is considered a highly  
 
 
effective method only if defined as refraining 
 
 
from heterosexual intercourse during the entire 
 
 
period of risk associated with the study  
 
 
treatments. The reliability of sexual abstinence 
 
 
needs to be evaluated in relation to the duration 
 
 
of the clinical trial and the preferred and 
 
 
usual lifestyle of the patient. 
10. Normal cardiac and pulmonary function as evidenced by a 
normal ECG with QTc ≤450 msec and peripheral oxygen 
saturation (SpO2) ≥92% on Room air by pulse oximetry   
Exclusion Criteria   
1. Radiotherapy treatment within 4 weeks of starting 
veledimex  
2. Prior treatment of disease with bevacizumab (NOTE: 
short use (< 4 doses) of bevacizumab for controlling 
edema is allowed) 
3. Subjects receiving systemic corticosteroids for treatment of 
disease-related symptoms during the 4 weeks prior to Day 
-7 
4. Subjects with clinically significant increased intracranial 
pressure (e.g., impending herniation or requirement for 
immediate palliative treatment) or uncontrolled seizures 
5. Uncontrolled infection with human immunodeficiency 
virus, hepatitis B or hepatitis C infection; or diagnosis of 
immunodeficiency.  
NOTE:        
• Subjects with known HIV infection who have 
controlled infection (undetectable viral load (HIV RNA 
PCR) and CD4 count above 350 either spontaneously 
or on a stable antiviral regimen) are permitted. For 


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Subjects with controlled HIV infection, monitoring will 
be performed per local standards.  
• Subjects with hepatitis B (HBsAg+) who have 
controlled infection (serum hepatitis B virus DNA PCR 
that is below the limit of detection AND receiving anti-
viral therapy for hepatitis B) are permitted. Subjects 
with controlled infections must undergo periodic 
monitoring of HBV DNA. Patients must remain on 
anti-viral therapy for at least 6 months beyond the last 
dose of investigational study drug.  
• Subjects who are hepatitis C virus antibody positive 
(HCV Ab+) who have controlled infection 
(undetectable HCV RNA by PCR either spontaneously 
or in response to a successful prior course of anti-HCV 
therapy) are permitted.  
6. 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. 
7. Use of enzyme-inducing antiepileptic drugs (EIAED) 
within 7 days prior to the first dose of study drug.  Note:  
Levetiracetam (Keppra®) is not an EIAED and is allowed. 
8. Other concurrent clinically active malignant disease, 
requiring treatment, except for non-melanoma cancers of 
the skin or carcinoma in situ of the cervix or non-
metastatic prostate cancer 
9. Nursing or pregnant females 
10. Prior exposure to veledimex 
11. Use of an investigational product within prior 30 days.  
12. Prior exposure to inhibitors of immuno-checkpoint 
pathways (e.g., anti-PD-1, anti-PD-L1, anti-PD-L2, 
anti-CD137, or anti-CTLA-4 antibody) or other agents 
specifically targeting T cells 
13. Use of medications that induce, inhibit, or are substrates of 
CYP450 3A4 prior to veledimex dosing without 
consultation with the Medical Monitor 


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14. Presence of any contraindication for a neurosurgical 
procedure 
15. Use of heparin or other anti-coagulation therapy, or 
acetylsalicylic acid (ASA), or anti-platelet drug within Day 
-7 to Day 21 should not be used unless necessary to treat a 
life-threatening illness. Prophylactic subcutaneous heparin 
per institutional protocol for prevention of deep vein 
thrombosis (DVT) may be allowed based on discussion 
with the Medical Monitor. Concomitant medications 
should continue to be reviewed in consultation with the 
Medical Monitor. 
16. Unstable or clinically significant medical condition that 
would, in the opinion of the Investigator or Medical 
Monitor, jeopardize the safety of a subject and/or their 
compliance with the protocol.  Examples include, but are 
not limited to, a history of myocarditis or congestive heart 
failure (as defined by New York Heart Association 
Functional Class III or IV), unstable angina, serious 
uncontrolled cardiac arrythmia, myocardial infarction 
within 6 months of screening, active interstitial lung 
disease (ILD)/pneumonitis or a history of ILD/pneumonitis 
requiring treatment with systemic steroids uncontrolled 
asthma, or colitis. 
Stopping Rules 
From Day -7 to 30 days after completion of Ad-RTS-hIL12 + 
veledimex dosing, if any subject experienced a death (other than 
death related to progressive disease); or if any subject, during the 
initial treatment period (Day -7 to Day 28) experiences a related 
SAE that has immediately life-threatening consequences requiring 
urgent intervention or results in death; requires major operative 
intervention; or is a related grade 4 hematologic toxicity that 
persists for 5 days: then enrollment of new subjects will be paused, 
pending review of the event by the Safety Review Committee.  
The SRC will recommend if changes to the enrollment of 
additional subjects are required, including, but not limited to, 
potentially modifying the dose and schedule of veledimex, to 
amend the protocol prior to enrollment of additional subjects, or to 
discontinue enrollment in the study. 
 
Statistical Methods  
Analysis Populations 
• The safety population will be comprised of all subjects 
who have received at least one dose of any of the 
investigational agents: cemiplimab-rwlc, Ad-RTS-hIL-12 
or veledimex 








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In addition, a toxicity boundary based on repeated significance 
testing provides a guideline for stopping the trial if the number of 
subjects experiencing unacceptable toxicity exceeds the 
proportions below, assuming a 30% toxicity rate is acceptable and 
60% would be unacceptable:  
 Low boundary:   3/5   5/10   8/15   9/20   11/25    
 High boundary:   3/5   6/10   8/15   10/20   11/25 
 
Note: A sample size of 25 to 30 subjects provides for an estimate 
of OS at a point in time with (at most) a 10% standard error of the 
estimate assuming the binomial estimation method.  
Study Duration 
The duration of this study from the time of initiating subject 
screening until the completion of survival follow-up is anticipated 
to be approximately 36 months, including 12 months for 
enrollment and 24 months of follow-up.   
The start of study is defined as the date when the first subject is 
consented into the study and the study stop date is the date of the 
last subject’s last visit. 
 
 


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Table 1: 
Schedule of Study Procedures 
Activity 
Screening 
Treatment 
Day -30 
to -8* 
Day -7 
**  
Day 0a 
Day 1 
Day 2 
Day 3 
Day 4 to 6 
Day 7 
Day 8 to 13 
Informed consent 
X 
 
 
 
 
 
 
 
 
Medical/Cancer historyd 
X 
 
 
 
 
 
 
 
 
Physical exame, including targeted 
neurological exam 
X 
X 
X 
X 
X 
X 
 
X 
 
Karnofsky PSf 
X 
X 
X 
 
 
 
 
 
 
Height (screen) and weight 
X 
 
 
 
 
 
 
X 
 
Vital signsg 
X 
X 
X 
X 
X 
X 
 
X 
 
Adverse eventsh 
CONTINUOUS 
Concomitant medicationsh 
CONTINUOUS 
Survival statusi 
CONTINUOUS  
Pregnancy testj 
X 
X 
X 
 
 
 
 
 
 
Hematologyk 
X 
X 
Xa 
X 
X 
X 
 
X 
 
Coagulationl 
X 
 
Xa 
X 
 
X 
 
X 
 
Serum chemistrym 
X 
X 
Xa 
X 
X 
X 
 
X 
 
Urinalysisn 
X 
X 
Xa 
 
 
X 
 
X 
 
Thyroid panelo 
X 
 
 
 
 
 
 
 
 
ECGp 
X 
 
X 
 
 
X 
 
X 
 
Confirm eligibility 
 
Xq 
 
 
 
 
 
 
 
Cemiplimab-rwlc doseq 
 
X 
 
 
 
 
 
 
 
Ad-RTS-hIL-12 
 
 
Xr,s 
 
 
 
 
 
 
Veledimex dose and diaryv 
 
 
Xs, t 
Xs, t 
X 
Xu 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
MRI scansz 
Xz 
 
 
Xz, aa 
 
 
 
 
 
Tumor sample and CSF (if available)bb 
 
 
X 
 
 
 
 
 
 
Neutralizing antibody status testingcc 
X 
 
 
 
 
 
 
X 
 
 


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Table 1: 
Schedule of Study Procedures (continued) 
Activity 
Treatment 
Long Term Follow-up 
 
Day 
14 
Day 
15 
Day 
22 
Day 
28 
Day 36 
±3 days 
Day 57 
±3 days 
Every 3 weeksb 
±7days 
Every 
8 weeksc  ±7days 
Informed consent 
 
 
 
 
 
 
 
 
Medical/Cancer historyd 
 
 
 
 
 
 
 
 
Physical exame, including targeted 
neurological exam 
X 
 
 
 
X 
 
X 
 
Karnofsky PSf 
X 
 
 
 
X 
 
X 
 
Height (screen) and weight 
X 
 
 
 
X 
 
 
 
Vital signsg 
X 
 
 
 
X 
 
X 
 
Adverse eventsh 
CONTINUOUS 
Concomitant medicationsh 
CONTINUOUS 
Survival statusi 
CONTINUOUS 
Pregnancy testj 
 
 
 
X 
X 
 
X 
 
Hematologyk 
X 
 
X 
 
X 
X 
X 
 
Coagulationl 
X 
 
 
 
X 
 
 
 
Serum chemistrym 
X 
 
X 
 
X 
X 
X 
 
Urinalysisn 
X 
 
X 
 
 
X 
X 
 
Thyroid panelo 
X 
 
 
 
X 
X 
X 
 
ECGp 
X 
 
 
 
X 
 
X 
 
Confirm eligibility 
 
 
 
 
 
 
 
 
Cemiplimab-rwlc doseq 
 
X 
 
 
X 
X 
X 
 
Ad-RTS-hIL-12 
 
 
 
 
 
 
 
 
Veledimex dose and diary 
Xv 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRI scansz 
 
 
 
 
 
Xz 
 
Xz 
Tumor sample and CSF if (available)bb 
 
 
 
 
 
 
 
 
Neutralizing antibody status testingcc 
X 
 
 
 
X 
 
 
* Screening assessments must be conducted within 30 days prior to dosing with Ad-RTS-hIL-12 + veledimex.  
** Day -7 dosing with cemiplimab-rwlc may be performed within ± 3 days.  
a  The PI will review all results of laboratory tests drawn within 24 hours prior to surgery. 
b  Every 3 weeks from Day 57 
c  Every 8 weeks from Day 57 in addition to assessments performed every 3 weeks 






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2. 
TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................................... 1 
1. 
CLINICAL PROTOCOL SYNOPSIS ......................................................................... 2 
2. 
TABLE OF CONTENTS ........................................................................................... 18 
3. 
LIST OF TABLES ..................................................................................................... 23 
4. 
LIST OF FIGURES .................................................................................................... 23 
5. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................ 24 
6. 
INTRODUCTION ...................................................................................................... 28 
6.1. 
Immunotherapy in Glioblastoma ................................................................................ 28 
6.2. 
Interleukin-12 and Cancer Immunotherapy ................................................................ 29 
6.3. 
Local IL-12 Delivery and Development of an Inducible IL-12 Immunotherapy ....... 30 
6.4. 
Adenoviral Vectors for Gene Therapy ....................................................................... 31 
6.4.1. 
Adenoviral Safety ....................................................................................................... 31 
6.4.1.1. 
Safety of Intratumoral Injection of IL-12 Gene Vectors ............................................ 32 
 
 
 
 
 
 
6.5.3. 
Veledimex ................................................................................................................... 34 
6.5.4. 
Cemiplimab-rwlc ........................................................................................................ 34 
6.6. 
Nonclinical Data in the GL-261 Glioma Mouse Model ............................................. 34 
6.6.1. 
Ad-RTS-hIL-12 and Veledimex in Combination With a PD-1 Inhibitor ................... 34 
6.7. 
Rationale for ose and Schedule Glioblastoma  ........................................................... 35 
6.8. 
Clinical Studies of Ad-RTS-hIL-12 and Veledimex .................................................. 36 
6.8.1. 
Melanoma Patient Population ..................................................................................... 37 
6.8.2. 
Breast Cancer Patient Population ............................................................................... 37 
6.8.3. 
Recurrent or Progressive Glioma Patient Population ................................................. 37 
6.9. 
Summary of Safety ..................................................................................................... 37 
7. 
STUDY OBJECTIVES .............................................................................................. 39 
7.1. 
Primary Objective ....................................................................................................... 39 
7.2. 
Secondary Objectives ................................................................................................. 39 
8. 
STUDY DESIGN ....................................................................................................... 40 
8.1. 
Overall Study Design ................................................................................................. 40 
8.2. 
Study Oversight for Safety Evaluation ....................................................................... 40 


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9. 
SUBJECT SELECTION ............................................................................................ 41 
9.1. 
Inclusion Criteria ........................................................................................................ 41 
9.2. 
Exclusion Criteria ....................................................................................................... 42 
9.3. 
Subject Enrollment ..................................................................................................... 43 
9.4. 
Withdrawal of Subjects from Study Treatment and/or Study .................................... 43 
9.5. 
Replacement of Subjects ............................................................................................ 44 
9.6. 
Premature Termination of Study or Study Site .......................................................... 44 
10. 
INVESTIGATIONAL PRODUCTS .......................................................................... 45 
10.1. 
Preparation of Ad-RTS-hIL-12 .................................................................................. 45 
10.2. 
Preparation of Veledimex ........................................................................................... 45 
10.3. 
Preparation of Cemiplimab-rwlc ................................................................................ 45 
10.4. 
Handling and Storage ................................................................................................. 45 
10.5. 
Monitoring of Subject Adherence and Managing Missed Doses ............................... 46 
10.5.1. 
Veledimex ................................................................................................................... 46 
10.5.2. 
Cemiplimab-rwlc ........................................................................................................ 46 
10.6. 
Disposition of Unused Drug ....................................................................................... 46 
10.7. 
Accountability and Dispensation ................................................................................ 46 
10.8. 
Treatment Plan ............................................................................................................ 46 
10.8.1. 
Cemiplimab-rwlc ........................................................................................................ 46 
10.8.2. 
Ad-RTS-hIL-12 + Veledimex .................................................................................... 46 
10.9. 
Stopping Rules ............................................................................................................ 47 
10.10. 
Dose Modifications and Dose Delays ........................................................................ 47 
10.11. 
Safety Monitoring and Adverse Effect Management ................................................. 49 
10.12. 
Severity Grading and Management of Local Reactions ............................................. 49 
10.13. 
Prophylactic Antipyretic and/or Analgesic Administration ....................................... 50 
11. 
CONCOMITANT THERAPY ................................................................................... 51 
11.1. 
Permitted Medications ................................................................................................ 51 
11.2. 
Prohibited Medications/Therapies .............................................................................. 51 
12. 
STUDY PROCEDURES ............................................................................................ 52 
12.1. 
Written Informed Consent .......................................................................................... 52 
12.2. 
Subject Registration .................................................................................................... 52 
12.3. 
Schedule of Assessments and Observations ............................................................... 52 
12.3.1. 
Study Tests, Exams, and Procedures .......................................................................... 52 
12.3.1.1. 
Demographics, Medical and Cancer History, and Concomitant Medications ........... 52 


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12.3.1.2. 
Physical Examinations ................................................................................................ 52 
12.3.1.3. 
Vital Signs, Height, and Weight ................................................................................. 52 
12.3.1.4. 
Karnofsky Performance Status ................................................................................... 52 
12.3.1.5. 
Pregnancy Testing ...................................................................................................... 53 
12.3.1.6. 
Monitoring of Adverse Events ................................................................................... 53 
12.3.1.7. 
Clinical Laboratory Assessments ............................................................................... 53 
12.3.1.8. 
MRI ............................................................................................................................. 53 
12.3.1.9. 
Viral Shedding Assessment ........................................................................................ 53 
12.3.1.10. Electrocardiogram ...................................................................................................... 53 
12.3.2. 
Schedule of Assessments ............................................................................................ 53 
12.3.2.1. 
Screening Period:  Assessments ................................................................................. 54 
12.3.2.2. 
Treatment Period: Day -7 ........................................................................................... 54 
12.3.2.3. 
Treatment Period: Day 0 (Ad-RTS-hIL-12 injection) ................................................ 55 
12.3.2.4. 
Treatment Period: Day 1 ............................................................................................ 55 
12.3.2.5. 
Treatment Period: Day 2 ............................................................................................ 55 
12.3.2.6. 
Treatment Period: Day 3 ............................................................................................ 56 
12.3.2.7. 
Treatment Period: Days 4 through 6 .......................................................................... 56 
12.3.2.8. 
Treatment Period: Day 7 ............................................................................................ 56 
12.3.2.9. 
Treatment Period: Day 8-13 ....................................................................................... 56 
12.3.2.10. Treatment Period: Day 14 .......................................................................................... 57 
12.3.2.11. Treatment Period: Day 15 .......................................................................................... 57 
12.3.2.12. Treatment Period: Day 22 .......................................................................................... 57 
12.3.2.13. Treatment Period: Day 28 .......................................................................................... 57 
12.3.2.14. Treatment Period: Day 36 .......................................................................................... 57 
12.3.2.15. Treatment Period: Day 57 .......................................................................................... 58 
12.3.2.16. Treatment Period: Every 3 weeks after Day 57 .......................................................... 58 
12.3.2.17. Treatment Period: Every 8 weeks after Day 57 .......................................................... 58 
12.3.2.18. Unscheduled Visits Collections .................................................................................. 58 
13. 
TUMOR RESPONSE ASSESSMENTS .................................................................... 59 
13.1. 
Tumor Response ......................................................................................................... 59 
13.2. 
Tumor Response Evaluation and Pseudo-Progression ............................................... 59 
13.3. 
Central Imaging Reads ............................................................................................... 60 
14. 
SAFETY ASSESSMENTS ........................................................................................ 61 
14.1. 
Adverse Events and Definitions ................................................................................. 61 


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14.1.1. 
Adverse Event ............................................................................................................ 61 
14.1.2. 
Suspected Adverse Reaction ...................................................................................... 61 
14.1.3. 
Adverse Reaction ........................................................................................................ 61 
14.1.4. 
Unexpected Adverse Reaction ................................................................................... 61 
14.2. 
Evaluation of Adverse Events .................................................................................... 61 
14.3. 
Determination of Seriousness ..................................................................................... 62 
14.3.1. 
Serious Adverse Event ............................................................................................... 62 
14.3.2. 
Non-Serious Adverse Event ....................................................................................... 62 
14.4. 
Determination of Severity .......................................................................................... 63 
14.5. 
Determination of Causality ......................................................................................... 63 
14.6. 
Documenting Adverse Events .................................................................................... 64 
14.7. 
Reporting Serious Adverse Events (SAE), and Adverse Events of Special interest 
(AESI) ......................................................................................................................... 64 
14.7.1. 
Time Frame for Reporting .......................................................................................... 64 
14.7.2. 
Information to be Provided by the Investigator .......................................................... 65 
14.8. 
Sponsor and Investigator Responsibility for Reporting Adverse Events ................... 65 
14.9. 
Follow-up Information for Adverse Events ............................................................... 66 
14.9.1. 
Required Follow-up for Adverse Events .................................................................... 66 
14.10. 
Pregnancies ................................................................................................................. 66 
14.11. 
Overdose ..................................................................................................................... 66 
 
 
 
 
 
 
 
 
 
 
16. 
STATISTICAL METHODS ...................................................................................... 69 
16.1. 
Populations for Analysis ............................................................................................. 69 
16.2. 
Sample Size and Power Calculations ......................................................................... 69 
16.3. 
Endpoints .................................................................................................................... 70 
16.3.1. 
Primary Endpoint ........................................................................................................ 70 
16.3.2. 
Secondary Endpoints .................................................................................................. 70 
16.4. 
Safety Evaluation ........................................................................................................ 70 
16.5. 
Efficacy Evaluation .................................................................................................... 70 
16.6. 
Analyses ..................................................................................................................... 71 


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16.6.1. 
Baseline Characteristics .............................................................................................. 71 
16.6.2. 
Safety Analyses .......................................................................................................... 71 
16.6.3. 
Overall Survival .......................................................................................................... 73 
16.6.4. 
Tumor Response Analyses ......................................................................................... 73 
16.6.5. 
Multi-Center Study ..................................................................................................... 73 
16.6.6. 
Adjustments for Covariates ........................................................................................ 73 
16.6.7. 
Procedures for Handling Missing, Unused, and Spurious Data ................................. 73 
16.6.8. 
Procedures for Reporting Deviations to Original Statistical Analysis Plan ............... 73 
17. 
STUDY MANAGEMENT ......................................................................................... 74 
17.1. 
Electronic Case Report Forms and Source Documentation ....................................... 74 
17.2. 
Good Clinical Practice ................................................................................................ 74 
17.3. 
Sponsor Monitoring .................................................................................................... 74 
17.4. 
Duration of the Study ................................................................................................. 75 
17.5. 
Records Retention ...................................................................................................... 75 
17.6. 
Institutional Review Board/ Independent Ethics Committee ..................................... 75 
17.7. 
Confidentiality and HIPAA ........................................................................................ 76 
17.8. 
Informed Consent ....................................................................................................... 76 
17.8.1. 
FDA Informed Consent Requirements ....................................................................... 76 
17.8.2. 
Subject Informed Consent Form ................................................................................ 76 
18. 
PROTOCOL APPROVAL PAGE ............................................................................. 77 
19. 
REFERENCES ........................................................................................................... 78 
20. 
APPENDICES ............................................................................................................ 82 
APPENDIX 1. ZIOPHARM CYTOKINE RELEASE SYNDROME WORKING 
DEFINITION - AD-RTS-HIL-12 + VELEDIMEX (VERSION 3, 07 JANUARY 
2019) ........................................................................................................................... 83 
APPENDIX 2. RECOMMENDED REGIMEN FOR ANTIPYRETIC AND/OR 
ANALGESIC PROPHYLAXIS ................................................................................. 84 
APPENDIX 3. PROHIBITED ENZYME-INDUCING AND NON-ENZYME-INDUCING 
ANTIEPILEPTIC DRUGS ........................................................................................ 85 
APPENDIX 4. IMMUNOTHERAPY RESPONSE ASSESSMENT IN NEURO-
ONCOLOGY: A REPORT OF THE RANO WORKING GROUP .......................... 86 
 




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5. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation or Specialist Term 
Explanation 
Ab 
Antibody 
Ad 
Ad-RTS-hIL-12 or Ad-RTS-mIL-12, depending on context 
Ad-RTS-hIL-12 
Adenovirus RheoSwitch Therapeutic System® human 
interleukin-12 
Ad-RTS-mIL-12  
Adenovirus RheoSwitch Therapeutic System® mouse 
interleukin-12 
ALVAC 
Canarypox virus viral vectors 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase 
aPTT 
Activated partial thromboplastin time 
ASA 
Acetylsalicylic acid 
AST 
Aspartate transaminase 
BBB 
(Putative) blood-brain barrier 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CD 
Cluster of differentiation 
CHO 
Chinese hamster ovary 
CR 
Complete response 
CRP 
C-reactive protein 
CSF 
Cerebrospinal fluid 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
Cytotoxic T lymphocyte-associated antigen 4 
CYP3A4 or CYP450 3A4 
Cytochrome P450 3A4 
DIPG 
Diffuse intrinsic pontine glioma 
DP 
Drug product 
DSMB 
Data and Safety Monitoring Board 
DVT 
Deep vein thrombosis  
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case report form 
EIAED 
Anti-epileptic drugs 


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Abbreviation or Specialist Term 
Explanation 
EMCV 
Encephalomyocarditis virus 
ESR 
Erythrocyte sedimentation rate 
FDA 
U.S. Food and Drug Administration 
Gal4-EcR 
Fusion protein between Gal4 DNA binding domain and ecdysone 
receptor ligand binding domain 
GalRE/P 
Gal4 responsive promoter 
GBM 
Glioblastoma (multiforme) 
GCP 
Good Clinical Practice 
HBsAg 
Hepatitis B Surface Antigen 
HCV 
Hepatitis C Virus 
hIL-12 
Human interleukin-12 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
HLA 
Human leukocyte antigen 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IFN-β 
Interferon-beta 
IFN-γ 
Interferon-gamma 
INR 
International normalized ratio 
IL-2 
Interleukin-2 
IL-12 
Interleukin-12 
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 
IUD 
Intrauterine device 
KDa 
kilo (K)- unified atomic mass units (Daltons or Da) 
LDH 
Lactate dehydrogenase 
MCV 
Mean cell volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 


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Abbreviation or Specialist Term 
Explanation 
NCI 
National Cancer Institute 
NK 
Natural killer 
NOS 
Not otherwise specified 
NPO 
Nothing by mouth (literally, nil per os) 
ORR 
Objective response rate 
OS 
Overall survival 
OSP 
Overall Safety Population 
PCR 
Polymerase chain reaction 
PD 
Progressive disease 
PFS 
Progression-free survival 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
PKP 
Pharmacokinetics Population 
PO 
Oral(ly) 
polyA 
polyadenylation signal 
PR 
Partial response 
PSP 
Pseudo-progression 
PUbC 
Ubiquitin C promoter 
Q 
Each/every (quaque), as in Q3W (every 3 weeks) 
QD 
Each day (quaque die) 
rAd 
Recombinant adenovirus 
RANO 
Response Assessment for Neuro-Oncology 
RBC 
Red blood cell 
rhIL-12 
Recombinant human IL-12 
RTS 
RheoSwitch Therapeutic System 
RXR 
Retinoid X receptor 
SAE 
Serious adverse event 
SD 
Stable disease 
SpO2 
Saturation of peripheral oxygen 
SRC 
Safety Review Committee 
TEAE 
Treatment-emergent adverse event   
Th1 
T-helper cell type 1 
ULN 
Upper limit of normal 


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Abbreviation or Specialist Term 
Explanation 
V 
Veledimex 
v 
Version (followed by number) 
vp 
Viral particles 
VP16-RXR 
Fusion between VP16 transcriptional activation domain and a 
chimeric RXR 
WBC 
White blood cell 
 


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6. 
INTRODUCTION 
6.1. 
Immunotherapy in Glioblastoma 
The revised 2016 World Health Organization Classification of Tumors of the Central Nervous System 
makes use of molecular genetic findings in addition to histology to define tumor entities on the basis of 
combined phenotypic and genotypic features to generate “integrated diagnoses” (Louis et al. 2016). It 
has resulted in substantial restructuring of the diffuse gliomas, as compared with the 2007 CNS WHO 
Classification.  In the revised classification the diffuse gliomas include the anaplastic astrocytomas 
(anaplastic astrocytoma, IDH-wildtype; anaplastic astrocytoma, IDH-mutant; and anaplastic 
astrocytoma, NOS [Not Otherwise Specified]) and anaplastic oligodendroglioma (with IDH-mutant 
and 1p/19q-codeleted subtypes) that are classified as WHO Grade III and the glioblastomas 
(glioblastoma, IDH-wildtype including giant cell glioblastoma, gliosarcoma, and epithelioid 
glioblastoma subtypes; glioblastoma, IDH-mutant; and glioblastoma, NOS) that are classified as WHO 
Grade IV.  Of the WHO Grade III and Grade IV tumors, glioblastomas make up 60% to 70%, 
anaplastic astrocytomas 10% to 15%, and several other anaplastic subtypes the rest (Central Brain 
Tumor Registry).  
Glioblastomas are by far the most frequent malignant glioma and are associated with a particularly 
aggressive course and dismal prognosis (Lieberman 2017). Standard of care treatment for 
glioblastomas is based on surgical resection with the intent to remove as much of the tumor as is 
feasible (Fernandes et al. 2017, Paolillo et al. 2018).  Resection is then followed by radiotherapy and 
concomitant adjuvant temozolomide.  However, such aggressive treatment is associated with only 
modest improvements in survival.  Newly diagnosed glioblastoma subjects have a median overall 
survival (OS) of 12 to 15 months (Ahmed et al. 2014) and 2-year OS rate of up to 27% (Omuro et al. 
2013), while OS in subjects that have failed TMZ and bevacizumab, or equivalent salvage 
chemotherapy, is reported as being as short as 3 to 5 months (Omuro et al., 2013; Iwamoto et al., 
2009).  To date, no salvage treatment has been validated by Phase III data for recurrent or progressive 
glioblastoma.  For subjects with recurrent glioblastoma, the median OS is 6 to 7 months (Omuro et al. 
2013), and median progression-free survival (PFS) is 2 to 3 months. 
The lack of standard and validated salvage therapies has prompted the use of nitrosoureas, 
temozolomide rechallenge, bevacizumab, and other targeted agents that are unsatisfactory treatment 
options.  This likely reflects the complexities of disease heterogeneity, and the treatment limitations of 
brain tumors given the low activity of antineoplastic agents, de novo or acquired drug resistance, the 
sensitivity of the brain to irreversible damage in response to treatment and the presence of the blood 
brain barrier (BBB), which maintains the brain as a privileged compartment.  Surgical resection may 
be offered for subjects with recurrent disease, with the goal of alleviating mass effect, improving 
symptoms, and achieving cytoreduction.  Surgical resection, however, is limited by the infiltrative 
nature of the disease and the lack of clear margins delimitating the tumor.  Given the poor overall 
prognosis and lack of effective treatments, new therapeutic approaches for malignant gliomas are 
needed. 
Immunotherapy for brain tumors is actively being investigated with an array of newer therapeutic 
modalities.  Only about a third of glioblastomas have been reported to demonstrate a robust CD8+ cell 
population present within the tumor microenvironment (Heimberger et al. 2008), and these cells are 
anergic (i.e., not secreting interferon gamma [IFN-γ] or incapable of cytolytic activity).  The immune 
infiltration in glioblastomas is highly variable and is likely driven by the genetic composition and 
mutational load of the tumor (Beier et al. 2012, Doucette et al. 2013). The anticipated specificity and 
efficiency of cytotoxic T-cells (CD8+), activated by local production of IL-12, is particularly attractive 


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and may both spare normal brain cells and minimize systemic toxicity.  We have shown in an 
orthotopic mouse model that survival and tumor killing was greatly enhanced by combining a 
checkpoint inhibitor and Ad-RTS-mIL-12 + veledimex (Barrett et al. 2016b).  Early clinical trials 
suggest that combining immunotherapeutic approaches with surgery, radiation, and chemotherapy may 
improve outcomes (Mitchell et al. 2008).  Preliminary results from the CheckMate 143 (NCT 
02017717) randomized clinical trial in first recurrence of glioblastoma, announced in a World 
Federation of Neuro-Oncology Societies (WFNOS) 2017 abstract, demonstrated a failure of nivolumab 
to prolong overall survival of patients with recurrent GBM, and this monotherapy arm of the trial was 
prematurely terminated (Filley et al 2017). However, an encouraging example of a combination 
immunotherapy approach to treating glioblastoma is a study of the safety and activity of nivolumab 
(human programmed death receptor-1 [PD-1] blocking antibody) in combination with ipilimumab 
(anti-cytotoxic T lymphocyte associated antigen 4 [CTLA-4] antibody) in patients with recurrent 
disease (Reardon et al. 2016).  In this ongoing dose escalation study, combination therapy was 
tolerable, with 12-month overall survival (OS) ranging from 25% to 40%.  
In Ziopharm’s ongoing Phase I trial of intratumoral viral delivery of Ad-RTS-hIL-12 + veledimex to 
date 31 subjects have been orally dosed in 4 cohorts:  10 mg (n=6), 20 mg (n=7), 30 mg (n=4), 40 mg 
(n=6), and an expansion cohort of 20 mg (n=8).  Results show that veledimex crossed the blood-brain-
barrier, with approximately 40% of plasma levels detected in the brain tumor.  Subjects in the 20 mg 
dose cohort (n=15) have better median OS (12.7 months) than in other cohorts. 
Immune checkpoint inhibitors penetration across the blood-brain-barrier to the tumor tissue remains 
controversial, but the goal is to achieve maximum therapeutic effect while limiting systemic toxicity, 
especially when CD8+ cells have been mobilized to the tumor as we have documented following 
treatment with Ad-RTS-hIL-12 + veledimex. 
6.2. 
 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-12 p70 molecule (Carra et al. 2000).  The expression of the p40 subunit 
is tightly regulated and requires specific priming and amplification signals through complex 
combinatorial matching of Toll receptor agonists and specific cytokines, thus limiting the cell types 
that can produce native biologically active IL-12 to activated antigen-presenting cells, neutrophils, and 
macrophages (Trinchieri 2003).  On a secondary level, IL-12 production can also be negatively 
regulated through various mechanisms including production of IL-10 and transforming growth factor β 
(TGFβ). 
Initial studies identified that IL-12 was produced by innate immune cells in response to pathogens and 
that it led to the production of interferon gamma (IFN-γ) and tumor necrosis alpha (TNFα) by T and 
natural killer (NK) cells (Micallef et al.1996, Trinchieri 2003).  When it was discovered that IL-12 
could drive naïve T-helper cell differentiation to the inflammatory T-helper cell type 1 (Th1) 
phenotype (Hsieh et al. 1993), a role for IL-12 was established as a bridge between innate immune 
cells and the adaptive immune response through polarization of naïve CD4+ cells.  More recent data 
demonstrate additional functional roles of IL-12 directly influencing CD8+ T-cell differentiation 
(Curtsinger et al. 2003, Kalinski et al. 1999) and the reactivation and survival of memory CD4+ T-cells 
(Yoo et al. 2002).  This is particularly important in the context of the tumor microenvironment where 
high levels of IL-12 have been shown to repolarize antigen-experienced CD4+ T-cells back to the 
functional antitumor Th1 phenotype (Wesa et al. 2007). 




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initiates hIL-12 transcription only in the presence of the promoter specific oral activator ligand, 
veledimex.  With this system, the IL-12 expression level can be modulated by the dose and frequency 
of veledimex administration, making it feasible to lower or terminate IL-12 expression in the event of 
severe or unexpected toxicities. 
6.4. 
 Adenoviral Vectors for Gene Therapy 
6.4.1. 
Adenoviral Safety 
Adenoviral vectors have been used extensively to deliver a variety of gene products to human subjects, 
including cancer subjects. Although adenoviral vectors are immunogenic, virtually all recipients have 
pre-existing humoral immunity to adenoviruses and they are generally considered a safe and well 
tolerated vehicle for gene delivery. Numerous studies have utilized adenoviral vectors to achieve 
intratumoral expression of a variety of genes. In a Phase I/II clinical trial of subjects with prostate 
cancer, direct intraprostatic injection of a replication-defective adenoviral vector encoding bacterial 
nitroreductase (dose levels 5 x 1010 -1 × 1012  viral particles [vp]) was well tolerated, with minimal 
adverse events (AEs)  (Patel et al. 2009) . A Phase I study of subjects with oral leukoplakia 
implemented multiple intraepithelial injections of recombinant adenovirus (rAd)-p53 (1 x 108  vp/cm2) 
and demonstrated good tolerance of the vector, with no evidence of dose-limiting toxicity (DLTs)  
(Zhang et al. 2009) . In another Phase I/II study of subjects with chemoradiation-resistant advanced 
esophageal carcinoma, intratumoral injections of adenovirus vector containing p53 (Ad.5CMV-p53) 
were well tolerated at doses ranging from 10 x 1011  to 25 x 1011  vp, with no DLTs, and generally mild 
to moderate adverse events (AEs)  (Shimada et al. 2006) . The most common AEs were fever (all 10 
subjects), pain (30% of subjects), and hyperglycemia, which was attributed to the use of total parental 
nutrition (30% of subjects). Hypocalcemia was reported in two subjects (20%) and one subject each 
(10%) experienced activated partial thromboplastin time (aPTT) prolongation, abnormally high serum 
amylase, and abnormally high serum creatinine. 
In a Phase I study of subjects with advanced pancreatic, colorectal, or primary liver tumors, 
intratumoral injection of an adenoviral vector encoding hIL-12 (Ad.IL-12) was well tolerated at doses 
of up to 3 × 1012 vp.  Common AEs were similar to symptoms observed with gene delivery by other 
adenoviral vectors, including transient, mild to moderate fever, malaise, sweating, and lymphopenia 
(Sangro et al. 2004). 
A recent randomized, open-label, Phase III study compared a regimen of surgical resection, 
adenovirus-mediated gene therapy (intraoperative perilesional sitimagene ceradenovec), intravenous 
ganciclovir, and standard of care interventions versus surgical resection plus standard of care 
interventions in 250 subjects with newly diagnosed high-grade glioma amenable to resection.  Results 
showed that although the time to death or re-intervention was prolonged, OS was not improved for the 
investigational regimen relative to the standard of care regimen (Westphal et al. 2013).  This apparent 
difference may have been due to the composite primary endpoint and/or that while OS is a robust 
endpoint, there is no discussion of effect size and for recently-diagnosed tumors it might be less 
suitable to capture meaningful treatment effects for the initial stages of disease because of uncontrolled 
therapy at relapse (ibid). Nevertheless, the authors concluded that the treatment had an increased 
hazard ratio for the primary analysis with a positive overall benefit-risk ratio, with similar AEs 
(hemiparesis [often transient], hyponatremia, and seizures, but no cerebral hemorrhages nor 
hematomas), as compared with the standard-of-care regimen.   


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6.4.1.1. 
Safety of Intratumoral Injection of IL-12 Gene Vectors 
In contrast with the systemic toxicity resulting from administration of recombinant IL-12 protein, local 
administration of IL-12 via injection of plasmid or adenoviral vectors containing the hIL-12 gene has 
proven to be well tolerated in subjects with various cancers, and therefore appears to provide an 
effective delivery method for this potent immunomodulatory cytokine.  Several studies have 
investigated the safety of intratumoral expression of IL-12 in subjects with metastatic melanoma.  A 
Phase I study investigated intratumoral expression of IL-12 together with the co-stimulatory molecule 
B7.1 via two separate canarypox virus viral vectors (ALVAC) in subjects with metastatic melanoma 
and reported mild to moderate injection site reactions, fever, chills, myalgia, and fatigue as AEs 
(Triozzi et al. 2005).  However, all subjects also developed antibodies to ALVAC.  Notably, serum 
IL-12 and IFN-γ levels were not increased after treatment.  Another Phase I trial showed that delivery 
by electroporation of a plasmid containing IL-12 to tumors in subjects with metastatic melanoma 
resulted in minimal systemic toxicity, with transient pain after electroporation being the most common 
AE (Daud et al. 2008).  Results from another Phase I study showed that intratumoral injection of DNA 
encoding hIL-12 in subjects with metastatic melanoma was well tolerated overall (Heinzerling et al. 
2005).  Eight of nine subjects experienced a transient response at the intratumoral injection site, and 
some subjects who had tumor responses also showed some increases in systemic in IL-12, interferon 
gamma-induced protein 10 (IP-10), and IFN-γ. 
Localized production of IL-12 also has been reported as well tolerated in subjects with other 
malignancies.  For example, a Phase I study in 17 subjects with metastatic pancreatic, colorectal, or 
primary liver cancer examined intratumoral injection of dendritic cells engineered to secrete IL-12 via 
a rAD vector (Mazzolini et al. 2005).  In that study, the most common AEs were lymphopenia, fever, 
and malaise.  Subjects also developed antibodies to the adenoviral capsid proteins.  Intraperitoneal 
injection of a plasmid containing the hIL-12 gene in women with chemotherapy-resistant, recurrent, 
ovarian cancer also was found to be generally safe and well tolerated (Anwer et al. 2010).  Low-grade 
fever and abdominal pain were the most common AEs.  Plasmid DNA was not detected in the subjects’ 
serum samples, and treatment-related increases in IFN-γ levels were observed in pleural fluid, but not 
in serum.  Similar data were reported in a study of subjects with advanced pancreatic, colorectal, or 
primary liver malignancies who received intratumoral injections of adenoviral vectors encoding hIL-12 
at doses ranging from 2.5 × 1010 to 3 × 1012 vp (Sangro et al. 2004).  In that study, treatment was well 
tolerated and a maximum tolerated dose (MTD) was not reached.  Transient lymphopenia was 
observed in 86% of subjects, and the severity was increased at higher vector doses.  Transient, mild to 
moderate fever, sometimes accompanied by malaise and sweating, was observed in ~ 60% of subjects 
during the first 2 days after the injection.  Five of the 21 subjects (24%) experienced nausea and/or 
vomiting on the day of the injection.  No cumulative toxicity was observed.  These events were 
deemed related to injection of the virus and not to transgene expression. 














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7. 
STUDY OBJECTIVES 
7.1. 
Primary Objective 
To determine the safety and efficacy of intratumoral Adenovirus RheoSwitch Therapeutic System® 
(RTS) human interleukin 12 (Ad-RTS-hIL-12) and oral (PO) veledimex (RTS activator ligand) in 
combination with cemiplimab-rwlc (Libtayo®) when treating subjects with recurrent or progressive 
glioblastoma.  This determination will be based on the safety profile observed for drug safety and on 
an estimate of Overall Survival (OS) for efficacy, respectively.  
7.2. 
Secondary Objectives 
• To determine the survival rates at 6, 12, 18 and 24 months 
• To determine the progression free survival (PFS), and rate of pseudo-progression (PSP) at 
6, 12, 18 and 24 months 
• To determine the Investigator’s assessment of response, including tumor objective response 
rate (ORR) at 6, 12, 18 and 24 months 
• To determine the tumor response rates at 6, 12, 18 and 24 months 
 
   
 


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8. 
STUDY DESIGN 
8.1. 
Overall Study Design 
This is a multicenter Phase II study of an intratumoral injection of Ad-RTS-hIL-12 
 
 and veledimex (20 mg) administered PO in combination with cemiplimab-rwlc (350 
mg) administered intravenously (IV) in subjects with recurrent or progressive glioblastoma.  This study 
will determine the safety and efficacy of Ad-RTS-hIL-12 + veledimex when administered in 
combination with cemiplimab-rwlc, based on the safety profile observed and overall survival, 
respectively.  
This study includes a Screening Period, Treatment Period, and Survival Follow-up.  After the informed 
consent form (ICF) is signed, subjects will enter the Screening Period to be assessed for eligibility. 
Subjects will receive cemiplimab-rwlc on Day -7 (±3 days). On Day 0 (day of Ad-RTS-hIL-12 
administration) subjects will take one dose of veledimex 3±2 hours prior to injection and 
Ad-RTS-hIL-12 
 will be administered by freehand injection.  Ad-RTS-hIL-12 will be 
delivered intratumorally or at the margin of the tumor for a total volume of 0.1 mL following resection 
(subtotal or gross total).  The total amount delivered to each site will be recorded in the eCRF.  If the 
total administered volume is less than planned, the reason will be provided.  Care should be taken to 
avoid intraventricular or basal cisternal injection or other critical locations. 
After the Ad-RTS-hIL-12 injection, veledimex will be administered orally for 14 days.  The first post 
craniotomy veledimex dose is to be given on Day 1. Subsequent veledimex doses are to be taken once 
daily, in the morning. Dosing on Days 2-14 should be at approximately the same time of day (+/- 1 
hours) as the Day 1 dosing. 
Subjects will receive a dose of cemiplimab-rwlc (350 mg) IV on Day 15 and every three weeks 
thereafter (Q3W) until documented progression by immunotherapy Response Assessment for Neuro 
Oncology (iRANO) criteria, unacceptable toxicity, subject withdrawal or completing the follow-up 
period. Delays in cemiplimab-rwlc dosing due to toxicities are allowed at the discretion of the 
Principal Investigator in consultation with the Medical Monitor, for up to 14 days. 
A formal Safety Review Committee (SRC) will be comprised of the study Investigators and the 
Medical Monitor. 
After the first six patients have been enrolled and administered Ad-RTS-hIL-12 and veledimex in 
combination with at least one post Ad-RTS-hIL-12 dose of cemiplimab-rwlc, enrollment will be 
paused to allow for additional safety follow-up and assessment. The SRC will review safety data after 
the 6th subject has reached Day 28 and decide if enrollment should occur at the same dose and schedule 
of the investigational products.  
8.2. 
Study Oversight for Safety Evaluation 
Safety oversight will occur through the site investigator and medical monitor.  A formal SRC, guided 
by the SRC charter, will include the study investigators, the medical monitor and other appropriate 
sponsor representatives and will provide overall safety oversight.  Additional external medical and 
scientific experts may also be invited to participate in the reviews as needed and appropriate and as 
decided by the SRC.  If a significant safety event occurs, the SRC will convene to evaluate the safety 
event(s) and make a recommendation and decision on the enrollment and continued treatment of 
subjects.  


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9. 
 SUBJECT SELECTION 
Subjects with supratentorial glioblastoma who have not previously been treated with inhibitors of 
immuno-checkpoint pathways (e.g., anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 
antibody) or other agents specifically targeting T cells. 
9.1. 
 Inclusion Criteria 
1. Male or female subject ≥18 and ≤75 years of age 
2. Provision of written informed consent for tumor resection (subtotal allowed), tumor biopsy, 
samples collection, and treatment with investigational products prior to undergoing any study-
specific procedures 
3. Histologically confirmed glioblastoma from archival tissue 
4. Evidence of tumor recurrence/progression by magnetic resonance imaging (MRI) according to 
Response Assessment in Neuro-Oncology (RANO) criteria after standard initial therapy. 
Multifocal disease is allowed. 
5. Previous standard-of-care antitumor treatment including surgery and/or biopsy and 
chemoradiation.  At the time of registration, subjects must have recovered from the toxic 
effects of previous treatments as determined by the treating physician.  The washout periods 
from prior therapies are intended as follows: (windows other than what is listed below should 
be allowed only after consultation with the Medical Monitor) 
a. Nitrosoureas:  6 weeks 
b. Other cytotoxic agents:  4 weeks  
c. Antiangiogenic agents:  4 weeks  
d. Targeted agents, including small molecule tyrosine kinase inhibitors:  2 weeks 
e. Vaccine-based or CAR-T therapy:  3 months 
6. Able to undergo standard MRI scans with contrast agent before enrollment and after treatment  
7. Karnofsky Performance Status ≥70 
8. Adequate bone marrow reserves and liver and kidney function, as assessed by the following 
laboratory requirements: 
a. Hemoglobin ≥9 g/L 
b. Lymphocytes >500/mm3 
c. Absolute neutrophil count ≥1500/mm3 
d. Platelets ≥100,000/mm3 
e. Serum creatinine ≤1.5 x upper limit of normal (ULN) 
f. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤2.5 x ULN.   
g. Total bilirubin <1.5 x ULN 
h. International normalized ratio (INR) and activated partial thromboplastin time (aPTT) or 
partial thromboplastin time (PTT) within normal institutional limits 


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9. Female of child bearing potential* and sexually active male subjects must agree to practice 
highly effective contraception prior to the start of the first treatment, during the study, and for 
at least 4 months after the last dose. Highly effective contraceptive measures include stable use 
of combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, 
transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation initiated 2 or more menstrual cycles prior to screening; 
intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal ligation; 
vasectomized partner; and or sexual abstinence**. 
* Postmenopausal women must be amenorrheic for at least 12 months in order not to be considered 
of childbearing potential. Pregnancy testing and contraception are not required for women with 
documented hysterectomy or tubal ligation. 
** Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatments. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial 
and the preferred and usual lifestyle of the patient. 
10. Normal cardiac and pulmonary function as evidenced by a normal ECG with QTc ≤450 msec 
and peripheral oxygen saturation (SpO2) ≥ 92% on Room air by pulse oximetry   
 
9.2. 
Exclusion Criteria 
1. Radiotherapy treatment within 4 weeks of starting veledimex  
2. Prior treatment with bevacizumab 
(NOTE: Brief use (< 4 doses) of bevacizumab for controlling edema is allowed) 
3. Subjects receiving systemic corticosteroids for treatment of disease-related symptoms during 
the 4 weeks prior to Day -7 
4. Subjects with clinically significant increased intracranial pressure (e.g., impending herniation 
or requirement for immediate palliative treatment) or uncontrolled seizures 
5. Uncontrolled infection with human immunodeficiency virus, hepatitis B or hepatitis 
C infection; or diagnosis of immunodeficiency.  
NOTE:        
• Subjects with known HIV infection who have controlled infection (undetectable viral load 
(HIV RNA PCR) and CD4 count above 350 either spontaneously or on a stable antiviral 
regimen) are permitted. For subjects with controlled HIV infection, monitoring will be 
performed per local standards.  
• Subjects with hepatitis B (HBsAg+) who have controlled infection (serum hepatitis B virus 
DNA PCR that is below the limit of detection AND receiving anti-viral therapy for hepatitis 
B) are permitted. Subjects with controlled infections must undergo periodic monitoring of 
HBV DNA. Subjects must remain on anti-viral therapy for at least 6 months beyond the last 
dose of investigational study drug.  
• Subjects who are hepatitis C virus antibody positive (HCV Ab+) who have controlled 
infection (undetectable HCV RNA by PCR either spontaneously or in response to a 
successful prior course of anti-HCV therapy) are permitted.  


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6. 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. 
7. Use of enzyme-inducing antiepileptic drugs (EIAED) within 7 days prior to the first dose of 
study drug.  Note:  Levetiracetam (Keppra®) is not an EIAED and is allowed. 
8. Other concurrent clinically active malignant disease, requiring treatment, except for 
non-melanoma cancers of the skin or carcinoma in situ of the cervix or non-metastatic prostate 
cancer 
9. Nursing or pregnant females 
10. Prior exposure to veledimex 
11. Use of an investigational product within prior 30 days.  
12. Prior exposure to inhibitors of immuno-checkpoint pathways (e.g., anti-PD-1, anti-PD-L1, 
anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody) or other agents specifically targeting T 
cells. 
13. Use of medications that induce, inhibit, or are substrates of CYP450 3A4 prior to veledimex 
dosing without consultation with the Medical Monitor 
14. Presence of any contraindication for a neurosurgical procedure 
15. Use of heparin or other anti-coagulation therapy, or acetylsalicylic acid (ASA), or anti-platelet 
drug within Day -7 to Day 21 should not be used unless necessary to treat a life-threatening 
illness. Prophylactic subcutaneous heparin per institutional protocol for prevention of DVT 
may be allowed based on discussion with the Medical Monitor. Concomitant medications 
should continue to be reviewed in consultation with the Medical Monitor. 
16. Unstable or clinically significant medical condition that would, in the opinion of the 
Investigator or Medical Monitor, jeopardize the safety of a subject and/or their compliance with 
the protocol.  Examples include, but are not limited to, history of myocarditis or congestive 
heart failure (as defined by New York Heart Association Functional Class III or IV), unstable 
angina, serious uncontrolled cardiac arrythmia, myocardial infarction within 6 months of 
screening, active interstitial lung disease (ILD)/pneumonitis or a history of ILD/pneumonitis 
requiring treatment with systemic steroids uncontrolled asthma, or colitis. 
9.3. 
Subject Enrollment 
Approximately 30 subjects may be enrolled.   
9.4. 
 Withdrawal of Subjects from Study Treatment and/or Study 
The sponsor may terminate this study at any time.  The investigator and/or the subject have the right to 
terminate the subject’s participation in the study at any time.  Efforts should be made to ask subjects 
who discontinue study drug to be available to complete the Follow-up assessments. 
A subject may withdraw or be withdrawn from the study treatment prematurely for any of the 
following reasons: 


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• Principal Investigator (PI) determines further participation is not in the subject’s best 
interest (e.g., subject experiences rapid clinical deterioration in the absence of confirmed 
disease progression) 
• Subject has confirmed disease progression  
• A subject must be withdrawn in the event of any of the following: 
• Subject withdraws informed consent. 
• Any treatment-related AEs that meet withdrawal criteria 
• Substantial noncompliance with study requirements 
• Subjects with a confirmed positive pregnancy test 
• Any intercurrent illness that would, in the judgement of the investigator or sponsor’s 
medical monitor, affect assessments of clinical status to a significant degree and require 
discontinuation of protocol therapy 
• Subjects who did not receive any study drugs 
• NOTE:  Any subject who wishes to withdraw from the study treatment may do so at any time but 
will be asked to be available for the safety, tumor response, and survival follow-up assessments. 
Every effort should be made to follow subjects who withdraw from study treatment for ongoing 
treatment-related AEs.  Subjects who withdraw during the treatment period should continue to have 
study assessments as clinically indicated.  
9.5. 
Replacement of Subjects 
Subjects who withdraw from the study or do not receive each study drug may be replaced.  All dosed 
subjects will be included in the overall safety assessment. 
9.6. 
 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 electronic case 
report forms (eCRF), study medication, etc.) must be stored or disposed of according to the sponsor’s 
instructions.  Events that may trigger premature termination of the study or closure of a center include 
but are not limited to the following:  new toxicity findings; decision to re-challenge patient who has 
experienced a Grade 4 event; interim analysis results; noncompliance with the protocol; changes in the 
development plans for the study drug; slow recruitment; and poor-quality data. 


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10. 
INVESTIGATIONAL PRODUCTS 
Ad-RTS-hIL-12 and Veledimex is an investigational product has two components: the 
Adenovirus-RheoSwitch Therapeutic System®-human interleukin-12 (Ad-RTS-hIL-12) and veledimex 
(RTS activator ligand).  Ad-RTS-hIL-12 is a replication-incompetent adenoviral vector containing the 
hIL-12 gene under the control of the RTS inducible promoter activated in the presence of the activator 
ligand, veledimex.  Veledimex is a small molecule RTS specific transcription factor that stabilizes the 
RTS promoter components and allows transcription of the hIL-12 target gene.  Since target gene 
expression is dependent on the dose and frequency of veledimex administration, the expression of 
hIL-12 can be modulated (turned on and off) by the optimal veledimex dose and schedule. 
Cemiplimab-rwlc is a covalent heterotetramer consisting of two disulfide-linked human heavy chains, 
each of which is covalently bonded through disulfide linkages to a human kappa light chain.  The 
antibody possesses an approximate molecular weight of 143.6 kilounified atomic mass unit (kDa) 
based on the primary sequence.  There is a single N-linked glycosylation site on each heavy chain, 
located within the constant region in the Fc portion of the molecule.  The cemiplimab-rwlc heavy chain 
possesses an IgG4 isotype constant region.  The variable domains of the heavy and light chains 
combine to form PD-1 binding site within the antibody. Please refer to the Pharmacy Manual for 
additional information. 
Antibody generation by VelocImmune® mice is carried out using standard techniques after 
immunization with PD-1. The genes encoding the heavy and light chains of cemiplimab-rwlc were 
introduced into Chinese Hamster Ovary (CHO) cells, and a stable expression cell line (Cell Line 1) 
was selected for the antibody. Later in development, a second stable expression cell line with higher 
titer (Cell Line 2) was developed for this antibody. For both cell lines, the expression of REGN2810 
was regulated, such that the recombinant CHO cells were de-repressed to initiate antibody expression 
and secretion into the cell culture medium in production bioreactors. Antibody is harvested via 
filtration and purified through a series of preparative column chromatographic and filtration steps to 
generate drug substance. Drug substance is then formulated and sterile-filtered to produce the final 
drug product (DP). 
10.1. 
 Preparation of Ad-RTS-hIL-12 
Ad-RTS-hIL-12 will be supplied as a sterile, single-use vial for injection. Each 0.1 mL contains 
Ad-RTS-hIL-12.  Information regarding the preparation of the Ad-RTS-hIL-12 dose is 
provided in the Pharmacy Manual. 
10.2. 
 Preparation of Veledimex 
Sponsor will provide veledimex capsules to be dispensed by the study site pharmacy to subjects for 
oral administration. Information regarding the veledimex is provided in the Pharmacy Manual. 
10.3. 
 Preparation of Cemiplimab-rwlc 
Cemiplimab-rwlc will be supplied in single-dose vials.  Information regarding the preparation of the 
cemiplimab-rwlc dose is provided in the Pharmacy Manual. 
10.4. 
Handling and Storage 
Study drugs must be stored in a restricted access area under the storage conditions indicated in the 
Investigator’s Brochure or Pharmacy Manual.  All necessary precautions while handling potentially 
toxic compounds must be strictly followed. 


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10.5. 
Monitoring of Subject Adherence and Managing Missed Doses 
10.5.1. 
Veledimex 
The first veledimex dose following Ad-RTS-hIL-12 injection is expected to be administered when the 
subject is at the clinical site, under careful medical supervision by the clinic staff to ensure that the 
subject does not have difficulty swallowing the capsules. Thereafter, subjects may be allowed to 
self-administer the remaining once daily doses as described.  Subjects are to be instructed to take the 
appropriate number of capsules in the same way for each of the remaining treatment period days and 
may be reminded to do so by phone on non-visit days. 
Subjects should NOT make up any missed doses. 
Subjects should be instructed to document veledimex dosing compliance in a subject diary, including 
the time subject took the once daily dose, the time subject ate breakfast, the number of capsules taken, 
whether subject missed any veledimex doses, and the study day and reason for any missed doses.  
Study drug container(s) with any remaining capsules should be returned to the study staff on Day 15, 
so that staff can properly assess dose compliance. 
10.5.2. 
Cemiplimab-rwlc 
The recommended dose of cemiplimab-rwlc is 350 mg administered as an intravenous infusion over 30 
minutes every 3 weeks (Q3W) until confirmed disease progression or unacceptable toxicity.  
10.6. 
Disposition of Unused Drug 
All unused study drug should be destroyed at the study site in accordance with standard institutional 
practice and in accordance with United States Occupational Safety and Health Administration 
procedures, after full accountability has been documented. Any study drug destruction at study site 
must be documented and the records maintained in the investigator’s study file. 
10.7. 
 Accountability and Dispensation 
The investigator must maintain accurate records accounting for the receipt and dispensation of study 
drugs.  The investigational materials are to be prescribed only by the investigator or the 
sub-investigators named on FDA Form 1572 and may only be dispensed by authorized personnel at the 
institution(s) listed therein.  Under no circumstances will the PI allow the investigational drug(s) to be 
used for purposes or in subjects other than as directed by the protocol. 
10.8. 
 Treatment Plan 
10.8.1. 
Cemiplimab-rwlc 
On Day -7, Day 15, and approximately every 3 weeks thereafter subjects will receive cemiplimab-rwlc 
until confirmed disease progression or unacceptable toxicity.   
10.8.2. 
Ad-RTS-hIL-12 + Veledimex 
• Subjects will be given 20 mg of veledimex by mouth, when NPO (excluding other medications) 
3 (± 2) hours before craniotomy (Day 0).  The actual time of veledimex administration should be 
noted and recorded. 
• Surgical planning will be performed on a diagnostic MRI acquired prior to the surgery as per 
standard of care. 
• At the time of tumor resection, tumor, CSF (if available), and blood samples will be collected. 


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• Immediately after tumor resection, when available, an intraoperative MRI can be performed to 
identify contrast enhancing or T2/FLAIR hyper intense residual tumor.  If intraoperative MRI is 
not available, the neurosurgeon will select sites for injection. 
• Subjects will receive Ad-RTS-hIL-12 
  This will be administered by freehand injection 
into approximately two sites within the residual tumor for a total volume of 0.1 mL selected by the 
neurosurgeon.  When available an intra-operative MRI can be performed to guide the 
Ad-RTS-hIL-12 injection to areas of contrast-enhancing tumor tissue. 
• The day of Ad-RTS-hIL-12 administration is designated as Day 0. If Ad-RTS-hIL-12 injection is 
not performed, subject will not continue with post-resection veledimex dosing. 
• After tumor resection and Ad-RTS-hIL-12 injection, veledimex will be administered orally for 
14 days.  The first post-resection veledimex dose is to be given on Day 1.  Subsequent veledimex 
doses are to be taken once daily, in the morning and within approximately 30 minutes of a regular 
meal. 
Subjects should be carefully monitored for possible local reactions and/or hypersensitivity reactions, 
according to standard practice.  Intracranial bleeding or other procedure-related events should be 
evaluated before the first veledimex dose is given post Ad-RTS-hIL-12 administration.  Any changes 
in neurological status should be reported to the investigator immediately, either during hospitalization 
or once subject is discharged.  Subjects should be instructed to call the study physician or study nurse 
if they develop any symptoms after they are released from the hospital. 
NOTE: It is important that subjects are instructed to maintain adequate oral hydration while subjects 
are being administered veledimex.  Study sites should monitor subjects for proper hydration and 
monitor blood pressure regularly.  The incidence of low blood pressure to date has been lower in 
glioblastoma subjects as compared with breast cancer or melanoma subjects, likely because a lower 
dose of veledimex is used in glioblastoma. 
10.9. 
 Stopping Rules 
From Day -7 to 30 days after completion of Ad-RTS-hIL12 + veledimex dosing, if any subject 
experienced a death (other than death related to progressive disease); or if any subject, during the 
initial treatment period (Day -7 to Day 28) experiences a related SAE that has immediately life-
threatening consequences requiring urgent intervention or results in death; requires major operative 
intervention; or is a related grade 4 hematologic toxicity that persists for 5 days: then enrollment of 
new subjects will be paused, pending review of the event by the Safety Review Committee.  The SRC 
will recommend if changes to the enrollment of additional subjects are required, including, but not 
limited to, potentially modifying the dose and schedule of veledimex, to amend the protocol prior to 
enrollment of additional subjects, or to discontinue enrollment in the study. 
10.10. 
Dose Modifications and Dose Delays  
Veledimex dose delays and dose reductions for individual subjects will be allowed in the event of an 
adverse event, according to the criteria shown in Table 2. 


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Table 2: 
Criteria for Dose Delay and Dose Reduction of veledimex  
Adverse Reaction 
Severity2 
Veledimex Dosage Modifications1 
Immediately life-threatening/ Potentially-Fatal Severe Adverse Reactions 
Any non-hematologic AE3 
Grade 4 non-hematologic adverse event at 
least possibly related to study drug, that is 
considered by the treating physician to be 
immediately life-threatening, and results in 
emergent medical and/or surgical 
intervention 
Discontinue 
Other Severe Adverse Reactions 
Cytokine Release Syndrome 
Grade 3 or higher (per the Ziopharm 
Working Definition of Cytokine Release 
Syndrome) 
Withhold4 
Any non-hematologic AE3, 5 
(except brain edema) 
Grade 3 or higher non-hematologic adverse 
event that is at least possibly related to study 
drug and persists at least 3 days 
Withhold4 
Cerebral edema5 
Grade 3 or higher 
Withhold4,6  
Thrombocytopenia 
Grade 3 or higher thrombocytopenia  
(< 50,000/mm3) at least possibly related to 
study drug 
Withhold4 
Lymphopenia or other 
hematologic toxicity 
Grade 4 or higher lymphopenia or other 
hematologic toxicity (except 
thrombocytopenia)  
Withhold4 
Increased transaminitis8 
Grade 3 or higher increase in ALT or AST 
Potentially Withhold7 
 
1. 
These recommendations are for general guidance only. Treating physicians should manage patients according to their clinical judgement, as informed 
by institutional guidelines, best practices and these guideline recommendations. 
2. 
Toxicity as graded per National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0. 
3. 
Nausea and vomiting will not be considered in this category unless at least Grade 3 or 4 and refractory to antiemetics (i.e., defined as symptoms not 
mitigated by maximal medical support as directed by the Investigator (per institutional guidelines) in consultation with the Sponsor Clinical Medical 
Monitor). 
4. 
Withhold the next and any successive doses of veledimex while the Grade 3 or 4 toxicity persists. Veledimex dosing may resume, after discussion with 
the Sponsor Clinical Medical Monitor, in subjects with rapid and substantial reversal of toxicity, either spontaneously or following appropriate medical 
treatment.  The Sponsor Clinical Study Coordinator will be notified in advance of veledimex dosage modifications. 
5. 
Seizures, headache, and cerebral edema are commonly observed in this population and will be recorded according to the grade of toxicity and therefore 
will not be considered in this category unless unresponsive to maximal medical support as directed by the Investigator (informed by institutional 
guidelines) and in consultation with the Sponsor Clinical Medical Monitor. 
6. 
Cerebral Edema Guideline Recommendations: As a general guideline, mannitol (Osmitrol), corticosteroid treatment (i.e., dexamethasone or Decadron) 
and/or withholding the next dose(s) of veledimex short-term are considered for cerebral edema, CTCAE v5.0 Grade 3 (or for “moderate” severity 
descriptively). For Grade 4 cerebral edema, mannitol (Osmitrol), higher dose corticosteroids and/or longer-term withholding or discontinuation of 
veledimex are considered, especially if the edema is not sufficiently mitigated by urgent medical intervention. It is expected that the use of 
corticosteroids will vary between sites and among subjects, and therefore, the precise extent and dosage of steroids cannot be specified per protocol.  
The treating physician will decide as is safe and appropriate for the individual subject according to their clinical judgement as informed by the label 
and institutional guidelines and should consider the minimum steroid dose or the lowest amount that adequately and rapidly controls the subject’s signs 
and symptoms (refer to Rationale section below). Consideration also may be given to a limited number of doses of bevacizumab (Avastin) if (typically 
high-dose) corticosteroids are not in the best interests of the subject in the treating physician’s clinical judgement and following consultation with the 
Medical Monitor. In the event of an immediately life-threatening event, the treating physician should consider surgical decompression. 
7. 
Rationale: Cerebral edema may pre-exist experimental treatment to a variable extent and usually is associated with the underlying disease and/or 
increase following surgical procedures.  The study treatment, particularly with combination therapy including an immune checkpoint inhibitor, also 
may possibly cause an increase in the severity of edema.  Patients with glioblastoma receiving more than 4 mg dexamethasone qd were reported to 
have decreased overall survival, possibly due to immunosuppression (British J Cancer 2015:113, 232–241). Preliminary data presented at the Society 
for Neuro-Oncology 2018 Annual Meeting by Ziopharm Oncology also suggests that overall survival is decreased in 20 mg veledimex craniotomy 
cohort subjects (i.e., administered more than a 20 mg cumulative dosage of dexamethasone) during the initial treatment period (Days 0-14); the relative 
contributions of severity of the condition vs immunosuppression to the negative effect observed on overall survival are presently uncertain. 
8. 
Withhold the next dose(s) of veledimex if the transaminitis is part of a constellation of findings consistent with Cytokine Release Syndrome (refer to 
Ziopharm Working Definition of Cytokine Release Syndrome). The treating physician may elect to follow the laboratory test trajectory and clinical 
status if an isolated transaminitis. 


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Cemiplimab-rwlc dose delays and dose reductions for individual subjects will be allowed in the event 
of an adverse event, according to the criteria shown in Table 3. 
Table 3: 
Criteria for Dose Delay and Dose Reduction of cemiplimab-rwlc 
Adverse Reaction 
Severity 
Cemiplimab-rwlc Dosage 
Modifications 
Severe and Fatal Immune-Mediated Adverse Reactions 
Pneumonitis 
Grade 2 
Withhold* 
Grades 3 or 4 
Permanently discontinue 
Colitis 
Grades 2 or 3 
Withhold* 
Grade 4 
Permanently discontinue 
Hepatitis 
If AST or ALT increases to more than 3 and 
up to 10 times the upper limit of normal 
(ULN) or if total bilirubin increases up to 3 
times the ULN 
Withhold*  
If AST or ALT increases to more than 10 
times the ULN or total bilirubin increases to 
more than 3 times the ULN 
Permanently discontinue 
Endocrinopathies 
Grades 2, 3, 4 
Withhold if clinically necessary* 
Other immune-mediated 
adverse reactions involving a 
major organ 
Grade 3 
Withhold* 
Grade 4 
Permanently discontinue 
Recurrent or persistent 
immune-mediated adverse 
events 
• 
Recurrent Grades 3 or 4 
• 
Grades 2 or 3 persistent for 12 weeks or 
longer after last cemiplimab-rwlc dose 
in spite of appropriate therapy 
• 
Requirement for 10 mg per day or 
greater prednisone or equivalent lasting 
12 weeks or longer after last 
cemiplimab-rwlc dose 
Permanently discontinue 
Severe and Fatal Immune-Mediated Adverse Reactions 
Infusion-related reactions  
Grades 1 or 2 
Interrupt or slow the rate of infusion 
Grades 3 or 4 
Permanently discontinue 
AE = adverse event 
*: Resume in patients with complete or partial resolution (Grade 0 to 1) after supraphysiologic dose of corticosteroids discontinued 
10.11. 
Safety Monitoring and Adverse Effect Management 
Each subject receiving cemiplimab-rwlc, Ad-RTS-hIL-12 or at least one dose of veledimex will be 
included in the Overall Safety Population (OSP).  Parameters used in the safety analysis of all 
populations will include all laboratory tests, physical examination, imaging scans, and spontaneous 
reports of AEs reported by subjects.  Each patient will be assessed according to the scheduled study 
procedures and any additional visits as a result of AEs. Cytokine release syndrome will be assessed per 
the Ziopharm Working Definition (Appendix 1). Other adverse events will be assessed according to 
the NCI CTCAE v5 criteria. 
10.12. 
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 criteria. 
As with all signs and symptoms, events should be recorded and graded as AEs according to NCI 
CTCAE v.5 criteria.  Study stopping rules will not apply to a specific event if it is clearly unrelated to 
the study treatment. 


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10.13. 
Prophylactic Antipyretic and/or Analgesic Administration 
The use of antipyretics and/or analgesics is allowed as a prophylactic measure perioperatively.  
Antipyretics and/or analgesics can be used anytime during study treatment, as indicated and required 
for patient safety and must be recorded as concomitant medications.  Please refer to exclusion criteria 
for acute clinically significant and/or chronic infections. 
NOTE:  Since fever and other flu-like symptoms (e.g., chills, body aches, malaise, loss of appetite, 
etc.) are sometimes experienced following Ad-RTS-hIL-12 + veledimex, it is reasonable for subjects to 
be administered prophylactic antipyretic and/or analgesic medication prior to Ad-RTS-hIL-12 injection 
and during the first week after injection at the discretion of the treating physician.  The incidence of 
pyrexia and flu-like symptoms to date has been lower in glioblastoma subjects as compared with breast 
cancer or melanoma subjects, likely because a lower dose of veledimex is used in glioblastoma. 
Please refer to Appendix 2 or the recommended regimen for the prophylactic administration of 
antipyretics and/or analgesics. 


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11. 
CONCOMITANT THERAPY 
Information on concomitant medications, including all medications, blood products, vitamins, and 
other supplements, will be collected through the Screening, Treatment, through 90 days after the 
subject’s last dose of any study drug.  
Subjects experiencing brain tumor-related symptoms or edema should be treated with corticosteroids 
as per standard practice. The treating physician should consider the minimum starting steroid dose for 
study subjects, if determined that it is safe and appropriate for that individual patient.  For study 
subjects who require a higher starting steroid dose, efforts should be made to taper steroids to the 
lowest amount that controls the subjects’ symptoms, as determined to be safe and appropriate by the 
treating physician 
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 that individual patient.  For study subjects who require a higher steroid 
dose, efforts should be made to taper steroids to the lowest amount that controls the 
subject’s symptoms, as determined to be safe and appropriate by the treating physician. 
Physiologic replacement doses of corticosteroids are also permitted (NOTE: Intranasal 
corticosteroids are excluded due to rapid systemic absorption). 
• Antidiarrheal therapy is permitted for study drug induced- diarrhea 
• Antiemetics are permitted for study drug- induced- nausea and vomiting 
NOTE: Care should be given when prescribing medications to avoid the use of drugs that are classified 
as CYP450 3A4 inducers, inhibitors, or substrates due to interactions with the study drug, unless 
needed for urgent intervention. All medications should be recorded in the case report form as indicated 
in the completion guidelines.  
11.2. 
 Prohibited Medications/Therapies 
The following medications are prohibited during the study: 
• Any other investigational agent or anticancer therapy (chemotherapy, radiotherapy, etc.) 
while receiving study treatment 
• Palliative radiotherapy is not permitted while on study 
• Enzyme inducing anti-epileptic drugs (EIAED) are listed in Appendix 3 and are NOT 
permitted.   
• Use of heparin or other anti-coagulation therapy, or acetylsalicylic acid (ASA), or anti-
platelet drug within Day -7 to Day 21 should not be used unless necessary to treat a life-
threatening illness 
NOTE: Care should be given when prescribing medications to avoid the use of drugs that are 
classified as CYP450 3A4 inducers, inhibitors, or substrates due to interactions with the study 
drug, unless needed for urgent intervention. All medications should be recorded in the case 
report form as indicated in the completion guidelines.  


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12. 
STUDY PROCEDURES 
12.1. 
Written Informed Consent 
The provided written ICF must be signed before any protocol specific procedures and assessments can 
be performed.  A copy of the signed ICF will be given to the subject and a copy should be filed in the 
medical record.  The original ICF should be kept on file with the study reports.  Standard of care 
evaluations performed as part of the subject’s routine treatment prior to signing the ICF can be used if 
they were conducted within the timeframe of the screening period.  Refer to Section 12.3.2.1  and 
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 are to be enrolled and assigned a unique study identification number before the 
planned cemiplimab-rwlc dose.  Once assigned, a subject’s identification number will not be reused. 
12.3. 
 Schedule of Assessments and Observations 
Screening assessments must be performed within 30 days prior to the Ad-RTS-hIL-12 injection.  Any 
screening tests, exams, or procedures outside of this range may be repeated at the investigator’s 
discretion.  All study visits must be completed as described in the protocol while subjects are taking 
veledimex capsules.  Follow-up assessments are allowed a window of ± 7 days. Refer to Table 1 
Schedule of Study Procedures for further information. 
12.3.1. 
Study Tests, Exams, and Procedures 
12.3.1.1. 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 90 days after the subject’s last dose of any study 
drug.  
12.3.1.2. Physical Examinations 
A complete physical examination will also include a neurological examination. 
12.3.1.3. Vital Signs, Height, and Weight 
Vital signs will include blood pressure, pulse rate, temperature, and respiration rate. Subject’s blood 
pressure should be monitored regularly, with hydration as needed to prevent hypotension for 72 hours 
after administration of Ad-RTS-hIL-12, as previously noted.  Assessment of vital signs is required 
prior to injection of Ad-RTS-hIL-12, and prior to veledimex dosing.  Height and weight will be 
measured and recorded according to Schedule of Study Procedures. 
12.3.1.4. Karnofsky Performance Status 
The Karnofsky Performance Status measures the ability of cancer subjects to perform ordinary tasks. 
Scores range from 0 to 100 with a higher score meaning that the patient is better able to carry out daily 
activities. The Karnofsky Performance Status is used to determine a patient's prognosis, to measure 
changes in a patient’s ability to function, or to decide if a patient could be included in a clinical trial. 


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Subjects must have a Karnofsky Performance Status score of ≥ 70 at the Screening Visit to be included 
in the study. 
12.3.1.5. Pregnancy Testing 
Females of childbearing potential will have a serum pregnancy test at the Screening Visit and a urine 
or serum pregnancy test on Day 0, with a negative pregnancy outcome prior to study drug initiation. 
12.3.1.6. Monitoring of Adverse Events 
Monitoring and recording of AEs and serious adverse events (SAEs) will be conducted throughout the 
study. Adverse events and SAEs that occur following the signing of the ICF through 90 days after the 
subject’s last dose of any study drug- must be recorded on the AE eCRF. 
Definitions, documentation, and reporting of AEs and SAEs are described in Section 13. 
NOTE: Subjects should be instructed to maintain adequate oral hydration while being administered 
veledimex.  Study sites must should monitor subjects for proper hydration and blood pressure should 
be monitored regularly.  Prophylactic antipyretic medications may also be considered. The incidence 
of adverse events to date has been lower in glioblastoma subjects as compared with breast cancer or 
melanoma subjects, likely because a lower dose of veledimex is used in glioblastoma. 
12.3.1.7. Clinical Laboratory Assessments 
The hematology panel comprises a complete blood count (CBC), including white blood cell (WBC) 
count with differential, red blood cell (RBC) count, hematocrit, hemoglobin, red blood cell indices, 
mean corpuscular volume (MCV), and platelet count. 
The serum chemistry panel comprises the following parameters:  AST, ALT, lactate dehydrogenase 
(LDH), alkaline phosphatase (ALP), creatinine, total bilirubin, total protein, albumin, amylase, blood 
urea nitrogen (BUN), glucose, sodium, potassium, chloride, calcium, phosphorus, and bicarbonate. 
The coagulation panel includes activated partial thromboplastin time (aPTT) or partial prothrombin 
time (PTT) and prothrombin time (PT) or INR. The acute phase reactants include erythrocyte 
sedimentation rate (ESR) and CRP. 
The urinalysis panel (dipstick) includes appearance, pH, specific gravity, glucose, protein/albumin, 
presence of blood, ketones, bilirubin, nitrates, and leukocyte esterase.  In addition, a microscopic exam 
for casts, crystals, and cells may be done if clinically indicated. 
12.3.1.8. MRI 
Subjects should be able to undergo MRI scans with contrast agent at screening and during study 
participation.  MRI scans should be available for collection upon sponsor request. 
12.3.1.9. Viral Shedding Assessment 
Urine, feces, saliva, buccal, and blood samples will be collected and tested for viral replication. 
12.3.1.10. Electrocardiogram 
A standard, single, 12-lead electrocardiogram (ECG) for evaluation of the QT/QTc interval will be 
performed. 
12.3.2. 
Schedule of Assessments 
The study design is outlined in Synopsis the sequence of assessments is provided in Synopsis Table 1. 










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• Thyroid Panel 
• ECG 
• Cemiplimab-rwlc dose  
•
  
12.3.2.15. Treatment Period: Day 57 
• Adverse events evaluation 
• Concomitant medications  
• Hematology Panel 
• Serum Chemistry Panel 
• Thyroid Panel 
• Urinalysis Panel 
• Cemiplimab-rwlc dose 
• MRI 
12.3.2.16. Treatment Period: Every 3 weeks after Day 57 
• Physical examination (including targeted neurological evaluation) 
• Vital signs including SpO2 
• Karnofsky Performance Status 
• Adverse events evaluation  
• Concomitant medications 
• Urine or serum pregnancy test 
• Hematology Panel 
• Serum Chemistry Panel 
• Urinalysis Panel 
• Thyroid Panel 
• ECG 
• Cemiplimab-rwlc dose 
12.3.2.17. Treatment Period: Every 8 weeks after Day 57 
• MRI scans 
• Adverse events evaluation 
• Concomitant medications 
• Survival Status 
12.3.2.18. Unscheduled Visits Collections 
In the event of subject termination or an unscheduled visit for a drug-related AE, an unscheduled visit 
kit should be obtained for cytokines and immunological markers for CSF evaluation, if applicable. 
At all visits, concomitant medications, adverse events, and survival status will be documented: 
Concomitant medications will be monitored and recorded throughout the study.  Medications received 
in the period preceding consent (~28 days), in addition to those ongoing at screening, will be captured 
in the eCRF.  Non-serious events from ICF signature until administration of first study drug that are 
not study related will be reported as medical history.  Concomitant medications and AEs/SAEs must be 
recorded in the eCRF through 90 days after the last dose of any study drug.  Ongoing drug-related AEs 
should be followed until resolution unless none is expected.  New anti-cancer medications should be 
captured through completion of survival follow-up.  
Refer to Synopsis Table 1 for Schedule of Study Procedures. 


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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 PFS, and ORR.  
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 should be 
performed within 24 hours (a + 48hr window is allowed) of Ad-RTS-hIL-12 administration.  The 
Ad-RTS-hIL-12 injected lesion and/or other measurable brain lesions will be measured according to 
the iRANO criteria guidelines attached in Appendix 4.  MRI scans will be collected and stored at the 
study site and each subject will be evaluated for response by the study investigator.  Subjects should be 
imaged throughout the study using the same method(s) as were used for the screening and baseline 
MRIs.  Independent tumor response assessments, as well as posttreatment tumor biopsies, may occur 
as available and at the discretion of the investigator.  A repeat scan to confirm progression should be 
completed at 12 weeks (per iRANO) after first documentation of progression. Consideration should be 
given to performing a diagnostic brain biopsy, which should be performed in accordance with the 
current iRANO guidelines. 
Tumor response will be assessed both locally and at an independent central imaging lab using the 
iRANO criteria. Copies of all scans will be provided to the independent central imaging lab for 
determination of tumor response. Final progression determinations will be made by the independent 
central imaging lab. Every effort should be made to continue study therapy until disease progression is 
confirmed per iRANO criteria. In the instance that a subject is withdrawn from study treatment due to 
investigator determined progression, scans should be obtained and provided to the central imaging lab 
until disease progression is confirmed centrally. 
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 (SD).  
For 2 years, subjects without confirmed disease progression should continue to have tumor 
assessments every 8 weeks as per standard practice until disease progression has been identified (first 
documentation) and confirmed (12 weeks after first documentation). 
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, treatment 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, the first tumor assessment MRI will be done on Day 57 (± 3 days).  Imaging assessments 
will be performed using iRANO criteria. 


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13.3. 
Central Imaging Reads 
An independent central imaging lab will review reported responses and progression events using 
iRANO criteria. An Imaging Charter will be developed to provide guidance and consistency. 
 


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14. 
SAFETY ASSESSMENTS 
The safety population will include all subjects who have received at least one dose of any of the 
investigational agents: cemiplimab-rwlc, Ad-RTS-hIL-12 or veledimex. 
14.1. 
Adverse Events and Definitions 
14.1.1. 
Adverse Event 
Any untoward medical occurrence associated with the use of a drug in humans, whether considered 
drug-related.  An AE can be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or 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. 
14.1.2. 
 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 less certainty about causality than an 
adverse reaction. 
14.1.3. 
 Adverse Reaction 
Any AE caused by 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. 
14.1.4. 
Unexpected Adverse Reaction 
Any AE that is (a) not listed in the Reference Safety Information (RSI) of 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 
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. 


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• If 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 unless the progression of disease is assessed by 
the investigator as related to the study treatments; however, the presenting sign or symptom 
of the disease progression should be documented as an AE (e.g., increase in pain). Death 
due to “progression of disease” within the SAE reporting period (from the signing of the 
ICF until 90 days after the last dose of any study treatments) should be reported as SAE. 
Adverse events will be followed from the next study until resolution or to the end of the follow-up 
period.  AEs that are 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 90 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. 
• 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. 
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. 


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14.4. 
 Determination of Severity 
The severity of AEs will be assessed according to the NCI CTCAE, Version 5.  If an AE is not 
specifically defined in the NCI CTCAE, v5.0, the investigator will determine the severity of an AE 
based on the following general definitions recommended (National Cancer Institute 2017): 
• 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 drugs based on his/her clinical judgment.  Assessment of causality will be based upon the 
following: 
• Alternative possible causes of the AE, including the subject’s underlying disease or 
comorbid conditions, other drugs, other host, and environmental factors 
• The temporal sequence between the exposure to study drug and the AE 
• Whether the clinical or laboratory manifestations of the AE are consistent with known 
actions or previously reported toxicity of the study drug or similar drugs 
• Whether the AE resolved or improved with decreasing the dose or stopping the study drug 
(i.e., dechallenge); or recurred or worsened with re-exposure to the drug (i.e., rechallenge). 
Relationship assessments that indicate “Not Related” to investigational product: 
• None:  The event is related to an etiology other than the investigational product (the 
alternative etiology must be documented in the study subject’s medical record and/or SAE 
form). 
• Unlikely or Remote:  The event is unlikely to be related to the investigational product and 
likely to be related to factors other than investigational product. 
Relationship assessments that indicate “Related” to investigational product: 
• Possible:  There is an association between the event and the administration of the 
investigational product and there is a plausible mechanism for the event to be related to 
investigational product; but there may also be alternative etiology, such as characteristics of 
the subject’s clinical status or underlying disease. 


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• Probable:  There is an association between the event and the administration of 
investigational product, a plausible mechanism for the event to be related to the 
investigational product and the event could not be reasonably explained by known 
characteristics of the subject’s clinical status or an alternative etiology is not apparent. 
• Definite:  There is an association between the event and the administration of 
investigational product, a plausible mechanism for the event to be related to the 
investigational product and causes other than the investigational product has been ruled out 
and/or the event re-appeared on re-exposure to the investigational product. 
For AEs that occur prior to the administration of investigational product, an assessment of protocol 
relatedness must be made.  AEs may occur due to procedures required during the screening process 
(e.g., blood collection, washout of an existing medication) prior to the initial administration of 
investigational product.  For AEs that occur before administration of investigational product, only 
those that are assessed by the investigator as protocol-related should be reported to the sponsor.  The 
following guidelines should be used by investigators to assess the relationship of an AE to a 
protocol-required procedure: 
• Protocol-related:  The event occurred due to a procedure or intervention that was described 
in the protocol for which there is no alternative etiology present in the subject’s medical 
record. 
• Not protocol-related:  The event is related to an etiology other than the study procedure (the 
alternative etiology must be documented in the study subject’s medical record). 
14.6. 
Documenting Adverse Events 
All AEs, including SAEs, are to be accurately recorded on the Adverse Event page of the subject’s 
eCRF from the time the subject signs the informed consent through 90 days after the subject’s last dose 
of any study drug.  Each event will be assessed for serious criteria, severity, and causality 
(Section 14.5). The date of onset, as well as the duration of the event will be recorded.  In addition, 
treatments provided to the subject, actions taken with the study drugs, and the outcome of the AE will 
also be noted. 
14.7. 
Reporting Serious Adverse Events (SAE), and Adverse Events of Special 
interest (AESI) 
14.7.1. 
Time Frame for Reporting 
All SAEs and AESIs must be reported to the sponsor or sponsor designee within 24 hours of 
awareness, regardless of initiation of new anticancer therapy including the following: 
• Any SAE or AESI experienced by the subject from the signing of informed consent to 
90 days after the last dose of any study drug, regardless of relationship to study drug. 
• Any SAE or AESI that the investigator becomes aware of, and believes to be study 
drug-related, that occurs more than 90 days after the subject last received study drug. 
 










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16. 
 STATISTICAL METHODS 
This is an uncontrolled single arm study to determine whether the intratumoral Adenovirus 
RheoSwitch Therapeutic System® (RTS) human interleukin-12 (Ad-RTS-hIL-12) and oral (PO) 
veledimex (RTS activator ligand) in combination with cemiplimab-rwlc (Libtayo®) is effective based 
on the estimate of Overall Survival (OS) when treating   subjects with recurrent or progressive 
glioblastoma. Where applicable, estimates of OS and other surrogate endpoints will be compared with 
well-matched historical control data to determine whether the estimates obtained in this study will be 
viewed as promising to support further development of this experimental combination of treatments. 
All populations for analyses and the types of analyses to be performed will be defined in more detail in 
the statistical analysis plan (SAP). 
16.1. 
Populations for Analysis 
• The safety population will comprise all subjects who have received at least one dose of any 
of the investigational agents: cemiplimab-rwlc, the injection of Ad-RTS-hIL-12 or any 
doses of veledimex 
• The per protocol population will comprise subjects who have received Day -7 of 
cemiplimab-rwlc, the injection of Ad-RTS-hIL-12 with at least one post Ad-RTS-hIL-12 
dose of veledimex, at least one post Ad-RTS-hIL-12 dose of cemiplimab-rwlc (e.g., Day 
15), and who have not had a major protocol violation (i.e., subjects who have had minor 
protocol violation(s) that are deemed not to impact efficacy will be included in this analysis 
population.) 
• The biomarker-evaluable population will comprise subjects who have adequate biomarker 
sample(s) at screening (baseline) and at least one follow-up assessment 
16.2. 
Sample Size and Power Calculations 
We plan to accrue up to 30 subjects to obtain approximately 25 subjects evaluable for efficacy.  This 
patient population will be heterogeneous and as such, it is difficult to define a clear safety threshold for 
evaluation in combination with determination of OS, ORR and PFS.    
NOTE:  a minimum of 20 subjects undergoing subtotal resection will be required to ensure that 
sufficient subjects have measurable disease for evaluation of overall response rate per iRANO criteria.   
A sample size of up to 25, will allow us to estimate an overall safety rate with a maximum 95% exact 
confidence interval half-width of approximately 0.19. Note:  a minimum of 20 subjects undergoing 
subtotal resection will be required to ensure that sufficient subjects have measurable disease for 
evaluation of overall response rate per iRANO criteria. In addition, a Toxicity boundary based on 
repeated significance testing provides for a guideline to seriously consider stopping the trial if the 
number of subjects experiencing unacceptable toxicity exceeds the proportions below assuming a 30% 
Toxicity rate is acceptable and 60% would be unacceptable:  
 Low boundary:   3/5   5/10   8/15   9/20   11/25    
 High boundary:   3/5   6/10   8/15   10/20   11/25 
The method for determination of the Toxicity boundary used the Toxbdry function in the Clinfun R 
package implementation of repeated significance testing methodology (Ivanova et al. 2005, Jennison 
and Turnbull 2000).  The operating characteristics of the boundary conditions will be specified in a 
separate statistical analysis plan (SAP). 






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• Documented progression 
• Symptomatic deterioration also denoted as 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 


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All treatment-emergent AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) and will be tabulated by number and percent of subjects, and according to relationship to 
the study drugs, severity, and seriousness.  Treatment-emergent is defined as any AE that occurs 
during or after administration of the first dose of study drug through the evaluation period for safety 
defined above, regardless of relationship to study drug; or any event that is present at baseline that 
worsens in intensity or is subsequently considered to be drug related by the investigator.  Deaths, 
SAEs, and AEs resulting in study discontinuation will be listed. 
Subjects who discontinue the trial as defined above will be followed for safety up to 90 days after 
discontinuation and until all safety events that have started during the safety evaluation period are 
classified as resolved or the end of the study is reached.  After the conclusion of the safety evaluation 
period is triggered by a discontinuation event, the subject continues to be followed only for OS. 
Listings of vital signs and physical examination data will be presented by visit. 
16.6.3. 
Overall Survival 
OS is defined as the duration of time from the first dose of study drug to the date of death or to the last 
follow-up contact date if the subject has not died, in which case the subject is censored if still alive up 
to 2 years from the first dose of study drug received. 
16.6.4. 
Tumor Response Analyses 
Investigator assessment of ORR and PFS will be determined according to iRANO criteria.  A 
two-sided confidence interval will be computed for the ORR.  PFS and OS will be estimated using the 
Kaplan-Meier method for appropriately-sized subject groups. 
Following completion of the study, best response will be determined for each subject in accordance 
with iRANO guidelines and the ORR will be presented for all subjects.  Where applicable, summary 
data of PFS, OS, and durability of response will be determined using Kaplan-Meier methodology; 
otherwise, a listing by-subject will display the data obtained.  Two-sided confidence intervals will be 
computed for the ORR.  Descriptive statistics will be performed for different patient populations. 
16.6.5. 
Multi-Center Study 
Tumor response and safety data will be presented over all study centers. 
16.6.6. 
Adjustments for Covariates 
No adjustments for covariates will be made. 
16.6.7. 
Procedures for Handling Missing, Unused, and Spurious Data 
No imputation of values for missing data will be performed.  Standard clinical monitoring and data 
management practices will be used to ensure the integrity of data. 
16.6.8. 
Procedures for Reporting Deviations to Original Statistical Analysis Plan 
A formal statistical plan for the analysis and presentation of data from this study will be prepared prior 
to database lock.  Deviations from the statistical analyses outlined in this protocol will be indicated in 
this plan; any further modifications will be noted in the final clinical study report. 


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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 to and sufficient training on the electronic data capture (EDC) application, to permit site 
personnel to enter or correct information in the eCRFs for the subjects for whom they are responsible. 
The eCRFs should be completed in a timely manner, and every effort should be made to have forms 
completed and up-to-date in anticipation of a visit by the sponsor’s monitor.  Specific instructions will 
be provided to the site.  All requested information must be entered on the eCRF in the spaces provided.  
If an item is not available or is not applicable, it should be documented as such; do not leave a space 
blank. 
It is the investigator’s responsibility to ensure the accuracy, completeness, clarity, and timeliness of the 
data reported in the subject’s eCRF.  Through the EDC application, the investigator must provide 
formal approval of all subject information in the eCRFs and changes to the eCRFs to endorse the final 
submitted data for the subjects for whom he/she is responsible.  The audit trail entry will show the 
user’s identification information and the date and time of any corrections. 
eCRF completion may be delegated to other study personnel; however, such delegation must be 
documented in writing.  If, for any reason, certain data are lacking to complete an individual report 
form, the investigator will provide a written statement explaining the reasons for the lack of data. 
Sponsor or designee will retain the eCRF data and corresponding audit trails.  A copy of the final 
archival eCRF in the form of a compact disk or other electronic media will be placed in the 
investigator’s study file. 
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. 
Sponsor Monitoring 
After satisfactory receipt of all necessary regulatory paperwork, the sponsor’s monitor will arrange that 
all study material be delivered to the study site at a mutually convenient time.  A site initiation visit 
(SIV) by Ziopharm and its monitoring personnel will be made.  At this meeting, all personnel expected 
to be involved in the conduct of the study will undergo an orientation to include review of study 
protocol, instruction for 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, and this 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 
source documents (e.g., hospital records, office records) will be made available for review by the 
Medical Monitor.  The monitor also will perform drug accountability checks and may periodically 
request review of the investigator’s study file to assure completeness of documentation in all respects 
of study conduct. 


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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 FDA. 
17.4. 
Duration of the Study 
The duration of this study from the time of initiating subject enrollment until the completion of 
survival follow-up is anticipated to be approximately 48 months, including 24 months for enrollment 
and 2 years of further follow-up. 
The overall duration is expected to be up to 2 years for an individual subject, including the following: 
• Screening period of up to 30 days prior to dosing with Ad-RTS-hIL-12 and veledimex 
• Initial Study treatment period of 3 weeks (Days -7 through 14) 
• Assessment of safety through the Follow-up Period 
• Assessment of tumor response at Day 57 (± 3 days), and every 2 months thereafter until the 
occurrence of confirmed tumor progression 
• Survival status through 2 years 
In addition, subjects who discontinue or complete study treatment without objective evidence of 
disease progression should continue to be followed until confirmed disease progression has been 
documented. Subjects will be followed for survival status for 2 years after enrollment, except for death 
or loss to follow-up.  The active study period refers to the study period from informed consent through 
the Initial 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 2 years following the date on which the test article is approved by 
FDA for marketing for the purposes that were investigated in the study.  If no application is to be filed 
or if the application is not approved for such indication, the records must be stored for two additional 
years and then returned to Ziopharm.  No records will be destroyed but will be indefinitely stored. 
17.6. 
Institutional Review Board/ Independent Ethics Committee 
This protocol and the study ICF must be reviewed and approved by the Institutional Biosafety 
Committee, where applicable, and IRB/IEC prior to the start of the study, and a copy of the approval 
letter supplied to Ziopharm.  During the study, the investigator shall make timely and accurate reports 
to the IRB/IEC on study progress at intervals not exceeding 1 year, as well as satisfying any other local 
IRB/IEC reporting regulations.  Copies of all reports to, and correspondence with, the IRB/IEC must 
be provided to Ziopharm.  Further, within 3 months of the completion or early termination of the study, 
a final report should be made to the IRB/IEC and Ziopharm by the investigator. 


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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 HIPAA 
The written ICF will explain that study data will be stored in a database, maintaining confidentiality in 
accordance with national data legislation.  All data processed by Ziopharm, or its representatives, will 
be identified by subject number and study code. 
The written ICF will also explain that, for data verification purposes, authorized representatives of 
Ziopharm, a regulatory authority (FDA), and/or the IRB/IEC may require direct access to parts of the 
hospital or clinic records relevant to the study that include the subject’s medical history. 
The written ICF will be accompanied by or include a separate document incorporating United States 
Health Insurance Portability and Accountability Act (HIPAA)-compliant wording by which the 
subjects authorize the use and disclosure of their Protected Health Information. 
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 should also indicate that, by signature, the prospective subject or, where 
appropriate, a legal guardian, permits access to relevant medical records by the sponsor and by 
representatives of the FDA.  If a prospective subject does not understand English, an appropriate 
translation into his or her primary language must be made available.  The investigator or designee will 
obtain written, informed, and witnessed consent.  The prospective subject will have ample time and 
opportunity to ask questions.  The prospective subject will be informed about the right to withdraw 
from the study at any time without any disadvantage and without having to provide a reason for this 
decision.  Following the discussion regarding the study, the prospective subject will be asked if he/she 
is willing to sign and personally date a statement of informed consent.  Only if the prospective subject 
voluntarily agrees to sign the informed consent statement and has done so, may he/she enroll into the 
study.  A copy of his/her signed and dated informed consent will be provided to each prospective 
subject.  The signed ICF is to remain in the investigator’s file. 
The ICF and any other written information provided to the subjects will be revised whenever important 
new information becomes available that may be relevant to the subject’s consent, or if there is an 
amendment to the protocol that necessitates a change to the content of the subject’s informed consent.  
The investigator will inform the subject of changes in a timely manner and will ask the subject to 
confirm continuation of his/her participation in the study by his/her signature on the revised ICF, if 
applicable.  Any written ICF and written information must receive IRB/IEC approval/favorable 
opinion in advance of use. 
17.8.2. 
Subject Informed Consent Form 
Ziopharm will provide a sample subject ICF for modification, as appropriate, by the investigator. 


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18. 
PROTOCOL APPROVAL PAGE 
A Phase II Study of Ad-RTS-hIL-12 + Veledimex in Combination with Cemiplimab-rwlc 
(Libtayo) in Subjects with Recurrent or Progressive Glioblastoma  
Except for a change intended to eliminate an immediate hazard to subjects, the study shall be 
conducted as described in the approved protocol.  All deviations from the protocol will be documented 
in the eCRF.  Any significant deviation or deviation related to dosing or safety evaluation will be 
reported to Ziopharm and documented in the eCRF. 
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: 
_____________________________________ 
 
Date:   
_____________________________________ 
 
 










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20. 
APPENDICES 


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APPENDIX 1. ZIOPHARM CYTOKINE RELEASE SYNDROME WORKING 
DEFINITION - AD-RTS-HIL-12 + VELEDIMEX (VERSION 3, 
07 JANUARY 2019) 
Cytokine release syndrome (CRS) is a multi-faceted immune disorder presenting clinically as a multi-system disorder. Elevated 
cytokine levels support the diagnosis of CRS in Ad-RTS-hIL-12 gene therapy study along with the grading criteria below:  
Grade 1 
Symptoms that are not life threatening and require symptomatic treatment only, e.g. (any of the following): 
 
General 
Influenza-like illness (flu-like symptoms): fever (temperature of 100°F [37.8°C] or 
greater) and fatigue, malaise, or myalgia 
 
 
Neurological 
Grade 1 headache 
 
 
 
Grade 1 decreased level of consciousness (e.g. somnolence, drowsiness, lethargy, 
disorientation) 
 
 
GI 
Grade 1 nausea or vomiting 
Grade 2 
Symptoms that require and respond to moderate interventions and occurrence of any of the following: 
 
1. 
Hypotension responsive to fluids or single, low dose vasopressor 
 
2. 
Oxygen requirement < 40%  
 
3. 
Grade 3 transaminitis (ALT/AST), lymphopenia, or Grade 2 organ toxicities, e.g.:  
 
 
Hematologic  
Grade 2 neutropenia, or platelets decrease/thrombocytopenia  
 
 
Renal 
Grade 2 creatinine increase 
 
4. 
Other symptoms, e.g.: 
 
 
General 
Grade 3 fever  
 
 
Neurological 
Grade 2 decreased level of consciousness (e.g., slow response to stimuli; limiting 
instrumental activities of daily living)  
 
 
 
Grade 2 or 3 headache 
 
 
GI 
Grade 2 nausea or vomiting  
Grade 3 
Symptoms that require and respond to aggressive interventions and occurrence of any of the following: 
 
1. 
Hypotension requiring high dose or multiple vasopressors 
 
2. 
Oxygen requirement ≥ 40% 
 
3. 
Grade 4 transaminitis (ALT/AST), lymphopenia, or Grade 3 organ toxicities, e.g.:  
                     Hematologic              ≥Grade 3 febrile neutropenia, or platelets decrease/thrombocytopenia  
                     Renal                        Grade 3 creatinine increase 
                     Cardiac                     Grade 3 arrhythmia, or acute heart failure 
                     Pulmonary                Grade 3 pulmonary edema, or dyspnea 
4. 
Other symptoms, e.g.: 
 
 
Neurological 
Grade 3 decreased level of consciousness (e.g. difficult to arouse) 
 
 
 
Aseptic meningitis 
 
 
GI 
Grade 3 nausea or vomiting 
Grade 4 
Life-threatening symptoms and occurrence of any of the following: 
 
1. Requirement for ventilator support 
 
2. Grade 4 organ toxicities (excluding lymphopenia and asymptotic elevated transaminitis), e.g.: 
 
 
Renal 
Renal failure and dialysis indicated 
 
 
Cardiac 
Cardiac arrest 
 
 
Pulmonary 
Respiratory failure 
 
 
Neurological 
Coma 
Grade 5 
Death 
 
 


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APPENDIX 2. RECOMMENDED REGIMEN FOR ANTIPYRETIC AND/OR 
ANALGESIC PROPHYLAXIS 
Recombinant adenoviral vectors have the potential to elicit potent cellular and humoral immune 
responses. While the mechanism responsible for these effects is poorly understood, transient low-grade 
fevers are common after systemic rAD vector administration* and temperatures up to 104° F with 
chills and generalized malaise have been observed with treatment. Because low-grade fever is very 
likely to occur, prophylaxis with acetaminophen is strongly recommended. 
Each site should follow its institutional protocol for the administration of acetaminophen. 
Acetaminophen is available without a prescription in 325 mg or 500 mg tablets. Common brand names 
of acetaminophen include Aspirin Free Anacin®, FeverAll®, Genapap®, Mapap®, NeoPAP®, 
Panadol®, Tempra®, and Tylenol®. 
In general, fever can be adequately prophylaxed or treated with acetaminophen.  If a fever occurs 
despite prophylactic medication or does not respond to usual doses of acetaminophen, then a 
combination of both acetaminophen and ibuprofen may be considered.  Alternating doses of ibuprofen 
with acetaminophen may effectively control fever while preventing accidental overdose of 
acetaminophen.  Acetaminophen is typically effective for controlling central fevers whereas ibuprofen 
is more potent as a peripheral analgesic/ anti-inflammatory medication.  Ibuprofen is available without 
a prescription at a dosage of 200 mg and by prescription in 400, 600 or 800 mg tablets or capsules. 
Common brand names of ibuprofen include Advil®, ElixSure®, Ibuprom®, Ibutab®, Motrin® and 
Tab-Profen®. 
Adverse events are uncommon although may be serious as some individuals are allergic to these 
medications.  Additionally, overdoses of acetaminophen may cause liver failure. Therefore, subjects 
with liver disease and chronic alcohol users should avoid acetaminophen.  Ibuprofen is excreted by the 
kidneys so should be avoided in patients with renal insufficiency, though most would be excluded from 
enrollment.  High dose ibuprofen also may increase the risk of blood clots, stroke, heart attack, and 
gastrointestinal bleeding, and being a potent anti-inflammatory agent could reduce the efficacy of the 
investigational controlled IL-12 therapy. 
 
 


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APPENDIX 3. PROHIBITED ENZYME-INDUCING AND NON-
ENZYME-INDUCING ANTIEPILEPTIC DRUGS 
Enzyme-inducing Antiepileptic Drugs 
Non-Enzyme-inducing Antiepileptic Drugs 
Cerebyx® (fosphenytoin) 
 
 
Zarontin® (ethosuximide) 
ONFI® (clobazam) 
 
Dilantin® (phenytoin) 
Gabitril® (tiagabine) 
Luminal®, Solfoton® (phenobarbital) 
Nembutal® (pentobarbital) 
Trileptal® (oxacarbazepine) 
Tegretol® (carbamazepine) 
Topamax® (topiramate) 
 
 
 
 


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APPENDIX 4. 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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1. 
CLINICAL PROTOCOL SYNOPSIS 
Title 
A Phase II Study of Ad-RTS-hIL-12 + Veledimex in Combination 
with Cemiplimab-rwlc (Libtayo®) in Subjects with Recurrent or 
Progressive Glioblastoma  
Protocol Number 
ATI001-204 
Clinical Phase 
Phase II 
Investigational Product(s) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ad-RTS-hIL12 + veledimex:  
Adenovirus RheoSwitch Therapeutic System® 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 an RTS inducible 
promoter activated in the presence of the activator ligand, 
veledimex.  Veledimex is a small molecule RTS specific 
transcription factor that stabilizes the RTS promoter components 
and allows transcription of the hIL-12 target gene.  Since target 
gene expression is dependent on the dose and frequency of 
veledimex administration, the expression of hIL-12 can be 
modulated by veledimex dose and schedule. 
Cemiplimab-rwlc 
Cemiplimab-rwlc (Libtayo®) is a programmed death receptor-1(PD-
1)-blocking antibody. 
Research Hypothesis 
Among subjects with recurrent or progressive glioblastoma, Ad-
RTS-hIL-12 and veledimex in combination with cemiplimab-rwlc 
(Libtayo®) can be safely administered, show evidence of efficacy, 
and can induce signals of immune activity. 
Study Objectives 
Primary Objectives 
To determine the safety and efficacy of intratumoral Adenovirus 
RheoSwitch Therapeutic System® (RTS) human interleukin-12 
(Ad-RTS-hIL-12) and oral (PO) veledimex (RTS activator ligand) 
in combination with cemiplimab-rwlc (Libtayo®) when treating 
subjects with recurrent or progressive glioblastoma.  This 
determination will be based on the safety profile observed for drug 
safety and on an estimate of Overall Survival (OS) for efficacy, 
respectively. 
Secondary Objectives 
• To determine the survival rates at 6, 12, 18 and 24 months 
• To determine the progression free survival (PFS), and rate 
of pseudo-progression (PSP) at 6, 12, 18 and 24 months 


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• To determine the Investigator’s assessment of response, 
including tumor objective response rate (ORR) at 6, 12, 18 
and 24 months 
• To determine the tumor response rates at 6, 12, 18 and 24 
months 
 
   
Investigational Product(s) 
Ad-RTS-hIL-12 + veledimex:  
Adenovirus-RheoSwitch Therapeutic System®-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 an RTS inducible 
promoter activated in the presence of the activator ligand, 
veledimex.  Veledimex is a small molecule RTS specific 
transcription factor that stabilizes the RTS promoter components 
and allows transcription of the hIL-12 target gene.  Since target 
gene expression is dependent on the dose and frequency of 
veledimex administration, the expression of hIL-12 can be turned 
on and off by veledimex dose and schedule. 
Cemiplimab-rwlc 
Cemiplimab-rwlc (Libtayo®) is a programmed death receptor-1 
(PD-1) blocking antibody. 
Number of Centers 
Approximately 10 centers 
Number of Subjects 
Approximately 30 subjects  
Study Design 
This is a multicenter Phase II study of an intratumoral injection of 
Ad-RTS-hIL-12 (
 viral particles [vp]) and veledimex (20 
mg) administered PO in combination with cemiplimab-rwlc (350 
mg) administered intravenously (IV) in subjects with recurrent or 
progressive glioblastoma.  This study will determine the safety and 
efficacy of Ad-RTS-hIL-12 + veledimex when administered in 
combination with cemiplimab-rwlc, based on the safety profile 
observed and overall survival, respectively, in the presence of 
variable systemic corticosteroid exposure.  
This study includes a Screening Period, Treatment Period, and 
Survival Follow-up. After the informed consent form (ICF) is 
signed, subjects will enter the Screening Period to be assessed for 
eligibility. Subjects will receive cemiplimab-rwlc on Day -7 
(±3days). On Day 0 (day of Ad-RTS-hIL-12 administration) 
subjects will take one dose of veledimex 3±2 hours prior to 
injection of Ad-RTS-hIL-12 and Ad-RTS-hIL-12 (2 × 1011 vp) 
will be administered by freehand injection.  Ad-RTS-hIL-12 will 


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be delivered intratumorally or at the margin of the tumor for a total 
volume of 0.1 mL following resection (subtotal or gross total).  
Note: a minimum of 20 subjects undergoing subtotal resection will 
be required to ensure that a sufficient number of subjects have 
measurable disease for evaluation of overall response rate by 
immunotherapy Response Assessment for Neuro-Oncology 
(iRANO) criteria. The total amount of virus delivered to each site 
will be recorded in the electronic Case Report Form (eCRF). If the 
total administered (injected) volume is less than planned, the 
reason will be provided. Care should be taken to avoid 
intraventricular or basal cisternal injection or other critical 
locations. 
After the Ad-RTS-hIL-12 injection, veledimex will be 
administered orally for 14 days.  The first post-craniotomy 
veledimex dose is to be given on Day 1. Subsequent veledimex 
doses are to be taken once daily, in the morning. Dosing on Days 
2-14 should be at approximately the same time of day (+/- 1 hours) 
as the Day 1 dosing. 
Subjects will receive a dose of cemiplimab-rwlc (350 mg) on Day 
15 and every three weeks thereafter (Q3W) until confirmed 
progression by immunotherapy Response Assessment for Neuro 
Oncology (iRANO) criteria, unacceptable toxicity, subject 
withdrawal or completing the safety follow-up period. Delays in 
cemiplimab-rwlc dosing due to toxicity are allowed at the 
discretion of the Principal Investigator in consultation with the 
Medical Monitor, for up to 14 days. 
A formal Safety Review Committee (SRC) will be comprised of 
the study Investigators and the Medical Monitor. 
After the first six subjects have been enrolled and administered 
Ad-RTS-hIL-12 and veledimex in combination with at least one 
post Ad-RTS-hIL-12 dose of cemiplimab-rwlc, enrollment will be 
paused. The SRC will review safety data after the 6th subject has 
reached Day 28 and decide if enrollment should occur at the same 
dose and schedule of the investigational products.   
The primary endpoint for evaluation of safety is: 
• The safety profile 
The primary endpoint for evaluation of efficacy is: 
• Overall survival (OS)  
Secondary endpoints include:  
• Overall Survival rate at 6, 12, 18 and 24 months 


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• PFS, and rate of pseudo-progression (PSP) at 6, 12, 18 and 
24 months 
• Objective Response Rate at 6, 12, 18 and 24 months 
• To determine the tumor response rate at 6, 12, 18 and 24 
months 
 
  
 
Dose & Schedule 
Ad-RTS-hIL-12:  intratumoral 
vp administered on Day 0 
Veledimex: 20 mg PO QD on Days 0 to 14 
 
Cemiplimab-rwlc: 350 mg IV on Day -7, Day 15, and 
approximately every 3 weeks (Q3W) until confirmed progression 
(iRANO), unacceptable toxicity or subject withdrawal. 
Therapy Duration 
From administration of the first study drug (cemiplimab-rwlc) 
until the subject has confirmed progressive disease per iRANO, 
unacceptable toxicity, the subject withdraws consent, or the end of 
the follow-up period. 
Eligible Population 
The eligible study population includes adult subjects with 
recurrent or progressive glioblastoma for which there is no 
alternative curative therapy.  
Eligibility Criteria 
Subjects with supratentorial glioblastoma who have not previously 
been treated with inhibitors of immuno-checkpoint pathways (e.g., 
anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 
antibody) or other agents specifically targeting T cells. 
Inclusion Criteria 
1. Male or female subject ≥18 and ≤75 years of age 
2. Provision of written informed consent for tumor resection 
(subtotal allowed), tumor biopsy, samples collection, and 
treatment with investigational products prior to undergoing 
any study-specific procedures 
3. Histologically confirmed glioblastoma from archival tissue 
4. Evidence of tumor recurrence/progression by magnetic 
resonance imaging (MRI) according to Response 
Assessment in Neuro-Oncology (RANO) criteria after 
standard initial therapy. Multi-focal disease is allowed. 
5. Previous standard-of-care antitumor treatment including 
surgery and/or biopsy and chemoradiation.  At the time of 
registration, subjects must have recovered from the toxic 


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effects of previous treatments as determined by the treating 
physician.  The washout periods from prior therapies are 
intended as follows: (windows other than what is listed 
below should be allowed only after consultation with the 
Medical Monitor) 
a. Nitrosoureas:  6 weeks 
b. Other cytotoxic agents:  4 weeks  
c. Antiangiogenic agents:  4 weeks  
d. Targeted agents, including small molecule tyrosine 
kinase inhibitors:  2 weeks 
e. Vaccine-based or CAR-T therapy:  3 months 
6. Able to undergo standard MRI scans with contrast agent 
before enrollment and after treatment  
7. Karnofsky Performance Status ≥70 
8. Adequate bone marrow reserves and liver and kidney 
function, as assessed by the following laboratory 
requirements: 
a. Hemoglobin ≥9 g/L 
b. Lymphocytes >500/mm3 
c. Absolute neutrophil count ≥1500/mm3 
d. Platelets ≥100,000/mm3 
e. Serum creatinine ≤1.5 x upper limit of normal (ULN) 
f. Aspartate transaminase (AST) and alanine 
transaminase (ALT) ≤2.5 x ULN 
g. Total bilirubin <1.5 x ULN 
h. International normalized ratio (INR) and activated 
partial thromboplastin time (aPTT) within normal 
institutional limits 
9. Female of child bearing potential* and sexually active 
male subjects must agree to practice highly effective 
contraception prior to the start of the first treatment, during 
the study, and for at least 4 months after the last dose. 
Highly effective contraceptive measures include stable use 
of combined (estrogen and progestogen containing) 
hormonal contraception (oral, intravaginal, transdermal) or 
progestogen-only hormonal contraception (oral, injectable, 
implantable) associated with inhibition of ovulation 
initiated 2 or more menstrual cycles prior to screening; 


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intrauterine device (IUD); intrauterine hormone-releasing 
system (IUS); bilateral tubal ligation; vasectomized 
partner; and or sexual abstinence**. 
 
 
* Postmenopausal women must be amenorrhoeic 
 
 
for at least 12 months in order not to be  
 
 
considered of childbearing potential. Pregnancy 
 
 
testing and contraception are not required for 
 
 
women with documented hysterectomy or tubal 
 
 
ligation. 
 
 
** Sexual abstinence is considered a highly  
 
 
effective method only if defined as refraining 
 
 
from heterosexual intercourse during the entire 
 
 
period of risk associated with the study  
 
 
treatments. The reliability of sexual abstinence 
 
 
needs to be evaluated in relation to the duration 
 
 
of the clinical trial and the preferred and 
 
 
usual lifestyle of the patient. 
10. Normal cardiac and pulmonary function as evidenced by a 
normal ECG and peripheral oxygen saturation (SpO2) 
≥90% by pulse oximetry 
Exclusion Criteria   
1. Radiotherapy treatment within 4 weeks of starting 
veledimex  
2. Prior treatment of disease with bevacizumab (NOTE: 
short use (< 4 doses) of bevacizumab for controlling 
edema is allowed) 
3. Subjects receiving systemic corticosteroids for treatment of 
disease-related symptoms during the 4 weeks prior to Day 
-7 
4. Subjects with clinically significant increased intracranial 
pressure (e.g., impending herniation or requirement for 
immediate palliative treatment) or uncontrolled seizures 
5. Uncontrolled infection with human immunodeficiency 
virus, hepatitis B or hepatitis C infection; or diagnosis of 
immunodeficiency.  
NOTE:        
• Subjects with known HIV infection who have 
controlled infection (undetectable viral load (HIV RNA 
PCR) and CD4 count above 350 either spontaneously 
or on a stable antiviral regimen) are permitted. For 
Subjects with controlled HIV infection, monitoring will 
be performed per local standards.  


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• Subjects with hepatitis B (HBsAg+) who have 
controlled infection (serum hepatitis B virus DNA PCR 
that is below the limit of detection AND receiving anti-
viral therapy for hepatitis B) are permitted. Subjects 
with controlled infections must undergo periodic 
monitoring of HBV DNA. Patients must remain on 
anti-viral therapy for at least 6 months beyond the last 
dose of investigational study drug.  
• Subjects who are hepatitis C virus antibody positive 
(HCV Ab+) who have controlled infection 
(undetectable HCV RNA by PCR either spontaneously 
or in response to a successful prior course of anti-HCV 
therapy) are permitted.  
6. 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. 
7. Use of enzyme-inducing antiepileptic drugs (EIAED) 
within 7 days prior to the first dose of study drug.  Note:  
Levetiracetam (Keppra®) is not an EIAED and is allowed. 
8. Other concurrent clinically active malignant disease, 
requiring treatment, except for non-melanoma cancers of 
the skin or carcinoma in situ of the cervix or non-
metastatic prostate cancer 
9. Nursing or pregnant females 
10. Prior exposure to veledimex 
11. Use of an investigational product within prior 30 days.  
12. Prior exposure to inhibitors of immuno-checkpoint 
pathways (e.g., anti-PD-1, anti-PD-L1, anti-PD-L2, 
anti-CD137, or anti-CTLA-4 antibody) or other agents 
specifically targeting T cells. 
13. Use of medications that induce, inhibit, or are substrates of 
CYP450 3A4 prior to veledimex dosing without 
consultation with the Medical Monitor 
14. Presence of any contraindication for a neurosurgical 
procedure 
15. Use of heparin or other anti-coagulation therapy, or 
acetylsalicylic acid (ASA), or anti-platelet drug within Day 


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-7 to Day 21 should not be used unless necessary to treat a 
life-threatening illness. Prophylactic subcutaneous heparin 
per institutional protocol for prevention of deep vein 
thrombosis (DVT) may be allowed based on discussion 
with the Medical Monitor. Concomitant medications 
should continue to be reviewed in consultation with the 
Medical Monitor. 
16. Unstable or clinically significant concurrent medical 
condition that would, in the opinion of the Investigator or 
Medical Monitor, jeopardize the safety of a subject and/or 
their compliance with the protocol.  Examples may 
include, but are not limited to, colitis, unstable angina, 
congestive heart failure, myocardial infarction within 2 
months of screening, and ongoing maintenance therapy for 
life-threatening ventricular arrhythmia or uncontrolled 
asthma. 
Stopping Rules 
If any subject, during the initial treatment period (Day -7 to Day 
28) experiences a related SAE that has immediately life-
threatening consequences requiring urgent intervention or results 
in death; requires major operative intervention; or is a related 
grade 4 hematologic toxicity that persists for 5 days: then 
enrollment of new subjects will be paused, pending review of the 
event by the Safety Review Committee.  The SRC will 
recommend if changes to the enrollment of additional subjects are 
required, including, but not limited to, potentially modifying the 
dose and schedule of veledimex, to amend the protocol prior to 
enrollment of additional subjects, or to discontinue enrollment in 
the study. 
 
Statistical Methods  
Analysis Populations 
• The safety population will be comprised of all subjects 
who have received at least one dose of any of the 
investigational agents: cemiplimab-rwlc, Ad-RTS-hIL-12 
or veledimex 
• The per protocol population will be comprised of subjects 
who have received Day -7 of cemiplimab-rwlc, the 
injection of Ad-RTS-hIL-12 with at least one post Ad-
RTS-hIL-12 dose of veledimex, at least 1 post Ad-RTS-
hIL-12 dose of cemiplimab-rwlc (e.g., Day 15), and who 
have not had a major protocol violation (i.e., subjects who 
have had minor protocol violation(s) that are deemed not to 
impact efficacy will be included in this analysis 
population.) 


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• The biomarker-evaluable population will comprise subjects 
who have adequate biomarker sample(s) at screening 
(baseline) and at least one follow-up assessment 
Safety Evaluation 
Safety will be evaluated based on frequency and severity 
of adverse events (AEs), Serious adverse events (SAEs), 
laboratory abnormalities, electrocardiograms (ECGs), vital 
signs and physical/neurologic examination findings. 
The severity of AEs will be graded using National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) v5.   
 The reporting period of safety data will be from the date of 
ICF signature through 90 days after the last dose of any 
study drug. 
Efficacy Evaluation 
• The primary analysis for efficacy is based on the per 
protocol population. 
• Secondary analyses for all efficacy endpoints will be based 
on the Safety population. 
The primary endpoint for evaluation of efficacy is: 
• The estimate of the OS which is performed by estimating 
the hazard rate based on the accrual and follow-up of all 
treated subjects.  
• The per protocol population will be followed from the first 
date of treatment up to 2 years for overall survival. 
Estimates of the single arm hazard rate will be determined 
and compared with historical control estimates   
All populations for analyses and the types of analyses to be 
performed will be defined in more detail in the statistical analysis 
plan (SAP). 
Secondary endpoints include:  
• The OS rate will be determined for 6, 12, 18 and 24 
months using a binomial estimate of subjects surviving for 
at least the amount of time established by the cutpoint 
• PFS, and rate of pseudo-progression (PSP) of 
Ad-RTS-hIL-12 + veledimex when administered in 
combination with cemiplimab-rwlc 
• ORR of Ad-RTS-hIL-12 + veledimex when administered 
in combination with cemiplimab-rwlc at 6, 12, 18 and 24 
months 






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Note: A sample size of 25 to 30 subjects provides for an estimate 
of OS at a point in time with (at most) a 10% standard error of the 
estimate assuming the binomial estimation method.  
Study Duration 
The duration of this study from the time of initiating subject 
screening until the completion of survival follow-up is anticipated 
to be approximately 36 months, including 12 months for 
enrollment and 24 months of follow-up.   
The start of study is defined as the date when the first subject is 
consented into the study and the study stop date is the date of the 
last subject’s last visit. 
 
 


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Table 1: 
Schedule of Study Procedures 
Activity 
Screening 
Treatment 
Day -30 
to -8* 
Day -7 
**  
Day 0a 
Day 1 
Day 2 
Day 3 
Day 4 to 6 
Day 7 
Day 8 to 13 
Informed consent 
X 
 
 
 
 
 
 
 
 
Medical/Cancer historyd 
X 
 
 
 
 
 
 
 
 
Physical exame, including targeted 
neurological exam 
X 
X 
X 
X 
X 
X 
 
X 
 
Karnofsky PSf 
X 
X 
X 
 
 
 
 
 
 
Height (screen) and weight 
X 
 
 
 
 
 
 
X 
 
Vital signsg 
X 
X 
X 
X 
X 
X 
 
X 
 
Adverse eventsh 
CONTINUOUS 
Concomitant medicationsh 
CONTINUOUS 
Survival statusi 
CONTINUOUS  
Pregnancy testj 
X 
X 
X 
 
 
 
 
 
 
Hematologyk 
X 
X 
Xa 
X 
X 
X 
 
X 
 
Coagulationl 
X 
 
Xa 
X 
 
X 
 
X 
 
Serum chemistrym 
X 
X 
Xa 
X 
X 
X 
 
X 
 
Urinalysisn 
X 
X 
Xa 
 
 
X 
 
X 
 
Thyroid panelo 
X 
 
 
 
 
 
 
 
 
ECGp 
X 
 
X 
 
 
X 
 
X 
 
Confirm eligibility 
 
Xq 
 
 
 
 
 
 
 
Cemiplimab-rwlc doseq 
 
X 
 
 
 
 
 
 
 
Ad-RTS-hIL-12 
 
 
Xr,s 
 
 
 
 
 
 
Veledimex dose and diaryv 
 
 
Xs, t 
Xs, t 
X 
Xu 
X 
X 
X 
Cytokine profile blood samplex 
X 
 
Xw 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
MRI scansz 
Xz 
 
 
Xz, aa 
 
 
 
 
 
Tumor sampleaa 
 
 
X 
 
 
 
 
 
 
Neutralizing antibody status testingbb 
X 
 
 
 
 
 
 
X 
 
 


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Table 1: 
Schedule of Study Procedures (continued) 
Activity 
Treatment 
Long Term Follow-up 
 
Day 14 
Day 15 
Day 22 
Day 28 Day 36 
±3 days 
Day 57 
±3 days 
Every 3 weeksb 
±7days 
Every 
8 weeksc  ±7days 
Informed consent 
 
 
 
 
 
 
 
 
Medical/Cancer historyd 
 
 
 
 
 
 
 
 
Physical exame, including targeted 
neurological exam 
X 
 
 
 
X 
 
X 
 
Karnofsky PSf 
X 
 
 
 
X 
 
X 
 
Height (screen) and weight 
X 
 
 
 
X 
 
 
 
Vital signsg 
X 
 
 
 
X 
 
X 
 
Adverse eventsh 
CONTINUOUS 
Concomitant medicationsh 
CONTINUOUS 
Survival statusi 
CONTINUOUS 
Pregnancy testj 
 
 
 
X 
 
 
X 
 
Hematologyk 
X 
 
X 
 
X 
X 
X 
 
Coagulationl 
X 
 
 
 
X 
 
 
 
Serum chemistrym 
X 
 
X 
 
X 
X 
X 
 
Urinalysisn 
X 
 
X 
 
 
X 
X 
 
Thyroid panelo 
X 
 
 
 
X 
X 
X 
 
ECGp 
X 
 
 
 
X 
 
X 
 
Confirm eligibility 
 
 
 
 
 
 
 
 
Cemiplimab-rwlc doseq 
 
X 
 
 
X 
X 
X 
 
Ad-RTS-hIL-12 
 
 
 
 
 
 
 
 
Veledimex dose and diary 
Xv 
 
 
 
 
 
 
 
Cytokine profile blood samplex 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRI scansz 
 
 
 
 
 
Xz 
 
Xz 
Tumor samplebb 
 
 
 
 
 
 
 
 
Neutralizing antibody status 
testingcc 
X 
 
 
 
X 
 
 
* Screening assessments must be conducted within 30 days prior to dosing with Ad-RTS-hIL-12 + veledimex.  
** Day -7 dosing with cemiplimab-rwlc may be performed within ± 3 days.  
a  The PI will review all results of laboratory tests drawn within 24 hours prior to surgery. 
b  Every 3 weeks from Day 57 




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8.2. 
Study Oversight for Safety Evaluation ....................................................................... 40 
9. 
SUBJECT SELECTION ............................................................................................ 41 
9.1. 
Inclusion Criteria ........................................................................................................ 41 
9.2. 
Exclusion Criteria ....................................................................................................... 42 
9.3. 
Subject Enrollment ..................................................................................................... 43 
9.4. 
Withdrawal of Subjects from Study Treatment and/or Study .................................... 43 
9.5. 
Replacement of Subjects ............................................................................................ 44 
9.6. 
Premature Termination of Study or Study Site .......................................................... 44 
10. 
INVESTIGATIONAL PRODUCTS .......................................................................... 45 
10.1. 
Preparation of Ad-RTS-hIL-12 .................................................................................. 45 
10.2. 
Preparation of Veledimex ........................................................................................... 45 
10.3. 
Preparation of Cemiplimab-rwlc ................................................................................ 45 
10.4. 
Handling and Storage ................................................................................................. 45 
10.5. 
Monitoring of Subject Adherence and Managing Missed Doses ............................... 46 
10.5.1. 
Veledimex ................................................................................................................... 46 
10.5.2. 
Cemiplimab-rwlc ........................................................................................................ 46 
10.6. 
Disposition of Unused Drug ....................................................................................... 46 
10.7. 
Accountability and Dispensation ................................................................................ 46 
10.8. 
Treatment Plan ............................................................................................................ 46 
10.8.1. 
Cemiplimab-rwlc ........................................................................................................ 46 
10.8.2. 
Ad-RTS-hIL-12 + Veledimex .................................................................................... 46 
10.9. 
Stopping Rules ............................................................................................................ 47 
10.10. 
Dose Modifications and Dose Delays ........................................................................ 47 
10.11. 
Safety Monitoring and Adverse Effect Management ................................................. 49 
10.12. 
Severity Grading and Management of Local Reactions ............................................. 49 
10.13. 
Prophylactic Antipyretic and/or Analgesic Administration ....................................... 50 
11. 
CONCOMITANT THERAPY ................................................................................... 51 
11.1. 
Permitted Medications ................................................................................................ 51 
11.2. 
Prohibited Medications/Therapies .............................................................................. 51 
12. 
STUDY PROCEDURES ............................................................................................ 52 
12.1. 
Written Informed Consent .......................................................................................... 52 
12.2. 
Subject Registration .................................................................................................... 52 
12.3. 
Schedule of Assessments and Observations ............................................................... 52 
12.3.1. 
Study Tests, Exams, and Procedures .......................................................................... 52 


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12.3.1.1. 
Demographics, Medical and Cancer History, and Concomitant Medications ........... 52 
12.3.1.2. 
Physical Examinations ................................................................................................ 52 
12.3.1.3. 
Vital Signs, Height, and Weight ................................................................................. 52 
12.3.1.4. 
Karnofsky Performance Status ................................................................................... 52 
12.3.1.5. 
Pregnancy Testing ...................................................................................................... 53 
12.3.1.6. 
Monitoring of Adverse Events ................................................................................... 53 
12.3.1.7. 
Clinical Laboratory Assessments ............................................................................... 53 
12.3.1.8. 
MRI ............................................................................................................................. 53 
12.3.1.9. 
Viral Shedding Assessment ........................................................................................ 53 
12.3.1.10. Electrocardiogram ...................................................................................................... 53 
12.3.2. 
Schedule of Assessments ............................................................................................ 53 
12.3.2.1. 
Screening Period:  Assessments ................................................................................. 54 
12.3.2.2. 
Treatment Period: Day -7 ........................................................................................... 54 
12.3.2.3. 
Treatment Period: Day 0 (Ad-RTS-hIL-12 injection) ................................................ 55 
12.3.2.4. 
Treatment Period: Day 1 ............................................................................................ 55 
12.3.2.5. 
Treatment Period: Day 2 ............................................................................................ 55 
12.3.2.6. 
Treatment Period: Day 3 ............................................................................................ 56 
12.3.2.7. 
Treatment Period: Days 4 through 6 .......................................................................... 56 
12.3.2.8. 
Treatment Period: Day 7 ............................................................................................ 56 
12.3.2.9. 
Treatment Period: Day 8-13 ....................................................................................... 56 
12.3.2.10. Treatment Period: Day 14 .......................................................................................... 57 
12.3.2.11. Treatment Period: Day 15 .......................................................................................... 57 
12.3.2.12. Treatment Period: Day 22 .......................................................................................... 57 
12.3.2.13. Treatment Period: Day 28 .......................................................................................... 57 
12.3.2.14. Treatment Period: Day 36 .......................................................................................... 57 
12.3.2.15. Treatment Period: Day 57 .......................................................................................... 58 
12.3.2.16. Treatment Period: Every 3 weeks after Day 57 .......................................................... 58 
12.3.2.17. Treatment Period: Every 8 weeks after Day 57 .......................................................... 58 
12.3.2.18. Unscheduled Visits Collections .................................................................................. 58 
13. 
TUMOR RESPONSE ASSESSMENTS .................................................................... 59 
13.1. 
Tumor Response ......................................................................................................... 59 
13.2. 
Tumor Response Evaluation and Pseudo-Progression ............................................... 59 
13.3. 
Central Imaging Reads ............................................................................................... 60 
14. 
SAFETY ASSESSMENTS ........................................................................................ 61 




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16.6. 
Analyses ..................................................................................................................... 71 
16.6.1. 
Baseline Characteristics .............................................................................................. 71 
16.6.2. 
Safety Analyses .......................................................................................................... 71 
16.6.3. 
Overall Survival .......................................................................................................... 72 
16.6.4. 
Tumor Response Analyses ......................................................................................... 72 
16.6.5. 
Multi-Center Study ..................................................................................................... 72 
16.6.6. 
Adjustments for Covariates ........................................................................................ 72 
16.6.7. 
Procedures for Handling Missing, Unused, and Spurious Data ................................. 72 
16.6.8. 
Procedures for Reporting Deviations to Original Statistical Analysis Plan ............... 72 
17. 
STUDY MANAGEMENT ......................................................................................... 73 
17.1. 
Electronic Case Report Forms and Source Documentation ....................................... 73 
17.2. 
Good Clinical Practice ................................................................................................ 73 
17.3. 
Sponsor Monitoring .................................................................................................... 73 
17.4. 
Duration of the Study ................................................................................................. 74 
17.5. 
Records Retention ...................................................................................................... 74 
17.6. 
Institutional Review Board/ Independent Ethics Committee ..................................... 74 
17.7. 
Confidentiality and HIPAA ........................................................................................ 75 
17.8. 
Informed Consent ....................................................................................................... 75 
17.8.1. 
FDA Informed Consent Requirements ....................................................................... 75 
17.8.2. 
Subject Informed Consent Form ................................................................................ 75 
18. 
PROTOCOL APPROVAL PAGE ............................................................................. 76 
19. 
REFERENCES ........................................................................................................... 77 
20. 
APPENDICES ............................................................................................................ 81 
APPENDIX 1. ZIOPHARM CYTOKINE RELEASE SYNDROME WORKING 
DEFINITION - AD-RTS-HIL-12 + VELEDIMEX (VERSION 3, 07 JANUARY 
2019) ........................................................................................................................... 82 
APPENDIX 2. RECOMMENDED REGIMEN FOR ANTIPYRETIC AND/OR 
ANALGESIC PROPHYLAXIS ................................................................................. 83 
APPENDIX 3. PROHIBITED ENZYME-INDUCING AND NON-ENZYME-INDUCING 
ANTIEPILEPTIC DRUGS ........................................................................................ 84 
APPENDIX 4. IMMUNOTHERAPY RESPONSE ASSESSMENT IN NEURO-
ONCOLOGY: A REPORT OF THE RANO WORKING GROUP .......................... 85 
 


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3. 
LIST OF TABLES 
Table 1: 
Schedule of Study Procedures .................................................................................... 14 
Table 2: 
Criteria for Dose Delay and Dose Reduction of veledimex ....................................... 48 
Table 3: 
Criteria for Dose Delay and Dose Reduction of cemiplimab-rwlc ............................ 49 
 
4. 
LIST OF FIGURES 
Figure 1: 
Study Schema ............................................................................................................. 17 
Figure 2: 
Schematic of RTS® Therapeutic System .................................................................... 33 
Figure 3: 
Schematic of Ad-RTS-hIL-12 (COMPONENT 1) ..................................................... 34 
Figure 4: 
Overall Survival in GL-261 Mice Treated With Ad-RTS-mIL-12 + Veledimex 
Plus Anti-PD-1 ........................................................................................................... 35 
 
 


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5. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation or Specialist Term 
Explanation 
Ab 
Antibody 
Ad 
Ad-RTS-hIL-12 or Ad-RTS-mIL-12, depending on context 
Ad-RTS-hIL-12 
Adenovirus RheoSwitch Therapeutic System® human 
interleukin-12 
Ad-RTS-mIL-12  
Adenovirus RheoSwitch Therapeutic System® mouse 
interleukin-12 
ALVAC 
Canarypox virus viral vectors 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase 
aPTT 
Activated partial thromboplastin time 
ASA 
Acetylsalicylic acid 
AST 
Aspartate transaminase 
BBB 
(Putative) blood-brain barrier 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CD 
Cluster of differentiation 
CHO 
Chinese hamster ovary 
CR 
Complete response 
CRP 
C-reactive protein 
CSF 
Cerebrospinal fluid 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
Cytotoxic T lymphocyte-associated antigen 4 
CYP3A4 or CYP450 3A4 
Cytochrome P450 3A4 
DIPG 
Diffuse intrinsic pontine glioma 
DP 
Drug product 
DSMB 
Data and Safety Monitoring Board 
DVT 
Deep vein thrombosis  
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case report form 
EIAED 
Anti-epileptic drugs 


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Abbreviation or Specialist Term 
Explanation 
EMCV 
Encephalomyocarditis virus 
ESR 
Erythrocyte sedimentation rate 
FDA 
U.S. Food and Drug Administration 
Gal4-EcR 
Fusion protein between Gal4 DNA binding domain and ecdysone 
receptor ligand binding domain 
GalRE/P 
Gal4 responsive promoter 
GBM 
Glioblastoma (multiforme) 
GCP 
Good Clinical Practice 
HBsAg 
Hepatitis B Surface Antigen 
HCV 
Hepatitis C Virus 
hIL-12 
Human interleukin-12 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
HLA 
Human leukocyte antigen 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IFN-β 
Interferon-beta 
IFN-γ 
Interferon-gamma 
INR 
International normalized ratio 
IL-2 
Interleukin-2 
IL-12 
Interleukin-12 
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 
IUD 
Intrauterine device 
KDa 
kilo (K)- unified atomic mass units (Daltons or Da) 
LDH 
Lactate dehydrogenase 
MCV 
Mean cell volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 


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Abbreviation or Specialist Term 
Explanation 
NCI 
National Cancer Institute 
NK 
Natural killer 
NOS 
Not otherwise specified 
NPO 
Nothing by mouth (literally, nil per os) 
ORR 
Objective response rate 
OS 
Overall survival 
OSP 
Overall Safety Population 
PCR 
Polymerase chain reaction 
PD 
Progressive disease 
PFS 
Progression-free survival 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
PKP 
Pharmacokinetics Population 
PO 
Oral(ly) 
polyA 
polyadenylation signal 
PR 
Partial response 
PSP 
Pseudo-progression 
PUbC 
Ubiquitin C promoter 
Q 
Each/every (quaque), as in Q3W (every 3 weeks) 
QD 
Each day (quaque die) 
rAd 
Recombinant adenovirus 
RANO 
Response Assessment for Neuro-Oncology 
RBC 
Red blood cell 
rhIL-12 
Recombinant human IL-12 
RTS 
RheoSwitch Therapeutic System 
RXR 
Retinoid X receptor 
SAE 
Serious adverse event 
SD 
Stable disease 
SpO2 
Saturation of peripheral oxygen 
SRC 
Safety Review Committee 
TEAE 
Treatment-emergent adverse event   
Th1 
T-helper cell type 1 
ULN 
Upper limit of normal 


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Abbreviation or Specialist Term 
Explanation 
V 
Veledimex 
v 
Version (followed by number) 
vp 
Viral particles 
VP16-RXR 
Fusion between VP16 transcriptional activation domain and a 
chimeric RXR 
WBC 
White blood cell 
 


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6. 
INTRODUCTION 
6.1. 
Immunotherapy in Glioblastoma 
The revised 2016 World Health Organization Classification of Tumors of the Central Nervous System 
makes use of molecular genetic findings in addition to histology to define tumor entities on the basis of 
combined phenotypic and genotypic features to generate “integrated diagnoses” (Louis et al. 2016). It 
has resulted in substantial restructuring of the diffuse gliomas, as compared with the 2007 CNS WHO 
Classification.  In the revised classification the diffuse gliomas include the anaplastic astrocytomas 
(anaplastic astrocytoma, IDH-wildtype; anaplastic astrocytoma, IDH-mutant; and anaplastic 
astrocytoma, NOS [Not Otherwise Specified]) and anaplastic oligodendroglioma (with IDH-mutant 
and 1p/19q-codeleted subtypes) that are classified as WHO Grade III and the glioblastomas 
(glioblastoma, IDH-wildtype including giant cell glioblastoma, gliosarcoma, and epithelioid 
glioblastoma subtypes; glioblastoma, IDH-mutant; and glioblastoma, NOS) that are classified as WHO 
Grade IV.  Of the WHO Grade III and Grade IV tumors, glioblastomas make up 60% to 70%, 
anaplastic astrocytomas 10% to 15%, and several other anaplastic subtypes the rest (Central Brain 
Tumor Registry).  
Glioblastomas are by far the most frequent malignant glioma and are associated with a particularly 
aggressive course and dismal prognosis (Lieberman 2017). Standard of care treatment for 
glioblastomas is based on surgical resection with the intent to remove as much of the tumor as is 
feasible (Fernandes et al. 2017, Paolillo et al. 2018).  Resection is then followed by radiotherapy and 
concomitant adjuvant temozolomide.  However, such aggressive treatment is associated with only 
modest improvements in survival.  Newly diagnosed glioblastoma subjects have a median overall 
survival (OS) of 12 to 15 months (Ahmed et al. 2014) and 2-year OS rate of up to 27% (Omuro et al. 
2013), while OS in subjects that have failed TMZ and bevacizumab, or equivalent salvage 
chemotherapy, is reported as being as short as 3 to 5 months (Omuro et al., 2013; Iwamoto et al., 
2009).  To date, no salvage treatment has been validated by Phase III data for recurrent or progressive 
glioblastoma.  For subjects with recurrent glioblastoma, the median OS is 6 to 7 months (Omuro et al. 
2013), and median progression-free survival (PFS) is 2 to 3 months. 
The lack of standard and validated salvage therapies has prompted the use of nitrosoureas, 
temozolomide rechallenge, bevacizumab, and other targeted agents that are unsatisfactory treatment 
options.  This likely reflects the complexities of disease heterogeneity, and the treatment limitations of 
brain tumors given the low activity of antineoplastic agents, de novo or acquired drug resistance, the 
sensitivity of the brain to irreversible damage in response to treatment and the presence of the blood 
brain barrier (BBB), which maintains the brain as a privileged compartment.  Surgical resection may 
be offered for subjects with recurrent disease, with the goal of alleviating mass effect, improving 
symptoms, and achieving cytoreduction.  Surgical resection, however, is limited by the infiltrative 
nature of the disease and the lack of clear margins delimitating the tumor.  Given the poor overall 
prognosis and lack of effective treatments, new therapeutic approaches for malignant gliomas are 
needed. 
Immunotherapy for brain tumors is actively being investigated with an array of newer therapeutic 
modalities.  Only about a third of glioblastomas have been reported to demonstrate a robust CD8+ cell 
population present within the tumor microenvironment (Heimberger et al. 2008), and these cells are 
anergic (i.e., not secreting interferon gamma [IFN-γ] or incapable of cytolytic activity).  The immune 
infiltration in glioblastomas is highly variable and is likely driven by the genetic composition and 
mutational load of the tumor (Beier et al. 2012, Doucette et al. 2013). The anticipated specificity and 
efficiency of cytotoxic T-cells (CD8+), activated by local production of IL-12, is particularly attractive 


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and may both spare normal brain cells and minimize systemic toxicity.  We have shown in an 
orthotopic mouse model that survival and tumor killing was greatly enhanced by combining a 
checkpoint inhibitor and Ad-RTS-mIL-12 + veledimex (Barrett et al. 2016b).  Early clinical trials 
suggest that combining immunotherapeutic approaches with surgery, radiation, and chemotherapy may 
improve outcomes (Mitchell et al. 2008).  Preliminary results from the CheckMate 143 (NCT 
02017717) randomized clinical trial in first recurrence of glioblastoma, announced in a World 
Federation of Neuro-Oncology Societies (WFNOS) 2017 abstract, demonstrated a failure of nivolumab 
to prolong overall survival of patients with recurrent GBM, and this monotherapy arm of the trial was 
prematurely terminated (Filley et al 2017). However, an encouraging example of a combination 
immunotherapy approach to treating glioblastoma is a study of the safety and activity of nivolumab 
(human programmed death receptor-1 [PD-1] blocking antibody) in combination with ipilimumab 
(anti-cytotoxic T lymphocyte associated antigen 4 [CTLA-4] antibody) in patients with recurrent 
disease (Reardon et al. 2016).  In this ongoing dose escalation study, combination therapy was 
tolerable, with 12-month overall survival (OS) ranging from 25% to 40%.  
In Ziopharm’s ongoing Phase I trial of intratumoral viral delivery of Ad-RTS-hIL-12 + veledimex to 
date 31 subjects have been orally dosed in 4 cohorts:  10 mg (n=6), 20 mg (n=7), 30 mg (n=4), 40 mg 
(n=6), and an expansion cohort of 20 mg (n=8).  Results show that veledimex crossed the blood-brain-
barrier, with approximately 40% of plasma levels detected in the brain tumor.  Subjects in the 20 mg 
dose cohort (n=15) have better median OS (12.7 months) than in other cohorts. 
Immune checkpoint inhibitors penetration across the blood-brain-barrier to the tumor tissue remains 
controversial, but the goal is to achieve maximum therapeutic effect while limiting systemic toxicity, 
especially when CD8+ cells have been mobilized to the tumor as we have documented following 
treatment with Ad-RTS-hIL-12 + veledimex. 
6.2. 
 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-12 p70 molecule (Carra et al. 2000).  The expression of the p40 subunit 
is tightly regulated and requires specific priming and amplification signals through complex 
combinatorial matching of Toll receptor agonists and specific cytokines, thus limiting the cell types 
that can produce native biologically active IL-12 to activated antigen-presenting cells, neutrophils, and 
macrophages (Trinchieri 2003).  On a secondary level, IL-12 production can also be negatively 
regulated through various mechanisms including production of IL-10 and transforming growth factor β 
(TGFβ). 
Initial studies identified that IL-12 was produced by innate immune cells in response to pathogens and 
that it led to the production of interferon gamma (IFN-γ) and tumor necrosis alpha (TNFα) by T and 
natural killer (NK) cells (Micallef et al.1996, Trinchieri 2003).  When it was discovered that IL-12 
could drive naïve T-helper cell differentiation to the inflammatory T-helper cell type 1 (Th1) 
phenotype (Hsieh et al. 1993), a role for IL-12 was established as a bridge between innate immune 
cells and the adaptive immune response through polarization of naïve CD4+ cells.  More recent data 
demonstrate additional functional roles of IL-12 directly influencing CD8+ T-cell differentiation 
(Curtsinger et al. 2003, Kalinski et al. 1999) and the reactivation and survival of memory CD4+ T-cells 
(Yoo et al. 2002).  This is particularly important in the context of the tumor microenvironment where 
high levels of IL-12 have been shown to repolarize antigen-experienced CD4+ T-cells back to the 
functional antitumor Th1 phenotype (Wesa et al. 2007). 




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initiates hIL-12 transcription only in the presence of the promoter specific oral activator ligand, 
veledimex.  With this system, the IL-12 expression level can be modulated by the dose and frequency 
of veledimex administration, making it feasible to lower or terminate IL-12 expression in the event of 
severe or unexpected toxicities. 
6.4. 
 Adenoviral Vectors for Gene Therapy 
6.4.1. 
Adenoviral Safety 
Adenoviral vectors have been used extensively to deliver a variety of gene products to human subjects, 
including cancer subjects. Although adenoviral vectors are immunogenic, virtually all recipients have 
pre-existing humoral immunity to adenoviruses and they are generally considered a safe and well 
tolerated vehicle for gene delivery. Numerous studies have utilized adenoviral vectors to achieve 
intratumoral expression of a variety of genes. In a Phase I/II clinical trial of subjects with prostate 
cancer, direct intraprostatic injection of a replication-defective adenoviral vector encoding bacterial 
nitroreductase (dose levels 5 x 1010 -1 × 1012  viral particles [vp]) was well tolerated, with minimal 
adverse events (AEs)  (Patel et al. 2009) . A Phase I study of subjects with oral leukoplakia 
implemented multiple intraepithelial injections of recombinant adenovirus (rAd)-p53 (1 x 108  vp/cm2) 
and demonstrated good tolerance of the vector, with no evidence of dose-limiting toxicity (DLTs)  
(Zhang et al. 2009) . In another Phase I/II study of subjects with chemoradiation-resistant advanced 
esophageal carcinoma, intratumoral injections of adenovirus vector containing p53 (Ad.5CMV-p53) 
were well tolerated at doses ranging from 10 x 1011  to 25 x 1011  vp, with no DLTs, and generally mild 
to moderate adverse events (AEs)  (Shimada et al. 2006) . The most common AEs were fever (all 10 
subjects), pain (30% of subjects), and hyperglycemia, which was attributed to the use of total parental 
nutrition (30% of subjects). Hypocalcemia was reported in two subjects (20%) and one subject each 
(10%) experienced activated partial thromboplastin time (aPTT) prolongation, abnormally high serum 
amylase, and abnormally high serum creatinine. 
In a Phase I study of subjects with advanced pancreatic, colorectal, or primary liver tumors, 
intratumoral injection of an adenoviral vector encoding hIL-12 (Ad.IL-12) was well tolerated at doses 
of up to 3 × 1012 vp.  Common AEs were similar to symptoms observed with gene delivery by other 
adenoviral vectors, including transient, mild to moderate fever, malaise, sweating, and lymphopenia 
(Sangro et al. 2004). 
A recent randomized, open-label, Phase III study compared a regimen of surgical resection, 
adenovirus-mediated gene therapy (intraoperative perilesional sitimagene ceradenovec), intravenous 
ganciclovir, and standard of care interventions versus surgical resection plus standard of care 
interventions in 250 subjects with newly diagnosed high-grade glioma amenable to resection.  Results 
showed that although the time to death or re-intervention was prolonged, OS was not improved for the 
investigational regimen relative to the standard of care regimen (Westphal et al. 2013).  This apparent 
difference may have been due to the composite primary endpoint and/or that while OS is a robust 
endpoint, there is no discussion of effect size and for recently-diagnosed tumors it might be less 
suitable to capture meaningful treatment effects for the initial stages of disease because of uncontrolled 
therapy at relapse (ibid). Nevertheless, the authors concluded that the treatment had an increased 
hazard ratio for the primary analysis with a positive overall benefit-risk ratio, with similar AEs 
(hemiparesis [often transient], hyponatremia, and seizures, but no cerebral hemorrhages nor 
hematomas), as compared with the standard-of-care regimen.   


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6.4.1.1. 
Safety of Intratumoral Injection of IL-12 Gene Vectors 
In contrast with the systemic toxicity resulting from administration of recombinant IL-12 protein, local 
administration of IL-12 via injection of plasmid or adenoviral vectors containing the hIL-12 gene has 
proven to be well tolerated in subjects with various cancers, and therefore appears to provide an 
effective delivery method for this potent immunomodulatory cytokine.  Several studies have 
investigated the safety of intratumoral expression of IL-12 in subjects with metastatic melanoma.  A 
Phase I study investigated intratumoral expression of IL-12 together with the co-stimulatory molecule 
B7.1 via two separate canarypox virus viral vectors (ALVAC) in subjects with metastatic melanoma 
and reported mild to moderate injection site reactions, fever, chills, myalgia, and fatigue as AEs 
(Triozzi et al. 2005).  However, all subjects also developed antibodies to ALVAC.  Notably, serum 
IL-12 and IFN-γ levels were not increased after treatment.  Another Phase I trial showed that delivery 
by electroporation of a plasmid containing IL-12 to tumors in subjects with metastatic melanoma 
resulted in minimal systemic toxicity, with transient pain after electroporation being the most common 
AE (Daud et al. 2008).  Results from another Phase I study showed that intratumoral injection of DNA 
encoding hIL-12 in subjects with metastatic melanoma was well tolerated overall (Heinzerling et al. 
2005).  Eight of nine subjects experienced a transient response at the intratumoral injection site, and 
some subjects who had tumor responses also showed some increases in systemic in IL-12, interferon 
gamma-induced protein 10 (IP-10), and IFN-γ. 
Localized production of IL-12 also has been reported as well tolerated in subjects with other 
malignancies.  For example, a Phase I study in 17 subjects with metastatic pancreatic, colorectal, or 
primary liver cancer examined intratumoral injection of dendritic cells engineered to secrete IL-12 via 
a rAD vector (Mazzolini et al. 2005).  In that study, the most common AEs were lymphopenia, fever, 
and malaise.  Subjects also developed antibodies to the adenoviral capsid proteins.  Intraperitoneal 
injection of a plasmid containing the hIL-12 gene in women with chemotherapy-resistant, recurrent, 
ovarian cancer also was found to be generally safe and well tolerated (Anwer et al. 2010).  Low-grade 
fever and abdominal pain were the most common AEs.  Plasmid DNA was not detected in the subjects’ 
serum samples, and treatment-related increases in IFN-γ levels were observed in pleural fluid, but not 
in serum.  Similar data were reported in a study of subjects with advanced pancreatic, colorectal, or 
primary liver malignancies who received intratumoral injections of adenoviral vectors encoding hIL-12 
at doses ranging from 2.5 × 1010 to 3 × 1012 vp (Sangro et al. 2004).  In that study, treatment was well 
tolerated and a maximum tolerated dose (MTD) was not reached.  Transient lymphopenia was 
observed in 86% of subjects, and the severity was increased at higher vector doses.  Transient, mild to 
moderate fever, sometimes accompanied by malaise and sweating, was observed in ~ 60% of subjects 
during the first 2 days after the injection.  Five of the 21 subjects (24%) experienced nausea and/or 
vomiting on the day of the injection.  No cumulative toxicity was observed.  These events were 
deemed related to injection of the virus and not to transgene expression. 














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7. 
STUDY OBJECTIVES 
7.1. 
Primary Objective 
To determine the safety and efficacy of intratumoral Adenovirus RheoSwitch Therapeutic System® 
(RTS) human interleukin 12 (Ad-RTS-hIL-12) and oral (PO) veledimex (RTS activator ligand) in 
combination with cemiplimab-rwlc (Libtayo®) when treating subjects with recurrent or progressive 
glioblastoma.  This determination will be based on the safety profile observed for drug safety and on 
an estimate of Overall Survival (OS) for efficacy, respectively.  
7.2. 
Secondary Objectives 
• To determine the survival rates at 6, 12, 18 and 24 months 
• To determine the progression free survival (PFS), and rate of pseudo-progression (PSP) at 
6, 12, 18 and 24 months 
• To determine the Investigator’s assessment of response, including tumor objective response 
rate (ORR) at 6, 12, 18 and 24 months 
• To determine the tumor response rates at 6, 12, 18 and 24 months 
 
   
 


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8. 
STUDY DESIGN 
8.1. 
Overall Study Design 
This is a multicenter Phase II study of an intratumoral injection of Ad-RTS-hIL-12 (
 
 
 and veledimex (20 mg) administered PO in combination with cemiplimab-rwlc (350 
mg) administered intravenously (IV) in subjects with recurrent or progressive glioblastoma.  This study 
will determine the safety and efficacy of Ad-RTS-hIL-12 + veledimex when administered in 
combination with cemiplimab-rwlc, based on the safety profile observed and overall survival, 
respectively.  
This study includes a Screening Period, Treatment Period, and Survival Follow-up.  After the informed 
consent form (ICF) is signed, subjects will enter the Screening Period to be assessed for eligibility. 
Subjects will receive cemiplimab-rwlc on Day -7 (±3 days). On Day 0 (day of Ad-RTS-hIL-12 
administration) subjects will take one dose of veledimex 3±2 hours prior to injection and 
Ad-RTS-hIL-12 (2 × 1011 vp) will be administered by freehand injection.  Ad-RTS-hIL-12 will be 
delivered intratumorally or at the margin of the tumor for a total volume of 0.1 mL following resection 
(subtotal or gross total).  The total amount delivered to each site will be recorded in the eCRF.  If the 
total administered volume is less than planned, the reason will be provided.  Care should be taken to 
avoid intraventricular or basal cisternal injection or other critical locations. 
After the Ad-RTS-hIL-12 injection, veledimex will be administered orally for 14 days.  The first post 
craniotomy veledimex dose is to be given on Day 1. Subsequent veledimex doses are to be taken once 
daily, in the morning. Dosing on Days 2-14 should be at approximately the same time of day (+/- 1 
hours) as the Day 1 dosing. 
Subjects will receive a dose of cemiplimab-rwlc (350 mg) IV on Day 15 and every three weeks 
thereafter (Q3W) until documented progression by immunotherapy Response Assessment for Neuro 
Oncology (iRANO) criteria, unacceptable toxicity, subject withdrawal or completing the follow-up 
period. Delays in cemiplimab-rwlc dosing due to toxicities are allowed at the discretion of the 
Principal Investigator in consultation with the Medical Monitor, for up to 14 days. 
A formal Safety Review Committee (SRC) will be comprised of the study Investigators and the 
Medical Monitor. 
After the first six patients have been enrolled and administered Ad-RTS-hIL-12 and veledimex in 
combination with at least one post Ad-RTS-hIL-12 dose of cemiplimab-rwlc, enrollment will be 
paused to allow for additional safety follow-up and assessment. The SRC will review safety data after 
the 6th subject has reached Day 28 and decide if enrollment should occur at the same dose and schedule 
of the investigational products.  
8.2. 
Study Oversight for Safety Evaluation 
Safety oversight will occur through the site investigator and medical monitor.  A formal SRC, guided 
by the SRC charter, will include the study investigators, the medical monitor and other appropriate 
sponsor representatives and will provide overall safety oversight.  Additional external medical and 
scientific experts may also be invited to participate in the reviews as needed and appropriate and as 
decided by the SRC.  If a significant safety event occurs, the SRC will convene to evaluate the safety 
event(s) and make a recommendation and decision on the enrollment and continued treatment of 
subjects.  


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9. 
 SUBJECT SELECTION 
Subjects with supratentorial glioblastoma who have not previously been treated with inhibitors of 
immuno-checkpoint pathways (e.g., anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 
antibody) or other agents specifically targeting T cells. 
9.1. 
 Inclusion Criteria 
1. Male or female subject ≥18 and ≤75 years of age 
2. Provision of written informed consent for tumor resection (subtotal allowed), tumor biopsy, 
samples collection, and treatment with investigational products prior to undergoing any study-
specific procedures 
3. Histologically confirmed glioblastoma from archival tissue 
4. Evidence of tumor recurrence/progression by magnetic resonance imaging (MRI) according to 
Response Assessment in Neuro-Oncology (RANO) criteria after standard initial therapy 
5. Previous standard-of-care antitumor treatment including surgery and/or biopsy and 
chemoradiation.  At the time of registration, subjects must have recovered from the toxic 
effects of previous treatments as determined by the treating physician.  The washout periods 
from prior therapies are intended as follows: (windows other than what is listed below should 
be allowed only after consultation with the Medical Monitor) 
a. Nitrosoureas:  6 weeks 
b. Other cytotoxic agents:  4 weeks  
c. Antiangiogenic agents:  4 weeks  
d. Targeted agents, including small molecule tyrosine kinase inhibitors:  2 weeks 
e. Vaccine-based or CAR-T therapy:  3 months 
6. Able to undergo standard MRI scans with contrast agent before enrollment and after treatment  
7. Karnofsky Performance Status ≥70 
8. Adequate bone marrow reserves and liver and kidney function, as assessed by the following 
laboratory requirements: 
f. Hemoglobin ≥9 g/L 
g. Lymphocytes >500/mm3 
h. Absolute neutrophil count ≥1500/mm3 
i. Platelets ≥100,000/mm3 
j. Serum creatinine ≤1.5 x upper limit of normal (ULN) 
k. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤2.5 x ULN.   
l. Total bilirubin <1.5 x ULN 
m. International normalized ratio (INR) and activated partial thromboplastin time (aPTT) or 
partial thromboplastin time (PTT) within normal institutional limits 


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9. Clinically stable on a consistent or decreasing dose of dexamethasone or equivalent of less than 
or equal to 2 mg per day for at least 7 days prior to Day -7 (i.e., Day -14) 
10. Male and female subjects must agree to practice highly effective contraception prior to the start 
of the first treatment, during the study, and for at least 4 months after the last dose. Highly 
effective contraceptive measures include stable use of combined (estrogen and progestogen 
containing) hormonal contraception (oral, intravaginal, transdermal) or progestogen-only 
hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation 
initiated 2 or more menstrual cycles prior to screening; intrauterine device (IUD); intrauterine 
hormone-releasing system (IUS); bilateral tubal ligation; vasectomized partner; and or sexual 
abstinence**. 
* Postmenopausal women must be amenorrheic for at least 12 months in order not to be considered 
of childbearing potential. Pregnancy testing and contraception are not required for women with 
documented hysterectomy or tubal ligation. 
** Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatments. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial 
and the preferred and usual lifestyle of the patient. 
9.2. 
Exclusion Criteria 
1. Radiotherapy treatment within 4 weeks of starting veledimex  
2. Prior treatment with bevacizumab 
(NOTE: Brief use (< 4 doses) of bevacizumab for controlling edema is allowed) 
3. Subjects with clinically significant increased intracranial pressure (e.g., impending herniation 
or requirement for immediate palliative treatment) or uncontrolled seizures 
4. Uncontrolled infection with human immunodeficiency virus, hepatitis B or hepatitis 
C infection; or diagnosis of immunodeficiency.  
NOTE:        
• Patients with known HIV infection who have controlled infection (undetectable viral load 
(HIV RNA PCR) and CD4 count above 350 either spontaneously or on a stable antiviral 
regimen) are permitted. For patients with controlled HIV infection, monitoring will be 
performed per local standards.  
• Patients with hepatitis B (HBsAg+) who have controlled infection (serum hepatitis B virus 
DNA PCR that is below the limit of detection AND receiving anti-viral therapy for hepatitis 
B) are permitted. Patients with controlled infections must undergo periodic monitoring of 
HBV DNA. Patients must remain on anti-viral therapy for at least 6 months beyond the last 
dose of investigational study drug.  
• Patients who are hepatitis C virus antibody positive (HCV Ab+) who have controlled 
infection (undetectable HCV RNA by PCR either spontaneously or in response to a 
successful prior course of anti-HCV therapy) are permitted.  


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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 (EIAED) within 7 days prior to the first dose of 
study drug.  Note:  Levetiracetam (Keppra®) is not an EIAED and is allowed. 
7. Other concurrent clinically active malignant disease, requiring treatment, except for 
non-melanoma cancers of the skin or carcinoma in situ of the cervix or non-metastatic prostate 
cancer 
8. Nursing or pregnant females 
9. Prior exposure to veledimex 
10. Prior exposure to inhibitors of immuno-checkpoint pathways (e.g., anti-PD-1, anti-PD-L1, 
anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody) or other agents specifically targeting T 
cells. 
11. Use of medications that induce, inhibit, or are substrates of CYP450 3A4 prior to veledimex 
dosing without consultation with the Medical Monitor 
12. Presence of any contraindication for a neurosurgical procedure 
13. Use of heparin or other anti-coagulation therapy, or acetylsalicylic acid (ASA), or anti-platelet 
drug within Day -7 to Day 21 should not be used unless necessary to treat a life-threatening 
illness. Prophylactic subcutaneous heparin per institutional protocol for prevention of DVT 
may be allowed based on discussion with the Medical Monitor. Concomitant medications 
should continue to be reviewed in consultation with the Medical Monitor. 
14. Unstable or clinically significant concurrent medical condition that would, in the opinion of the 
Investigator or Medical Monitor, jeopardize the safety of a subject and/or their compliance with 
the protocol.  Examples may include, but are not limited to, colitis, unstable angina, congestive 
heart failure, myocardial infarction within 2 months of screening, and ongoing maintenance 
therapy for life-threatening ventricular arrhythmia or uncontrolled asthma. 
9.3. 
Subject Enrollment 
Approximately 30 subjects may be enrolled.   
9.4. 
 Withdrawal of Subjects from Study Treatment and/or Study 
The sponsor may terminate this study at any time.  The investigator and/or the subject have the right to 
terminate the subject’s participation in the study at any time.  Efforts should be made to ask subjects 
who discontinue study drug to be available to complete the Follow-up assessments. 
A subject may withdraw or be withdrawn from the study treatment prematurely for any of the 
following reasons: 
• Principal Investigator (PI) determines further participation is not in the subject’s best 
interest (e.g., subject experiences rapid clinical deterioration in the absence of confirmed 
disease progression) 
• Subject has confirmed disease progression 


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A subject must be withdrawn in the event of any of the following: 
• Subject withdraws informed consent. 
• Any treatment-related AEs that meet withdrawal criteria 
• Substantial noncompliance with study requirements 
• Subjects with a confirmed positive pregnancy test 
• Any intercurrent illness that would, in the judgement of the investigator or sponsor’s 
medical monitor, affect assessments of clinical status to a significant degree and require 
discontinuation of protocol therapy 
• Subjects who did not receive any study drugs 
• NOTE:  Any subject who wishes to withdraw from the study treatment may do so at any time but 
will be asked to be available for the safety, tumor response, and survival follow-up assessments. 
Every effort should be made to follow subjects who withdraw from study treatment for ongoing 
treatment-related AEs.  Subjects who withdraw during the treatment period should continue to have 
study assessments as clinically indicated.  
9.5. 
Replacement of Subjects 
Subjects who withdraw from the study or do not receive each study drug may be replaced.  All dosed 
subjects will be included in the overall safety assessment. 
9.6. 
 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 electronic case 
report forms (eCRF), study medication, etc.) must be stored or disposed of according to the sponsor’s 
instructions.  Events that may trigger premature termination of the study or closure of a center include 
but are not limited to the following:  new toxicity findings; decision to re-challenge patient who has 
experienced a Grade 4 event; interim analysis results; noncompliance with the protocol; changes in the 
development plans for the study drug; slow recruitment; and poor-quality data. 


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10. 
INVESTIGATIONAL PRODUCTS 
Ad-RTS-hIL-12 and Veledimex is an investigational product has two components: the 
Adenovirus-RheoSwitch Therapeutic System®-human interleukin-12 (Ad-RTS-hIL-12) and veledimex 
(RTS activator ligand).  Ad-RTS-hIL-12 is a replication-incompetent adenoviral vector containing the 
hIL-12 gene under the control of the RTS inducible promoter activated in the presence of the activator 
ligand, veledimex.  Veledimex is a small molecule RTS specific transcription factor that stabilizes the 
RTS promoter components and allows transcription of the hIL-12 target gene.  Since target gene 
expression is dependent on the dose and frequency of veledimex administration, the expression of 
hIL-12 can be modulated (turned on and off) by the optimal veledimex dose and schedule. 
Cemiplimab-rwlc is a covalent heterotetramer consisting of two disulfide-linked human heavy chains, 
each of which is covalently bonded through disulfide linkages to a human kappa light chain.  The 
antibody possesses an approximate molecular weight of 143.6 kilounified atomic mass unit (kDa) 
based on the primary sequence.  There is a single N-linked glycosylation site on each heavy chain, 
located within the constant region in the Fc portion of the molecule.  The cemiplimab-rwlc heavy chain 
possesses an IgG4 isotype constant region.  The variable domains of the heavy and light chains 
combine to form PD-1 binding site within the antibody. Please refer to the Pharmacy Manual for 
additional information. 
Antibody generation by VelocImmune® mice is carried out using standard techniques after 
immunization with PD-1. The genes encoding the heavy and light chains of cemiplimab-rwlc were 
introduced into Chinese Hamster Ovary (CHO) cells, and a stable expression cell line (Cell Line 1) 
was selected for the antibody. Later in development, a second stable expression cell line with higher 
titer (Cell Line 2) was developed for this antibody. For both cell lines, the expression of REGN2810 
was regulated, such that the recombinant CHO cells were de-repressed to initiate antibody expression 
and secretion into the cell culture medium in production bioreactors. Antibody is harvested via 
filtration and purified through a series of preparative column chromatographic and filtration steps to 
generate drug substance. Drug substance is then formulated and sterile-filtered to produce the final 
drug product (DP). 
10.1. 
 Preparation of Ad-RTS-hIL-12 
Ad-RTS-hIL-12 will be supplied as a sterile, single-use vial for injection. Each 0.1 mL contains 
 
 Ad-RTS-hIL-12.  Information regarding the preparation of the Ad-RTS-hIL-12 dose is 
provided in the Pharmacy Manual. 
10.2. 
 Preparation of Veledimex 
Sponsor will provide veledimex capsules to be dispensed by the study site pharmacy to subjects for 
oral administration. Information regarding the veledimex is provided in the Pharmacy Manual. 
10.3. 
 Preparation of Cemiplimab-rwlc 
Cemiplimab-rwlc will be supplied in single-dose vials.  Information regarding the preparation of the 
cemiplimab-rwlc dose is provided in the Pharmacy Manual. 
10.4. 
Handling and Storage 
Study drugs must be stored in a restricted access area under the storage conditions indicated in the 
Investigator’s Brochure or Pharmacy Manual.  All necessary precautions while handling potentially 
toxic compounds must be strictly followed. 


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10.5. 
Monitoring of Subject Adherence and Managing Missed Doses 
10.5.1. 
Veledimex 
The first veledimex dose following Ad-RTS-hIL-12 injection is expected to be administered when the 
subject is at the clinical site, under careful medical supervision by the clinic staff to ensure that the 
subject does not have difficulty swallowing the capsules. Thereafter, subjects may be allowed to 
self-administer the remaining once daily doses as described.  Subjects are to be instructed to take the 
appropriate number of capsules in the same way for each of the remaining treatment period days and 
may be reminded to do so by phone on non-visit days. 
Subjects should NOT make up any missed doses. 
Subjects should be instructed to document veledimex dosing compliance in a subject diary, including 
the time subject took the once daily dose, the time subject ate breakfast, the number of capsules taken, 
whether subject missed any veledimex doses, and the study day and reason for any missed doses.  
Study drug container(s) with any remaining capsules should be returned to the study staff on Day 15, 
so that staff can properly assess dose compliance. 
10.5.2. 
Cemiplimab-rwlc 
The recommended dose of cemiplimab-rwlc is 350 mg administered as an intravenous infusion over 30 
minutes every 3 weeks (Q3W) until confirmed disease progression or unacceptable toxicity.  
10.6. 
Disposition of Unused Drug 
All unused study drug should be destroyed at the study site in accordance with standard institutional 
practice and in accordance with United States Occupational Safety and Health Administration 
procedures, after full accountability has been documented. Any study drug destruction at study site 
must be documented and the records maintained in the investigator’s study file. 
10.7. 
 Accountability and Dispensation 
The investigator must maintain accurate records accounting for the receipt and dispensation of study 
drugs.  The investigational materials are to be prescribed only by the investigator or the 
sub-investigators named on FDA Form 1572 and may only be dispensed by authorized personnel at the 
institution(s) listed therein.  Under no circumstances will the PI allow the investigational drug(s) to be 
used for purposes or in subjects other than as directed by the protocol. 
10.8. 
 Treatment Plan 
10.8.1. 
Cemiplimab-rwlc 
On Day -7, Day 15, and approximately every 3 weeks thereafter subjects will receive cemiplimab-rwlc 
until confirmed disease progression or unacceptable toxicity.   
10.8.2. 
Ad-RTS-hIL-12 + Veledimex 
• Subjects will be given a cohort-specific dose of veledimex by mouth, when NPO (excluding other 
medications) 3 (± 2) hours before craniotomy (Day 0).  The actual time of veledimex 
administration should be noted and recorded. 
• Surgical planning will be performed on a diagnostic MRI acquired prior to the surgery as per 
standard of care. 
• At the time of tumor resection, tumor, CSF (if available), and blood samples will be collected. 


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• Immediately after tumor resection, when available, an intraoperative MRI can be performed to 
identify contrast enhancing or T2/FLAIR hyper intense residual tumor.  If intraoperative MRI is 
not available, the neurosurgeon will select sites for injection. 
• Subjects will receive Ad-RTS-hIL-12 
 
  This will be administered by freehand injection 
into approximately two sites within the residual tumor for a total volume of 0.1 mL selected by the 
neurosurgeon.  When available an intra-operative MRI can be performed to guide the 
Ad-RTS-hIL-12 injection to areas of contrast-enhancing tumor tissue. 
• The day of Ad-RTS-hIL-12 administration is designated as Day 0. If Ad-RTS-hIL-12 injection is 
not performed, subject will not continue with post-resection veledimex dosing. 
• After tumor resection and Ad-RTS-hIL-12 injection, veledimex will be administered orally for 
14 days.  The first post-resection veledimex dose is to be given on Day 1.  Subsequent veledimex 
doses are to be taken once daily, in the morning and within approximately 30 minutes of a regular 
meal. 
Subjects should be carefully monitored for possible local reactions and/or hypersensitivity reactions, 
according to standard practice.  Intracranial bleeding or other procedure-related events should be 
evaluated before the first veledimex dose is given post Ad-RTS-hIL-12 administration.  Any changes 
in neurological status should be reported to the investigator immediately, either during hospitalization 
or once subject is discharged.  Subjects should be instructed to call the study physician or study nurse 
if they develop any symptoms after they are released from the hospital. 
NOTE: It is important that subjects are instructed to maintain adequate oral hydration while subjects 
are being administered veledimex.  Study sites should monitor subjects for proper hydration and 
monitor blood pressure regularly.  The incidence of low blood pressure to date has been lower in 
glioblastoma subjects as compared with breast cancer or melanoma subjects, likely because a lower 
dose of veledimex is used in glioblastoma. 
10.9. 
 Stopping Rules 
If any subject, during the initial treatment period (Day -7 to Day 28) experiences a related SAE that 
has immediately life-threatening consequences requiring urgent intervention or results in death; 
requires major operative intervention; or is a related grade 4 hematologic toxicity that persists for 5 
days: then enrollment of new subjects will be paused, pending review of the event by the Safety 
Review Committee.  The SRC will recommend if changes to the enrollment of additional subjects are 
required, including, but not limited to, potentially modifying the dose and schedule of veledimex, to 
amend the protocol prior to enrollment of additional subjects, or to discontinue enrollment in the study. 
10.10. 
Dose Modifications and Dose Delays  
Veledimex dose delays and dose reductions for individual subjects will be allowed in the event of an 
adverse event, according to the criteria shown in Table 2. 


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Table 2: 
Criteria for Dose Delay and Dose Reduction of veledimex  
Adverse Reaction 
Severity2 
Veledimex Dosage Modifications1 
Immediately life-threatening/ Potentially-Fatal Severe Adverse Reactions 
Any non-hematologic AE3 
Grade 4 non-hematologic adverse event at 
least possibly related to study drug, that is 
considered by the treating physician to be 
immediately life-threatening, and results in 
emergent medical and/or surgical 
intervention 
Discontinue 
Other Severe Adverse Reactions 
Cytokine Release Syndrome 
Grade 3 or higher (per the Ziopharm 
Working Definition of Cytokine Release 
Syndrome) 
Withhold4 
Any non-hematologic AE3, 5 
(except brain edema) 
Grade 3 or higher non-hematologic adverse 
event that is at least possibly related to study 
drug and persists at least 3 days 
Withhold4 
Cerebral edema5 
Grade 3 or higher 
Withhold4,6  
Thrombocytopenia 
Grade 3 or higher thrombocytopenia  
(< 50,000/mm3) at least possibly related to 
study drug 
Withhold4 
Lymphopenia or other 
hematologic toxicity 
Grade 4 or higher lymphopenia or other 
hematologic toxicity (except 
thrombocytopenia)  
Withhold4 
Increased transaminitis8 
Grade 3 or higher increase in ALT or AST 
Potentially Withhold7 
 
1. 
These recommendations are for general guidance only. Treating physicians should manage patients according to their clinical judgement, as informed 
by institutional guidelines, best practices and these guideline recommendations. 
2. 
Toxicity as graded per National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0. 
3. 
Nausea and vomiting will not be considered in this category unless at least Grade 3 or 4 and refractory to antiemetics (i.e., defined as symptoms not 
mitigated by maximal medical support as directed by the Investigator (per institutional guidelines) in consultation with the Sponsor Clinical Medical 
Monitor). 
4. 
Withhold the next and any successive doses of veledimex while the Grade 3 or 4 toxicity persists. Veledimex dosing may resume, after discussion with 
the Sponsor Clinical Medical Monitor, in subjects with rapid and substantial reversal of toxicity, either spontaneously or following appropriate medical 
treatment.  The Sponsor Clinical Study Coordinator will be notified in advance of veledimex dosage modifications. 
5. 
Seizures, headache, and cerebral edema are commonly observed in this population and will be recorded according to the grade of toxicity and therefore 
will not be considered in this category unless unresponsive to maximal medical support as directed by the Investigator (informed by institutional 
guidelines) and in consultation with the Sponsor Clinical Medical Monitor. 
6. 
Cerebral Edema Guideline Recommendations: As a general guideline, mannitol (Osmitrol), corticosteroid treatment (i.e., dexamethasone or Decadron) 
and/or withholding the next dose(s) of veledimex short-term are considered for cerebral edema, CTCAE v5.0 Grade 3 (or for “moderate” severity 
descriptively). For Grade 4 cerebral edema, mannitol (Osmitrol), higher dose corticosteroids and/or longer-term withholding or discontinuation of 
veledimex are considered, especially if the edema is not sufficiently mitigated by urgent medical intervention. It is expected that the use of 
corticosteroids will vary between sites and among subjects, and therefore, the precise extent and dosage of steroids cannot be specified per protocol.  
The treating physician will decide as is safe and appropriate for the individual subject according to their clinical judgement as informed by the label 
and institutional guidelines and should consider the minimum steroid dose or the lowest amount that adequately and rapidly controls the subject’s signs 
and symptoms (refer to Rationale section below). Consideration also may be given to a limited number of doses of bevacizumab (Avastin) if (typically 
high-dose) corticosteroids are not in the best interests of the subject in the treating physician’s clinical judgement and following consultation with the 
Medical Monitor. In the event of an immediately life-threatening event, the treating physician should consider surgical decompression. 
7. 
Rationale: Cerebral edema may pre-exist experimental treatment to a variable extent and usually is associated with the underlying disease and/or 
increase following surgical procedures.  The study treatment, particularly with combination therapy including an immune checkpoint inhibitor, also 
may possibly cause an increase in the severity of edema.  Patients with glioblastoma receiving more than 4 mg dexamethasone qd were reported to 
have decreased overall survival, possibly due to immunosuppression (British J Cancer 2015:113, 232–241). Preliminary data presented at the Society 
for Neuro-Oncology 2018 Annual Meeting by Ziopharm Oncology also suggests that overall survival is decreased in 20 mg veledimex craniotomy 
cohort subjects (i.e., administered more than a 20 mg cumulative dosage of dexamethasone) during the initial treatment period (Days 0-14); the relative 
contributions of severity of the condition vs immunosuppression to the negative effect observed on overall survival are presently uncertain. 
8. 
Withhold the next dose(s) of veledimex if the transaminitis is part of a constellation of findings consistent with Cytokine Release Syndrome (refer to 
Ziopharm Working Definition of Cytokine Release Syndrome). The treating physician may elect to follow the laboratory test trajectory and clinical 
status if an isolated transaminitis. 


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Cemiplimab-rwlc dose delays and dose reductions for individual subjects will be allowed in the event 
of an adverse event, according to the criteria shown in Table 3. 
Table 3: 
Criteria for Dose Delay and Dose Reduction of cemiplimab-rwlc 
Adverse Reaction 
Severity 
Cemiplimab-rwlc Dosage 
Modifications 
Severe and Fatal Immune-Mediated Adverse Reactions 
Pneumonitis 
Grade 2 
Withhold* 
Grades 3 or 4 
Permanently discontinue 
Colitis 
Grades 2 or 3 
Withhold* 
Grade 4 
Permanently discontinue 
Hepatitis 
If AST or ALT increases to more than 3 and 
up to 10 times the upper limit of normal 
(ULN) or if total bilirubin increases up to 3 
times the ULN 
Withhold*  
If AST or ALT increases to more than 10 
times the ULN or total bilirubin increases to 
more than 3 times the ULN 
Permanently discontinue 
Endocrinopathies 
Grades 2, 3, 4 
Withhold if clinically necessary* 
Other immune-mediated 
adverse reactions involving a 
major organ 
Grade 3 
Withhold* 
Grade 4 
Permanently discontinue 
Recurrent or persistent 
immune-mediated adverse 
events 
• 
Recurrent Grades 3 or 4 
• 
Grades 2 or 3 persistent for 12 weeks or 
longer after last cemiplimab-rwlc dose 
in spite of appropriate therapy 
• 
Requirement for 10 mg per day or 
greater prednisone or equivalent lasting 
12 weeks or longer after last 
cemiplimab-rwlc dose 
Permanently discontinue 
Severe and Fatal Immune-Mediated Adverse Reactions 
Infusion-related reactions  
Grades 1 or 2 
Interrupt or slow the rate of infusion 
Grades 3 or 4 
Permanently discontinued 
AE = adverse event 
*: Resume in patients with complete or partial resolution (Grade 0 to 1) after supraphysiologic dose of corticosteroids discontinued 
10.11. 
Safety Monitoring and Adverse Effect Management 
Each subject receiving cemiplimab-rwlc, Ad-RTS-hIL-12 or at least one dose of veledimex will be 
included in the Overall Safety Population (OSP).  Parameters used in the safety analysis of all 
populations will include all laboratory tests, physical examination, imaging scans, and spontaneous 
reports of AEs reported by subjects.  Each patient will be assessed according to the scheduled study 
procedures and any additional visits as a result of AEs. Cytokine release syndrome will be assessed per 
the Ziopharm Working Definition (Appendix 1). Other adverse events will be assessed according to 
the NCI CTCAE v5 criteria. 
10.12. 
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 criteria. 
As with all signs and symptoms, events should be recorded and graded as AEs according to NCI 
CTCAE v.5 criteria.  Study stopping rules will not apply to a specific event if it is clearly unrelated to 
the study treatment. 


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10.13. 
Prophylactic Antipyretic and/or Analgesic Administration 
The use of antipyretics and/or analgesics is allowed as a prophylactic measure perioperatively.  
Antipyretics and/or analgesics can be used anytime during study treatment, as indicated and required 
for patient safety and must be recorded as concomitant medications.  Please refer to exclusion criteria 
for acute clinically significant and/or chronic infections. 
NOTE:  Since fever and other flu-like symptoms (e.g., chills, body aches, malaise, loss of appetite, 
etc.) are sometimes experienced following Ad-RTS-hIL-12 + veledimex, it is reasonable for subjects to 
be administered prophylactic antipyretic and/or analgesic medication prior to Ad-RTS-hIL-12 injection 
and during the first week after injection at the discretion of the treating physician.  The incidence of 
pyrexia and flu-like symptoms to date has been lower in glioblastoma subjects as compared with breast 
cancer or melanoma subjects, likely because a lower dose of veledimex is used in glioblastoma. 
Please refer to Appendix 2 or the recommended regimen for the prophylactic administration of 
antipyretics and/or analgesics. 


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11. 
CONCOMITANT THERAPY 
Information on concomitant medications, including all medications, blood products, vitamins, and 
other supplements, will be collected through the Screening, Treatment, through 90 days after the 
subject’s last dose of any study drug.  
Subjects experiencing brain tumor-related symptoms or edema should be treated with corticosteroids 
as per standard practice. The treating physician should consider the minimum starting steroid dose for 
study subjects, if determined that it is safe and appropriate for that individual patient.  For study 
subjects who require a higher starting steroid dose, efforts should be made to taper steroids to the 
lowest amount that controls the subjects’ symptoms, as determined to be safe and appropriate by the 
treating physician 
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 that individual patient.  For study subjects who require a higher steroid 
dose, efforts should be made to taper steroids to the lowest amount that controls the 
subject’s symptoms, as determined to be safe and appropriate by the treating physician. 
Physiologic replacement doses of corticosteroids are also permitted (NOTE: Intranasal 
corticosteroids are excluded due to rapid systemic absorption). 
• Antidiarrheal therapy is permitted for study drug induced- diarrhea 
• Antiemetics are permitted for study drug- induced- nausea and vomiting 
NOTE: Care should be given when prescribing medications to avoid the use of drugs that are classified 
as CYP450 3A4 inducers, inhibitors, or substrates due to interactions with the study drug, unless 
needed for urgent intervention. All medications should be recorded in the case report form as indicated 
in the completion guidelines.  
11.2. 
 Prohibited Medications/Therapies 
The following medications are prohibited during the study: 
• Any other investigational agent or anticancer therapy (chemotherapy, radiotherapy, etc.) 
while receiving study treatment 
• Palliative radiotherapy is not permitted while on study 
• Enzyme inducing anti-epileptic drugs (EIAED) are listed in Appendix 3 and are NOT 
permitted.   
• Use of heparin or other anti-coagulation therapy, or acetylsalicylic acid (ASA), or anti-
platelet drug within Day -7 to Day 21 should not be used unless necessary to treat a life-
threatening illness 
NOTE: Care should be given when prescribing medications to avoid the use of drugs that are 
classified as CYP450 3A4 inducers, inhibitors, or substrates due to interactions with the study 
drug, unless needed for urgent intervention. All medications should be recorded in the case 
report form as indicated in the completion guidelines.  


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12. 
STUDY PROCEDURES 
12.1. 
Written Informed Consent 
The provided written ICF must be signed before any protocol specific procedures and assessments can 
be performed.  A copy of the signed ICF will be given to the subject and a copy should be filed in the 
medical record.  The original ICF should be kept on file with the study reports.  Standard of care 
evaluations performed as part of the subject’s routine treatment prior to signing the ICF can be used if 
they were conducted within the timeframe of the screening period.  Refer to Section 12.3.2.1  and 
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 are to be enrolled and assigned a unique study identification number before the 
planned cemiplimab-rwlc dose.  Once assigned, a subject’s identification number will not be reused. 
12.3. 
 Schedule of Assessments and Observations 
Screening assessments must be performed within 30 days prior to the Ad-RTS-hIL-12 injection.  Any 
screening tests, exams, or procedures outside of this range may be repeated at the investigator’s 
discretion.  All study visits must be completed as described in the protocol while subjects are taking 
veledimex capsules.  Follow-up assessments are allowed a window of ± 7 days. Refer to Table 1 
Schedule of Study Procedures for further information. 
12.3.1. 
Study Tests, Exams, and Procedures 
12.3.1.1. 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 90 days after the subject’s last dose of any study 
drug.  
12.3.1.2. Physical Examinations 
A complete physical examination will also include a neurological examination. 
12.3.1.3. Vital Signs, Height, and Weight 
Vital signs will include blood pressure, pulse rate, temperature, and respiration rate. Subject’s blood 
pressure should be monitored regularly, with hydration as needed to prevent hypotension for 72 hours 
after administration of Ad-RTS-hIL-12, as previously noted.  Assessment of vital signs is required 
prior to injection of Ad-RTS-hIL-12, and prior to veledimex dosing.  Height and weight will be 
measured and recorded according to Schedule of Study Procedures. 
12.3.1.4. Karnofsky Performance Status 
The Karnofsky Performance Status measures the ability of cancer subjects to perform ordinary tasks. 
Scores range from 0 to 100 with a higher score meaning that the patient is better able to carry out daily 
activities. The Karnofsky Performance Status is used to determine a patient's prognosis, to measure 
changes in a patient’s ability to function, or to decide if a patient could be included in a clinical trial. 


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Subjects must have a Karnofsky Performance Status score of ≥ 70 at the Screening Visit to be included 
in the study. 
12.3.1.5. Pregnancy Testing 
Females of childbearing potential will have a serum pregnancy test at the Screening Visit and a urine 
or serum pregnancy test on Day 0, with a negative pregnancy outcome prior to study drug initiation. 
12.3.1.6. Monitoring of Adverse Events 
Monitoring and recording of AEs and serious adverse events (SAEs) will be conducted throughout the 
study. Adverse events and SAEs that occur following the signing of the ICF through 90 days after the 
subject’s last dose of any study drug- must be recorded on the AE eCRF. 
Definitions, documentation, and reporting of AEs and SAEs are described in Section 13. 
NOTE: Subjects should be instructed to maintain adequate oral hydration while being administered 
veledimex.  Study sites must should monitor subjects for proper hydration and blood pressure should 
be monitored regularly.  Prophylactic antipyretic medications may also be considered. The incidence 
of adverse events to date has been lower in glioblastoma subjects as compared with breast cancer or 
melanoma subjects, likely because a lower dose of veledimex is used in glioblastoma. 
12.3.1.7. Clinical Laboratory Assessments 
The hematology panel comprises a complete blood count (CBC), including white blood cell (WBC) 
count with differential, red blood cell (RBC) count, hematocrit, hemoglobin, red blood cell indices, 
mean corpuscular volume (MCV), and platelet count. 
The serum chemistry panel comprises the following parameters:  AST, ALT, lactate dehydrogenase 
(LDH), alkaline phosphatase (ALP), creatinine, total bilirubin, total protein, albumin, amylase, blood 
urea nitrogen (BUN), glucose, sodium, potassium, chloride, calcium, phosphorus, and bicarbonate. 
The coagulation panel includes activated partial thromboplastin time (aPTT) or partial prothrombin 
time (PTT) and prothrombin time (PT) or INR. The acute phase reactants include erythrocyte 
sedimentation rate (ESR) and CRP. 
The urinalysis panel (dipstick) includes appearance, pH, specific gravity, glucose, protein/albumin, 
presence of blood, ketones, bilirubin, nitrates, and leukocyte esterase.  In addition, a microscopic exam 
for casts, crystals, and cells may be done if clinically indicated. 
12.3.1.8. MRI 
Subjects should be able to undergo MRI scans with contrast agent at screening and during study 
participation.  MRI scans should be available for collection upon sponsor request. 
12.3.1.9. Viral Shedding Assessment 
Urine, feces, saliva, buccal, and blood samples will be collected and tested for viral replication. 
12.3.1.10. Electrocardiogram 
A standard, single, 12-lead electrocardiogram (ECG) for evaluation of the QT/QTc interval will be 
performed. 
12.3.2. 
Schedule of Assessments 
The study design is outlined in Synopsis the sequence of assessments is provided in Synopsis Table 1. 


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12.3.2.1. Screening Period:  Assessments 
The screening exams, tests, and procedures must be conducted within 30 days prior to dosing with Ad-
RTS-hIL-12 + veledimex: 
• Signed informed consent form 
• Medical/cancer history 
• Physical examination (including targeted neurological examination) 
• Height and weight 
• Vital signs including SpO2 
• ECG 
• Karnofsky Performance Status 
• History of prior treatments and any associated residual toxicity 
• Medications taken during the 28 days prior to consent, in addition to those ongoing during 
screening 
• Adverse events evaluation 
• MRI 
• Serum pregnancy test 
• Hematology Panel including: complete blood count (CBC), white blood cell (WBC) count 
with differential, red blood cell (RBC) count, hematocrit, hemoglobin, red blood cell indices, 
and platelet count 
• Serum Chemistry Panel including: aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), creatinine, 
total bilirubin, total protein, albumin, blood urea nitrogen (BUN), lipase, amylase, glucose, 
sodium, potassium, chloride, calcium, phosphorus, and bicarbonate. 
• Coagulation Panel including: activated partial thromboplastin time (aPTT), international 
normalized ratio (INR) ESR (erythrocyte sedimentation rate) and CRP (C-reactive protein). 
• Urinalysis Panel (dipstick) including: appearance, pH, specific gravity, glucose, 
protein/albumin, presence of blood, ketones, bilirubin, nitrates, and leukocyte esterase. In 
addition, a microscopic exam for casts, crystals, and cells may be done if clinically indicated 
• Thyroid Panel: free triiodothyronine (FT3), free thyroxine (FT4), and thyroid-stimulating 
hormone (TSH) 
• Viral shedding assessment 
• Ad-RTS-hIL-12 neutralizing antibodies sample 
• Serum sample for evaluation of cytokine profile 
• Blood sample for immune function evaluation 
• Subject registration 
12.3.2.2. Treatment Period: Day -7  
• Physical examination (including neurological examination) 
• Karnofsky Performance Status 
• Vital signs including SpO2 
• Adverse events evaluation 
• Concomitant medications 
• Urine or serum pregnancy test (within 72 hours prior to cemiplimab-rwlc dosing) 
• Hematology Panel 
• Serum Chemistry Panel 


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• Urinalysis Panel 
• Confirm eligibility 
• Cemiplimab-rwlc dose 
12.3.2.3. Treatment Period: Day 0 (Ad-RTS-hIL-12 injection) 
• Physical examination (including neurological examination) 
• Karnofsky Performance Status 
• Vital signs including SpO2 
• Adverse events evaluation 
• Concomitant medications 
• Urine or serum pregnancy test 
• Hematology Panel (All labs should be collected prior to the subject’s pre-op dose of veledimex) 
• Coagulation Panel 
• Serum Chemistry Panel 
• Urinalysis Panel 
• ECG 
• Dose of veledimex 3 (± 2) hours prior to resection, on an empty stomach (excluding other 
medications) AND compliance diary. Intratumoral Ad-RTS-hIL-12 will be administered by 
freehand injection. 
• Serum sample for evaluation of cytokine profile 
• Blood sample for immune function evaluation 
• Tumor and CSF (if available), will be collected at time of resection  
12.3.2.4. Treatment Period: Day 1 
• Once daily veledimex AND compliance diary 
• Physical examination (including targeted neurological evaluation) 
• Vital signs 
• Adverse events evaluation 
• Concomitant medications 
• Hematology Panel 
• Coagulation Panel 
• Serum Chemistry Panel 
• Blood sample for immune function evaluation 
• MRI scan: to be done within 24 hours (a +48hr window is allowed) of Ad-RTS-hIL-12 
administration and to be used as the baseline MRI for tumor response assessment 
• Serum sample for evaluation of cytokine profile 
12.3.2.5. Treatment Period: Day 2 
• Once daily veledimex AND compliance diary 
• Physical examination (including targeted neurological evaluation) 
• Vital signs 
• Adverse events evaluation 
• Concomitant medications 
• Hematology Panel 
• Serum Chemistry Panel 


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12.3.2.6. Treatment Period: Day 3 
• Once daily veledimex dose AND compliance diary (The Day 3 dose should be held until Day 3 
labs have been reviewed. Subjects should not be dosed unless lymphocyte counts, platelet 
counts, and liver function tests have changed by ≤ 20% from baseline values and the Grade of 
any abnormality has not increased. Medical monitor consultation is then advised.) 
• Physical Examination (including targeted neurological evaluation)  
• Vital signs including SpO2 
• Adverse events evaluation 
• Concomitant medications 
• Hematology Panel 
• Coagulation Panel 
• Serum Chemistry Panel 
• Urinalysis Panel 
• Viral shedding assessment from urine, feces, saliva, buccal and blood samples 
• Blood sample for evaluation of serum cytokine profile 
• Blood sample for immune function evaluation 
• ECG 
12.3.2.7. Treatment Period: Days 4 through 6 
• Once daily veledimex dose AND compliance diary 
• Adverse events evaluation 
• Concomitant medications 
12.3.2.8. Treatment Period: Day 7 
• Once daily veledimex dose AND compliance diary 
• Physical examination (including targeted neurological evaluation) 
• Vital signs including SpO2 
• Weight 
• Adverse events evaluation 
• Concomitant medications 
• Hematology Panel 
• Serum Chemistry Panel 
• Coagulation Panel 
• Urinalysis Panel 
• ECG 
• Blood sample for evaluation of serum cytokine profile  
• Blood sample for immune function evaluation 
• Serum samples for evaluation of neutralizing antibodies 
12.3.2.9. Treatment Period: Day 8-13 
• Once daily veledimex dose AND compliance diary 


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12.3.2.10. Treatment Period: Day 14 
• Once daily veledimex dose AND compliance diary 
• Physical examination (including targeted neurological evaluation) 
• Vital signs including SpO2 
• Weight 
• Karnofsky Performance Status 
• Adverse events evaluation 
• Concomitant medications 
• Hematology Panel 
• Serum Chemistry Panel 
• Coagulation Panel 
• Urinalysis Panel 
• Thyroid Panel 
• ECG 
• Blood sample for evaluation of serum cytokine profile  
• Blood sample for immune function evaluation 
• Ad-RTS-hIL-12 neutralizing antibodies sample  
• Viral shedding assessment from urine, feces, saliva, buccal and blood (as blood volume 
permits) samples 
12.3.2.11. Treatment Period: Day 15 
• Cemiplimab-rwlc dose 
12.3.2.12. Treatment Period: Day 22 
• Hematology Panel 
• Serum Chemistry Panel 
• Urinalysis Panel 
12.3.2.13. Treatment Period: Day 28 
• Urine or serum pregnancy test 
• Blood sample for evaluation of serum cytokine profile  
• Blood sample for immune function evaluation 
• Viral shedding assessment from urine, feces, saliva, buccal and blood (as blood volume 
permits) samples 
12.3.2.14. Treatment Period: Day 36 
• Physical examination (including targeted neurological evaluation) 
• Vital signs including SpO2 
• Weight 
• Karnofsky Performance Status 
• Adverse events evaluation 
• Concomitant medications 
• Urine or serum pregnancy test 
• Hematology Panel 
• Serum Chemistry Panel 
• Coagulation Panel 


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• Thyroid Panel 
• ECG 
• Cemiplimab-rwlc dose  
• Ad-RTS-hIL-12 neutralizing antibodies sample  
12.3.2.15. Treatment Period: Day 57 
• Adverse events evaluation 
• Concomitant medications  
• Hematology Panel 
• Serum Chemistry Panel 
• Thyroid Panel 
• Urinalysis Panel 
• Cemiplimab-rwlc dose 
• MRI 
12.3.2.16. Treatment Period: Every 3 weeks after Day 57 
• Physical examination (including targeted neurological evaluation) 
• Vital signs including SpO2 
• Karnofsky Performance Status 
• Adverse events evaluation  
• Concomitant medications 
• Urine or serum pregnancy test 
• Hematology Panel 
• Serum Chemistry Panel 
• Urinalysis Panel 
• Thyroid Panel 
• ECG 
• Cemiplimab-rwlc dose 
12.3.2.17. Treatment Period: Every 8 weeks after Day 57 
• MRI scans 
• Adverse events evaluation 
• Concomitant medications 
• Survival Status 
12.3.2.18. Unscheduled Visits Collections 
In the event of subject termination or an unscheduled visit for a drug-related AE, an unscheduled visit 
kit should be obtained for cytokines and immunological markers for CSF evaluation, if applicable. 
At all visits, concomitant medications, adverse events, and survival status will be documented: 
Concomitant medications will be monitored and recorded throughout the study.  Medications received 
in the period preceding consent (~28 days), in addition to those ongoing at screening, will be captured 
in the eCRF.  Non-serious events from ICF signature until administration of first study drug that are 
not study related will be reported as medical history.  Concomitant medications and AEs/SAEs must be 
recorded in the eCRF through 90 days after the last dose of any study drug.  Ongoing drug-related AEs 
should be followed until resolution unless none is expected.  New anti-cancer medications should be 
captured through completion of survival follow-up.  
Refer to Synopsis Table 1 for Schedule of Study Procedures. 


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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 PFS, and ORR.  
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 should be 
performed within 24 hours (a + 48hr window is allowed) of Ad-RTS-hIL-12 administration.  The 
Ad-RTS-hIL-12 injected lesion and/or other measurable brain lesions will be measured according to 
the iRANO criteria guidelines attached in Appendix 4.  MRI scans will be collected and stored at the 
study site and each subject will be evaluated for response by the study investigator.  Subjects should be 
imaged throughout the study using the same method(s) as were used for the screening and baseline 
MRIs.  Independent tumor response assessments, as well as posttreatment tumor biopsies, may occur 
as available and at the discretion of the investigator.  A repeat scan to confirm progression should be 
completed at 12 weeks (per iRANO) after first documentation of progression. Consideration should be 
given to performing a diagnostic brain biopsy, which should be performed in accordance with the 
current iRANO guidelines. 
Tumor response will be assessed both locally and at an independent central imaging lab using the 
iRANO criteria. Copies of all scans will be provided to the independent central imaging lab for 
determination of tumor response. Final progression determinations will be made by the independent 
central imaging lab. Every effort should be made to continue study therapy until disease progression is 
confirmed per iRANO criteria. In the instance that a subject is withdrawn from study treatment due to 
investigator determined progression, scans should be obtained and provided to the central imaging lab 
until disease progression is confirmed centrally. 
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 (SD). 
Tumor response assessments will occur at 8 weeks (Day 57 ± 3 days), and every 8 weeks thereafter for 
all subjects, including those who may have experienced a dose delay or missed a dose, until the 
occurrence of confirmed tumor progression, initiation of alternative therapy, or one year, whichever 
occurs first. 
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, treatment 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, the first tumor assessment MRI will be done on Day 57 (± 3 days).  Imaging assessments 
will be performed using iRANO criteria. 


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13.3. 
Central Imaging Reads 
An independent central imaging lab will review reported responses and progression events using 
iRANO criteria. An Imaging Charter will be developed to provide guidance and consistency. 
 


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14. 
SAFETY ASSESSMENTS 
The safety population will include all subjects who have received at least one dose of any of the 
investigational agents: cemiplimab-rwlc, Ad-RTS-hIL-12 or veledimex. 
14.1. 
Adverse Events and Definitions 
14.1.1. 
Adverse Event 
Any untoward medical occurrence associated with the use of a drug in humans, whether considered 
drug-related.  An AE can be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or 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. 
14.1.2. 
 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 less certainty about causality than an 
adverse reaction. 
14.1.3. 
 Adverse Reaction 
Any AE caused by 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. 
14.1.4. 
Unexpected Adverse Reaction 
Any AE that is (a) not listed in the Reference Safety Information (RSI) of 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 
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. 


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• If 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 unless the progression of disease is assessed by 
the investigator as related to the study treatments; however, the presenting sign or symptom 
of the disease progression should be documented as an AE (e.g., increase in pain). Death 
due to “progression of disease” within the SAE reporting period (from the signing of the 
ICF until 90 days after the last dose of any study treatments) should be reported as SAE. 
Adverse events will be followed from the next study until resolution or to the end of the follow-up 
period.  AEs that are 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 90 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. 
• 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. 
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. 


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14.4. 
 Determination of Severity 
The severity of AEs will be assessed according to the NCI CTCAE, Version 5.  If an AE is not 
specifically defined in the NCI CTCAE, v5.0, the investigator will determine the severity of an AE 
based on the following general definitions recommended (National Cancer Institute 2017): 
• 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 drugs based on his/her clinical judgment.  Assessment of causality will be based upon the 
following: 
• Alternative possible causes of the AE, including the subject’s underlying disease or 
comorbid conditions, other drugs, other host, and environmental factors 
• The temporal sequence between the exposure to study drug and the AE 
• Whether the clinical or laboratory manifestations of the AE are consistent with known 
actions or previously reported toxicity of the study drug or similar drugs 
• Whether the AE resolved or improved with decreasing the dose or stopping the study drug 
(i.e., dechallenge); or recurred or worsened with re-exposure to the drug (i.e., rechallenge). 
Relationship assessments that indicate “Not Related” to investigational product: 
• None:  The event is related to an etiology other than the investigational product (the 
alternative etiology must be documented in the study subject’s medical record and/or SAE 
form). 
• Unlikely or Remote:  The event is unlikely to be related to the investigational product and 
likely to be related to factors other than investigational product. 
Relationship assessments that indicate “Related” to investigational product: 
• Possible:  There is an association between the event and the administration of the 
investigational product and there is a plausible mechanism for the event to be related to 
investigational product; but there may also be alternative etiology, such as characteristics of 
the subject’s clinical status or underlying disease. 


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• Probable:  There is an association between the event and the administration of 
investigational product, a plausible mechanism for the event to be related to the 
investigational product and the event could not be reasonably explained by known 
characteristics of the subject’s clinical status or an alternative etiology is not apparent. 
• Definite:  There is an association between the event and the administration of 
investigational product, a plausible mechanism for the event to be related to the 
investigational product and causes other than the investigational product has been ruled out 
and/or the event re-appeared on re-exposure to the investigational product. 
For AEs that occur prior to the administration of investigational product, an assessment of protocol 
relatedness must be made.  AEs may occur due to procedures required during the screening process 
(e.g., blood collection, washout of an existing medication) prior to the initial administration of 
investigational product.  For AEs that occur before administration of investigational product, only 
those that are assessed by the investigator as protocol-related should be reported to the sponsor.  The 
following guidelines should be used by investigators to assess the relationship of an AE to a 
protocol-required procedure: 
• Protocol-related:  The event occurred due to a procedure or intervention that was described 
in the protocol for which there is no alternative etiology present in the subject’s medical 
record. 
• Not protocol-related:  The event is related to an etiology other than the study procedure (the 
alternative etiology must be documented in the study subject’s medical record). 
14.6. 
Documenting Adverse Events 
All AEs, including SAEs, are to be accurately recorded on the Adverse Event page of the subject’s 
eCRF from the time the subject signs the informed consent through 90 days after the subject’s last dose 
of any study drug.  Each event will be assessed for serious criteria, severity, and causality 
(Section 14.5). The date of onset, as well as the duration of the event will be recorded.  In addition, 
treatments provided to the subject, actions taken with the study drugs, and the outcome of the AE will 
also be noted. 
14.7. 
Reporting Serious Adverse Events (SAE), and Adverse Events of Special 
interest (AESI) 
14.7.1. 
Time Frame for Reporting 
All SAEs and AESIs must be reported to the sponsor or sponsor designee within 24 hours of 
awareness, regardless of initiation of new anticancer therapy including the following: 
• Any SAE or AESI experienced by the subject from the signing of informed consent to 
90 days after the last dose of any study drug, regardless of relationship to study drug. 
• Any SAE or AESI that the investigator becomes aware of, and believes to be study 
drug-related, that occurs more than 90 days after the subject last received study drug. 
 










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16. 
 STATISTICAL METHODS 
This is an uncontrolled single arm study to determine whether the intratumoral Adenovirus 
RheoSwitch Therapeutic System® (RTS) human interleukin-12 (Ad-RTS-hIL-12) and oral (PO) 
veledimex (RTS activator ligand) in combination with cemiplimab-rwlc (Libtayo®) is effective based 
on the estimate of Overall Survival (OS) when treating   subjects with recurrent or progressive 
glioblastoma. Where applicable, estimates of OS and other surrogate endpoints will be compared with 
well-matched historical control data to determine whether the estimates obtained in this study will be 
viewed as promising to support further development of this experimental combination of treatments. 
All populations for analyses and the types of analyses to be performed will be defined in more detail in 
the statistical analysis plan (SAP). 
16.1. 
Populations for Analysis 
• The safety population will comprise all subjects who have received any of the 
investigational agents: cemiplimab-rwlc, the injection of Ad-RTS-hIL-12 or any doses of 
veledimex 
• The per protocol population will comprise subjects who have received Day -7 of 
cemiplimab-rwlc, the injection of Ad-RTS-hIL-12 with at least one post IL-12 dose of 
veledimex, at least one post IL-12 dose of cemiplimab-rwlc (e.g., Day 15), and who have 
not had a major protocol violation 
• The biomarker-evaluable population will comprise subjects who have adequate biomarker 
sample(s) at screening (baseline) and at least one follow-up assessment 
16.2. 
Sample Size and Power Calculations 
We plan to accrue up to 30 subjects to obtain approximately 25 subjects evaluable for efficacy.  This 
patient population will be heterogeneous and as such, it is difficult to define a clear safety threshold for 
evaluation in combination with determination of OS, ORR and PFS.    
NOTE:  a minimum of 20 subjects undergoing subtotal resection will be required to ensure that 
sufficient subjects have measurable disease for evaluation of overall response rate per iRANO criteria.   
A sample size of up to 30, will allow us to estimate an overall safety rate with a maximum 95% exact 
confidence interval half-width of approximately 0.19. In addition, a Toxicity boundary based on 
repeated significance testing provides for a guideline to seriously consider stopping the trial if the 
number of subjects experiencing a grade 3 or grade 4 toxicity exceeds the proportions below assuming 
a 30% Toxicity rate is acceptable and 60% would be unacceptable:  
 Low boundary:   3/5   5/10   8/15   9/20   11/25    
 High boundary:   3/5   6/10   8/15   10/20   11/25 
The method for determination of the Toxicity boundary used the Toxbdry function in the Clinfun R 
package implementation of repeated significance testing methodology (Ivanova et al. 2005, Jennison 
and Turnbull 2000).  The operating characteristics of the boundary conditions will be specified in a 
separate statistical analysis plan (SAP). 
If the study continues to completion, a sample size of 25 to 30 subjects provides for an estimate of OS 
at a point in time with (at most) approximately 10% standard error of the estimate assuming the 
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The primary endpoint for evaluation of efficacy is: 
• the estimate of the OS which is performed by estimating the hazard rate based on the 
accrual and follow-up of all treated subjects.  
• The per protocol population will be followed from the first date of treatment up to 24 
months for overall survival. Estimates of the single arm hazard rate will be determined and 
compared with historical control estimates   
Secondary endpoints include:  
• In addition, the OS rate will be determined for 6, 12, 18 and 24 months using a binomial 
estimate of subjects surviving for at least the amount of time established by the cutpoint. 
• PFS, and rate of pseudo-progression (PSP) of Ad-RTS-hIL-12 + veledimex when 
administered in combination with cemiplimab-rwlc will be determined based on the 
investigator assessment 
• ORR of Ad-RTS-hIL-12 + veledimex when administered in combination with cemiplimab-
rwlc at 6, 12, 18 and 24 months will be determined based on an investigator assessment. 
16.6. 
Analyses 
16.6.1. 
Baseline Characteristics 
Demographic and baseline disease characteristic data will be summarized.  Data to be tabulated will 
include at least demographic features such as sex, age, and race, as well as disease-specific status and 
medical history. 
Categorical data will be summarized using counts and percentages for a particular category.  For 
continuous variables, the number of subjects with non-missing values, mean, median, standard 
deviation, minimum, and maximum values will be presented.    
16.6.2. 
Safety Analyses 
The safety population will be used to perform safety evaluations for all safety variables. 
Safety evaluations will be based on the incidence, intensity, and type of AEs and SAEs.  Clinically 
significant changes in the subjects’ physical examinations, vital signs, and ECG evaluations, and 
abnormal laboratory values will be captured as AEs.  Safety will also be assessed based on medical 
history and prior/concomitant medications. 
The safety evaluation period extends from the date the patient signs the ICF until 90 days after the last 
dose of study drug, unless the patient discontinues the trial due to one of the following reasons: 
• Documented progression 
• Symptomatic deterioration also denoted as 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 


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All treatment-emergent AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) and will be tabulated by number and percent of subjects, and according to relationship to 
the study drugs, severity, and seriousness.  Treatment-emergent is defined as any AE that occurs 
during or after administration of the first dose of study drug through the evaluation period for safety 
defined above, regardless of relationship to study drug; or any event that is present at baseline that 
worsens in intensity or is subsequently considered to be drug related by the investigator.  Deaths, 
SAEs, and AEs resulting in study discontinuation will be listed. 
Subjects who discontinue the trial as defined above will be followed for safety up to 90 days after 
discontinuation and until all safety events that have started during the safety evaluation period are 
classified as resolved or the end of the study is reached.  After the conclusion of the safety evaluation 
period is triggered by a discontinuation event, the subject continues to be followed only for OS. 
Listings of vital signs and physical examination data will be presented by visit. 
16.6.3. 
Overall Survival 
OS is defined as the duration of time from the first dose of study drug to the date of death or to the last 
follow-up contact date if the subject has not died, in which case the subject is censored if still alive up 
to 2 years from the first dose of study drug received. 
16.6.4. 
Tumor Response Analyses 
Investigator assessment of ORR and PFS will be determined according to iRANO criteria.  A 
two-sided confidence interval will be computed for the ORR.  PFS and OS will be estimated using the 
Kaplan-Meier method for appropriately-sized subject groups. 
Following completion of the study, best response will be determined for each subject in accordance 
with iRANO guidelines and the ORR will be presented for all subjects.  Where applicable, summary 
data of PFS, OS, and durability of response will be determined using Kaplan-Meier methodology; 
otherwise, a listing by-subject will display the data obtained.  Two-sided confidence intervals will be 
computed for the ORR.  Descriptive statistics will be performed for different patient populations. 
16.6.5. 
Multi-Center Study 
Tumor response and safety data will be presented over all study centers. 
16.6.6. 
Adjustments for Covariates 
No adjustments for covariates will be made. 
16.6.7. 
Procedures for Handling Missing, Unused, and Spurious Data 
No imputation of values for missing data will be performed.  Standard clinical monitoring and data 
management practices will be used to ensure the integrity of data. 
16.6.8. 
Procedures for Reporting Deviations to Original Statistical Analysis Plan 
A formal statistical plan for the analysis and presentation of data from this study will be prepared prior 
to database lock.  Deviations from the statistical analyses outlined in this protocol will be indicated in 
this plan; any further modifications will be noted in the final clinical study report. 


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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 to and sufficient training on the electronic data capture (EDC) application, to permit site 
personnel to enter or correct information in the eCRFs for the subjects for whom they are responsible. 
The eCRFs should be completed in a timely manner, and every effort should be made to have forms 
completed and up-to-date in anticipation of a visit by the sponsor’s monitor.  Specific instructions will 
be provided to the site.  All requested information must be entered on the eCRF in the spaces provided.  
If an item is not available or is not applicable, it should be documented as such; do not leave a space 
blank. 
It is the investigator’s responsibility to ensure the accuracy, completeness, clarity, and timeliness of the 
data reported in the subject’s eCRF.  Through the EDC application, the investigator must provide 
formal approval of all subject information in the eCRFs and changes to the eCRFs to endorse the final 
submitted data for the subjects for whom he/she is responsible.  The audit trail entry will show the 
user’s identification information and the date and time of any corrections. 
eCRF completion may be delegated to other study personnel; however, such delegation must be 
documented in writing.  If, for any reason, certain data are lacking to complete an individual report 
form, the investigator will provide a written statement explaining the reasons for the lack of data. 
Sponsor or designee will retain the eCRF data and corresponding audit trails.  A copy of the final 
archival eCRF in the form of a compact disk or other electronic media will be placed in the 
investigator’s study file. 
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. 
Sponsor Monitoring 
After satisfactory receipt of all necessary regulatory paperwork, the sponsor’s monitor will arrange that 
all study material be delivered to the study site at a mutually convenient time.  A site initiation visit 
(SIV) by Ziopharm and its monitoring personnel will be made.  At this meeting, all personnel expected 
to be involved in the conduct of the study will undergo an orientation to include review of study 
protocol, instruction for 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, and this 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 
source documents (e.g., hospital records, office records) will be made available for review by the 
Medical Monitor.  The monitor also will perform drug accountability checks and may periodically 
request review of the investigator’s study file to assure completeness of documentation in all respects 
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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 FDA. 
17.4. 
Duration of the Study 
The duration of this study from the time of initiating subject enrollment until the completion of 
survival follow-up is anticipated to be approximately 48 months, including 24 months for enrollment 
and 2 years of further follow-up. 
The overall duration is expected to be up to 2 years for an individual subject, including the following: 
• Screening period of up to 30 days prior to dosing with Ad-RTS-hIL-12 and veledimex 
• Initial Study treatment period of 3 weeks (Days -7 through 14) 
• Assessment of safety through the Follow-up Period 
• Assessment of tumor response at Day 57 (± 3 days), and every 2 months thereafter until the 
occurrence of confirmed tumor progression 
• Survival status through 2 years 
In addition, subjects who discontinue or complete study treatment without objective evidence of 
disease progression should continue to be followed until confirmed disease progression has been 
documented. Subjects will be followed for survival status for 2 years after enrollment, except for death 
or loss to follow-up.  The active study period refers to the study period from informed consent through 
the Initial 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 2 years following the date on which the test article is approved by 
FDA for marketing for the purposes that were investigated in the study.  If no application is to be filed 
or if the application is not approved for such indication, the records must be stored for two additional 
years and then returned to Ziopharm.  No records will be destroyed but will be indefinitely stored. 
17.6. 
Institutional Review Board/ Independent Ethics Committee 
This protocol and the study ICF must be reviewed and approved by the Institutional Biosafety 
Committee, where applicable, and IRB/IEC prior to the start of the study, and a copy of the approval 
letter supplied to Ziopharm.  During the study, the investigator shall make timely and accurate reports 
to the IRB/IEC on study progress at intervals not exceeding 1 year, as well as satisfying any other local 
IRB/IEC reporting regulations.  Copies of all reports to, and correspondence with, the IRB/IEC must 
be provided to Ziopharm.  Further, within 3 months of the completion or early termination of the study, 
a final report should be made to the IRB/IEC and Ziopharm by the investigator. 


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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 HIPAA 
The written ICF will explain that study data will be stored in a database, maintaining confidentiality in 
accordance with national data legislation.  All data processed by Ziopharm, or its representatives, will 
be identified by subject number and study code. 
The written ICF will also explain that, for data verification purposes, authorized representatives of 
Ziopharm, a regulatory authority (FDA), and/or the IRB/IEC may require direct access to parts of the 
hospital or clinic records relevant to the study that include the subject’s medical history. 
The written ICF will be accompanied by or include a separate document incorporating United States 
Health Insurance Portability and Accountability Act (HIPAA)-compliant wording by which the 
subjects authorize the use and disclosure of their Protected Health Information. 
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 should also indicate that, by signature, the prospective subject or, where 
appropriate, a legal guardian, permits access to relevant medical records by the sponsor and by 
representatives of the FDA.  If a prospective subject does not understand English, an appropriate 
translation into his or her primary language must be made available.  The investigator or designee will 
obtain written, informed, and witnessed consent.  The prospective subject will have ample time and 
opportunity to ask questions.  The prospective subject will be informed about the right to withdraw 
from the study at any time without any disadvantage and without having to provide a reason for this 
decision.  Following the discussion regarding the study, the prospective subject will be asked if he/she 
is willing to sign and personally date a statement of informed consent.  Only if the prospective subject 
voluntarily agrees to sign the informed consent statement and has done so, may he/she enroll into the 
study.  A copy of his/her signed and dated informed consent will be provided to each prospective 
subject.  The signed ICF is to remain in the investigator’s file. 
The ICF and any other written information provided to the subjects will be revised whenever important 
new information becomes available that may be relevant to the subject’s consent, or if there is an 
amendment to the protocol that necessitates a change to the content of the subject’s informed consent.  
The investigator will inform the subject of changes in a timely manner and will ask the subject to 
confirm continuation of his/her participation in the study by his/her signature on the revised ICF, if 
applicable.  Any written ICF and written information must receive IRB/IEC approval/favorable 
opinion in advance of use. 
17.8.2. 
Subject Informed Consent Form 
Ziopharm will provide a sample subject ICF for modification, as appropriate, by the investigator. 


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18. 
PROTOCOL APPROVAL PAGE 
A Phase II Study of Ad-RTS-hIL-12 + Veledimex in Combination with Cemiplimab-rwlc 
(Libtayo) in Subjects with Recurrent or Progressive Glioblastoma  
Except for a change intended to eliminate an immediate hazard to subjects, the study shall be 
conducted as described in the approved protocol.  All deviations from the protocol will be documented 
in the eCRF.  Any significant deviation or deviation related to dosing or safety evaluation will be 
reported to Ziopharm and documented in the eCRF. 
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: 
_____________________________________ 
 
Date:   
_____________________________________ 
 
 










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20. 
APPENDICES 


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APPENDIX 1. ZIOPHARM CYTOKINE RELEASE SYNDROME WORKING 
DEFINITION - AD-RTS-HIL-12 + VELEDIMEX (VERSION 3, 
07 JANUARY 2019) 
Cytokine release syndrome (CRS) is a multi-faceted immune disorder presenting clinically as a multi-system disorder. Elevated 
cytokine levels support the diagnosis of CRS in Ad-RTS-hIL-12 gene therapy study along with the grading criteria below:  
Grade 1 
Symptoms that are not life threatening and require symptomatic treatment only, e.g. (any of the following): 
 
General 
Influenza-like illness (flu-like symptoms): fever (temperature of 100°F [37.8°C] or 
greater) and fatigue, malaise, or myalgia 
 
 
Neurological 
Grade 1 headache 
 
 
 
Grade 1 decreased level of consciousness (e.g. somnolence, drowsiness, lethargy, 
disorientation) 
 
 
GI 
Grade 1 nausea or vomiting 
Grade 2 
Symptoms that require and respond to moderate interventions and occurrence of any of the following: 
 
1. 
Hypotension responsive to fluids or single, low dose vasopressor 
 
2. 
Oxygen requirement < 40%  
 
3. 
Grade 3 transaminitis (ALT/AST), lymphopenia, or Grade 2 organ toxicities, e.g.:  
 
 
Hematologic  
Grade 2 neutropenia, or platelets decrease/thrombocytopenia  
 
 
Renal 
Grade 2 creatinine increase 
 
4. 
Other symptoms, e.g.: 
 
 
General 
Grade 3 fever  
 
 
Neurological 
Grade 2 decreased level of consciousness (e.g., slow response to stimuli; limiting 
instrumental activities of daily living)  
 
 
 
Grade 2 or 3 headache 
 
 
GI 
Grade 2 nausea or vomiting  
Grade 3 
Symptoms that require and respond to aggressive interventions and occurrence of any of the following: 
 
1. 
Hypotension requiring high dose or multiple vasopressors 
 
2. 
Oxygen requirement ≥ 40% 
 
3. 
Grade 4 transaminitis (ALT/AST), lymphopenia, or Grade 3 organ toxicities, e.g.:  
                     Hematologic              ≥Grade 3 febrile neutropenia, or platelets decrease/thrombocytopenia  
                     Renal                        Grade 3 creatinine increase 
                     Cardiac                     Grade 3 arrhythmia, or acute heart failure 
                     Pulmonary                Grade 3 pulmonary edema, or dyspnea 
4. 
Other symptoms, e.g.: 
 
 
Neurological 
Grade 3 decreased level of consciousness (e.g. difficult to arouse) 
 
 
 
Aseptic meningitis 
 
 
GI 
Grade 3 nausea or vomiting 
Grade 4 
Life-threatening symptoms and occurrence of any of the following: 
 
1. Requirement for ventilator support 
 
2. Grade 4 organ toxicities (excluding lymphopenia and asymptotic elevated transaminitis), e.g.: 
 
 
Renal 
Renal failure and dialysis indicated 
 
 
Cardiac 
Cardiac arrest 
 
 
Pulmonary 
Respiratory failure 
 
 
Neurological 
Coma 
Grade 5 
Death 
 
 


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APPENDIX 2. RECOMMENDED REGIMEN FOR ANTIPYRETIC AND/OR 
ANALGESIC PROPHYLAXIS 
Recombinant adenoviral vectors have the potential to elicit potent cellular and humoral immune 
responses. While the mechanism responsible for these effects is poorly understood, transient low-grade 
fevers are common after systemic rAD vector administration* and temperatures up to 104° F with 
chills and generalized malaise have been observed with treatment. Because low-grade fever is very 
likely to occur, prophylaxis with acetaminophen is strongly recommended. 
Each site should follow its institutional protocol for the administration of acetaminophen. 
Acetaminophen is available without a prescription in 325 mg or 500 mg tablets. Common brand names 
of acetaminophen include Aspirin Free Anacin®, FeverAll®, Genapap®, Mapap®, NeoPAP®, 
Panadol®, Tempra®, and Tylenol®. 
In general, fever can be adequately prophylaxed or treated with acetaminophen.  If a fever occurs 
despite prophylactic medication or does not respond to usual doses of acetaminophen, then a 
combination of both acetaminophen and ibuprofen may be considered.  Alternating doses of ibuprofen 
with acetaminophen may effectively control fever while preventing accidental overdose of 
acetaminophen.  Acetaminophen is typically effective for controlling central fevers whereas ibuprofen 
is more potent as a peripheral analgesic/ anti-inflammatory medication.  Ibuprofen is available without 
a prescription at a dosage of 200 mg and by prescription in 400, 600 or 800 mg tablets or capsules. 
Common brand names of ibuprofen include Advil®, ElixSure®, Ibuprom®, Ibutab®, Motrin® and 
Tab-Profen®. 
Adverse events are uncommon although may be serious as some individuals are allergic to these 
medications.  Additionally, overdoses of acetaminophen may cause liver failure. Therefore, subjects 
with liver disease and chronic alcohol users should avoid acetaminophen.  Ibuprofen is excreted by the 
kidneys so should be avoided in patients with renal insufficiency, though most would be excluded from 
enrollment.  High dose ibuprofen also may increase the risk of blood clots, stroke, heart attack, and 
gastrointestinal bleeding, and being a potent anti-inflammatory agent could reduce the efficacy of the 
investigational controlled IL-12 therapy. 
 
 


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APPENDIX 3. PROHIBITED ENZYME-INDUCING AND NON-
ENZYME-INDUCING ANTIEPILEPTIC DRUGS 
Enzyme-inducing Antiepileptic Drugs 
Non-Enzyme-inducing Antiepileptic Drugs 
Cerebyx® (fosphenytoin) 
 
 
Zarontin® (ethosuximide) 
ONFI® (clobazam) 
 
Dilantin® (phenytoin) 
Gabitril® (tiagabine) 
Luminal®, Solfoton® (phenobarbital) 
Nembutal® (pentobarbital) 
Trileptal® (oxacarbazepine) 
Tegretol® (carbamazepine) 
Topamax® (topiramate) 
 
 
 
 


Ad-RTS-hIL-12 + veledimex 
 
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Original Protocol ATI001-204 (07 February 2019) 
 
 
Confidential 
 
Page 85 of 85 
APPENDIX 4. 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 

SAP_001.pdf: 




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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..................................................................................................... - 8 - 
1. 
INTRODUCTION ...................................................................................................... 10 
2. 
OBJECTIVES ............................................................................................................. 11 
3. 
INVESTIGATIONAL PLAN ..................................................................................... 12 
3.1. 
Study Design and Plan ................................................................................................ 12 
3.2. 
Stopping Rules ............................................................................................................ 12 
3.3. 
Study Endpoints .......................................................................................................... 13 
3.3.1. 
Primary Endpoint ........................................................................................................ 13 
3.3.2. 
Secondary Endpoints................................................................................................... 13 
3.4. 
Treatments ................................................................................................................... 13 
3.5. 
Dose Adjustment/Modifications .................................................................................. 14 
3.6. 
Inclusion and Exclusion Criteria ................................................................................. 14 
4. 
STATISTICAL METHODS ....................................................................................... 15 
4.1. 
Sample Size ................................................................................................................. 15 
4.2. 
Randomization, Stratification, and Blinding ............................................................... 16 
4.3. 
Interim Analyses ......................................................................................................... 16 
4.4. 
Data Management ....................................................................................................... 16 
4.4.1. 
Locking the Database .................................................................................................. 17 
4.5. 
Populations for Analysis ............................................................................................. 17 
4.5.1. 
Screened for eligibility and not treated: (Screen Failures) .......................................... 17 
4.5.2. 
Full Analysis Set (FAS) .............................................................................................. 18 
4.5.3. 
Per Protocol (PP) ......................................................................................................... 18 
4.5.4. 
Evaluable Safety Population (ESP) ............................................................................. 18 
 
 
4.5.6. 
Completers .................................................................................................................. 18 
4.6. 
General Statistical Considerations .............................................................................. 18 
4.7. 
Data Presentation Conventions ................................................................................... 19 
4.7.1. 
Overview of Statistical Summaries by Defined Populations ...................................... 20 
4.7.2. 
Protocol Deviations ..................................................................................................... 20 
4.7.3. 
Relevant Protocol Deviations (RPD) .......................................................................... 21 
5. 
SUBJECT DISPOSITION .......................................................................................... 22 


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5.1. 
Disposition: Subjects Screened and not treated with any experimental study 
treatment......................................................................................................................22 
5.2. 
Disposition: The FAS Population ...............................................................................22 
6. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ..................................24 
6.1. 
Demographics .............................................................................................................24 
6.2. 
Baseline Disease Characteristics .................................................................................24 
6.3. 
Alcohol, Tobacco and Caffeine Usage ........................................................................25 
6.4. 
Medical History ..........................................................................................................25 
6.4.1. 
General Medical History .............................................................................................25 
6.4.2. 
Disease-Specific History .............................................................................................25 
7. 
TREATMENTS AND MEDICATIONS ....................................................................26 
7.1. 
Prior and Concomitant Medications ............................................................................26 
7.1.1. 
Prior Medications ........................................................................................................27 
7.1.2. 
Concomitant Medications ...........................................................................................27 
7.2. 
Study Treatments ........................................................................................................27 
7.2.1. 
Extent of Exposure ......................................................................................................27 
7.2.1.1. 
Ad-RTS-hIL-12 ...........................................................................................................27 
7.2.1.2. 
Veledimex ...................................................................................................................27 
7.2.1.3. 
Cemiplimab and Veledimex, Duration of Exposure ...................................................28 
7.2.2. 
Treatment Compliance and Modifications ..................................................................28 
8. 
EFFICACY ANALYSIS .............................................................................................29 
8.1. 
Primary Efficacy Endpoint ..........................................................................................29 
8.2. 
Primary Analysis for OS .............................................................................................29 
8.2.1. 
Assumption Testing ....................................................................................................29 
8.2.2. 
Exploratory Analyses for OS ......................................................................................30 
8.2.3. 
Estimation of OS using Parametric Survival Assumptions for S(t) ............................31 
8.3. 
Secondary Efficacy Endpoints ....................................................................................31 
8.3.1. 
The OS rate at fixed timepoints 6, 12, 18 and 24 months ...........................................31 
8.3.2. 
Overall PFS and PFS rate at fixed timepoints 6, 12, 18 and 24 months .....................31 
8.3.3. 
Objective Response Rate (ORR) at 6, 12, 18 and 24 months .....................................32 
8.3.4. 
Tumor Response Rate .................................................................................................32 
8.3.5. 
Best Overall Response (BOR) ....................................................................................32 






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LIST OF TABLES 
 
 
Table 2: 
List of Relevant Protocol Deviations ..........................................................................21 
 
LIST OF FIGURES 
Figure 1: 
Patient Disposition for Protocol Defined Populations ................................................23 


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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Transaminase 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Transaminase 
BMI 
Body Mass Index 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CD 
Cluster of Differentiation 
CI 
Confidence Interval 
CR 
Complete Response 
CRF 
Case Report Form 
CRP 
C-Reactive Protein 
CTLA-4 
Cytotoxic T Lymphocyte-Associated Antigen 
ECG 
Electrocardiogram 
ESR 
Erythrocyte Sedimentation Rate 
GBM 
Glioblastoma 
HEENT 
Head, Eyes, Ears, Nose, And Throat 
hIL-12 
Human Interleukin-12 
ICF 
Informed Consent Form 
IFN-γ 
Interferon Gamma 
IL 
Interleukin 
INR 
International Normalized Ratio 
IP-10 
Interferon Gamma-Induced Protein 10 
iRANO 
Immunotherapy Response Assessment for Neuro Oncology 
IV 
Intravenous(Ly) 
LDH 
Lactate Dehydrogenase 
MCV 
Mean Corpuscular Volume 
MedDRA Medical Dictionary for Regulatory Activities 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PFS 
Progression-Free Survival 
PO 
Oral(Ly) 


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PP 
Per Protocol 
PR 
Partial Response 
PSP 
Pseudo-Progression 
PT 
Preferred Term 
PT 
Prothrombin Time 
PTT 
Partial Prothrombin Time 
Q3W 
Every 3 Weeks 
QD 
Each Day 
RBC 
Red Blood Cell 
RTS 
Rheoswitch Therapeutic System® 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SOC 
System Organ Class 
SRC 
Safety Review Committee 
TCR 
Tumor T Cell Receptor 
TEAE 
Treatment-Emergent Adverse Events 
WBC 
Including White Blood Cell 
WFNOS 
World Federation of Neuro-Oncology Societies 


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1. 
INTRODUCTION 
This Statistical Analysis Plan (SAP) describes the proposed statistical analyses in concert with 
Ziopharm Protocol ATI001-204 Amendment 2 entitled: A Phase II Study of Ad-RTS-hIL-12 + 
Veledimex in Combination with Cemiplimab(Libtayo®) in Subjects with Recurrent or 
Progressive Glioblastoma. 
Importantly, and where applicable, all references pertaining to the protocol in this SAP are meant 
to imply “contains a more detailed explanation of the statistical analyses” in the Protocol 
ATI001-204 Amendment 2. 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. 
Glioblastomas are by far the most frequent malignant glioma and are associated with a 
particularly aggressive course and dismal prognosis (Lieberman, 2017). Standard of care 
treatment for glioblastomas is based on surgical resection with the intent to remove as much of 
the tumor as is feasible (Fernandes et al., 2017; Paolillo, Boselli, & Schinelli, 2018). Resection 
is then followed by radiotherapy and concomitant adjuvant temozolomide. However, such 
aggressive treatment is associated with only modest improvements in survival. Newly diagnosed 
glioblastoma subjects have a median overall survival (OS) of 12 to 15 months (Ahmed, Oborski, 
Hwang, Lieberman, & Mountz, 2014) and 2-year OS rate of up to 27% (Omuro & DeAngelis, 
2013), while OS in subjects that have failed TMZ and bevacizumab, or equivalent salvage 
chemotherapy, is reported as being as short as 3 to 5 months (Iwamoto et al., 2009; Omuro & 
DeAngelis, 2013). To date, no salvage treatment has been validated by Phase III data for 
recurrent or progressive glioblastoma. For subjects with recurrent glioblastoma, the median OS 
is 6 to 7 months (Omuro & DeAngelis, 2013), and median progression-free survival (PFS) is 2 to 
3 months. 
Please refer to the finalized protocol and its amendments to follow the plan as originally 
envisioned. 
Protocol Chronology 
• Amendment 2: 08Jan2020 
• Amendment 1: 09May2019 
• Original: 07Feb2019 


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2. 
OBJECTIVES 
Primary Objective 
• To determine the safety and efficacy of intratumoral 
 
(Ad-RTS-hIL-12) and oral (PO) 
veledimex (RTS activator ligand) in combination with cemiplimab(Libtayo®) when 
treating subjects with recurrent or progressive glioblastoma. This determination will 
be based on the drug safety profile in combination with the estimate of Overall 
Survival (OS), representing the potential clinical efficacy for which late-stage clinical 
trials may be planned based on the estimates obtained. 
Secondary Objectives 
• To determine the survival rates at 6, 12, 18 and 24 months 
• To determine the progression free survival (PFS), and rate of pseudo-progression 
(PSP) at 6, 12, 18 and 24 months 
• To determine the Investigator’s assessment of response, including tumor objective 
response rate (ORR) at 6, 12, 18 and 24 months 
• To determine the tumor response rates at 6, 12, 18 and 24 months 
 
 


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3. 
INVESTIGATIONAL PLAN 
3.1. 
Study Design and Plan 
This is  multicenter Phase II uncontrolled study of an intratumoral injection of Ad-RTS-hIL-12 
 
 and veledimex (20 mg) administered PO in combination with 
cemiplimab (350 mg) administered intravenously (IV) in subjects with recurrent or progressive 
glioblastoma. 
This study includes a Screening Period, Treatment Period, and Survival Follow-up. After the 
informed consent form (ICF) is signed, subjects will enter the Screening Period to be assessed 
for eligibility. 
A detailed account of the study procedures is illustrated in ATI001-204 Protocol Amendment-2 
Section 12 Table 1 Schedule of Study Procedures. 
3.2. 
Stopping Rules 
The stopping rules of the study are portrayed in section 10.9 of the Protocol. Specifically from 
Day -7 to 30 days after completion of Ad-RTS-hIL12 + veledimex dosing, Subject stopping rules 
criteria were defined along the lines of the following: 
• If any subject experienced a death (other than death related to progressive disease). 
• If any subject, during the initial treatment period (Day -7 to Day 28) experiences a 
related SAE that has immediately life-threatening consequences requiring urgent 
intervention or: 
− Results in death; 
− Requires major operative intervention; 
− Or is a related grade 4 hematologic toxicity that persists for 5 days: 
If any of the above occurred, then enrollment of new subjects will be paused, pending review of 
the event by the Safety Review Committee. 
A formal Safety Review Committee (SRC) was to be comprised of the study Investigators and 
the Medical Monitor. The SRC was to evaluate whether to recommend if changes to the 
enrollment of additional subjects should be modified, after its review of an event(s) described 
above including, but not limited to, 
• Potentially modifying the dose and schedule of veledimex. 
• To amend the protocol prior to enrollment of additional subjects, or, 
• To discontinue enrollment in the study. 
Section 10.10 of the protocol enumerates dose modification and dose delay specifications 
according to the criteria shown in Table 2. 
Concomitant therapy described in section 11 of the protocol, conveys permitted and prohibited 
medications/therapies. 




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given on Day 1. Subsequent veledimex doses are to be taken once daily, in the 
morning and within approximately 30 minutes of a regular meal. The first 
veledimex dose following Ad-RTS-hIL-12 injection is expected to be 
administered when the subject is at the clinical site, under careful medical 
supervision by the clinic staff to ensure that the subject does not have difficulty 
swallowing the capsules. 
− Thereafter, subjects may be allowed to self-administer the remaining once daily 
doses as described. Subjects are to be instructed to take the appropriate number of 
capsules in the same way for each of the remaining treatment period days and 
may be reminded to do so by phone on non-visit days. 
− Subjects should NOT make up any missed doses. 
− Subjects should be instructed to document veledimex dosing compliance in a 
subject diary, including the time subject took the once daily dose, the time subject 
ate breakfast, the number of capsules taken, whether subject missed any 
veledimex doses, and the study day and reason for any missed doses. Study drug 
container(s) with any remaining capsules should be returned to the study staff on 
Day 15, so that staff can properly assess dose compliance. 
3.5. 
Dose Adjustment/Modifications 
After the first six patients have been enrolled and administered Ad-RTS-hIL-12 and veledimex 
in combination with at least one post Ad-RTS-hIL-12 dose of cemiplimab, enrollment will be 
paused to allow for additional safety follow-up and assessment. The SRC will review safety data 
after the 6th subject has reached Day 28 and decide if enrollment should occur at the same dose 
and schedule of the investigational products. 
Veledimex and cemiplimab dose delays and dose reductions for individual subjects will be 
allowed in the event of an adverse event, according to the criteria specified in protocol section 
10.10. 
3.6. 
Inclusion and Exclusion Criteria 
The details of Inclusion and Exclusion criteria are listed in Section 9.1 and 9.2 of the protocol. 
All inclusion/exclusion information on safety patients will be included in a by-patient listing. For 
patients who did not satisfy these criteria, the criteria numbers will be listed with the deviation. 
The key change to the inclusion criteria depicted in amendment 2 was that multifocal disease 
was not prohibited; although, subjects must not have more than 5 enhancing lesions. 


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4. 
STATISTICAL METHODS 
4.1. 
Sample Size 
Sample Size and Power Calculations 
Based on Amendment 2, the plan was updated to accrue up to 36 subjects instead of 30 subjects 
(originally planned) to obtain approximately 25 subjects evaluable for efficacy. 
A sample size of up to 25, will allow us to estimate an overall safety rate with a maximum 95% 
exact confidence interval half-width of approximately 0.19. 
In addition, a Toxicity boundary based on repeated significance testing provided for a guideline 
to seriously consider stopping the trial if the number of subjects experiencing unacceptable 
toxicity exceeded the proportions below. The method for determination of the Toxicity boundary 
used the Toxbdry function in the Clinfun R package implementation of repeated significance 
testing methodology (Ivanova, Qaqish, & Schell, 2005). 
Low boundary: 3/5, 5/10, 8/15, 9/20, 11/25 
High boundary: 3/5, 6/10, 8/15, 10/20, 11/25 
The boundaries above were created assuming a 30% Toxicity rate is acceptable and 60% would 
be unacceptable. According to boundary conditions stated herein, a review was to be performed 
if applicable, after 5, 10, 15, 20 and 25 subjects reach Day 30. Serious consideration for stopping 
the clinical trial should be given if the number of subjects meeting the Stopping Rules criteria is 
determined to be greater than 3/5, 5/10, 8/15, 9/20, or 11/25, the values which form the lower 
boundary condition. The operating characteristics of the boundary conditions are calculated and 
displayed below. 
Operating Characteristics: 
 
Prob 
toxicity 
Prob 
Cross. 
lower 
Prob 
Stop 
lower 
Expected 
Sample 
Size lo 
Prob 
Cross. 
Hi bound 
Prob 
Stop 
hi 
Expected 
Sample 
Size hi 
0.30 
0.101 
0.090 
23.8 
0.074 
0.050 
24.2 
0.36 
0.239 
0.205 
22.3 
0.193 
0.122 
23.2 
0.42 
0.441 
0.377 
20.2 
0.388 
0.248 
21.6 
0.48 
0.661 
0.578 
17.5 
0.617 
0.426 
19.3 
0.54 
0.839 
0.763 
14.6 
0.812 
0.625 
16.5 
0.60 
0.943 
0.894 
11.9 
0.932 
0.800 
13.6 
 
This patient population will be heterogeneous and as such, it is difficult to define a clear safety 
threshold for evaluation in combination with determination of OS, ORR and PFS. 
Assuming the binomial estimation method, if the study continues to completion, a sample size of 
25 to 30 subjects provides for an estimate of OS at a point in time with approximately 10% 
standard error of the estimate. 




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• For completeness it is noted that there are subjects who also have data in the database 
who are classified as screen failures for whom we are not counting for the purpose of 
this description. Subjects that were enrolled but did not receive treatment were 
withdrawn and will not be included in any analysis population. 
• A summary of the number of screen failures signing an informed consent is provided 
in the subject disposition. 
• Extraction of Raw SAS datasets from the EDC database will be converted into Study 
Data Tabulation Model (SDTM) SAS datasets based on CDISC. 
 
 
 
4.4.1. 
Locking the Database 
Preparation for locking the ATI001-204 clinical database will occur when all subjects (n=40) 
have been reviewed and it has been established that there are no outstanding queries to be 
resolved. 
4.5. 
Populations for Analysis 
4.5.1. 
Screened for eligibility and not treated: (Screen Failures) 
Screen Failures are subjects who signed an informed consent and subsequently: 
• Did not meet the eligibility criteria of the protocol, or, 




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Subjects will be identified in the listings by the subject identification number concatenated with 
the investigator number. 
When count data are presented, the percentage will be suppressed when the count is zero to draw 
attention to the non-zero counts. A row denoted “Missing” will be included in count tabulations 
where specified on the shells to account for dropouts and missing values. The denominator for all 
percentages will be the number of subjects in that treatment within the analysis set of interest, 
unless otherwise specified. 
Unless otherwise specified, baseline will be defined as the last non-missing evaluation prior to 
the first dose of treatment (any of the Ad-RTS-hIL-12, veledimex and cemiplimab) is taken. The 
study day will be calculated as assessment date - first dose date + 1. 
All analyses will be conducted using SAS Version 9.4 or higher. 
All data are summarized based on the visit name collected on the CRF page. 
4.7. 
Data Presentation Conventions 
The presentation of summary statistics and the conventions for preparing data listings for 
combining the data for all treated FAS subjects (n=40) are described along the lines of what 
follows: 
• Unless otherwise specified, baseline is the last observation before the first study drug 
administration. (See section on data handling conventions for more details.) The 
baseline lesion assessment is considered within 72 hours following Ad-RTS-hIL-12 
injection. 
• Unless otherwise specified, percentages will be calculated based on the number of 
patients based on non-missing data as the denominator. 
• A missing values category will also be defined to ensure all subjects are 
accounted for in prespecified populations for analyses. 
• In analyses presented over time by visit, no imputations will be performed on missing 
data. All analyses will be based on the observed data. 
• The effective sample sizes at each assessment visit will be based on the total 
number of subjects with non-missing data for the parameter of interest at that 
visit. 
• When applicable, additional derived variables will be created based on 
specifications with or without protocol deviations and violations to assess the 
comparability and the influence of such deviations. Summary statistics will be 
provided for continuous variables (e.g., age). 
o Unless otherwise stated, this will consist of the number of subjects with a non- 
missing value of the variable (n), mean, standard deviation, median, minimum 
and maximum. 
• The same number of decimal places as in the raw data will be presented when 
reporting the minimum and the maximum summary statistics, 
o One more decimal place than in the raw data will be presented when reporting 
the mean, and the median. 


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o Two more decimal places than in the raw data will be presented when 
reporting the standard deviation. 
• Frequency counts will be provided for categorical variables (e.g., gender). 
o Unless otherwise stated, this will consist of the number of subjects with a 
response in a particular category and the percentage of the total number of 
subjects in that column. 
o Unless otherwise stated, categories for missing responses will be included in 
both the display and in the calculation of percentages (i.e., they will be 
included in the denominator). 
o Percentages will be rounded to one decimal place. 
o Percents equal to 100 will be presented as 100% and percents will not be 
presented for zero frequencies. 
4.7.1. 
Overview of Statistical Summaries by Defined Populations 
Subject populations will be evaluated and used for presentation and analysis of the following: 
• The FAS will be used for summaries of subject disposition, baseline characteristics 
and for safety. In addition, the FAS will be used in secondary analyses of OS, ORR, 
and PFS. 
• The PP population is to be used for the primary analysis of OS, ORR, PFS and OS. 
• When applicable the ESP will be used for analysis of dose limiting toxicities. 
• 
. 
4.7.2. 
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. In general, no 
subject was planned to be removed from any analysis population because of a protocol 
deviation. 
In accordance with ICH E3, patient eligibility violations and important post- treatment protocol 
deviations will be identified and listed by patient 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. 
• Deviation from inclusion/exclusion criteria. 
• Withdrawal criteria met during the study, but subject was not withdrawn. 
• Prohibited concomitant medications. 
• Treatment deviation. 
• Other protocol deviation. 


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All protocol deviations will be categorized as either major or minor. The list of protocol 
deviations along with whether the deviation is classified denoting a major or minor 
categorization will be finalized prior to database lock. 
Major protocol deviations will be presented in a summary table by protocol deviation category 
for the FAS. Protocol deviations will be presented in a listing. 
4.7.3. 
Relevant Protocol Deviations (RPD) 
Originally, relevant deviations from the study protocol were to be documented and accounted for 
in presenting the data listings and descriptive statistical analyses. Any changes from planned 
protocol-specified analyses were to be defined in the SAP and reported in the CSR. Instead, 
protocol deviations will not be produced by Biostatistics. Instead, protocol deviations will be 
described with an in-text table as applicable in the final CSR. The relevant protocol deviations 
are described in the Table 2 below. 
Table 2: 
List of Relevant Protocol Deviations 
 
Number 
RPD Criteria 
1 
Poor treatment compliance for either cemiplimab or veledimex (less than 80% of expected 
total dose of either treatment) 
2 
Taking prohibited concomitant medication including CYP3A4 inhibitor 
3 
Others 


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5. 
SUBJECT DISPOSITION 
5.1. 
Disposition: Subjects Screened and not treated with any 
experimental study treatment 
Subjects screened for study eligibility for whom experimental study treatment was not received 
regardless of the reason will be denoted as Screen Failures. The number of subjects screened and 
not treated is reported as part of the subject disposition and nowhere else. These subjects are not 
included in any study listings or analyses and are not part of the study population for whom the 
results of the study are reported. 
5.2. 
Disposition: The FAS Population 
After displaying the number of subjects screened and not treated, the subject disposition presents 
the number of subjects in the FAS population as the starting point. All percentages will be based 
on the number of FAS subjects. Subsequently the table illustrates: 
• The number and percent of subjects who: 
− Complete the study, 
− Discontinue from the study by reason for treatment discontinuation and study 
discontinuation. 
• Subjects who discontinued from veledimex. 
• Subjects who discontinued from cemiplimab. 
• The number and percentage of subjects in each analysis population: 
− PP population and 
 
. 
− If applicable, important protocol deviations will be summarized and listed. 
• A summary of the subjects excluded from the PP population and the reasons for 
exclusion. 
− Patients could be excluded from the PP population for more than one reason. 


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Full Analysis Set (FAS) Population 
N=40 
Per Protocol (PP) Population 
Treated and Compliant with 
Protocol (cemi only 462-047) 
N=39 
Treated but had one or more Major 
Protocol Deviations: 
Ineligible 
Replaced 
Not compliant with Treatment 
specified in Protocol 
Missing key data 
Other 
Screened Population 
Patients who signed informed 
consent and evaluated for eligibility. 
N=47 
Per Protocol Population 
Eligible, Treated, No Major 
protocol Deviation 
Figure 1: 
Patient Disposition for Protocol Defined Populations 
 
 


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6. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
6.1. 
Demographics 
A summary of demographics and baseline information will be presented. The demographic 
characteristics consist of age (years), sex, race, and ethnicity. The baseline characteristics consist 
of baseline height (cm) and baseline body mass index (BMI) (kg/m^2). Body mass index is 
calculated as (body weight in kilograms)/(height in meters)2. 
Age (years), baseline height (unit), and baseline BMI (kg/m^2) will be summarized using 
descriptive statistics. The number and percentage of sex (Male, Female), race (White, African 
American, Asian, American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, 
Unknown and Other) and ethnicity (Hispanic or Latino, Not Hispanic or Latino and Unknown), 
will also be reported. Percentages will be based on the total number of subjects in the FAS. 
Age is taken to be the subject's age on the date of the Screening visit. Conversions for height 
and weight are as follows: 
• Height (cm) = Height (inches) x 2.54 
• Weight (kg) = Weight (lb) x 0.454 
Demographics will be listed and tabulated using descriptive statistics. 
Subject demographic and baseline characteristics will be presented in a listing. 
6.2. 
Baseline Disease Characteristics 
Subject’s baseline disease characteristics will be summarized according to the conventions 
described previously for descriptive statistics of continuous and categorical variables. In 
addition, baseline characteristics will be transformed into subject characteristic grouping 
variables for further exploration of the FAS illustrated below. 
• Age category 
<65 vs ≥65 
• Gender 
Female vs Male 
• MGMT 
unmethylated vs methylated 
• Hispanic or Latino 
yes =1 vs no=0 
• Race 
White vs not White 
• IDH 
wild-type vs mutated 


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• Prior Steroid use > four weeks before day -7 
yes=1 vs no=0 
• Enhanced Lesion 
unifocal vs Multifocal 
• Number of Lesions at Entry 
1 vs > 1 
• KPS Screening, N(%) 
≥70 to 90 vs ≥90 
6.3. 
Alcohol, Tobacco and Caffeine Usage 
Not Applicable 
6.4. 
Medical History 
6.4.1. 
General Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 23.0. The number and percentage of subjects with any medical history will be 
summarized overall and for each system organ class and preferred term. Percentages will be 
calculated based on number of subjects in the FAS. 
Subject medical history data including specific details will be presented in a listing. 
6.4.2. 
Disease-Specific History 
Disease specific history will consist of initial disease status, grade at initial diagnosis, initial 
MGMT gene promoter status and initial IDH status. Disease specific history will be summarized 
by frequency count and percentage based on FAS population. 
Subject disease-specific history data including specific details will be presented in a listing. 


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7. 
TREATMENTS AND MEDICATIONS 
7.1. 
Prior and Concomitant Medications 
Verbatim terms on case report forms will be mapped to Anatomical/Therapeutic/Chemical 
(ATC) class and Generic Drug Names using the World Health Organization Drug Dictionary 
(WHO-DD V5). 
• Prior medications are defined as medications with a stop date occurring before the 
first dose of treatment (any of the Ad-RTS-hIL-12, veledimex and cemiplimab) is 
taken. 
• Concomitant medications are those medications taken after the initial dose of study 
drug. Concomitant medications are defined as medications that are ongoing on the 
first dose date, or with a start date missing or occurring on or after the first dose date. 
• 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 90 days 
after the subject’s last dose of any study drug. 
For inclusion in prior and/or concomitant medication tables, incomplete medication start and 
stop dates will be imputed as follows: 
Missing start dates (where UK, UKN and UNKN indicate unknown or missing day, month and 
year respectively): 
• UK-MMM-YYYY: If the month and year are different from the month and year of 
the first dose of study drug, assume 01-MMM-YYYY. If the month and year are the 
same as the first dose of study drug month and year and the end date (after any 
imputation) is on or after the first dose of study drug, then assume the date of the first 
dose of study drug. If the month and year are the same as the first dose of study drug 
month and year and the end date (after any imputation) is prior to the first dose of 
study drug, then assume the end date for the start date. 
• DD-UKN-YYYY/UK-UKN-YYYY: If the year is different from the year of the first 
dose of study drug, assume 01-JAN-YYYY of the collected year. If the year is the 
same as the first dose of study drug year and the end date (after any imputation) is on 
or after the first dose of study drug, then assume the date of the first dose of study 
drug. If the year is the same as the first dose of study drug and the end date (after any 
imputation) is prior to the first dose of study drug, then assume the end date for the 
start date. 
Missing stop dates (where UK, UKN and UNKN indicate unknown or missing day, month and 
year respectively): 
• UK-MMM-YYYY: Assume the last day of the month. 
• DD-UKN-YYYY/UK-UKN-YYYY: Assume 31-DEC-YYYY. 
If start date is completely missing and end date is not prior to the first dose, then the medication 
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end date is within 28 days prior to the first dose of study drug, then the medication will be 
classified as prior. If the end date is missing, then the medication will be classified as ongoing. 
Medications for which the start and end dates are missing will be classified as prior and 
concomitant. 
7.1.1. 
Prior Medications 
The total number of prior medications and the number and percentages of subjects with at least 
one prior medication will be summarized. The number and percentages of all prior medications 
will be summarized and listed by drug class and preferred term. All summaries will be performed 
using the FAS. 
7.1.2. 
Concomitant Medications 
The total number of concomitant medications and the number and percentages of subjects with at 
least one concomitant medication will be summarized. The number and percentages of all 
concomitant medications will be summarized and listed by drug class and preferred term. All 
summaries will be performed using the FAS. 
7.2. 
Study Treatments 
For Ad-RTS-hIL-12, cemiplimab and veledimex, separate summaries will be provided for details 
in administration using descriptive statistics based on FAS. All administration details will be 
presented in a listing. 
7.2.1. 
Extent of Exposure 
Details of study drug administration and dose modifications will be listed as follows. 
7.2.1.1. 
Ad-RTS-hIL-12 
Total volume received, number of sites and whether the dose was modified will be tabulated. 
7.2.1.2. 
Veledimex 
The total dose received (mg) for each study treatment will be calculated based on the Drug 
Accountability CRFs including the oral dosing diaries. Dosing details are summarized per 
subjects for each dosing cohort. Dose and dose modifications per subject treated will be listed. 
The number of doses received will be tabulated. 
Subject veledimex dosing compliance will be determined for each subject as the total number of 
tablets dispensed minus the total number of tablets reported as not taken, divided by the total 
number of tablets dispensed, multiplied by 100. 
• Subgroups for dosing compliance may be explored (e.g. compare subgroup of 
subjects who are 100% (80%) dosing compliant with subgroup of subjects <100% 
(<80%) dosing compliant). 
• Extent of exposure will not be calculated for Ad-RTS-hIL-12 as it will be 
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7.2.1.3. 
Cemiplimab and Veledimex, Duration of Exposure 
For cemiplimab and veledimex, duration of exposure is defined as the total number of days a 
subject is exposed to any study drug and will be presented as the total number of days from the 
first dose date (Day -7 for cemiplimab and Day 0 for veledimex) to the last dose date (date of last 
dose minus the date of first dose + 1) as recorded on the End of Treatment page on the CRF. If 
the last dose date on the End of Treatment page is missing, or if a subject is lost to follow-up, but 
the drug accountability log confirms that the subject has taken study drug, the visit date 
following the last completed drug accountability log will be used. 
• The duration of exposure to study drug will be summarized for cemiplimab and 
veledimex for all subjects in the FAS. 
• The total dose for each study drug will be summarized for cemiplimab and veledimex 
for all subjects in the FAS. 
• A summary of each subject’s exposure will be presented in a listing. 
7.2.2. 
Treatment Compliance and Modifications 
For Ad-RTS-hIL-12 and cemiplimab, the number and proportion of subjects receiving treatment 
will be summarized at each scheduled dosing visit. 
For veledimex, compliance will be calculated for each subject by making the determination 
whether a subject takes all doses of study drug as instructed. The number of capsules taken will 
be calculated by subtracting the number of capsules returned from the number of capsules 
dispensed. The overall study drug compliance (%) will be calculated by dividing the total 
number of capsules taken during subject’s study period by the total number of capsules expected 
to be received based on the schedule of events and then multiplying by 100. 
Compliance (%) = [(total no. of capsules dispensed – total no. of capsules returned) / (No. of 
days in interval *No. of capsules prescribed per day)] * 100. 
Summary statistics on percentage of veledimex compliance as well as the number and percentage 
of subjects in each compliance category (<80%, 80-100% compliant) will be presented overall. 
A subject is considered compliant to veledimex if overall study drug compliance is greater than 
or equal to 80%. A categorical summary of whether subjects were compliant (yes/no) will be 
presented. 
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8. 
EFFICACY ANALYSIS 
No formal hypothesis testing will be performed for primary and secondary endpoints. Estimates 
of the single arm will be determined and will be compared numerically with historical control 
estimates, wherever applicable. 
Observed data will be presented over all study centers. No imputation of values for missing data 
will be performed. 
In general, all estimates will be calculated considering two-sided 5% level of significance. No 
adjustments for covariates will be made. 
• See Section 10 of this document for all changes to originally preplanned efficacy 
analyses. 
8.1. 
Primary Efficacy Endpoint 
The primary endpoint for evaluation of efficacy is the OS hazard rate which is performed by 
estimating the hazard rate based on the accrual and follow-up of all treated subjects. Subjects 
will be followed from the first date of treatment up to 2 years for overall survival. 
OS is defined as the duration of time from the first dose of study drug (i.e., cemiplimab at Day - 
7) to the date of death from any cause. Censoring will be considered as below: 
• Subjects who discontinue study will be censored at date of discontinuation. 
• Subjects who are lost to follow-up will be censored at last follow-up contact date. 
• If the subject has not died, the subject is censored if still alive up to 2 years from the 
first dose of study drug received. 
All summaries and analyses for the primary efficacy endpoint will be based on per-protocol 
population. 
8.2. 
Primary Analysis for OS 
The primary analysis for estimating the hazard rate for the time to OS denoted as the function 
S(t) will be performed on the PP population using the Kaplan Meier (KM) Product-Limit 
estimation method. A secondary analysis will also be implemented for the FAS. Using the KM 
method: 
• The median survival time along with the 95% Confidence Interval (CI) will be 
constructed. 
• The 25Th and 75th quartile of survival time will also be provided supplemented by the 
Kaplan-Meier plot of OS. 
8.2.1. 
Assumption Testing 
No assumption check is planned for the Kaplan-Meier method. 




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Number of Lesions at Entry 
• 1 vs > 1 
KPS Screening, N (%) 
• ≥70 to 90 vs ≥90 
veledimex Dosing Compliance 
• <100% (<80%) vs 100% (≥80%) 
8.2.3. 
Estimation of OS using Parametric Survival Assumptions for S(t) 
In addition to estimating S(t) based on the KM method, S(t) will be estimated under the 
assumption that S(t) is Weibull distributed for shape and scale parameters to be explored. 
8.3. 
Secondary Efficacy Endpoints 
All secondary endpoint determination related to tumor assessment is based on the investigator 
assessment. If applicable an independent review committee (IRC) will also perform tumor 
response and tumor progression assessments based on the methods of tumor assessment defined 
in the IRC charter. Secondary endpoints for estimation include: 
8.3.1. 
The OS rate at fixed timepoints 6, 12, 18 and 24 months 
• OS rates will be derived from the KM estimate along with the corresponding two- 
sided 95% CI estimated using Greenwood’s formula for the variance and the log-log 
transformation applied to the survivor function S(t) 
8.3.2. 
Overall PFS and PFS rate at fixed timepoints 6, 12, 18 and 24 months 
• Overall PFS and the PFS rate of pseudo-progression (PSP) will also be estimated. at 
month 6, 12, 18 and 24 with corresponding 95% confidence interval (CI). 
PFS is defined as the duration of time from the first dose of study drug (i.e., cemiplimab at Day - 
7) to the confirmed progression (as determined by immunotherapy Response Assessment for 
Neuro Oncology (iRANO) criteria) or death from any cause, whichever occurs first. Censoring 
will be considered as below: 
• Subjects who discontinue study without any event will be censored at date of 
discontinuation. 
• Subjects who are lost to follow-up without any event will be censored at last follow- 
up contact date. 
• If the subject has no progression or not died, the subject is censored if still alive up to 
2 years from the first dose of study drug received. 
The time to PFS will be estimated on the PP population using the Kaplan Meier (KM) Product- 
Limit estimation method. The median PFS will be summarized along with corresponding 95% 
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Pseudo-progression (PSP) 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, treatment 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. 
Number and proportion of subjects with PSP will be summarized with corresponding two-sided 
95% confidence interval (CI). 
8.3.3. 
Objective Response Rate (ORR) at 6, 12, 18 and 24 months 
The ORR, determined according to Recist 1.1 confirmed response criteria instead of iRANO 
criteria will be summarized at month 6, 12, 18 and 24 with corresponding two-sided 95% 
confidence interval (CI). 
8.3.4. 
Tumor Response Rate 
• Determination of tumor response will be performed on each subject in the PP 
population. 
• The Tumor response rate of Ad-RTS-hIL-12 + veledimex when administered in 
combination with cemiplimab will be estimated at 6, 12, 18 and 24 months. 
• Tumor response will be 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 bi-dimensional tumor size as per Recist 1.1 criteria. In 
addition, changes in neurologic function and steroid use will be considered to 
determine stable disease (SD). 
8.3.5. 
Best Overall Response (BOR) 
The BOR was not originally included in the protocol and has been added as a new secondary 
endpoint. The BOR will be determined for each subject based on the applicable tumor 
assessment results for both the investigator and the IRC. 
The best overall response (BOR) is a derived variable that summarizes for each treated subject 
the best tumor response recorded on the eCRF based on the investigator assessment. 
• Tumor response data collected before evidence that the subject received a new 
anticancer treatment. 
The BOR categories are defined as: 
• Complete Response 
• Partial Response 
• Stable Disease 
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9. 
SAFETY ANALYSIS 
All analyses of safety will be conducted using the FAS. Abnormal laboratory test results, will be 
captured as Adverse Events (AE)s. Safety evaluations will use calculations to determine 
estimates of the incidence, intensity, and the type of AE and SAE’s based on preferred term 
coding. 
All clinical findings will be further inspected through a clinical review of relevant parameters 
including AEs, serious adverse events (SAEs), laboratory values (hematology, serum chemistry, 
and urinalysis), body weight, vital signs, physical examinations, and ECOG performance status. 
Where applicable the Safety will also be summarized using the ESP. Exposure to study drug and 
reasons for discontinuation of study treatment will be tabulated. 
9.1. 
Adverse Events 
9.1.1. 
Treatment-Emergent Adverse Effects (TEAE)s 
The primary presentation of AE’s will be prepared without regard to causality or relationship to 
study treatment. In addition, summaries of all TEAEs, treatment-related TEAEs and of all SAEs 
will be tabulated by System Organ Class (SOC), Preferred Term (PT), and Common 
Terminology Criteria for Adverse Events (CTCAE) grade of TEAE. 
A TEAE is defined as an AE that meets any of the following conditions: 
• Begins on or after the first dose of study drug and before the stop of study drug + 90 
days. 
• Begins before the first dose of study drug and worsens in severity on or after the first 
dose of study drug and before the stop of study drug + 90 days. 
• Is completely missing an onset date and an end date. 
• Is completely missing an onset date and the end date is on or after the first dose of 
study drug. 
Verbatim terms captured on the eCRF will be mapped to PTs and SOC using the Medical 
Dictionary for Regulatory Activities (MedDRA®) Version 23.0 or higher for purposes of TEAE 
summarization. 
9.1.2. 
Incomplete Onset or end date Imputation Conventions 
If the onset date or the end date of an AE is incomplete, the following conventions for date 
imputation of the AE onset and end dates will be applied. 
Missing onset dates (where UK and UKN indicate unknown or missing day and month 
respectively): 
• UK-MMM-YYYY: If the month and year are different from the month and year of 
the first dose of study drug, assume 01-MMM-YYYY. If the month and year are the 
same as the first dose of study drug month and year, and the end date (after any 
imputation) is on or after the first dose of study drug, then assume the date of the first 
dose of study drug. If the month and year are the same as the first dose of study drug 


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month, and year and the end date (after any imputation) is prior to the first dose of 
study drug, then assume the end date for the onset date. 
• DD-UKN-YYYY/UK-UKN-YYYY: If the year is different from the year of first 
dose of study drug, assume 01-JAN-YYYY of the collected year. If the year is the 
same as the first dose of study drug year, and the end date (after any imputation) is on 
or after the first dose of study drug, then assume the date of the first dose of study 
drug. If the year is the same as the first dose of study drug, and the end date (after any 
imputation) is prior to the first dose of study drug, then assume the end date for the 
onset date. 
Missing end dates (where UK and UKN indicate unknown or missing day and month 
respectively): 
• UK-MMM-YYYY: Assume the last day of the month. 
• DD-UKN-YYYY/UK-UKN-YYYY: Assume 31-DEC-YYYY. 
9.1.3. 
Incidence of Adverse Events 
An overview summary of the number and percentage of subjects with any TEAE, serious TEAE, 
study drug-related TEAE, study drug-related serious TEAE, TEAE leading to treatment 
discontinuation, TEAE leading to study termination, and AE leading to death will be presented. 
Summaries of the total number of TEAEs and the number and percentage of subjects with at 
least one TEAE will be provided. The number and percentage of subjects and the number of 
events will also be presented by SOC and PT. At each level of summarization, a subject is 
counted once if the subject reported one or more events. Percentages will be calculated out of the 
number of subjects in the FAS. The number of events at each level of SOC and PT will also be 
summarized. 
A summary of TEAEs will also be presented in descending order from the SOC with the highest 
total incidence to the SOC with the lowest total incidence. If the total incidence for any two or 
more SOCs is equal, the SOCs will be presented in alphabetical order. Within each SOC, the PTs 
will be presented in alphabetical order. 
All AEs will be provided in subject listings. 
9.1.4. 
Relationship of Adverse Events to Study Drug 
A summary of TEAEs by relationship (i.e., “Related” and “Not Related”) to Ad-RTS-hIL-12 + 
veledimex and cemiplimab will be presented separately in a table by incidence of occurrence. 
The investigator will provide an assessment of the relationship of the event to the study drug. 
The possible relationships are “Not Related”, “Unlikely”, “Possible”, “Probable”, and 
“Definite”. In the TEAE relationship table, if a subject reports multiple occurrences of the same 
TEAE, only the most closely related occurrence will be presented. TEAEs that are missing a 
relationship or with a relationship other than “Not Related” or “Unlikely” will be presented in 
the summary table as “Related” but will be presented in the data listing with a missing 
relationship or the actual relationship respectively. Percentages will be calculated out of the 
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As described in Section 9.1.1 , the TEAE data will be categorized and presented by SOC, PT, 
and relationship. 
9.1.5. 
Severity of Adverse Event 
A summary of TEAEs by severity will be presented in a table. The severity that will be presented 
represents the most extreme severity captured on the case report form (CRF) page. The possible 
severities are “Mild,” “Moderate”, “Severe”, “Life-threatening” and “Death”. In the TEAE 
severity table, if a subject reported multiple occurrences of the same TEAE, only the most severe 
level will be presented. TEAEs that are missing severity will be presented in tables as “Severe” 
but will be presented in the data listing with a missing severity. Percentages will be calculated 
out of the number of subjects in the FAS. 
The TEAE data will be categorized and presented by SOC, PT, and severity, similar to that 
described in Section 9.1.1 . 
9.1.6. 
Serious Adverse Events 
The seriousness of an AE should be assessed by the investigator independently from the severity 
of the AE. An AE is considered a serious adverse event (SAE) if at least one of the following 
conditions applies: 
• Death: An AE that results in death during the active study period or within 90 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. 
• 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 that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based upon medical judgment, they 


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may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed above. 
SAEs will be presented in a table. Treatment-emergent SAEs by relationship to study drug will 
be presented in a table. A treatment-related treatment-emergent SAE is a treatment-emergent 
SAE with any relation to study drug other than “Not Related” or “Unlikely”. Treatment- 
emergent SAEs that are missing a relationship will be presented in the table as “Related” but will 
be presented in the data listing with a missing relationship. At each level of subject 
summarization, a subject is counted once if the subject reported one or more events. Percentages 
will be calculated out of the number of subjects in the FAS. 
The treatment-emergent SAE data will be categorized and presented by SOC and PT, similar to 
that described in Section 9.1.1. 
9.1.7. 
Adverse Events Leading to Treatment Discontinuation 
A summary of TEAEs with a study drug action taken of “Drug Withdrawn” will be presented in 
a table separately for Ad-RTS-hIL-12, veledimex and cemiplimab. At each level of subject 
summarization, a subject is counted once if the subject reported one or more events. Percentages 
will be calculated out of the number of subjects in the FAS within the subgroup category. 
The summary of TEAEs with a study drug action taken of “Drug Withdrawn” will also be 
presented in descending order of frequency from the SOC with the highest total incidence to the 
SOC with the lowest total incidence. Within each SOC, the PTs will be presented in alphabetical 
order. 
9.1.8. 
Death 
A summary of AEs where the answer to “Outcome” is “Fatal” will be presented in a table. At 
each level of subject summarization, a subject is counted once if the subject reported one or more 
events. Percentages will be calculated based on the FAS. 
The summary of AEs where the answer to “Outcome” is “Fatal” will also be presented in 
descending order of frequency from the SOC with the highest incidence to the SOC with the 
lowest incidence. Within each SOC, the PTs will be presented in alphabetical order. 
All subjects who have an AE with an outcome of “Fatal” will be presented in a listing. The 
listing will include the primary cause of death and the number of days elapsed between (day -7) 
and death. 
9.2. 
Clinical Laboratory Evaluations 
Laboratory assessments will be performed by a central laboratory. All summaries will be based 
on the units provided by the central laboratory, no conversion will be done. 
Summary tables will be presented for clinical laboratory tests with numeric values for subjects in 
the FAS. Observed results at each visit will be presented. 
All relevant clinical laboratory tests will be classified as Low, Normal, and High, or 
Normal/Abnormal according to the normal ranges. This categorical data will be summarized in 
shift tables comparing the results at each scheduled post-baseline visit with those at the baseline 
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Summary Listings for vital sign data include: 
• the observed results for each scheduled visit. 
• the change from baseline for each scheduled post-baseline visit. for: 
− systolic blood pressure (mmHg), diastolic blood pressure (mmHg), temperature 
(°C), pulse (bpm), respiration (breaths/minute) and weight for subjects in the 
FAS. 
See variables under Section 10.6 under Section 10 describing the changes to the planned 
analysis. 
9.4. 
Physical and Neurological Examination 
Originally, all physical and neurological examination data by patient were planned for data 
summarization along the lines of the following. In general, 
• Physical examination data were to be provided in patient listings. 
• Results of the targeted neurological exam were also to be listed and summarized. 
• Clinically significant abnormalities that are identified during physical examinations 
were to be reported as adverse events. 
• The disposition of each physical examination (whether performed or not) and the date 
the physical examination was performed was to be provided in individual patient 
listings. 
A table was being planned to produce a summary of the physical examination results for the 
FAS. Each visit captures the status of a body system and any finding associated with the body 
system as normal, abnormal, or not done. The summary was planned to include the number and 
percentage of subjects with each physical examination outcome for the following body systems: 
skin, head, eyes, ears, nose, and throat (HEENT), respiratory, cardiovascular, gastrointestinal, 
endocrine/metabolic, genitourinary, neurological, blood/lymphatic, musculoskeletal and other. 
Physical examination results for all subjects were also planned for presentation in listings. 
See variables under Section 10.6 , a subsection under Section 10 describing the changes to the 
planned analysis. 
9.5. 
Electrocardiogram 
Originally, electrocardiogram data by patient were planned for data summarization along the 
lines of the following. All subjects were to have a standard 12-lead electrocardiogram (ECG) 
performed during the study as clinically indicated. QT intervals were to be corrected according 
to the Bazett and Fridericia's formula. For summarization, results were to be converted into 
Bazett’s correction. Electrocardiogram data for all subjects were to be presented in a listing. 
The ECG interpretations was to be summarized in shift tables comparing the ECG values of each 
post-baseline visit with the value at the baseline visit for the FAS. In addition, the worst post- 
baseline ECG value was to be compared with the value at the baseline visit (with worst of all 
being Abnormal Clinically Significant and best being Normal). 


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Summary tables presenting observed values and changes from baseline were to be presented for 
heart rate (bpm), PR Interval (msec), RR Interval (msec), QRS Duration (msec), QT Interval 
(msec), QTcB Interval (msec) for subjects in the FAS. Changes from baseline to each scheduled 
post-baseline visit will be presented. 
See variables under Section 10.6 a subsection under Section 10 describing the changes to the 
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11. 
GENERAL METHODS FOR PERFORMING STATISTICAL 
ANALYSES AND DATA HANDLING CONVENTIONS 
The data conventions for preparing applicable tables and data listings for combining the data for 
all treated FAS subjects (n=40) are as follows: 
11.1. 
Missing Data 
• No imputations for missing or partial data will be made 
• In analyses presented over time by visit, no imputations will be performed on missing 
data. 
• All analyses will be based on observed data only without protocol deviations and 
violations. 
• The effective sample sizes at each assessment visit will be based on the total number 
of subjects with non-missing data for the parameter of interest at that visit. 
Unless otherwise specified, 
• percentages will be calculated based on the number of patients with non-missing data 
as the denominator. 
• A missing values category will also be defined to ensure all subjects are accounted for 
in prespecified populations for analyses 
• In general, other than for partial dates, missing data will not be imputed and will be 
treated as missing. 
The algorithms for imputation of partial dates vary depending on the parameter. These will be 
provided in the programming specifications that will be prepared for this study. 
When applicable, unless otherwise specified, the following general imputation rules will be used 
for a missing date in the assessment of an event: 
• If all parts of the date are missing, the date will not be imputed. 
• In the case where only the start day of an event is missing, it will be replaced by the 
start day of study treatment if the event occurs in the same month and year. 
Otherwise, it will be replaced by the first of the month. 
• If the stop day is missing, the stop day of the event will be replaced by the stop day of 
study treatment. Otherwise, the last day of the month will be used to replace the 
missing stop day. 
• If both the start day and month of an event are missing, the start day and month will 
be replaced by the start day and month of study treatment if the event and the start of 
the treatment occur in the same year; otherwise, it will be replaced by 1st of January. 
• All imputed dates must be prior to the dates of withdrawal of consent, lost to follow- 
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11.2. 
Baseline Data 
• Unless otherwise specified, baseline is the last observation before the first study drug 
administration. 
• The baseline lesion assessment is considered to be the one within 72 hours following 
Ad-RTS-hIL-12 administration. 
• If the schedule of events includes a baseline value (i.e. Day -7) lab just before study 
drug administration) that is not collected as planned for any reason, then the data 
collected for the variable known to be the last observation before the first dose of 
study drug will serve as the baseline value. 
• In addition, the relevant section for each endpoint will describe the baseline values of 
subjects recorded as taken before study treatment according to schedule along with 
subjects for whom measurements should have been taken before study treatment but 
for whom those measurements were taken after study dosing was received. 
11.3. 
Change from baseline 
• Change from baseline is performed for Serum Chemistry, Hematology, Urinalysis, 
Vital Signs, ECG Results and the Karnofsky Performance Status (KPS) Score. 
11.4. 
Measurements Collected Excluded from Predefined Analysis 
• Populations or extra measurements that were repeated or obtained based on 
unscheduled visits may not be included in summary tables unless specified. 
• Regardless of data inclusion for any analysis 
− Subject Listings will present all available data received in the electronic CRF 
(eCRF) 
− Where applicable subject listings will also present all final data received from 
data sources for which data external to the eCRF were captured for which data 
transfer agreement specifications were established. 
11.5. 
Derived and Computed Variables 
• Day 0 corresponds to the date of Ad-RTS-hIL-12 administration. 
• Then more generally, Day n represents the elapsed number of days from Day 0, 
inclusive. 
• Day n = Date of assessment – Date of Day 0. 
• Unless otherwise specified, the timing of all study-related events, assessments, and 
interventions will be calculated relative to Day 0. Day −1 will be the day before Day 
0, and in general, negative days will be measured backwards starting from Day −1. 
• Day -7 corresponds to the first dosing date of subjects treated with Ad-RTS-hIL-12 
and cemiplimab. 


ATI001-204 
Statistical Analysis Plan 
Ziopharm Oncology 
Version 1.0 
45 
 
 
• 1 year = 365.25 days. Year is calculated as (days / 365.25) and will be rounded up to 
1 significant digit for purposes of presentation. 
• 1 month = 30.4375 days. Month is calculated as (days / 30.4375) and will be rounded 
up to 1 significant digit for purposes of presentation. 
• Age will be calculated in years relative to the date of informed consent based on the 
following SAS statement: Age = floor ((intck(‘month’, date of birth, date of informed 
consent) – (day (informed consent) < day (date of birth))) / 12 (Check with LLX and 
Ziopharm Programming) 
• 1 pound = 0.454 kg 
• 1 inch = 2.54 cm 
• Pregnancy test data will be listed only. 
11.6. 
Continuous Variables 
• Summary statistics will be provided for continuous variables (e.g., age). 
• Unless otherwise stated, summary statistics will report: 
− The number of subjects with a non-missing value of the variable (n), mean, 
standard deviation, median, minimum, and maximum. 
− The same number of decimal places as in the raw data will be presented when 
reporting minimum and maximum 
− One more decimal place than in the raw data will be presented when reporting 
mean and median 
− Two more decimal places than in the raw data will be presented when reporting 
standard deviation. 
11.7. 
Categorical Variables 
• Frequency counts will be provided for categorical variables (e.g., gender). 
• Unless otherwise stated, frequency statistics will consist of the number of subjects 
with a response in a particular category and the percentage of the total number of 
subjects in that column. 
• Unless otherwise stated, missing responses will be included in both the display and in 
the calculation of percentages (i.e., they will be included in the denominator). 
• Percentages will be rounded to one decimal place. 
• Percentages equal to 100 will be presented as 100% and percentages will not be 
presented for zero frequencies. 


ATI001-204 
Statistical Analysis Plan 
Ziopharm Oncology 
Version 1.0 
46 
 
 
11.8. 
Visit Windows Derived and Computed Variables Observed Cases 
and Last Observation Carried Forward, Missing Data and Outliers 
• The statistical analysis planned for this study will be performed according to the 
actual visit dates and times and do not require the calculation of visit windows. 
• However, for analyses that require a particular visit as planned, measurements 
included in that visit must have occurred during the acceptable window defined for 
the visit in the protocol, unless otherwise specified in this plan. 
• As needed, visit windows will also be created for analysis, to include data collected at 
unscheduled visits. 
• Visit windows will apply to all treatment arms. 
− When multiple visits occur within the same window, the visit closest to the target 
visit day will be selected. 
− When two visits are equidistant from the target day, the visit occurring latest in 
the window will be used for analysis. 
11.9. 
Statistical Programming Conventions and Considerations 
• SAS version 9.4 or higher will be utilized for all data analyses, summary tables, 
subject listings and figures. 
• Derived datasets are also created using (SAS®) software unless specified otherwise. 
• The definition of all derived variables and decodes for coded data must appear in the 
notes. 
• Due to space limitations, tables and listings may require a page of notes as a one-time 
preface to the output. 
• In general, summary tables and listings (e.g., post text tables and individual subject 
data listings) include a “footer” providing explanatory notes that indicate at a 
minimum: 
− Date of data extraction 
− Date of output generation 
− SAS complete program name, and path where it is stored including the path that 
generates the output 
− Any other output specific details that require further elaboration (e.g. CRF pages 
from which the data were obtained) 
− Post text tables also include reference(s) to the subject data listing(s) that supports 
the summary data. The data extraction date links the output to the archived 
database that is locked to ensure the replication of the results. 


ATI001-204 
Statistical Analysis Plan 
Ziopharm Oncology 
Version 1.0 
47 
 
 
• In general, the listings should be sorted and presented by treatment assignment, 
investigational site, and subject number. Treatment assignment and site can appear in 
the banner of the listing. 
− From left to right, the subject number, visit number, visit date, and relative day 
should appear. 
− When applicable, the data management tools and methods used in the processing 
of the data should be mentioned. The SOP dictating the data storage, data transfer, 
and data cleaning process should be stated. 
11.10. 
Appendices to Distinguish Between Original and Revised ATI001- 
204 for TLF’s 
Statistical considerations were implemented in support of producing an abbreviated study 
report which led to a modification to the originally planned TLF specifications. 
The modifications to the originally planned TLF specifications are described in the excel 
spreadsheet, “ATI001-204 Final TLF Shells”. 
• The Table of Contents (first tab of spreadsheet) describing the “Original ATI001-204 
TLFs” has been extracted from the spreadsheet and is displayed in Appendix 1. 
• The Table of Contents (second tab of spreadsheet) describing the “Revised ATI001- 
204 TLFs” has been extracted from the spreadsheet and is displayed in Appendix 2. 


ATI001-204 
Statistical Analysis Plan 
Ziopharm Oncology 
Version 1.0 
48 
 
 
12. 
REFERENCES 
 
Ahmed, R., Oborski, M. J., Hwang, M., Lieberman, F. S., & Mountz, J. M. (2014). Malignant 
gliomas: current perspectives in diagnosis, treatment, and early response assessment using 
advanced quantitative imaging methods. Cancer Management and Research, 6, 149-170. 
Fernandes, C., Costa, A., Osorio, L., Lago, P., Linhares, B., & Carvalho and Caeiro, C. (2017). 
Current Standards of Care in Glioblastoma Therapy. Glioblastoma, 197-241. 
doi:http://dx.doi.org/10.15586/codon.glioblastoma.2017.ch11 
Ivanova, A., Qaqish, B., & Schell, M. (2005). Continuous Toxicity Monitoring in Phase II Trials 
in Oncology. Biometrics, 61, 540-545. 
Iwamoto, F. M., Abrey, L. E., Beal, K., Gutin, P. H., Rosenblum, M. K., Reuter, V. E., . . . 
Lassman, A. B. (2009). Patterns of relapse and prognosis after bevacizumab failure in 
recurrent gliobastoma. Neurology, 73, 1200-1206. 
Lieberman, F. (2017). Glioblastoma update: molecular biology, diagnosis, treatment, response 
assessment, and translational clinical trials (version 1; referees: 2 approved). 
F1000Research, 1892, 1-8. 
Omuro, A., & DeAngelis, L. M. (2013). Glioblastoma and Other Malignant Gliomas: A Clinical 
Review. Journal of the American Medical Association, 310(17), 1842-1850. 
Paolillo, M., Boselli, C., & Schinelli, S. (2018). Glioblastoma under Siege: An Overview of 
Current Therapeutic Strategies. Brain Sciences, 8(15). doi:10.3390/brainsci8010015 


ATI001-204 
Statistical Analysis Plan 
Ziopharm Oncology 
Version 1.0 
49 
 
 
13. 
APPENDICES 
 
APPENDIX 1: ORIGINAL ATI001-204 TLFS 
APPENDIX 2: REVISED ATI001-204 TLFS 




ATI001-204 Final TFL Shells.xlsx 
 
Table 14.3.6.7 
Summary of Urinalysis Results 
Full Analysis Population 
Lab 
Table 14.3.6.8 
Clinical Significance of Urinalysis Results 
Full Analysis Population 
Lab2 
Table 14.3.7 
Summary of KPS 
Full Analysis Population 
KPS 
Table 14.3.8 
Summary of Vital Signs 
Full Analysis Population 
Vitals 
Table 14.3.9 
Summary of Weight 
Full Analysis Population 
Weight 
Table 14.3.10 
Targeted Neurological Exam 
Full Analysis Population 
Neuro 
Table 14.3.11 
ECG Findings 
Full Analysis Population 
ECG1 
Table 14.3.12 
Summary of ECG Results 
Full Analysis Population 
ECG2 
Table 14.3.13 
Dose Limiting Toxicities 
Per Protocol Population 
DLT 
Figure 14.2.3 
Kaplan Meier plot of Progression Free Survival by Veledimex Dose 
Figure 14.2.4 
Kaplan Meier plot of Overall Survival by Veledimex Dose 
Figure 14.2.5 
Kaplan Meier plot of Progression Free Survival by Group 
Figure 14.2.6 
Kaplan Meier plot of Overall Survival by Group 
Figure 14.2.7 
Forest Plot 
Per Protocol Population 
FPLT 
Listing 16.2.1 
Subject Disposition 
Full Analysis Population 
L Disp 
Listing 16.2.3.1 
Eligibility 
Full Analysis Population 
L Elig 
Listing 16.2.3.2 
Subject Population 
Full Analysis Population 
L Pop 
Listing 16.2.2 
Protocol Deviations 
Full Analysis Population 
L Dev 
Listing 16.2.4.1 
Demography and Baseline Characteristics 
Full Analysis Population 
L Demo 
Listing 16.2.4.2 
Medical and Surgical History 
Full Analysis Population 
L Mhx 
Listing 16.2.4.3 
High Grade Glioma Diagnosis 
Full Analysis Population 
L Hgg 
Listing 16.2.4.4 
Prior Cancer Treatment 
Full Analysis Population 
L_PriCnt 
Listing 16.2.4.5 
Previous Medications 
Full Analysis Population 
L Conm 
Listing 16.2.4.6 
Concomitant Medications 
Full Analysis Population 
L Conm 
Listing 16.2.4.7 
Corticosteroid Dosage 
Full Analysis Population 
L CDD 
Listing 16.2.4.8 
Post Treatment Anti-Cancer Therapy 
Full Analysis Population 
L PostCnt 
Listing 16.2.4.9 
Concurrent Medical Procedures 
Full Analysis Population 
L Npmed 
Listing 16.2.5.1 
Ad-RTS-hIL-12 Injection 
Full Analysis Population 
L DS1 
Listing 16.2.5.2 
Veledimex Capsule Diary 
Full Analysis Population 
L DS2 
Listing 16.2.5.3 
Veledimex Dose Modification 
Full Analysis Population 
L DS3 
Listing 16.2.6.1 
Pre-Baseline Lesion Assessment 
Full Analysis Population 
L Pbla 
Listing 16.2.6.2 
Assessment of Target Lesions 
Full Analysis Population 
L Tar 
Listing 16.2.6.3 
Assessment of Non-Target Lesions 
Full Analysis Population 
L NTar 
Enhancing Non Measurable Lesions 
Full Analysis Population 
L Enh 
Listing 16.2.6.4 
Non-Enhancing Lesions 
Full Analysis Population 
L Nenh 
Listing 16.2.6.5 
Evaluation of Overall Response 
Full Analysis Population 
L Tovr 
Listing 16.2.7.7 
Dose Limiting Toxicities 
Full Analysis Population 
L Dlt 
Listing 16.2.7.1 
Adverse Events 
Full Analysis Population 
L Ae 
Listing 16.2.7.2 
Treatment Emergent Adverse Events 
Full Analysis Population 
L Ae 
Listing 16.2.7.3 
Serious Adverse Events 
Full Analysis Population 
L Ae 
Listing 16.2.7.4 
TEAEs leading to Study Drug Dose Modification 
Full Analysis Population 
Listing 16.2.7.5 
TEAEs leading to Study Discontinuation 
Full Analysis Population 
L Ae 
Listing 16.2.7.6 
TEAEs with CTCAE Toxicity Grade ≥ 3 
Full Analysis Population 
Listing 16.2.7.8 
Deaths 
Overall Safety Population 
L Deat 
Listing 16.2.6.6 
Survival 
Full Analysis Population 
L Surv 
Listing 16.2.6.7 
Progression Free Survival Data 
Full Analysis Population 
L_Pfs 
Listing 16.2.6.8 
Kaplan Meier Survival and Censoring Times 
Full Analysis Population 
L Surv2 


ATI001-204 Final TFL Shells.xlsx 
 
Listing 16.2.8.5 
SI Units and Conversion Factors 
Full Analysis Population 
L Conv 
Listing 16.2.8.1 
Serum Chemistry Data 
Full Analysis Population 
L Labs 
Listing 16.2.8.2 
Hematology and Coagulation Data 
Full Analysis Population 
L Labs 
Listing 16.2.8.3 
Hematology and Coagulation Data 
Full Analysis Population 
L Labs 
Listing 16.2.8.4 
Urinalysis Data 
Full Analysis Population 
L Labs 
Listing 16.2.9 
Pregnancy Test 
Full Analysis Population 
L_Preg 
Listing 16.2.10 
Vital Signs 
Full Analysis Population 
L Vit 
Listing 16.2.11 
ECG Data 
Full Analysis Population 
L Ecg 
Listing 16.2.12 
Physical Examination 
Full Analysis Population 
L Phys 
Listing 16.2.13 
Neurological Examination 
Full Analysis Population 
L Neuro 
Listing 16.2.14 
Karnofsky Performance Status 
Full Analysis Population 
L Kps 
Listing 16.2.15 
Visits 
Full Analysis Population 
L_Vis 
 
 
 
 
 
 
 














 
Electronic Record and Signature Disclosure created on: 26-Feb-2020 | 15:21 
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