Conditions: Metastatic Breast Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 9
Healthy volunteers: no

Brief summary:
This is a single-arm, phase Ib/II study to examine the safety, tolerability and preliminary efficacy of one cycle of Ad-RTS-hIL-12 immunotherapy in women with advanced breast cancer and pre-study SD or PR after completion of a minimum 12 week course of standard first- or second-line chemotherapy. The patient population will include patients with locally advanced or metastatic breast cancer of all subtypes.

Detailed description:
Subjects who have PD or a CR after the standard chemotherapy are not eligible for the study. Following entry into the trial, patients will go on a treatment holiday from chemotherapy and enter an immunotherapy phase of treatment. Continuation of HER2-targeted antibody therapy is permitted during this immunotherapy phase for women with HER2+ disease. Scans will be conducted at 6 and 12 weeks after the start of Ad-RTS-hIL-12 immunotherapy to determine tumor response. Radiographic PD at week 6 must be confirmed at least 4 weeks later, either at week 12 or earlier if clinically necessitated.

Arms:
arm 1: Intratumoral injection of Ad-RTS-hIL-12 in combination with veledimex

Interventions: intervention 1: Ad-RTS-hIL-12 intervention 2: Veledimex
Intervention descriptions: intervention 1: Approximately 1.0x10\^12 viral particles (vp) per injection intervention 2: 7 oral doses of veledimex

Protocol document:
Prot_000.pdf: 




Ad-RTS-hIL-12 (INXN-2001) + Veledimex (INXN-1001) 
ZIOPHARM Oncology, Inc. 
Protocol ATI001-203 – Amendment 2 
Final: 16 May 2016 
Confidential 
 
 
 
entry into the trial, patients will go on a treatment holiday from chemotherapy and enter an immunotherapy 
phase of treatment.  Continuation of HER2-targeted antibody therapy is permitted during this immunotherapy 
phase for women with HER2+ disease. Scans will be conducted at 6 and 12 weeks after the start of Ad-RTS-hIL-
12 immunotherapy to determine tumor response.  Radiographic PD at week 6 must be confirmed at least 4 weeks 
later, either at week 12 or earlier if clinically necessitated, except in cases of unequivocal progression.   
The assessment of response will be based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 
using tumor measurements from contrast-enhanced computed tomography (CT).  Tumor response will also be 
assessed by Immune-Related Response Criteria (irRC) (Wolchok et al, 2009).  Eligible subjects will also be 
asked to consent to allow ZIOPHARM to obtain scans and tumor measurements taken both a) prior to initiating 
the pre-study standard chemotherapy and b) after a minimum of 12 weeks of pre-study standard chemotherapy, 
and not more than 4 weeks prior to study enrollment, in order to confirm their SD, PR status.  
For subjects with HER2- disease, the Ad-RTS-hIL-12 immunotherapy is intended to be given as a chemotherapy 
break, for example, to avoid intolerable or undesirable toxicity of the standard chemotherapy.  Ad-RTS-hIL-12 
immunotherapy must be started within 4 weeks of stopping the pre-study standard chemotherapy.   
Subjects with HER2+ disease will receive the Ad-RTS-hIL-12 immunotherapy in conjunction with first- or 
second-line anti-HER2 antibody therapy, i.e., subjects may continue anti-HER2 antibody directed therapy during 
the study period.  Anti-HER2 therapy will be administered according to the manufacturer’s recommendations. 
Subjects with HER2+ breast cancer who continue the anti-HER 2 antibody therapy need to recover from any 
anti-HER2 related adverse event (AE) or serious adverse events (SAE), i.e., the event must have resolved to 
Grade 1 or baseline, before starting Ad-RTs-hIL-12 immunotherapy.   
The Ad-RTS-hIL-12 immunotherapy cycle is a 21-day cycle comprised of investigational product administration 
on days 1 through 7 followed by rest on days 8 through 21. On day 1, enrolled subjects will receive the first dose 
of veledimex followed 3 hours ± 3 hours later by an intratumoral injection of Ad-RTS-hIL-12.  The veledimex 
will continue to be given once daily on days 2 through 7 (see Synopsis subsection “Investigational Product 
Description, Dose, and Administration,” below, for details).   
A safety review committee (SRC) will convene after every 5th subject with HER2- disease has completed the 
Ad-RTS-hIL-12 immunotherapy cycle (i.e., after all 5 subjects have completed 21 days on study). The SRC will 
also convene after the first 5 subjects with HER2+ disease have completed the Ad-RTS-hIL-12 immunotherapy 
cycle (i.e., after all 5 subjects have completed 21 days on study).  The SRC will consist of the investigator, 
medical monitor, and other appropriate Sponsor representatives.  The SRC will review all available safety 
information (AEs/SAEs, laboratory parameter data, electrocardiogram [ECG], etc.).  Tolerability and efficacy 
will be evaluated separately for subjects with HER2- and HER2+ disease.   
The safety evaluation will be based on the occurrence of related, treatment refractory Grade 3 and 4 AEs within 
21 days following the start of Ad-RTS-hIL-12 immunotherapy.  
The primary endpoint is safety/tolerability, defined as the proportion of patients who are able to complete 
12 weeks on study without Grade 3 or higher toxicity as defined by Section 12.4.2.  
The secondary endpoints include the progression rate calculated 12 weeks after the start of Ad-RTS-hIL-12 
immunotherapy.  For the overall study, a rate of progression at 12 weeks of 50% is deemed acceptable, while an 
80% rate is deemed unacceptable.  From the progression rate, which is defined below under the efficacy analysis 
of the Statistical Methods section, the proportion of subjects who are progression-free can also be derived.   
Additional secondary endpoints are the ORR, the DCR and the proportion of subjects who experience an 
improvement from a baseline tumor status from SD to PR/CR or from PR to CR. Disease responses by RECIST 
versus irRC will be explored. 
The effect of treatment on blood biomarkers [including IL-12, IL-10 and interferon-gamma (IFN-γ)] and tumoral 
immune cell subtypes (including CD8+ effector cells and T-regulatory cells) will also be explored.  
Upon completion of week 12, patients who are considered to be SD or better will enter into long-term follow-up 
for up to an additional 36 weeks.  In the long-term follow-up period, scans will be performed at 18, 24, 36, and 
48 weeks until a radiographic response of PD is confirmed. 
Number of Centers 
Single center:  Memorial Sloan Kettering Cancer Center, New York, New York, United States 
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Ad-RTS-hIL-12 (INXN-2001) + Veledimex (INXN-1001) 
ZIOPHARM Oncology, Inc. 
Protocol ATI001-203 – Amendment 2 
Final: 16 May 2016 
Confidential 
 
 
 
Number of Subjects 
40 subjects may be enrolled, including up to 20% (8 subjects) with HER2+ breast cancer. 
Study Population 
Inclusion Criteria 
1. Female, age ≥ 18 years 
2. Histologically-confirmed, locally advanced or metastatic adenocarcinoma of the breast, irrespective of 
hormone receptor or human epidermal growth factor receptor 2 (HER2) status (triple negative receptor 
status is permitted) 
a. 
Endocrine resistant hormone receptor-positive breast cancer subject who in the opinion of the 
physician requires chemotherapy is eligible 
b. 
Inflammatory breast cancer permitted with 2 injectable lesions 
c. 
Subjects who have received prior (neo) adjuvant chemotherapy, hormonal therapy or 
trastuzumab are eligible 
3. Achievement of SD or PR after a minimum of 12 weeks of pre-study first-, second-, or third-line 
standard chemotherapy 
NOTE: A prior therapy that is not completed due to toxicity will not be considered a line of therapy for 
eligibility determination. 
4. Presence of at least 2 measurable lesions as assessed by RECIST v1.1 criteria: one lesion is to be 
injected with Ad-RTS-IL-12 and defined as a non-target lesion  
5. Standard treatment interrupted, except if anti-HER2 therapy 
6. All treatment-related or radiation-related toxicities resolved to Grade 1 or lower 
7. Submission of copies of tumor measurements and scans taken a) prior to starting the pre-study standard 
chemotherapy and b) at the end of a minimum of 12 weeks of the pre-study therapy 
8. Life expectancy > 12 weeks at study entry 
9. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 (see Appendix 16.1) 
10. Adequate bone marrow function as assessed by the following:  
a. 
ANC ≥ 1500/μL (without use of growth factors within 7 days of screening) 
b. 
ALC > 700/μL  
c. 
PLT ≥ 100,000/μL 
d. 
 Hb ≥ 9 g/dL  
11. Adequate liver function as assessed by the following:  
a. 
Serum bilirubin ≤ 1.5 mg/dL, except as follows 
i. 
Patients with Gilbert’s disease:  serum bilirubin < 5 mg/dL  
b. 
AST, ALT, and ALP ≤ 2.5 × ULN, except as follows 
i. 
Patients with hepatic metastases:  ALT and AST ≤ 5 × ULN 
ii. Patients with hepatic and/or bone metastases: alkaline phosphatase ≤ 5 × ULN 
12. Adequate renal function as assessed by the following:  
a. 
Serum creatinine ≤ 1.5 mg/dL OR  
b. 
Creatinine clearance of ≥ 60 mL/min based on a 24-hour urine collection 
13. Female subjects and their male partners must agree must agree to use a highly reliable method of birth 
control (expected failure rate less than 5% per year) from the screening visit through 28 days after the 
last dose of investigational product. Women of childbearing potential (perimenopausal women must be 
amenorrheic for at least 12 months to be considered of non-childbearing potential) must have a negative 
pregnancy test at screening  
14. Able to swallow oral medication 
15. Willing to comply with study procedures for the duration of the study and able to provide informed 
consent 
 
 
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Ad-RTS-hIL-12 (INXN-2001) + Veledimex (INXN-1001) 
ZIOPHARM Oncology, Inc. 
Protocol ATI001-203 – Amendment 2 
Final: 16 May 2016 
Confidential 
 
 
 
Exclusion Criteria 
1. Metastatic breast cancer patients currently on hormonal therapy as first- or second-line are not permitted 
2. Prior radiation therapy encompassing > 25% of bone marrow 
3. Any congenital or acquired condition leading to compromised ability to generate an immune response, 
including concomitant immunosuppressive therapy 
4. Immunosuppressive therapy 
a. 
Use of systemic immunosuppressive drugs including corticosteroids (prednisone equivalent ≥ 
10 mg/day) within 6 weeks 
b. Requirement for continual immune suppression with immunosuppressive drugs (eg, subjects 
with organ allografts) 
5. Major surgery within 4 weeks of study treatment, or major surgery planned for duration of study 
participation 
6. An active, second potentially life-threatening cancer, adequately treated basal cell or squamous cell skin 
cancer, or carcinoma in situ of the cervix, low grade thyroid is permitted 
7. Presence of brain or subdural metastases, unless local therapy has been completed and corticosteroids have 
been discontinued for this indication for ≥ 4 weeks before starting study treatment: 
a. 
Any signs (e.g., radiologic) and/or symptoms of brain metastases must be stable for ≥ 4 weeks 
before starting study treatment 
b. Radiographic stability should be determined by comparing contrast-enhanced CT or magnetic 
resonance imaging (MRI) scans at screening to scans obtained by the same method at least 4 
weeks earlier 
NOTE:  Screening for brain lesions is not required for all potential subjects; however, if there are any 
neurological signs or symptoms consistent with brain metastases, then a brain CT or MRI should be performed 
as clinically indicated. 
8. Presence or documented history of any of the following autoimmune conditions:  
a. 
Inflammatory bowel disease 
b. Rheumatoid arthritis, systemic progressive sclerosis (scleroderma), systemic lupus 
erythematosus, autoimmune vasculitis (e.g., Wegener's granulomatosis) 
c. 
Motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre Syndrome)  
9. Presence of meningeal carcinomatosis 
10. Use of any medications that induce, inhibit, or are substrates of cytochrome P450 (CYP450) 3A4 within 7 
days prior to the first dose of investigational product without consultation with the medical monitor 
11. History or evidence of cardiac disease as indicated by any of the following: 
a. 
Congestive heart failure greater than New York Heart Association (NYHA) Class II (see 
protocol Appendix 16.4) 
b. Unstable angina (anginal symptoms at rest), or new-onset angina (begun within the last 3 
months), or myocardial infarction within the 6 months prior to enrollment 
c. 
Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy 
d. Congenital long QT syndrome or taking drugs known to prolong the QT interval 
12. Current use of any drugs with a known risk of causing torsades de pointes 
13. Evidence or history of thromboembolic, venous, or arterial events such as a cerebrovascular accident 
including transient ischemic attacks within the past 3 months 
14. Evidence or history of bleeding diathesis or coagulopathy at the time of screening 
15. International normalized ratio (INR) and activated partial thromboplastin time (aPTT) > 1.5 x ULN, in 
subject who is not therapeutically anticoagulated. Subjects who are being therapeutically anticoagulated 
with an agent such as Coumadin (warfarin sodium) or subcutaneous heparin may be included provided there 
is not prior evidence of underlying abnormality in coagulation parameters, the screening test results are in an 
appropriate therapeutic range, and the anticoagulation regimen is stable and closely monitored 
16. History of malabsorption syndrome or other condition that would interfere with enteral absorption 
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Ad-RTS-hIL-12 (INXN-2001) + Veledimex (INXN-1001) 
ZIOPHARM Oncology, Inc. 
Protocol ATI001-203 – Amendment 2 
Final: 16 May 2016 
Confidential 
 
 
 
17. Presence of active clinically serious infection (Grade 3 or higher by National Cancer Institute Common 
Toxicity Criteria for Adverse Events (NCI-CTCAE v.4.03, see Appendix 16.5) 
18. Diagnosis of infection with human immunodeficiency virus (HIV) or chronic infection with hepatitis B or C 
virus 
19. Any other 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 
20. Pregnant or breast-feeding 
21. Use of any investigational, non-United States Food and Drug Administration (US FDA) approved drug 
within 28 days or 5 half-lives, whichever is longer, preceding screening 
22. Current participation in any other clinical trial without consultation with the medical monitor 
23. Presence of any condition which, in the investigator or medical monitor’s opinion, makes the patient 
unsuitable for the study participation 
Investigational Product Description, Dose, and Administration 
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.   
Veledimex oral activator ligand  
Veledimex will be supplied by the Sponsor as gelatin capsules for oral administration.  Subjects will receive 
80 mg of veledimex on days 1 through 7.  On day 1, subjects will receive veledimex 3 hours ± 3 hours before 
intratumoral injection of Ad-RTS-hIL-12.  On days 2 through 7, subjects will be directed to take the veledimex 
in a fed state (preferably within 30 minutes following a normal meal), once daily, and at the same time 
(± 1 hour) each day. All daily capsules must be taken together on the same day and within a few minutes. 
Subjects should NOT make up any missed doses.  If any dose is missed, a subject should take the next dose as 
scheduled on the next day.   
Ad-RTS-hIL-12 
Ad-RTS-hIL-12 will be supplied by the Sponsor as a sterile suspension for injection. Subjects will receive an 
intratumoral injection of 
 a volume of 0.5 mL on day 1, 3 hours ± 3 hours after 
administration of veledimex.  
The 0.5 mL dose of Ad-RTS-hIL-12 should be injected into the same lesion and should be delivered by multiple 
injections with a fine needle (no finer than 27-gauge) directly into each quadrant of the lesion.  Attention must be 
paid to adequately infiltrate the circumference of the tumor margins. Should the tumor selected for injection not 
support the entire Ad-RTS-hIL-12 injection volume (approximately 0.5 cc), another tumor should be injected 
with the remaining volume to ensure that all subjects receive 
. If another tumor is not 
available, then the remaining volume should be injected into a draining, pathologic lymph node of the injected 
tumor. Lesions displaying signs of localized infection should not be injected. The lesion chosen for injection will 
be designated as a non-target lesion. 
Each subject will be carefully monitored for possible local reactions at the injection site and/or hypersensitivity 
reactions for at least 2 hours following the Ad-RTS-hIL-12 injection. 
All subjects receiving Ad-RTS-hIL-12 immunotherapy must be adequately hydrated with approximately 
2000 ml of oral liquid preferably containing electrolytes every 24 hours for the first 72 hours.  Subjects must be 
instructed to maintain good oral hydration on and between dosing days.  Additional details regarding the number 
and selection of lesions and injection of Ad-RTS-hIL-12 is provided in Section 6.1 of the protocol.   
Only one cycle of Ad-RTS-hIL-12 immunotherapy will be given.   
 
 
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Ad-RTS-hIL-12 (INXN-2001) + Veledimex (INXN-1001) 
ZIOPHARM Oncology, Inc. 
Protocol ATI001-203 – Amendment 2 
Final: 16 May 2016 
Confidential 
 
 
 
Study Assessments and Criteria for Evaluation 
Safety Assessments 
Safety parameters will include AEs, SAEs, physical examinations (PEs), ECGs, vital signs, clinical laboratory 
evaluations, medical history, and prior/concomitant medications.  All AEs/SAEs will be collected from the 
signing of informed consent until the end of Week 12.  Subjects who experience drug-related Grade 3 AEs 
during the first 7 days of oral dosing with veledimex will interrupt/discontinue further dosing at the discretion of 
the investigator. Subjects who experience drug-related Grade 4 AEs during the first 7 days of oral dosing with 
veledimex will discontinue therapy.  The decision as to whether subjects who experience severe or serious 
treatment-related adverse events will remain on treatment will be made by the investigator in conjunction with 
the Sponsor medical monitor.  
Efficacy Assessments 
Tumor response will use RECIST v 1.1 (see Section 9 of the main protocol).  Injected and non-injected lesions 
will be assessed and recorded separately. Up to 5 measureable lesions may be selected and designated as target 
lesions.  One measurable lesion will be injected and will be consequently designated a non-target lesion.  Target 
lesions will be used to evaluate the systemic effect of Ad-RTS-hIL-12, as defined by RECIST v1.1.  Additional 
non-injected, non-target lesions also may be followed, according RECIST v1.1. Target and non-target lesions 
will be assessed by CT at 6 weeks and 12 weeks after the start of Ad-RTS-hIL-12 immunotherapy. Tumor 
response will also be assessed by Immune-Related Response Criteria (irRC) (Wolchok et al, 2009).  The imaging 
method used for the week 6 and week 12 assessments of response must be the same as that used for the pre-study 
assessments.  The tumor assessment at 12 weeks after the start of Ad-RTS-hIL-12 immunotherapy will be 
compared with the pre-study tumor assessment when SD or PR was achieved. 
Biologic/immunologic assessments will be performed using blood samples obtained at screening, days 1, 3, 8, 
and weeks 6 and 12.  Tumor biopsies will be obtained by interventional radiology prior to the intratumoral 
vector injection and again at 6 weeks. 
Duration of Each Subject’s Participation 
Enrolled subjects will participate for up to 52 weeks, including up to 4 weeks for screening activities.   
Statistical Methods 
Because there is little data on this treatment approach, there will be two stopping rules based on repeated 
significance testing to ensure safety (Jennison and Turnbull, 2000; Ivanova et al, 2005).  The first rule is based 
on related, treatment refractory Grade 3 or 4 AEs.  A rate of 50% is deemed unacceptable, a rate of 25% is 
deemed acceptable.  Tolerability and efficacy will be evaluated separately for subjects with HER2- and HER2+ 
disease.  The safety evaluation will be based on the occurrence of related, treatment refractory Grade 3 and 4 
AEs within 21 days following the start of Ad-RTS-hIL-12 immunotherapy. The boundaries to stop the study are 
given as follows: 
If 4 of the first 5 patients have related, treatment refractory Grade 3 or 4 AE, stop the study. 
If 6 of the first 10 patients have related, treatment refractory Grade 3 or 4 AE, stop the study. 
If 8 of the first 15 patients have related, treatment refractory Grade 3 or 4 AE, stop the study. 
If 9 of the first 20 patients have related, treatment refractory Grade 3 or 4 AE, stop the study. 
If 11 of the first 25 patients have related, treatment refractory Grade 3 or 4 AE, stop the study. 
If 12 of the first 30 patients have related, treatment refractory Grade 3 or 4 AE, stop the study. 
If 14 of the first 35 patients have related, treatment refractory Grade 3 or 4 AE, stop the study. 
If 15 of the first 40 patients have related, treatment refractory Grade 3 or 4 AE, stop the study.   
 
The second stopping rule is based on the progression rate during the 12 weeks of the study.  A progression rate 
of 50% is deemed acceptable, while an 80% rate is deemed unacceptable.   The boundaries to stop the study 
using a repeated significance testing approach are given as follows:  
If 5 of the first 5 patients progress, stop the study. 
If 9 of the first 10 patients progress, stop the study. 
If 12 of the first 15 patients progress, stop the study. 
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Ad-RTS-hIL-12 (INXN-2001) + Veledimex (INXN-1001) 
ZIOPHARM Oncology, Inc. 
Protocol ATI001-203 – Amendment 2 
Final: 16 May 2016 
Confidential 
 
 
 
If 15 of the first 20 patients progress, stop the study. 
If 18 of the first 25 patients progress, stop the study. 
If 20 of the first 30 patients progress, stop the study. 
If 23 of the first 35 patients progress, stop the study. 
If 26 of the first 40 patients progress, stop the study.   
Primary endpoints: 
 
To evaluate the safety and tolerability of one cycle of Ad-RTS-hIL-12 immunotherapy a) following a 
first-, second-, or third-line standard treatment in HER2-negative (HER2-) subjects, or b) together with 
a first-, second-, or third-line anti-HER2 antibody therapy in HER2-positive (HER2+) subjects as 
defined by Section 12.4.2.  
Secondary endpoints 
 
To estimate the progression rate at 12 weeks after the start of one cycle of Ad-RTS-hIL-12 
immunotherapy  
 
To evaluate the overall response rate (ORR), defined as the rate of complete response (CR) plus the rate 
of PR at 12 weeks following the start of Ad-RTS-hIL-12 immunotherapy 
 
To evaluate the disease control rate (DCR), defined as the proportion of subjects who have a CR, PR, or 
SD at 12 weeks following the start of one cycle of Ad-RTS-hIL-12 immunotherapy 
 
To evaluate the number of subjects whose baseline tumor status (SD or PR) improves to PR or better at 
12 weeks following the start of Ad-RTS-hIL-12 immunotherapy 
 
To compare radiographic responses by irRC with conventional reporting by RECIST 
 
To explore the impact of treatment on tumor and serum immune biomarkers 
Analysis Populations 
 
The safety population will comprise all subjects who have received either the injection of Ad-RTS-hIL-
12 or any doses of veledimex 
 
The veledimex-treated population will comprise subjects who have received the injection of Ad-RTS-
hIL-12 and at least one dose of veledimex 
 
The veledimex-evaluable population will comprise subjects who have received the injection of Ad-
RTS-hIL-12 and all 7 doses of veledimex 
Safety Analysis  
Exposure to investigational product and reasons for discontinuation of study treatment will be tabulated. All 
treatment-emergent AEs will be coded according to the system organ class and preferred term using the Medical 
Dictionary for Regulatory Affairs (MedDRA®), and will be tabulated by number and percent of subjects, and 
according to relationship to the investigational product, severity, and seriousness. Laboratory parameters will be 
summarized by visit. Vital signs and physical examination data will be presented by visit. 
Toxicity stopping rules, when applicable, will be determined based on a clinical assessment made by the SRC 
after a formal evaluation of safety data after every 5 subjects with HER2- disease have completed one cycle of 
Ad-RTS-hIL-12 immunotherapy.  The SRC will review data separately for subjects with HER2+ disease to 
assess toxicity after the first 5 subjects with HER2+ disease have completed one cycle of Ad-RTS-hIL-12 
immunotherapy. 
Efficacy Analysis 
Tumor response  
Tumor response (CR, PR, SD, and PD) will be determined according to RECIST v1.1 (see Section 9 of the main 
protocol).  Tumor response will also be assessed by Immune-Related Response Criteria (irRC) (Wolchok et al, 
2009).   
Progression-free rate 
Proportion of subjects who are progression-free 12 weeks following the start of Ad-RTS-hIL-12 
immunotherapy.  
ORR 
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Ad-RTS-hIL-12 (INXN-2001) + Veledimex (INXN-1001) 
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Protocol ATI001-203 – Amendment 2 
Final: 16 May 2016 
Confidential 
 
 
 
The ORR is defined as the percentage of subjects who have CR or PR at 12 weeks following the start of Ad-
RTS-hIL-12 immunotherapy. 
DCR 
The disease control rate is the proportion of subjects who have a CR, PR, or SD at 12 weeks following the start 
of Ad-RTS-hIL-12 immunotherapy. 
Sample Size Determination 
Approximately 40 patients will be treated.  This patient population will be heterogeneous and as such, it is 
difficult to define a threshold for a clear null and alternative hypothesis.   This sample size will allow us to 
estimate an overall progression rate with a maximum 95% exact confidence interval half-width of 0.16. 
 
 
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Ad-RTS-hIL-12 (INXN-2001) + Veledimex (INXN-01) 
ZIOPHARM Oncology, Inc. 
Protocol ATI001-203 – Amendment 2 
 
Final: 16 May 2016 
Confidential
a.
A physical exam is required during screening and at Weeks 6 and 12. Otherwise, a symptom-directed physical exam should be performed where indicated.
b.
Vital signs include blood pressure, pulse, temperature, and respirations.  On Days 1 and 3 vital signs will be recorded prior to administration of veledimex.  On Day 1, vital signs will also be 
recorded prior to administration of Ad-RTS-hIL-12.  At all indicated time points, blood pressure should be monitored closely, 
 
 
 Subjects must be instructed to maintain adequate oral hydration while taking veledimex; sites must closely monitor subjects’ hydration status. Oral hydration 
(approximately 2000 mL oral electrolyte solution over 24-hours x 3 days) and administration of prophylactic antipyretics are highly recommended after injection of Ad-RTS-hIL-12.
c.
Concomitant medications should be collected from screening through Week 12. In addition, any new anti-cancer medication started prior to confirmation of radiographic response of PD should be 
collected. 
d.
Females of childbearing potential will have a serum pregnancy test during screening (within 14 days of dosing) and a urine pregnancy test at Day 1. A serum pregnancy test should be completed on 
Day 1 if the urine pregnancy test is positive.
e.
The hematology panel includes complete blood count (CBC) and white blood cell (WBC) count, differential white blood cell count, red blood cell (RBC) count, hematocrit, hemoglobin, red 
blood cell indices (MCV, MCH, MCHC), and platelet count.
f.
The coagulation panel includes activated partial thromboplastin time (aPTT) and the international normalized ratio (INR).
g.
The serum chemistry panel includes aspartate transaminase (AST), alanine transaminase (ALT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), creatinine, total bilirubin, total
protein, albumin, blood urea nitrogen (BUN), glucose, sodium, potassium, chloride, calcium, phosphorus, and bicarbonate.
h.
The urinalysis panel (dipstick) includes appearance, pH, specific gravity, glucose, protein/albumin, blood, ketones, bilirubin, nitrates, and leukocyte esterase.  In addition, a microscopic exam
for casts, crystals, and cells may be done if clinically indicated.
i.
Standard, 12-lead ECG.
j.
Oral veledimex to be taken daily on Days 1-7. The first dose of veledimex will be given at the clinical site in a fasting state. The remaining 6 doses can be self-administered at the same time as
on Day 1 (±1 hour) by subjects, in the fed state, on Days 2-7.  Study sites must verify adherence with veledimex dosing.  Subjects should return bottles of veledimex to the clinical site to
determine extent of subject adherence to self-administration preferably on Day 8.
k.
Days 2, 4, 5, 6, and 7 are not shown, but veledimex is also to be taken on those days.
l.
The intratumoral Ad-RTS-hIL-12 (
) should be administered 3 hours ± 3 hours after oral veledimex.  Lesions displaying signs of localized infection should not be injected.  Subjects
must be instructed to maintain good oral hydration while taking veledimex.  Oral hydration (approximately 2000 mL in the first 24h) and administration of prophylactic antipyretics is highly
recommended after injection of Ad-RTS-hIL-12 
. Each subject will be carefully monitored for possible local reactions at the injection
site and/or hypersensitivity reactions for at least 2 hours following the Ad-RTS-hIL-12 injection. A detailed description of physical location(s) of the injected tumor(s) and surrounding tissue,
and any visible local reactions will be documented.  The subject should be instructed to call the clinical site if any such reactions develop or don’t resolve within 24 to 48 hours.
m.
Study sites must determine compliance of veledimex dosing. Veledimex will be dispensed to the subject on Day 1 for the next 6 days along with the veledimex subject diary.
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 last meal, the number of
capsules taken, whether subject missed any veledimex doses and the study day and reason for any missed doses.  Investigational product container(s) with any remaining capsules should be
returned to the study staff on Day 8 (or after last dose), so that staff can properly assess dose compliance.
n.
Appropriate cancer staging procedures should be performed during screening. Copies of tumor measurements and scans taken a) before the start of the pre-study standard chemotherapy and b)
following a minimum of 12 weeks of the pre-study chemotherapy are required for study entry. In the event that IV contrast cannot be used, the medical monitor should be consulted. All
imaging should be of diagnostic quality and include intravenous (IV) contrast. Please refer to Appendix 16.3 for RECIST v 1.1. guidelines.
o.
Research bloods consist of blood for cytokines and immune cell activation by flow cytometry as noted in Section 11.
p.
The Day 21 visit will collect adverse events and concomitant medication. This visit may be completed via phone call.
q.
If radiographic PD is recorded at 6 weeks, PD must be confirmed 4 weeks later. In cases of slow tumor growth, the investigator may wait until confirmation of the PD at 12 weeks to resume
chemotherapy.  In cases of unequivocal progression, the investigator may resume chemotherapy prior to 12 weeks.
r.
Subjects who have SD or better at Week 12 will continue into the long-term follow-up period where imaging should continue per the schedule until a radiographic response of PD is confirmed.
s.
Biopsy on Day 1 is to be taken 3 hours ± 3 hours after administration of veledimex and prior to injection of Ad-RTS-hIL-12.
t.
After Week 6, only SAEs suspected of being related to investigational product will be collected.
u.
The follow-up visits can be performed within + 1 week.
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Confidential 
 
 
 
TABLE OF CONTENTS 
STUDY PROTOCOL .......................................................................................................................................... 1 
PROTOCOL SYNOPSIS .................................................................................................................................... 2 
STUDY SCHEMA ............................................................................................................................................. 10 
SCHEDULE OF STUDY PROCEDURES ...................................................................................................... 11 
TABLE OF CONTENTS .................................................................................................................................. 13 
LIST OF TABLES ............................................................................................................................................. 17 
LIST OF FIGURES ........................................................................................................................................... 17 
LIST OF ABBREVIATIONS ........................................................................................................................... 18 
1 
INTRODUCTION ................................................................................................................................. 20 
1.1 
DISEASE BACKGROUND ................................................................................................................... 20 
1.2 
INTERLEUKIN-12 AND CANCER IMMUNOTHERAPY ........................................................................ 21 
1.3 
LOCAL IL-12 DELIVERY AND DEVELOPMENT OF AN INDUCIBLE IL-12 IMMUNOTHERAPY ........ 22 
1.4 
ADENOVIRAL VECTORS FOR GENE THERAPY ................................................................................ 22 
1.4.1 
Adenoviral Safety ......................................................................................................................... 22 
1.4.2 
Safety of Intratumoral Injection of IL-12 Gene Vectors ............................................................... 23 
1.5 
AD-RTS-HIL-12 GENE THERAPY COMPONENTS .......................................................................... 24 
1.5.1 
Ad-RTS-hIL-12 ............................................................................................................................. 24 
 
 
 
1.5.3 
Veledimex ..................................................................................................................................... 25 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.7 
RATIONALE FOR CURRENT STUDY ................................................................................................. 32 
2 
STUDY OBJECTIVES ......................................................................................................................... 33 
2.1 
PRIMARY OBJECTIVE ...................................................................................................................... 33 
2.2 
SECONDARY OBJECTIVES ............................................................................................................... 33 
3 
STUDY DESIGN ................................................................................................................................... 34 
3.1 
OVERALL STUDY DESIGN ............................................................................................................... 34 
3.2 
DOSE ESCALATION COHORTS......................................................................................................... 35 
3.3 
STUDY OVERSIGHT FOR SAFETY EVALUATION ............................................................................. 35 
4 
SUBJECT SELECTION ...................................................................................................................... 35 
4.1 
INCLUSION CRITERIA ...................................................................................................................... 35 
4.2 
EXCLUSION CRITERIA ..................................................................................................................... 37 
4.3 
SUBJECT ENROLLMENT .................................................................................................................. 39 
4.4 
WITHDRAWAL OF SUBJECTS FROM STUDY TREATMENT AND/OR STUDY ..................................... 39 
4.5 
REPLACEMENT OF SUBJECTS .......................................................................................................... 40 
4.6 
PREMATURE TERMINATION OF STUDY .......................................................................................... 40 
5 
INVESTIGATIONAL PRODUCT ...................................................................................................... 40 
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5.1 
PREPARATION OF AD-RTS-HIL-12 ................................................................................................ 40 
5.2 
PREPARATION OF VELEDIMEX ....................................................................................................... 40 
5.3 
HANDLING AND STORAGE ............................................................................................................... 41 
5.4 
MONITORING OF SUBJECT ADHERENCE AND MANAGING MISSED VELEDIMEX DOSES .............. 41 
5.5 
DISPOSITION OF UNUSED DRUG ...................................................................................................... 41 
5.6 
ACCOUNTABILITY AND DISPENSATION .......................................................................................... 41 
6 
TREATMENT PLAN ........................................................................................................................... 42 
6.1 
AD-RTS-HIL-12 DOSAGE AND ADMINISTRATION PROCEDURES .................................................. 42 
6.2 
VELEDIMEX DOSAGE AND ADMINISTRATION ................................................................................ 42 
6.3 
DOSE ESCALATION .......................................................................................................................... 42 
6.4 
MODIFICATION OF DOSE SCHEDULE .............................................................................................. 43 
6.5 
DOSE-LIMITING TOXICITY ............................................................................................................. 43 
6.6 
MAXIMUM TOLERATED DOSE ........................................................................................................ 43 
6.7 
DOSE MODIFICATIONS AND DOSE DELAYS .................................................................................... 43 
6.8 
SEVERITY GRADING AND MANAGEMENT OF LOCAL REACTIONS ................................................. 43 
6.9 
PROPHYLACTIC ANTIPYRETIC AND/OR ANALGESIC ADMINISTRATION ....................................... 43 
7 
CONCOMITANT THERAPY ............................................................................................................. 44 
7.1 
PERMITTED MEDICATIONS ............................................................................................................. 44 
7.2 
PROHIBITED MEDICATIONS ............................................................................................................ 44 
8 
STUDY PROCEDURES ....................................................................................................................... 44 
8.1 
WRITTEN INFORMED CONSENT ...................................................................................................... 44 
8.2 
SUBJECT REGISTRATION................................................................................................................. 45 
8.3 
DESCRIPTION OF PROCEDURES AND OBSERVATIONS .................................................................... 45 
8.3.1 
Study Tests, Exams and Procedures .............................................................................................. 45 
8.4 
LIST OF ASSESSMENTS BY STUDY PERIOD ..................................................................................... 47 
8.4.1 
Screening ...................................................................................................................................... 47 
8.4.2 
Immunotherapy Cycle:  Day 1 (Ad-RTS-hIL-12 injection) .......................................................... 48 
8.4.3 
Immunotherapy Cycle:  Day 2 ...................................................................................................... 48 
8.4.4 
Immunotherapy Cycle:  Day 3 ...................................................................................................... 48 
8.4.5 
Immunotherapy Cycle:  Day 4-7 ................................................................................................... 48 
8.4.6 
Immunotherapy Cycle:  Day 8 ...................................................................................................... 49 
8.4.7 
Immunotherapy Cycle: Day 21 ..................................................................................................... 49 
8.4.8 
Initial Follow-Up Period: Week 6 ................................................................................................. 49 
8.4.9 
Initial Follow-Up Period: Week 12 ............................................................................................... 49 
8.4.10 
Long-Term Follow-Up Period: Week 18 ...................................................................................... 50 
8.4.11 
Long-Term Follow-Up Period: Week 24 ...................................................................................... 50 
8.4.12 
Long-Term Follow-Up Period: Week 36 ...................................................................................... 50 
8.4.13 
Long-Term Follow-Up Period: Week 48 ...................................................................................... 50 
9 
TUMOR RESPONSE ASSESSMENTS .............................................................................................. 50 
9.1 
MEASURABILITY OF TUMOR AT BASELINE .................................................................................... 50 
9.1.1 
Measurable Lesions ...................................................................................................................... 50 
9.1.2 
Non-measurable Lesions ............................................................................................................... 51 
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9.1.3 
Special Considerations Regarding Lesion Measurability.............................................................. 51 
9.1.4 
Methods of Tumor Measurement .................................................................................................. 52 
9.2 
TUMOR RESPONSE EVALUATION .................................................................................................... 52 
9.2.1 
Designation of Target and Non-Target Lesions ............................................................................ 52 
9.2.2 
Definitions of Response ................................................................................................................ 53 
10 
SAFETY ASSESSMENTS ................................................................................................................... 56 
10.1 
ADVERSE EVENTS (AES) AND DEFINITIONS ................................................................................... 56 
10.2 
EVALUATION OF ADVERSE EVENTS ............................................................................................... 56 
10.3 
DETERMINATION OF SERIOUSNESS................................................................................................. 57 
10.3.1 
Serious Adverse Event (SAE) ....................................................................................................... 57 
10.3.2 
Non-Serious Adverse Event .......................................................................................................... 58 
10.4 
DETERMINATION OF SEVERITY ...................................................................................................... 58 
10.5 
DETERMINATION OF CAUSALITY .................................................................................................... 59 
10.6 
DOCUMENTING ADVERSE EVENTS ................................................................................................. 60 
10.7 
REPORTING SERIOUS ADVERSE EVENTS ........................................................................................ 60 
10.8 
SPONSOR AND INVESTIGATOR RESPONSIBILITY FOR REPORTING ADVERSE EVENTS ................. 61 
10.9 
FOLLOW-UP INFORMATION FOR ADVERSE EVENTS ...................................................................... 61 
10.10  PREGNANCY ..................................................................................................................................... 62 
10.11  OVERDOSE ....................................................................................................................................... 62 
11 
BIOLOGIC AND IMMUNE RESPONSE ASSESSMENTS ............................................................. 62 
11.1 
BLOOD CYTOKINE AND IMMUNE FUNCTION ASSESSMENTS FROM BLOOD .................................. 62 
11.2 
CYTOKINE AND IMMUNOLOGIC MARKERS ASSESSMENT FROM TUMOR TISSUE ......................... 62 
12 
STATISTICAL METHODS ................................................................................................................ 63 
12.1 
POPULATIONS FOR ANALYSIS ......................................................................................................... 63 
12.2 
SAMPLE SIZE AND POWER CALCULATIONS ................................................................................... 63 
12.3 
ENDPOINTS ...................................................................................................................................... 63 
12.3.1 
Primary Endpoint .......................................................................................................................... 63 
12.3.2 
Secondary Endpoints .................................................................................................................... 63 
12.4 
ANALYSES ........................................................................................................................................ 64 
12.4.1 
Baseline Characteristics ................................................................................................................ 64 
12.4.2 
Safety Analyses ............................................................................................................................. 64 
12.4.3 
Efficacy Analyses ......................................................................................................................... 65 
12.4.4 
Adjustments for Covariates ........................................................................................................... 66 
12.4.5 
Procedures for Handling Missing, Unused, and Spurious Data .................................................... 66 
12.4.6 
Interim Analysis ............................................................................................................................ 66 
12.4.7 
Procedures for Reporting Deviations to Original Statistical Analysis Plan .................................. 66 
13 
STUDY MANAGEMENT .................................................................................................................... 66 
13.1 
ELECTRONIC CASE REPORT FORMS AND SOURCE DOCUMENTATION ......................................... 66 
13.2 
GOOD CLINICAL PRACTICE ............................................................................................................ 67 
13.3 
SPONSOR MONITORING .................................................................................................................. 67 
13.4 
DURATION OF THE STUDY ............................................................................................................... 68 
13.5 
RECORDS RETENTION ..................................................................................................................... 68 
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LIST OF ABBREVIATIONS  
Abbreviation 
Definition 
Ad 
Adenovirus 
AE 
Adverse event 
ALC 
Absolute lymphocyte count 
ALT 
Alanine transaminase 
ALP 
Alkaline Phosphatase 
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate transaminase 
BUN 
Blood Urea Nitrogen 
CBC 
Complete blood count 
GCP 
Good Clinical Practice 
CBC 
Complete blood count 
CD 
Cluster of differentiation 
CR 
Complete response 
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria For Adverse Events 
CYP 
Cytochrome p 
DCR 
Disease control rate 
DLT 
Dose-limiting toxicity 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EcR 
Ecdysone receptor 
FDA 
Food and Drug Administration 
FNA 
Fine needle aspiration 
Hb 
Hemoglobin 
HER2 
Human epidermal growth factor receptor 2 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
hIL-12 
Human interleukin-12 
HIV 
Human Immunodeficiency Virus 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IFN-γ 
Interferon gamma 
IL 
Interleukin 
INXN-1001 
Veledimex oral activator ligand 
INXN-2001 
Ad-RTS-hIL-12 vector for injection 
IV 
Intravenous 
INR 
International Normalized Ratio 
IRB 
irRC 
Institutional Review Board 
Immune-Related Response Criteria 
LDH 
Lactate dehydrogenase 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
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Confidential 
 
 
 
Abbreviation 
Definition 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
NK 
Natural killer 
NYHA 
New York Heart Association 
ORR 
Overall Response Rate 
PD 
Progressive disease 
PE 
Physical examination 
PET 
Positron emission tomography 
PLT 
Platelet 
PR 
Partial response 
PTT 
Partial thromboplastin time 
QOL 
Quality of life 
RBC 
Red Blood Cell Count 
RECIST 
Response Evaluation Criteria in Solid Tumor  
 
 
RXR 
Retinoid X receptor 
SAE 
Serious adverse event 
SD 
Stable disease 
SOP 
Standard operating procedure 
SRC 
Safety Review Committee 
TEAE 
Treatment-emergent adverse event 
TNF 
Tumor necrosis factor 
ULN 
Upper limit of normal 
US FDA 
United States Food and Drug Administration 
Vp 
Viral particles 
WBC 
White Blood Cell Count 
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quality of life and to prolong survival (Howlader et al, 2012).  Combination therapy is a mainstay 
of anticancer treatment, with optimal combinations producing synergistic antitumor responses, 
achieved by combining agents with non-overlapping mechanisms of action and safety profiles. 
1.2 
Interleukin-12 and Cancer Immunotherapy 
Interleukin-12 (IL-12) is a pro-inflammatory cytokine and has been recognized as a master 
regulator of cell mediated immunity in response to intracellular pathogens and neoplastic 
transformation.  Structurally IL-12 is a heterodimeric protein composed of p35 and p40 subunits 
covalently linked to form the biologically active IL-12p70 molecule (Carra et al, 2000).  It has 
been shown that IL-12 has the profound impacts upon the tumor environment.  The IL-12 could 
mediate the recruitment of lymphocytes, activation of tumor infiltrating lymphocytes as well as 
direct effects on tumor cells to decrease angiogenesis. 
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) and tumor necrosis alpha 
(TNF) by T and natural killer (NK) cells (Micallef et al, 1996; Trinchieri, 2003).  When it was 
discovered that IL-12 could, indeed, drive naïve T helper cell (Th0) differentiation to the 
inflammatory 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 (Kalinski et al, 1999; Curtsinger et al, 2003) and the 
reactivation and survival of memory CD4+ T cells (Yoo et al, 2002).  This is particularly 
important in the context of the tumor microenvironment where high levels of IL-12 have been 
shown to repolarize antigen-experienced CD4+ T cells back to the functional antitumor Th1 
phenotype (Wesa et al, 2007).   
Evidence that IL-12 is able to trigger innate and adaptive immunity and modulate the tumor 
microenvironment supports the relevance of IL-12 as an important immunotherapeutic agent.  Its 
ability to activate and recruit dendritic cells that facilitate the cross-priming of tumor antigen-
specific T cells, along with its influence on NK and CD8+ T cell cytotoxic activities and antigen-
specific antitumor responses (Mosmann and Coffman, 1989; Trinchieri, 1995; Tsung et al, 1997; 
Mailliard et al, 2002) warrant further study in cancer therapy.  Additionally, IL-12 has also been 
shown to stimulate the production of superoxides and nitric oxide and possess potent 
antiangiogenic activity through INF (Voest et al, 1995; Wigginton et al, 1996; Coughlin et al, 
1998).  The potent anti-tumor activity of IL-12 has been well documented in various cancer 
mouse models including melanoma, mammary carcinoma, sarcoma, colon and renal carcinoma 
(Colombo et al, 2002).  The potent nature of its biological activity and signaling complexity has 
also prompted the study of different delivery mechanism with a focus on intratumoral delivery 
and tumor microenvironment modulation.   
Based on such data, human studies of IL-12 as an anticancer agent were initiated.  The first of 
these studies was a Phase 1 dose escalation of IV administered recombinant human IL-12 in 
patients with either melanoma or renal cell carcinoma.  The study reported a transient complete 
response (CR) in melanoma and a partial response (PR) in renal cell carcinoma with significant 
toxicities.  The Phase 2 trial observed similar toxicities and two IL-12 related deaths prompting 
the FDA to suspend the trial (Atkins et al, 1997; Leonard et al, 1997).  Additional studies 
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Confidential 
 
 
 
well tolerated at doses ranging from 10 × 1011 to 25 × 1011 vp, with no DLTs, and generally mild 
to moderate adverse events (AEs) (Shimada et al, 2006).  The most common AEs were fever (all 
10 subjects), pain (30% of subjects), and hyperglycemia, which was attributed to the use of total 
parental nutrition (30% of subjects).  Hypocalcemia was reported in two subjects (20%) and one 
subject each (10%) experienced activated partial thromboplastin time (aPTT) elongation, 
abnormally high serum amylase, and abnormally high serum creatinine.  
In a Phase 1 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). 
1.4.2 
Safety of Intratumoral Injection of IL-12 Gene Vectors  
In contrast with the systemic toxicity resulting from administration of recombinant IL-12 protein, 
local administration of IL-12 via injection of plasmid or adenoviral vectors containing the hIL-12 
gene has proven to be well tolerated in patients 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 patients with 
metastatic melanoma.  A Phase 1 study investigated intratumoral expression of IL-12 together 
with the co-stimulatory molecule B7.1 via two separate canarypox virus viral vectors in patients 
with metastatic melanoma and reported mild to moderate injection site reactions, fever, chills, 
myalgia, and fatigue as AEs (Triozzi et al, 2005).  However, all patients also developed 
antibodies to canarypox virus viral vectors.  Notably, serum IL-12 and IFN-gamma levels were 
not increased after treatment.  Another Phase I trial showed that delivery by electroporation of a 
plasmid containing interleukin-12 to tumors in patients 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 1 study showed that intratumoral injection of 
DNA encoding hIL-12 in patients with metastatic melanoma was well tolerated overall 
(Heinzerling et al, 2005).  Eight of nine patients experienced a transient response at the 
intratumoral injection site, and some patients who had tumor responses also showed some 
increases in systemic IL-12, 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 1 study in 17 patients with metastatic pancreatic, colorectal, 
or primary liver cancer examined intratumoral injection of dendritic cells engineered to secrete 
interleukin-12 via a recombinant adenovirus vector (Mazzolini et al, 2005).  In that study, the 
most common AEs were lymphopenia, fever, and malaise.  Patients 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 side effects.  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 
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Ad-RTS-hIL-12 (INXN-2001) + Veledimex (INXN-1001) 
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Final: 16 May 2016 
Confidential 
 
 
 
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1.7 
Rationale for Current Study 
Metastatic breast cancer is an incurable disease with palliative therapeutic goals that include   
prolongation of survival with good quality of life (QOL) and symptom control.  Chemotherapy is 
generally recommended in patients with HR negative tumors, endocrine resistant disease and 
rapidly proliferative and/or symptomatic disease.  Although endocrine therapy, chemotherapy, 
and, more recently, targeted or biotherapy, may produce an objective response, almost all 
patients subsequently experience PD.  Numerous monotherapy drugs as well as combinations of 
cytotoxic drugs have been used to treat patients with advanced breast cancer.  The optimal 
duration of therapy in first-line chemotherapy in the treatment of metastatic breast cancer is 
unknown and controversial.  Clinical trials have reported prolonged duration of remission with 
continuous chemotherapy beyond an initial induction of several weeks; however, its effect on 
survival and QOL are less consistent (Coates et al, 1987; Ejlertsen et al, 1993; Falkson et al, 
1998; Nooij et al, 2003)  
The relative benefits of tumor regression and improvement in disease related symptoms must be 
balanced with treatment induced toxicity and its impact on QOL.  The physicians are generally 
using a continuous chemotherapy despite the insufficient and inconsistent evidence of improved 
overall survival because continuous chemotherapy has consistently been associated with longer 
median time to progression than a short, mostly four to six-course induction regimen followed by 
observation (Muss et al, 1991).  In addition, reports have indicated that in patients with objective 
PR or disease stabilization, no difference in survival is obtained when chemotherapy is continued 
(Harris et al, 1990).  There are however, known risks from cumulative drug-associated toxicities, 
such as peripheral neuropathy associated with the prolong use of taxanes, as well as mucositis, 
hand-foot syndrome, and diarrhea associated with the use of capecitabine, and cardiac toxicity 
associated with doxorubicin. 
Although patients who achieve benefit with initial therapy may continue to receive 
chemotherapy until disease progression or unacceptable toxicity, chemotherapy can also be 
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stopped after maximal benefit has been obtained and patients can then be followed for the 
occurrence of disease progression. 
Immunotherapy has recently shown evidence as a potentially promising approach to treating 
patients with invasive and metastatic breast cancers (Hudis, 2003; Zhou and Zhong, 2004; 
Emens et al, 2005).  Continued chemotherapy must be assessed in relationship to QOL and 
increased frequency of AEs compared to stopping chemotherapy.  Patients and their physicians 
may discuss how long to continue the chemotherapy treatment and if some chemotherapy breaks 
may be considered either when AEs occur to allow the patient to recover or to allow the patient 
to carry on other personal plans and re-start chemotherapy later on. 
An effective and convenient therapy that could be used to maintain benefits from prior cytotoxic 
chemotherapy such as prolonged disease stability might offer a useful addition to the 
pharmacologic management of patients with locally advance, recurrent or metastatic breast 
cancer. 
This Phase Ib/II study was designed to assess the safety and efficacy of a new immunotherapy 
product, Ad-RTS-hIL-12 (also known as INXN-2001) + veledimex (also known as INXN-1001), 
in patients with locally advanced, recurrent or metastatic breast cancer who achieved clinical 
benefit, i.e., stable disease (SD) or a PR with standard therapy.  The study will evaluate whether 
Ad-RTS-hIL-12 + veledimex (also referred to in this protocol as Ad-RTS-hIL-12 
immunotherapy) allows maintenance of clinical benefit in patients who stop first-, second-, or 
third-line standard therapy after having achieved a PR or SD.  
2 
STUDY OBJECTIVES  
2.1 
Primary Objective 
 To evaluate the safety and tolerability of one cycle of Ad-RTS-hIL-12 immunotherapy  
a) following a first-, second-, or third-line standard treatment in HER2-negative (HER2-) 
subjects, or b) together with a first-, second-, or third-line anti-HER2 antibody therapy in 
HER2-positive (HER2+) subjects as defined by Section 12.4.2.   
2.2 
Secondary Objectives 
 To estimate the progression rate at 12 weeks after the start of one cycle of Ad-RTS-hIL-
12 immunotherapy.  
 To evaluate the overall response rate (ORR), defined as the rate of complete response 
(CR) plus the rate of PR at 12 weeks following the start of Ad-RTS-hIL-12 
immunotherapy.    
 To evaluate the disease control rate (DCR), defined as the proportion of subjects who 
have a CR, PR, or SD at 12 weeks following the start of one cycle of Ad-RTS-hIL-12 
immunotherapy. 
 To evaluate the number of subjects whose baseline tumor status (SD or PR) improves to 
PR or better at 12 weeks following the start of Ad-RTS-hIL-12 immunotherapy. 
 To compare radiographic responses by irRC with conventional reporting by RECIST 
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 
To explore the impact of treatment on tumor and serum immune biomarkers 
3 
STUDY DESIGN  
3.1 
Overall Study Design 
This is a single-arm, single-center phase Ib/II study to examine the safety, tolerability and 
preliminary efficacy of providing one cycle of Ad-RTS-hIL-12 immunotherapy following 
achievement of SD or PR on standard first-, second-, or third-line chemotherapy in breast cancer 
subjects.  The patient population will include patients with locally advanced or metastatic breast 
cancer of all subtypes. The safety of this therapy and the preliminary evidence of efficacy will 
guide further studies. Patients will be required to be in SD or PR after completion of a minimum 
of 12 weeks on standard chemotherapy.  Subjects who have PD or a CR after the standard 
chemotherapy are not eligible for the study.  Following entry into the trial, patients will go on a 
treatment holiday from the standard chemotherapy and enter an immunotherapy phase of 
treatment.   
Scans will be conducted 6 and 12 weeks after the start of Ad-RTS-hIL-12 immunotherapy for 
determination of tumor response.  Radiographic PD at week 6 must be confirmed at least 4 
weeks later either at week 12 or earlier if clinically necessitated.  In cases of slow tumor growth, 
the investigator may wait until confirmation of PD at 12 weeks to resume chemotherapy.  In 
cases of unequivocal progression, the investigator may resume chemotherapy prior to 12 weeks 
and the subject will be considered as treatment failure at 12 weeks.   
Upon completion of Week 12, subjects who are considered to have SD or better will enter into 
long-term follow-up for up to an additional 36 weeks.  In the long-term follow-up period, scans 
will be performed at 18, 24, 36, and 48 weeks until a radiographic response of PD is confirmed. 
The assessment of response will be based on Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.1 using tumor measurements from contrast-enhanced computed tomography (CT).  
Tumor response will also be assessed by Immune-Related Response Criteria (irRC) (Wolchok et 
al, 2009).  Eligible subjects will also be asked to consent to allow ZIOPHARM to obtain scans 
and tumor measurements taken both a) prior to initiating the pre-study standard chemotherapy 
and b) after a minimum of 12 weeks of pre-study standard chemotherapy, and not more than 4 
weeks prior to study enrollment, in order to confirm their SD, PR status.  
For subjects with HER2- disease, the Ad-RTS-hIL-12 immunotherapy is intended to be given as 
a chemotherapy holiday, for example, to avoid intolerable or undesirable toxicity of the standard 
therapy.  Ad-RTS-hIL-12 immunotherapy must be started within 4 weeks of stopping the pre-
study standard chemotherapy.   
Subjects with HER2+ disease will receive the Ad-RTS-hIL-12 immunotherapy in conjunction 
with first-, second-, or third-line anti-HER2 antibody therapy, i.e., subjects may continue anti-
HER2-directed antibody therapy during the study period.  Anti-HER2 antibody therapy will be 
administered according to the manufacturer’s recommendations.  Subjects with HER2+ breast 
cancer who continue the anti-HER2 antibody therapy need to recover from any anti-HER2 
related AE/SAE, i.e., the event must have resolved to Grade 1 or baseline, before starting Ad-
RTS-hIL-12 immunotherapy. 
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2. 
Histologically-confirmed, locally advanced or metastatic adenocarcinoma of the breast, 
irrespective of hormone receptor or human epidermal growth factor receptor 2 (HER2) 
status (triple negative receptor status is permitted) 
a. Endocrine resistant hormone receptor-positive breast cancer subject who in 
the opinion of the physician requires chemotherapy is eligible 
b. Inflammatory breast cancer permitted with 2 injectable lesions 
c. Subjects who have received prior (neo) adjuvant chemotherapy, hormonal 
therapy or trastuzumab are eligible 
3. 
Achievement of SD or PR after a minimum of 12 weeks of pre-study first-, second-, or 
third-line standard chemotherapy 
NOTE: A prior therapy that is not completed due to toxicity will not be considered a line 
of therapy for eligibility determination. 
4. 
Presence of at least 2 measurable lesions as assessed by RECIST v1.1 criteria:  one lesion 
is to be injected with Ad-RTS-IL-12 and defined as a non-target lesion  
5. 
Standard treatment interrupted, except if anti-HER2 therapy 
6. 
All treatment-related or radiation-related toxicities resolved to Grade 1 or lower 
7. 
Submission of copies of tumor measurements and scans taken a) prior to starting the pre-
study standard chemotherapy and b) at the end of a minimum of 12 weeks of the pre-
study chemotherapy 
8. 
Life expectancy > 12 weeks at study entry 
9. 
Eastern Cooperative Oncology Groups (ECOG) performance status of 0 to 1 (see 
Appendix 16.1) 
10. Adequate bone marrow function as assessed by the following:  
a. ANC ≥ 1500/μL (without use of growth factors within 7 days of screening) 
b. ALC > 700/μL  
c. PLT ≥ 100,000/μL 
d.  Hb ≥ 9 g/dL  
11. Adequate liver function as assessed by the following:  
a. Serum bilirubin ≤ 1.5 mg/dL, except as follows 
i. Patients with Gilbert’s disease:  serum bilirubin < 5 mg/dL  
b. AST, ALT, and ALP ≤ 2.5 × ULN, except as follows 
i. Patients with hepatic metastases:  ALT and AST ≤ 5 × ULN 
ii. Patients with hepatic and/or bone metastases:  alkaline phosphatase ≤ 5 
× ULN 
12. Adequate renal function as assessed by the following:  
a. Serum creatinine ≤ 1.5 mg/dL OR  
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b. creatinine clearance of ≥ 60 mL/min based on a 24-hour urine collection 
13. Female subjects and their male partners must agree to use a highly reliable method of 
birth control (expected failure rate less than 5% per year) from the screening visit through 
28 days after the last dose of investigational product. Women of childbearing potential 
(perimenopausal women must be amenorrheic for at least 12 months to be considered of 
non-childbearing potential) must have a negative pregnancy test at screening  
14. Able to swallow oral medication 
15. Willing to comply with study procedures for the duration of the study and able to provide 
informed consent 
4.2 
Exclusion Criteria 
1. 
Metastatic breast cancer patients currently on hormone therapy as first- or second-line are 
not permitted 
2. 
Prior radiation therapy encompassing > 25% of bone marrow 
3. 
Any congenital or acquired condition leading to compromised ability to generate an 
immune response, including concomitant immunosuppressive therapy 
4. 
Immunosuppressive therapy 
a. Use of systemic immunosuppressive drugs including corticosteroids 
(prednisone equivalent ≥ 10 mg/day) within 6 weeks 
b. Requirement for continual immune suppression with immunosuppressive 
drugs (e.g., subjects with organ allografts) 
5. 
Major surgery within 4 weeks of study treatment, or major surgery planned for duration 
of study participation 
6. 
An active, second potentially life-threatening cancer, adequately treated basal cell or 
squamous cell skin cancer or carcinoma in situ of the cervix, low grade thyroid is 
permitted  
7. 
Presence of brain or subdural metastases, unless local therapy has been completed and 
corticosteroids have been discontinued for this indication for ≥ 4 weeks before starting 
study treatment:  
a. Any signs (e.g., radiologic) and/or symptoms of brain metastases must be 
stable for ≥ 4 weeks before starting study treatment 
b. Radiographic stability should be determined by comparing contrast-enhanced 
CT or magnetic resonance imaging (MRI) scans at screening to scans obtained 
by the same method at least 4 weeks earlier 
NOTE:  Screening for brain lesions is not required for all potential subjects; however, if 
there are any neurological signs or symptoms consistent with brain metastases, then a 
brain CT or MRI should be performed as clinically indicated. 
8. 
Presence or documented history of any of the following autoimmune conditions:  
a. Inflammatory bowel disease 
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b. Rheumatoid arthritis, systemic progressive sclerosis (scleroderma), systemic 
lupus erythematosus, autoimmune vasculitis (e.g., Wegener's granulomatosis) 
c. Motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre 
Syndrome)  
9. 
Presence of meningeal carcinomatosis 
10. Use of any medications that induce, inhibit, or are substrates of cytochrome P450 
(CYP450) 3A4 within 7 days prior to the first dose of investigational product without 
consultation of the medical monitor 
11. History or evidence of cardiac disease as indicated by any of the following: 
a. Congestive heart failure greater than New York Heart Association (NYHA) 
Class II (see protocol Appendix 16.4) 
b. Unstable angina (anginal symptoms at rest), or new-onset angina (begun 
within the last 3 months), or myocardial infarction within the 6 months prior 
to enrollment 
c. Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy 
d. Congenital long QT syndrome or taking drugs known to prolong the QT 
interval 
12. Current use of any drugs with a known risk of causing torsades de pointes 
13. Evidence or history of thromboembolic, venous, or arterial events such as a 
cerebrovascular accident including transient ischemic attacks within the past 3 months 
14. Evidence or history of bleeding diathesis or coagulopathy at the time of screening 
15. International normalized ration (INR) and activated partial thromboplastin time 
(aPTT) >1.5 × ULN, in subject who is not therapeutically anticoagulated.  Subjects who 
are being therapeutically anticoagulated with an agent such as Coumadin (warfarin 
sodium) or subcutaneous heparin may be included provided there is not prior evidence of 
underlying abnormality in coagulation parameters, the screening test results are in an 
appropriate therapeutic range, and the anticoagulation regimen is stable and closely 
monitored 
16. History of malabsorption syndrome or other condition that would interfere with enteral 
absorption 
17. Presence of active clinically serious infection (Grade 3 or higher by National Cancer 
Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE v.4.03) 
18. Diagnosis of infection with human immunodeficiency virus (HIV) or chronic infection 
with hepatitis B or C virus 
19. Any other 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 
20. Pregnant or breast-feeding 
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21. Use of any investigational, non-United States Food and Drug Administration (US FDA) 
approved drug within 28 days or 5 half-lives, whichever is longer, preceding screening 
22. Current participation in any other clinical trial without consultation with the medical 
monitor 
23. Presence of any condition which, in the investigator or medical monitor’s opinion, makes 
the patient unsuitable for the study participation 
4.3 
Subject Enrollment 
Forty subjects may be enrolled, including up to 8 subjects (20% of overall cohort) with HER2+ 
breast cancer. 
4.4 
Withdrawal of Subjects from Study Treatment and/or Study 
The Sponsor may terminate this study at any time.  The investigator and/or the subject have the 
right to terminate the subject’s participation in the study at any time.  
A subject may discontinue study treatment prematurely for any of the following reasons: 
 The investigator determines further participation is not in subject’s best interest (for 
example, subject experiences rapid clinical deterioration in the absence of confirmed 
disease progression) 
 Subject has confirmed disease progression  
 
A subject MUST discontinue study treatment in the event of any of the following: 
 Subject request to end study treatment 
 Any treatment-related AE(s) that meet withdrawal criteria 
 Substantial noncompliance with study requirements 
 Confirmed positive pregnancy test 
 Any intercurrent illness that would, in the judgement of the investigator or Sponsor’s 
medical monitor, affect assessments of clinical status to a significant degree and require 
discontinuation of protocol therapy 
A subject MUST be withdrawn from the study in the event of any of the following: 
 Withdrawal of informed consent for the study 
 The Ad-RTS-hIL-12 injection was not received 
NOTE: Any subject receiving veledimex will be included in the safety analysis group even if 
the Ad-RTS-hIL-12 injection was not received.  
Every effort should be made to follow subjects who withdraw from study treatment for ongoing 
treatment-related AEs until resolved, no resolution is expected, or the study has ended. 
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6.4 
Modification of Dose Schedule 
Subjects will receive only one cycle of Ad-RTS-hIL-12 immunotherapy.  If a dose of veledimex 
(up to 2 doses) is held for related toxicity, the treatment related AEs must have resolved to Grade 
2 or less for dosing to resume.  The held doses will not be made up; the patient will complete 
dosing according to the remaining schedule. 
  
If a patient misses a dose, the patient is allowed to resume dosing at the next scheduled dose, but 
must complete dosing according to the remaining schedule.  The missed dose will not be made 
up. 
6.5 
Dose-Limiting Toxicity 
Not applicable. 
6.6 
Maximum Tolerated Dose 
Not applicable. 
6.7 
Dose Modifications and Dose Delays 
Please refer to Section 6.4.  
Subjects who experience drug-related Grade 3 AEs during the first 7 days of oral dosing with 
veledimex will interrupt/discontinue further dosing at the discretion of the investigator. Subjects 
who experience drug-related Grade 4 AEs during the first 7 days of oral dosing with veledimex 
will discontinue therapy.  The decision as to whether subjects who experience severe or serious 
treatment-related adverse events will remain on study will be made by the investigator in 
conjunction with the Sponsor medical monitor.  
6.8 
Severity Grading and Management of Local Reactions 
Injection of agents into tissue carries a potential risk of local reactions that may be characterized 
as intense immunologic reaction at or near the injection site.  Local reactions will be graded 
according to the NCI CTCAE v.4.03 criteria. 
As with all signs and symptoms, events should be recorded and graded as AEs according to NCI 
CTCAE v.4.03 criteria.  Study stopping rules will not apply to a specific event if it is clearly 
unrelated to the Ad-RTS-hIL-12 injection.  
6.9 
Prophylactic Antipyretic and/or Analgesic Administration 
The use of antipyretics and/or analgesics is allowed as a prophylactic measure.  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.    
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NOTE:  Since fever and flu-like symptoms (e.g., fever, headache, chills, dehydration, etc.) are 
commonly experienced following adenoviral vector administration, it is highly recommended 
that subjects be treated with prophylactic, antipyretic and/or analgesic medication prior to Ad-
RTS-hIL-12 injection and during the first week after injection. 
Please refer to Appendix 16.2 for the recommended regimen for the prophylactic administration 
of antipyretics and/or analgesics. 
7 
CONCOMITANT THERAPY 
Information on concomitant medications, including all medications, blood products, vitamins, 
and other supplements, will be collected from the Screening visit through the end of the Initial 
Follow-up Period (Week 12).  Any new anti-cancer therapy that is started prior to confirmation 
of a radiographic response of PD, should be collected and entered as a concomitant medication.  
7.1 
Permitted Medications  
 HER-directed antibody therapies in patients with HER2+ disease 
 Subjects may receive standard treatments, including palliative and supportive care for any 
illness or symptom management during study treatment.   
 Anti-pyretics, analgesics, NSAIDs; Antidiarrheal therapy is permitted for investigational 
product-induced diarrhea. 
 Anti-emetics, with the exception of CYP450 3A4 inducers, inhibitors and substrates, are 
permitted for investigational product-induced nausea and vomiting.  
7.2 
Prohibited Medications 
 Any other investigational agent or anticancer therapy (chemotherapy, radiotherapy, 
including corticosteroids, etc.) while receiving study treatment. 
NOTE: Care should be given when prescribing medications that are classified as CYP450 
3A4 inducers, inhibitors, or substrates due to potential interactions with the investigational 
product.  In the event that one is prescribed, consultation with the medical monitor is advised.  
All medications should be recorded in the case report form (CRF) as indicated in the CRF 
completion guidelines. 
8 
STUDY PROCEDURES 
8.1 
Written Informed Consent 
The provided written informed consent form (ICF) must be signed before any protocol specific 
procedures and assessments can be performed.  A copy of the signed ICF will be given to the 
subject and a copy should be filed in the medical record.  The original ICF should be kept on file 
with the study reports.  Standard of care evaluations performed as part of the subject’s routine 
treatment prior to signing the ICF can be used if they were conducted within the timeframe of the 
screening period.  Refer to Section 13.8 for further information. 
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All imaging should be of diagnostic quality and include intravenous (IV) contrast. Please refer to 
Appendix 16.3 for RECIST v 1.1 guidelines. NOTE: In the event that IV contrast cannot be used, 
the medical monitor should be consulted.    
The same imaging method used for screening/baseline scans should be used for the tumor 
assessment performed at 6 and 12 weeks for the primary assessment of efficacy.  Scans should 
be available for collection upon Sponsor request. 
8.3.1.9 
Electrocardiogram  
A standard 12-lead ECG for evaluation of the QT/QTc interval will be performed at screening. 
8.4 
List of Assessments by Study Period 
8.4.1 
Screening 
The screening exams, tests and procedures must be done within 28 days of Ad-RTS-hIL-12 
injection.   
 Signed Informed Consent Form 
 Medical/Cancer History, including history of prior treatments and any associated residual 
toxicity  
 Physical Examination  
 ECOG performance status 
 Height and weight 
 Vital signs 
 Adverse events 
 Concomitant medications, i.e., medications taken within 28 days of Ad-RTS-hIL-12 
injection 
 Serum pregnancy test  
 Hematology panel:  CBC, WBC count with differential, RBC count, hematocrit, 
hemoglobin, red blood cell indices (MCV, MCG, MCHC), and platelet count 
 Coagulation panel:  aPTT and INR 
 Serum chemistry panel:  AST, ALT, LDH, ALP, creatinine, total bilirubin, total protein, 
albumin, BUN, glucose, sodium, potassium, chloride, calcium, phosphorus, and 
bicarbonate (as CO2) 
 Screening hepatitis B, hepatitis C, and HIV serology in subjects without documented 
negative results, or in subjects with known risk factors for infection 
 Baseline TSH 
 Tumor markers: CEA and Ca 15-3 
 Research bloods: for cytokines and immune cell activation by flow cytometry  
 Urinalysis panel:  appearance, pH, specific gravity, glucose, protein/albumin, presence of 
blood, ketones, bilirubin, nitrates, and leukocyte esterase.  In addition, a microscopic exam 
for casts, crystals, and cells may be done if clinically indicated 
 ECG at screening  
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 Receipt of copies of tumor measurements and scans taken a) before the start of the pre-
study standard chemotherapy and b) at after a minimum of 12 weeks of the pre-study 
chemotherapy. Tumor response imaging must be completed within 4 weeks of study 
enrollment.  
8.4.2 
Immunotherapy Cycle:  Day 1 (Ad-RTS-hIL-12 injection) 
 Physical examination (symptom-directed) 
 ECOG performance status  
 Weight 
 Vital signs 
 Adverse events  
 Concomitant medications 
 Hematology panel  
 Research bloods  
 Urinalysis 
 Urine pregnancy test 
 Tumor biopsy (prior to injection of Ad-RTS-hIL-12) 
 Oral veledimex 3 hours ± 3 hours before injection of Ad-RTS-hIL-12 
 Ad-RTS-hIL-12 injection 
 Veledimex dose compliance/subject diary 
 Veledimex dispensed for the following 6 days (the first dose is to be given in clinic) 
8.4.3 
Immunotherapy Cycle:  Day 2 
 Oral veledimex  
 Veledimex dose compliance/subject diary 
8.4.4 
Immunotherapy Cycle:  Day 3  
 ECOG performance status 
 Vital signs 
 Physical examination (symptom-directed) 
 Adverse events  
 Concomitant medications 
 Hematology panel  
 Research bloods 
 Oral veledimex 
 Veledimex dose compliance/subject diary 
8.4.5 
Immunotherapy Cycle:  Day 4-7  
 Oral veledimex 
 Veledimex dose compliance/subject diary 
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8.4.6 
Immunotherapy Cycle:  Day 8 
 ECOG performance status 
 Vital signs 
 Physical examination (symptom-directed) 
 Adverse events  
 Concomitant medications 
 Hematology panel  
 Coagulation panel 
 Serum chemistry panel  
 Research bloods 
 Collect veledimex dose compliance/subject diary 
8.4.7 
Immunotherapy Cycle: Day 21 
 Adverse events 
 Concomitant medications 
8.4.8 
Initial Follow-Up Period: Week 6 
 ECOG performance status 
 Vital signs 
 Physical examination  
 Adverse events  
 Weight 
 Concomitant medications 
 Hematology panel  
 Serum chemistry panel  
 Research bloods 
 Tumor markers 
 Tumor Biopsy 
 Imaging studies for tumor response. If radiographic PD is detected at 6 weeks, PD must 
be confirmed with repeat imaging 4 weeks later.  In case of slow tumor growth, the 
investigator may wait until confirmation of the PD at 12 weeks to resume chemotherapy.  
In case of unequivocal progression, the investigator may resume chemotherapy prior to 
12 weeks and the subject will be considered as treatment failure at 12 weeks. 
8.4.9 
Initial Follow-Up Period: Week 12  
 ECOG performance status 
 Vital signs 
 Physical examination  
 Adverse events  
 Weight 
 Concomitant medications (including any new anti-cancer therapies) 
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 Hematology panel  
 Serum chemistry panel  
 Research bloods 
 Tumor markers 
 Imaging studies for tumor response 
8.4.10 
Long-Term Follow-Up Period: Week 18 
 Imaging studies for tumor response 
8.4.11 
Long-Term Follow-Up Period: Week 24 
 Imaging studies for tumor response 
8.4.12 
Long-Term Follow-Up Period: Week 36 
 Imaging studies for tumor response 
8.4.13 
Long-Term Follow-Up Period: Week 48 
 Imaging studies for tumor response 
 
9 
TUMOR RESPONSE ASSESSMENTS 
Tumor response is based on the RECIST v.1.1.  A copy of the full article is provided as 
Appendix 16.3.  Key elements of the criteria are summarized below. Tumor response will also be 
assessed by Immune-Related Response Criteria (irRC) (Wolchok et al, 2009). 
9.1 
Measurability of Tumor at Baseline 
RECIST v.1.1 provides the following definitions for designating the tumor lesion/lymph node as 
measurable or non-measurable at baseline. 
9.1.1 
Measurable Lesions 
9.1.1.1 
Tumor Lesions 
Must be accurately measured in at least one dimension (longest diameter in the plane of 
measurement is to be recorded) with a minimum size as follows: 
 10 mm by CT scan (CT scan slice thickness no greater than 5 mm; see Appendix II of 
Eisenhauer et al, 2009 for imaging guidance) 
 10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with caliper should be recorded as non-measurable) 
 20 mm by chest X-ray 
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9.1.1.2 
Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph node must be ≥ 15 mm in 
short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater 
than 5 mm).  At baseline and in follow-up, only the short axis will be measured and followed. 
For additional information on lymph node measurement, see notes in Eisenhauer et al, 2009 
under the heading “Baseline documentation of target and non-target lesions,” as well as a 
companion paper on lymph node assessment using RECIST (Schwartz et al, 2009). 
9.1.2 
Non-measurable Lesions 
Non-measurable lesions are all other lesions, including small lesions (longest diameter < 10 mm 
or pathological lymph nodes with ≥ 10 to < 15 mm short axis) as well as truly non-measurable 
lesions. Truly non-measurable lesions include leptomeningeal disease, ascites, pleural or 
pericardial effusions, inflammatory breast disease, lymphangitic involvement of skin or lung, and 
abdominal masses/abdominal organomegaly identified by physical exam that is not measureable 
by reproducible imaging techniques. 
9.1.3 
Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment.   
9.1.3.1 
Bone Lesions 
Bone scan, PET scan, or plain films are not considered adequate imaging techniques to measure 
bone lesions.  However, these techniques can be used to confirm the presence or disappearance 
of bone lesions. 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross-sectional imaging techniques such as CT or MRI can be considered as 
measurable lesions if the soft tissue component meets the definition of measurability described 
above. 
Blastic bone lesions are non-measurable. 
9.1.3.2 
Cystic Lesions 
Lesions that meet the criteria for radiographically defined simple cysts should not be considered 
as malignant lesions (i.e., neither measurable nor non-measurable) since they are, by definition, 
simple cysts. 
Cystic lesions thought to represent cystic metastases can be considered as measurable lesions if 
they meet the definition of measurability described above.  However, if non-cystic lesions are 
present in the same individual, these are preferred for selection as target lesions. 
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9.1.3.3 
Lesions with Prior Local Treatment 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-
regional therapy, are usually not considered measurable unless there has been demonstrated 
progression in the lesion.  
9.1.4 
Methods of Tumor Measurement 
Please refer to Eisenhauer et al, 2009, Section 3.2 for details concerning details of how 
measurements of lesions/lymph nodes should be done.  For the current study, CT is the only 
acceptable measurement method. 
9.2 
Tumor Response Evaluation 
9.2.1 
Designation of Target and Non-Target Lesions 
When more than one measurable lesion is present at baseline, all lesions, up to a maximum of 5 
lesions (and a maximum of 2 lesions per involved organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline.  In the 
current study, the baseline measurement will be based on the scans and measurements taken at 
the end of the pre-study standard chemotherapy, as submitted by the investigator.  
Study entry requires the presence of at least 2 measurable lesions at baseline, one of which 
will be injected with Ad-RTS-hIL-12 and the other of which will be followed for response. 
Per RECIST v.1.1 (see Appendix 16.3), the injected lesion must be considered a non-target 
lesion. Remaining measurable lesions should be designated as target or non-target lesions 
as described above. 
Target lesions should be selected on the basis of their size (lesions with longest diameter) and be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements.  It may be the case that on occasion, the largest lesion does 
not lend itself to reproducible measurement; in such cases, the next largest lesion that can be 
reproducibly measured should be selected.  
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. The baseline sum 
diameters will be used as the reference to characterize any objective changes in the measurable 
dimension of disease. 
All other lesions or sites of disease (i.e., non-measurable lesions), including pathological lymph 
nodes, should be identified as non-target lesions. Measurements of non-target lesions, even if 
measurable, are not required, as they are intended to be assessed qualitatively and should be 
designated as present or absent at baseline. It is also possible to record multiple non-target 
lesions in the same organ as a single item, e.g., “multiple enlarged pelvic lymph nodes.” 
 
 
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9.2.2 
Definitions of Response 
9.2.2.1 
Target Lesions 
Definitions of response for individual patients at each assessment time point for target lesions are 
shown in Table 9.2.2.1-1. 
Table 9.2.2.1-1 Evaluation of Response in Target Lesions 
Response Category 
Definition 
CR 
Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-
target) must have reduction in short axis to < 10 mm. 
PR 
At least a 30% decrease in the sum of diameters of target lesions, taking as reference the 
baseline sum diameters. 
PD 
At least a 20% increase in the sum of diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline sum if that is the smallest on study). In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression).  For this study, PD should be confirmed at least 4 weeks later. 
SD 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, 
taking as reference the smallest sum diameters while on study 
Abbreviations:  CR, complete response; PR, partial response; PD, progressive disease; SD, stable disease 
9.2.2.1.1 
Lymph Nodes as Target Lesions 
Please refer to RECIST v.1.1 in Appendix 16.3 for special notes on the assessment of lymph 
nodes as target lesions, lesions that become too small to measure, and lesions that split or 
coalesce after treatment.  
9.2.2.2 
Non-target Lesions 
Definitions of response for individual patients at each assessment time point for non-target 
lesions are shown in Table 9.2.2.2-1. Non-target lesions, even if measurable, are to be evaluated 
qualitatively, as noted above, and are to be designated as CR, non-CR/non-PD, or PD, as defined 
in Table 9.2.2.2-1. 
 
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Table 9.2.2.2-1 Evaluation of Response at Each Time Point in Non-target Lesions  
Response Category 
Definition 
CR 
Disappearance of all non-target lesions and normalization of tumor marker level. 
All lymph nodes must be non-pathological in size (<10 mm short axis). 
Non-CR/Non-PD 
Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
PD 
Unequivocal progression (see comments below) of existing non-target lesions. 
(Note: the appearance of one or more new lesions is also considered progression).a 
Abbreviations:  CR, complete response; SD, stable disease; PD, progressive disease. 
a Although a clear progression of “non-target” lesions only is exceptional, in such circumstances, the opinion of 
the treating physician should prevail. 
9.2.2.2.1 
Special Notes on Designation of Progression in Non-Target Disease 
The concept of progression of non-target disease in the setting of concurrent measurable disease 
as in this study requires further explanation.  In this setting, to assign unequivocal progression on 
the basis of the non-target disease (see determination of overall response in Section 9.2.2.5), 
there must be an overall level of substantial worsening in non-target disease such that, even in 
the presence of SD or PR in the target disease, the overall tumor burden has increased 
sufficiently to warrant discontinuation of therapy (see examples in the RECIST v.1.1 guidelines 
in Appendix 16.3).  A modest increase in the size of one or more non-target lesions is usually not 
sufficient to qualify for a designation as unequivocal progression. The designation of overall 
progression solely on the basis of change in non-target disease in the face of SD or PR of target 
disease will therefore be extremely rare. 
9.2.2.3 
New Lesions 
The appearance of new malignant lesions denotes disease progression.  Refer to RECIST v.1.1 in 
Appendix 16.3 for notes concerning the detection of new lesions. 
9.2.2.4 
Missing Data 
When no imaging/measurement is done at all at a particular time point, the subject is not 
evaluable (NE) at that time point. If only a subset of lesion measurements is made at an 
assessment, usually the case is also considered NE at that time point, unless a convincing 
argument can be made that the contribution of the individual missing lesions would not change 
the assigned time point response.  This would be most likely to happen in the case of PD.  For 
example, if a subject had a baseline sum of 50 mm with three measured lesions and at the 
assessment only two lesions were assessed, but those gave a sum of 80 mm, the subject will have 
achieved PD status regardless of the contribution of the missing lesion measurement. 
9.2.2.4.1 
Additional Notes Relevant to Designations of Disease Progression 
Per RECIST v.1.1, patients with a global deterioration of health status requiring discontinuation 
of treatment without objective evidence of disease progression should be reported as 
“symptomatic deterioration,” and every effort should be made to document objective progression 
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even after discontinuation of treatment.  Symptomatic deterioration is not a descriptor of an 
objective response; it is a reason for stopping study therapy.  The objective response of such 
subjects is to be determined by evaluation of target and non-target disease as shown in Table 
9.2.2.1-1 and Table 9.2.2.2-1.  In the current study, scans are to be done at week 6 and 12 weeks, 
and at any time deemed appropriate by the investigator (i.e., when progression is suspected).  PD 
at week 6 must be confirmed at least 4 weeks later.  The definition of progression rate for this 
study, is given in Section 12.4.3.2. 
9.2.2.5 
Overall Response for Each Subject at Each Assessment Time Point 
Overall response at each assessment time point is based on the totality of the responses for target 
and non-target lesions, as shown in Table 9.2.2.5-1. 
Table 9.2.2.5-1 Rubric for Determination of Overall Response at Each Assessment Time Point for 
Each Patient 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviations:  CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease 
9.2.2.6 
Additional Information Concerning RECIST v1.1 
Full details concerning the use of RECIST v.1.1 may be found in the full article by Eisenhauer 
et, al (2009), which is attached as Appendix 16.3. 
9.2.2.7    Immune Related Response Criteria (irRC) 
At the baseline tumor assessment, the sum of the products of the two largest perpendicular 
diameters (SPD) of all index lesions (five lesions per organ, up to 10 visceral lesions and five 
cutaneous index lesions) is calculated.  At each subsequent tumor assessment, the SPD of the 
index lesions and of new, measurable lesions (≥ 5 × 5 mm; up to 5 new lesions per organ:  5 new 
cutaneous lesions and 10 visceral lesions) are added together to provide the total tumor burden: 
Tumor Burden = SPDindex lesions + SPDnew, measurable lesions 
Percentage changes in tumor burden per assessment time point describe the size and growth 
kinetics of both conventional and new, measurable lesions as they appear. At each tumor 
assessment, the response in index and new, measurable lesions is defined based on the change in 
tumor burden (after ruling out irPD).  Decreases in tumor burden must be assessed relative to 
baseline measurements (i.e., the SPD of all index lesions at screening). 
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Overall response using the irRC:  The overall response according to the irRCis derived from 
time-point response assessments (based on tumor burden) as follows: 
 irCR, complete disappearance of all lesions (whether measurable or not, and no new 
lesions) confirmation by a repeat, consecutive assessment no less than 4 weeks from the 
date first documented 
 irPR, decrease in tumor burden ≥50% relative to baseline confirmed by a consecutive 
assessment at least 4 weeks after first documentation 
 irSD, not meeting criteria for irCR or irPR, in absence of irPD 
 irPD, increase in tumor burden ≥25% relative to nadir (minimum recorded tumor burden) 
confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first 
documented 
10 
SAFETY ASSESSMENTS 
10.1 
Adverse Events (AEs) and Definitions 
Adverse Event:  Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product that does not necessarily have a causal relationship to the 
treatment. An AE can therefore be any unfavorable and unintended sign including an abnormal 
laboratory finding, symptom, or disease temporarily associated with the use of a medicinal 
product, and any worsening of pre-existing conditions, regardless of causality to the medicinal 
product.   
Suspected Adverse Reaction: Any AE for which there is evidence to suggest a causal relationship 
(reasonable possibility) between the drug and the AE.  A suspected adverse reaction implies a 
lesser degree of certainty about causality than an adverse reaction. 
Adverse Reaction: Any AE caused by the use of a drug.  Adverse reactions are a subset of all 
suspected adverse reactions for which there is reason to conclude that the drug caused the event. 
Unexpected Adverse Reaction: Any AE that is (a) not listed in the Investigator’s Brochure, (b) 
not listed with the specificity and severity that is being observed, (c) not consistent with the risk 
information described in the general investigational plan or elsewhere in the current application 
(in the absence of an investigator brochure), and (d) listed as occurring with a class of drugs, but 
not specifically mentioned as occurring with the particular drug under investigation. 
Adverse events may be treatment-emergent (i.e., occurring after initial receipt of investigational 
product) or nontreatment-emergent.  A nontreatment-emergent AE is any new sign or symptom, 
disease, or other untoward medical event that begins after written informed consent has been 
obtained but before the subject has received investigational product. 
10.2 
Evaluation of Adverse Events 
Adverse events include: 
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 Suspected adverse drug reactions 
 Reactions from investigational product 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 investigational product. 
 Other untoward medical events, regardless of their relationship to the investigational 
product, such as injury, events that require surgery, accidents, extensions of symptoms, or 
apparently unrelated illnesses 
The following items should be considered when identifying an AE: 
 Anticipated day-to-day fluctuations of pre-existing conditions, including the disease 
under study, that do not represent a clinically significant exacerbation or worsening need 
not be considered AEs.  
 In the event that a constellation of symptoms results in a confirmed diagnosis, the 
diagnosis (not the symptoms) should be recorded as the AE term. 
 If a diagnosis cannot be established, the symptoms should be recorded as the AE(s).  
 If an ongoing symptom has been included in the medical history, an associated severity 
grade and frequency should also be documented so that a worsening in severity or 
frequency of a symptom can be readily identified as an AE. 
 Progression of disease is not itself an AE; however, the presenting sign or symptom of 
the disease progression should be documented as an AE (e.g. pleural effusion).  
Exception:  If a subject experiences progression of disease that results in death, 
‘progression of disease’ may be reported as an SAE if, by medical opinion, the term best 
describes the cause of death. 
10.3 
Determination of Seriousness 
10.3.1 
Serious Adverse Event (SAE) 
An AE is considered an SAE if any of the following conditions applies: 
 
 Death:  An AE that results in death during the active study period or within 30 days 
following investigational product administration.  In addition, a reported death at any 
time post-study that is thought to be related to investigational product administration; 
 Life-threatening adverse event:  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. 
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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 in the offspring of a subject:  A fixed, permanent 
impairment established at or before birth; 
 An important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above. Medical judgment should be 
used to decide if an adverse event should be considered an important medical event. 
Examples of medically important events are intensive treatment for allergic 
bronchospasm or convulsions that do not result in hospitalizations 
 New cancer: Occurrence or diagnosis of a new cancer during the trial is considered an 
SAE. (This does not pertain to metastasis of current disease); 
 Any AE associated with an overdose of the investigational product:  An overdose of 
investigational product is defined as an occurrence of administered dose exceeding that 
which is prescribed by the investigator per protocol. 
10.3.2 
Non-Serious Adverse Event 
An AE that does not fulfill the criteria for a SAE is classified as a non-serious AE. See 
Section 10.1. 
10.4 
Determination of Severity 
Assessment of severity is one of the responsibilities of the investigator in the evaluation of AEs 
and SAEs.  The severity of AEs will be assessed according to the NCI CTCAE, v.4.03, which 
will be provided to the site as a separate document.  If the AE is not defined in the NCI CTCAE, 
v.4.03, the investigator will determine the severity of an AE based on the following definitions: 
 Mild (Grade 1): The AE is noticeable to the subject, but does not interfere with routine 
activity. The AE does not require discontinuing administration or reducing the dose of the 
investigational product. 
 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 
discontinuing administration of the investigational product. 
 Severe (Grade 3): The AE significantly limits the subject’s ability to perform routine 
activities despite symptomatic therapy. In addition, the AE leads to discontinuing 
administration or reducing the dose of the investigational product. 
 Life Threatening (Grade 4): The AE requires discontinuing administration of the 
investigational product. The subject is at immediate risk of death. 
 Death (Grade 5): The subject dies as a direct result of the complication or condition  
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10.5 
Determination of Causality 
The investigator is required to provide an assessment of relationship of AEs and SAEs to the 
investigational product.  A number of factors should be considered in making this assessment 
including:   
 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 investigational product and the AE 
 Whether the clinical or laboratory manifestations of the AE are consistent with known 
actions or previously reported toxicity of the investigational product or similar drugs 
 Whether the AE resolved or improved with decreasing the dose or stopping the 
investigational product (i.e., dechallenge); or recurred or worsened with re-exposure to 
the drug (i.e., rechallenge). 
Relationship assessments that indicate “Not Related” to investigational product:  
 None: The event is related to an etiology other than the investigational product (the 
alternative etiology must be documented in the study subject’s medical record and/or 
SAE form). 
 Unlikely or Remote: The event is unlikely to be related to the investigational product and 
likely to be related to factors other than investigational product. 
Relationship assessments that indicate “Related” to investigational product: 
 Possible:  There is an association between the event and the administration of the 
investigational product and there is a plausible mechanism for the event to be related to 
investigational product; but there may also be alternative etiology, such as characteristics 
of the subject’s clinical status or underlying disease. 
 Probable:  There is an association between the event and the administration of 
investigational product, a plausible mechanism for the event to be related to the 
investigational product and the event could not be reasonably explained by known 
characteristics of the subject’s clinical status or an alternative etiology is not apparent. 
 Definite:  There is an association between the event and the administration of 
investigational product, a plausible mechanism for the event to be related to the 
investigational product and causes other than the investigational product have been ruled 
out and/or the event re-appeared on re-exposure to the investigational product. 
For AEs that occur prior to the administration of investigational product, an assessment of 
protocol relatedness must be made.  AEs may occur as a result of procedures required during the 
screening process (e.g., blood collection, washout of an existing medication) prior to the initial 
administration of investigational product.   For AEs that occur before administration of 
investigational product, only those that are assessed by the investigator as protocol-related 
should be reported to the Sponsor.  The following guidelines should be used by investigators to 
assess the relationship of an AE to a protocol-required procedure: 
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dated by the investigator.  The SAE Report form and copies of source documents (with subject 
identifiers redacted) will be transmitted by fax.  A hospital discharge summary should be 
provided if the subject was hospitalized.  An SAE report will be considered final once all 
relevant information has been received and reviewed by the Sponsor. 
The SAE Report form is provided in the investigator study files.  Please refer to the investigator 
study files for instructions on how to complete this form.  The investigator will provide all of the 
following information related to the event: 
 
 Investigator identification 
 Subject identification (e.g., subject number, initials, sex, age or date of birth) 
 Information regarding investigational product administration (e.g. start/stop date, dose, 
and frequency) 
 Cycle and day of SAE occurrence documentation on SAE report forms 
 Description of event 
 Action taken with the investigational product in relation to the SAE  
 Outcome of the SAE  
In addition to the above information, the investigator must provide, for each event term, an 
assessment of: 
 Severity/intensity 
 Relationship to the investigational product (causality assessment) 
10.8 
Sponsor and Investigator Responsibility for Reporting Adverse Events 
All AEs and SAEs will be reported to regulatory authorities, IRBs/IECs, and investigators in 
accordance with all applicable global laws and regulations.  The investigator must submit all 
Safety Letters received from the Sponsor to his/her IRB/IEC per agreements and local 
requirements.  The investigator must keep copies of all safety reports/letters, including 
correspondence with ZIOPHARM and the IRB/IEC, in the study file. 
10.9 
Follow-up Information for Adverse Events 
Appropriate diagnostic tests should be performed and therapeutic measures, as medically 
indicated, per the investigator, should be instituted.  Appropriate consultation and follow-up 
evaluations should be carried out until the event has resolved, stabilized, returned to baseline, or 
is otherwise explained by the investigator. 
Required Follow-up for Adverse Events  
All AEs and SAEs will be collected from the signing of the ICF through Week 6. After Week 6, 
only SAEs suspected of being related to investigational product will be collected. Follow up 
information for ongoing SAEs will be requested by the Sponsor until one of the following 
occurs: 
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12 
STATISTICAL METHODS  
12.1 
Populations for Analysis 
The following subject populations will be evaluated and used for presentation and analysis of the 
data:  
 The safety population will comprise all subjects who have received either the injection of 
Ad-RTS-hIL-12 or any doses of veledimex 
 The veledimex-treated population will comprise subjects who have received the injection 
of Ad-RTS-hIL-12 and at least one dose of veledimex 
 The veledimex-evaluable population will comprise subjects who have received the 
injection of Ad-RTS-hIL-12 and all 7 doses of veledimex 
12.2 
Sample Size and Power Calculations 
A maximum of 40 patients will be treated.  This patient population will be heterogeneous and as 
such, it is difficult to define a threshold for a clear null and alternative hypothesis.   This sample 
size will allow us to estimate an overall progression rate at 12 weeks with a maximum 95% exact 
confidence interval half-width of 0.16.  This is based on an exact binomial calculation and is an 
estimate.  However, analysis of progression-free survival will be conducted using Kaplan-Meier 
methods. 
12.3 
Endpoints 
12.3.1 
Primary Endpoint 
 To evaluate the safety and tolerability of one cycle of Ad-RTS-hIL-12 immunotherapy  
a) following a first-, second-, or third-line standard treatment in HER2-negative (HER2-) 
subjects, or b) together with a first-, second-, or third-line anti-HER2 antibody therapy in 
HER2-positive (HER2+) subjects as defined by section 12.4.2.   
12.3.2 
Secondary Endpoints 
 To estimate the progression rate at 12 weeks after the start of one cycle of Ad-RTS-hIL-
12 immunotherapy.  
 To evaluate the overall response rate (ORR), defined as the rate of complete response 
(CR) plus the rate of PR at 12 weeks following the start of Ad-RTS-hIL-12 
immunotherapy.    
 To evaluate the disease control rate (DCR), defined as the proportion of subjects who 
have a CR, PR, or SD at 12-weeks following the start of one cycle of Ad-RTS-hIL-12 
immunotherapy 
 To evaluate the number of subjects whose baseline tumor status (SD or PR) improves to 
PR or better at 12 weeks following the start of Ad-RTS-hIL-12 immunotherapy 
 To compare radiographic responses by irRC with conventional reporting by RECIST 
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 If 9 of the first 20 patients have related, treatment refractory Grade 3 or 4 AE, stop the 
study. 
 If 11 of the first 25 patients have related, treatment refractory Grade 3 or 4 AE, stop the 
study. 
 If 12 of the first 30 patients have related, treatment refractory Grade 3 or 4 AE, stop the 
study. 
 If 14 of the first 35 patients have related, treatment refractory Grade 3 or 4 AE, stop the 
study. 
 If 15 of the first 40 patients have related, treatment refractory Grade 3 or 4 AE, stop the 
study. 
12.4.3 
Efficacy Analyses 
Efficacy will be based on the tumor response at 12 weeks.   
12.4.3.1 
Tumor response  
Tumor response (CR, PR, SD, and PD) will be determined according to RECIST v.1.1 (see 
Section 9). 
12.4.3.2 
Progression rate 
The proportion failed by 12 weeks is denoted as the progression rate survival and is derived 
based on the sum of progression events, death events and subjects who discontinue the trial due 
to an AE. 
The second stopping rule is based on the progression rate during the 12 weeks of 
immunotherapy.  A progression rate of 50% is deemed acceptable, while an 80% rate is deemed 
unacceptable.   The boundaries to stop the study using a repeated significance testing approach 
are given as follows:  
 If 5 of the first 5 patients progress, stop the study. 
 If 9 of the first 10 patients progress, stop the study. 
 If 12 of the first 15 patients progress, stop the study. 
 If 15 of the first 20 patients progress, stop the study. 
 If 18 of the first 25 patients progress, stop the study. 
 If 20 of the first 30 patients progress, stop the study. 
 If 23 of the first 35 patients progress, stop the study. 
 If 26 of the first 40 patients progress, stop the study. 
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12.4.3.3 
Progression-free Rate 
Proportion of subjects who have 12-week progression free survival (proportion failed) after the 
start of Ad-RTS-hIL-12 immunotherapy.  
12.4.3.4 
ORR 
The ORR is defined as the percentage of subjects who have CR or PR at 12 weeks after the start 
of Ad-RTS-hIL-12 immunotherapy. 
12.4.3.5 
DCR 
The disease control rate is the proportion of subjects who have a CR, PR, or SD at 12 weeks after 
the start of Ad-RTS-hIL-12 immunotherapy. 
12.4.3.6 
Multi-Center Study 
Not applicable.  This is a single center study at the Memorial Sloan Kettering Cancer Center 
(MSKCC).  
12.4.4 
Adjustments for Covariates 
No adjustments for covariates will be made. 
12.4.5 
Procedures for Handling Missing, Unused, and Spurious Data 
No imputation of values for missing data will be performed.  Standard clinical monitoring and 
data management practices will be used to ensure the integrity of data. 
12.4.6 
Interim Analysis 
See pre-specified stopping rules in Section 12.4.2 and Section 12.4.3.2. 
12.4.7 
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. 
13 
STUDY MANAGEMENT 
13.1 
Electronic Case Report Forms and Source Documentation 
For each subject, eCRFs and corresponding source records will be maintained at the clinical site.  
The Sponsor or designee will provide the study site with secure access to and sufficient training 
on the electronic data capture application, to permit site personnel to enter or correct information 
in the eCRFs for the subjects for whom they are responsible.   
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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 electronic data capture application, the 
investigator must provide formal approval of all subject information in the eCRFs and changes to 
the eCRFs to endorse the final submitted data for the subjects for whom he/she is responsible.  
The audit trail entry will show the user’s identification information and the date and time of any 
corrections.   
eCRF completion may be delegated to other study personnel; however, such delegation must be 
documented in writing.  If, for any reason, certain data are lacking to complete an individual 
report form, the investigator will provide a written statement explaining the reasons for the lack 
of data. 
Sponsor or designee will retain the eCRF data and corresponding audit trails.  A copy of the final 
archival eCRF in the form of a compact disk or other electronic media will be placed in the 
investigator’s study file. 
13.2 
Good Clinical Practice 
The study will be conducted in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Conference on Harmonization 
(ICH) Good Clinical Practice (GCP) guidelines, applicable regulatory requirements, and 
ZIOPHARM policies. 
13.3 
Sponsor Monitoring 
After satisfactory receipt of all necessary regulatory paperwork, the Sponsor’s monitor will 
arrange that all study material be delivered to the study site at a mutually convenient time.  An 
initiation visits by ZIOPHARM and its monitoring personnel will be made.  At this meeting, all 
personnel expected to be involved in the conduct of the study will undergo an orientation to 
include review of study protocol, instruction for CRF completion and overall responsibilities, 
including those for drug accountability and study file maintenance. 
Throughout the course of the study, the Sponsor’s monitor will make frequent contact with the 
investigator, and this will include telephone and/or on-site visits.  During these visits, CRFs will 
be reviewed for completeness and adherence to protocol.  As part of the data audit, it is expected 
that source documents (e.g. hospital records, office records) will be made available for review by 
the monitor.  The monitor also will perform drug accountability checks, and may periodically 
request review of the investigator’s study file to assure completeness of documentation in all 
respects of study conduct. 
Upon study completion, the monitor will arrange for a final review of the study files, after which 
the file should be secured by storage for the appropriate period as specified in Section 13.5. The 
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investigator or appointed delegate will receive the Sponsor’s representative during these on-site 
visits and will cooperate in providing the documents for inspection and responding to inquiries 
that may arise as part of this review.  The investigator will also permit inspection of the study 
files by authorized representatives of the FDA. 
13.4 
Duration of the Study 
Enrolled subjects will participate for up to 52 weeks, including up to 4 weeks for screening 
activities.   
The overall duration of the entire study (screening, treatment, and follow-up for all subjects) is 
expected to be approximately 3.5 years. 
13.5 
Records Retention 
Records of drug disposition, CRFs, and reports of the clinical trial must be maintained by the 
investigator for a period of at least 2 years following the date on which the test article is 
approved by FDA for marketing for the purposes that were investigated in the study.  If no 
application is to be filed or if the application is not approved for such indication, the records 
must be stored for 2 additional years and then returned to ZIOPHARM.  No records will be 
destroyed, but will be indefinitely stored. 
13.6 
Institutional Review Board 
This protocol and the study informed consent form must be reviewed and approved by the 
Institutional Biosafety Committee (where applicable) and IRB/IEC prior to the start of the study, 
and a copy of the approval letter supplied to ZIOPHARM.  During the course of the study, the 
investigator shall make timely and accurate reports to the IRB/IEC on study progress at intervals 
not exceeding one year, as well as satisfying any other local IRB/IEC reporting regulations.  
Copies of all reports to, and correspondence with, the IRB/IEC must be provided to 
ZIOPHARM.  Further, within three months of the completion or early termination of the study, a 
final report should be made to the IRB/IEC and ZIOPHARM by the investigator. 
All protocol revisions must originate with and be documented by ZIOPHARM.  If the requested 
revision is an amendment, the investigator must sign it.  The FDA will be notified of all revisions 
by ZIOPHARM.  The investigator must submit the amendment to his/her IRB/IEC for review 
and approval prior to implementation.  Documentation of approval signed by the chairperson or 
designee of the IRB/IEC must be sent to ZIOPHARM.  
It is the investigator’s obligation to maintain an IRB/IEC correspondence file and to make this 
available for review to ZIOPHARM representatives as part of the routine study monitoring 
process. 
13.7 
Confidentiality and HIPAA 
The written Informed Consent 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. 
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ZIOPHARM Oncology, Inc. 
Protocol ATI001-203 –Amendment 2 
Final: 16 May 2016 
Confidential 
 
 
 
The written Informed Consent 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 Informed Consent Form will be accompanied by or include a separate document 
incorporating US Health Insurance Portability and Accountability Act (HIPAA)-compliant 
wording by which the subjects authorize the use and disclosure of their Protected Health 
Information. 
13.8 
Informed Consent 
13.8.1 
FDA Informed Consent Requirements 
The investigator or his/her staff will explain the nature of the study, its purpose and associated 
procedures, the expected duration, and the potential risks involved to the prospective subject 
prior to enrollment.  The Informed Consent should also indicate that, by signature, the subject or, 
where appropriate, a legal guardian, permits access to relevant medical records by the Sponsor 
and by representatives of the US 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 individual 
will have ample time and opportunity to ask questions.  He/she 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 individual 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 subject.  The signed Informed Consent Form is to remain in the investigator’s 
file.  
The Informed Consent Form and any other written information provided to the subjects will be 
revised whenever important new information becomes available that may be relevant to the 
subject’s consent, or if there is an amendment to the protocol that necessitates a change to the 
content of the subject’s informed consent.  The investigator will inform the subject of changes in 
a timely manner and will ask the subject to confirm continuation of his/her participation in the 
study by his/her signature on the revised Informed Consent Form (if applicable).  Any written 
Informed Consent Form and written information must receive IRB/IEC approval/favorable 
opinion in advance of use. 
13.8.2 
Subject Informed Consent Form 
ZIOPHARM will provide a sample subject Informed Consent Form for modification, as 
appropriate, by the investigator. 
 
 
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Ad-RTS-hIL-12 (INXN-2001) + Veledimex (INXN-1001) 
ZIOPHARM Oncology, Inc. 
Protocol ATI001-203 –Amendment 2 
Final: 16 May 2016 
Confidential 
 
 
 
14 
PROTOCOL APPROVAL PAGE 
Title:  A Single-arm, Open-label Study of Ad-RTS-hIL-12 + Veledimex Following First- or 
Second-Line Standard Treatment in Subjects with Locally Advanced or Metastatic Breast 
Cancer 
With the exception of a change intended to eliminate an immediate hazard to subjects, the study 
shall be conducted as described in the approved protocol. All deviations from the protocol will 
be documented.  Any significant deviation or deviation related to dosing or safety evaluation will 
be reported to ZIOPHARM. 
I agree to the terms of this study protocol.  I will conduct the study according to the procedures 
specified herein, and according to principles of Good Clinical Practice and local regulations and 
requirements. 
 
Study Site   
 
Center Name:   ____________________________________ 
 
Principal Investigator 
Print Name:  _____________________________________ 
 
Signature: 
_____________________________________ 
 
Date:   
_____________________________________ 
 
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Ad-RTS-hIL-12 (INXN-2001) + Veledimex (INXN-1001) 
ZIOPHARM Oncology, Inc. 
Protocol ATI001-203 –Amendment 2 
Final: 16 May 2016 
Confidential 
 
 
 
16 
APPENDICES 
16.1 
Eastern Oncology Performance Status 
ECOG PERFORMANCE STATUS37 
Grade 
Performance Status 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, eg, light house work, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed 
or chair. 
5 
Dead. 
37 Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity and Response 
Criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-55, 1982. 
 
 
 
 
 
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ZIOPHARM Oncology, Inc. 
Protocol ATI001-203 –Amendment 2 
Final: 16 May 2016 
Confidential 
 
 
 
16.2 
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 recombinant adenovirus vector administration and 
temperatures up to 104° F with chills and generalized malaise have been observed with 
treatment.  Because low grade fever is very likely to occur, prophylaxis with acetaminophen is 
strongly recommended.   
 While meta-analyses suggest that ibuprofen is a better anti-pyretic medication than 
acetaminophen, acetaminophen also prevents and or reduces a fever.  Acetaminophen is 
available without a prescription in 325 mg or 500 mg tablets.  One to two tablets every 4 
hours should be used to eliminate fever.  The maximum dose of acetaminophen in adults 
should not exceed 4 grams in a 24-hour period. 
 Side effects are rare, but some people are allergic to the medication.  Over doses may cause 
liver failure.  Therefore, people with liver disease and chronic alcohol users should avoid this 
medication.  
 Common brand names of acetaminophen are Aspirin Free Anacin®, Feverall®, Genapap®, 
Panadol®, Tempra®, and Tylenol®.  
In general, a fever can be treated with acetaminophen.  Alternating doses of ibuprofen with 
acetaminophen will also effectively control fever and prevent accidental overdose.  If a fever 
occurs in spite of prophylactic medication or does not respond to usual doses of acetaminophen, 
then a combination of both acetaminophen and ibuprofen may be needed to stop the fever.   
 
 
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ZIOPHARM Oncology, Inc. 
Protocol ATI001-203 –Amendment 2 
Final: 16 May 2016 
Confidential 
 
 
 
16.3 
RECIST v. 1.1  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
 
 
Protocol Title: 
A Single-arm, Open-label Study of Ad-RTS-hIL-12 + 
Veledimex Following First- or Second-Line Standard 
Treatment in Subjects with Locally Advanced or 
Metastatic Breast Cancer 
Protocol Number: 
ATI001-203 
Study Drugs: 
INXN-2001 (Ad-RTS-hIL-12) 
INXN-1001 (oral activator ligand)  
Date of Protocol: 
Amendment 1:       05 November 2014 
Original protocol:  08 July 2014   
 
 
 
  
 
 
 
 
 
 
 
CONFIDENTIAL 


Ad-RTS-hIL-12 (INXN-2001) + Veledimex (INXN-1001) 
ZIOPHARM Oncology, Inc. 
Protocol ATI001-203 – Amendment 1 
 
Final:  05 November 2014 
Confidential 
 
 
 
 
 
Page 2 of 10 
Tabular Summary of Revisions Implemented in the Amended Protocol 
Section in Amended 
Protocol 
Revised or Deleted Text/Section 
Rationale for Change 
Title Page, Page 
Headings and Footers 
(page 1) 
Specified “Original” for Date of Protocol (08 July 2014) and added Amendment 1, 05 
November 2014. 
To differentiate the original protocol 
from Amendment 1 
Title Page, Page 
Headings and Footers 
(page 1) 
Updated the primary contact for safety reporting from medical monitor to Safety 
Hotline Number. 
SAEs should be reported by calling the 
Safety Hotline Number instead of the  
medical monitor 
Protocol Synopsis (page 
2) 
In Research Hypothesis, specified standard therapy to be “chemotherapy” and 
changed anti-HER2 regimen to anti-HER 2 “antibody therapy”; these changes 
were also made throughout the document. 
Requested by principal investigator 
 
Primary Objective and 
Primary Endpoints 
(pages 2, 8, 35, 73) 
Primary Objective, changed from “To evaluate the safety and tolerability of one cycle 
of Ad-RTS-hIL-12 immunotherapy a) following a first-or second-line standard 
treatment in HER2-negative (HER2-) subjects, or b) together with a first- or second-
line anti-HER2 treatment  in  HER2-positive (HER2+) subjects” to “To evaluate the 
safety and tolerability of one cycle of Ad-RTS-hIL-12 immunotherapy a) following a 
first-or second-line standard treatment in HER2-negative (HER2-) subjects, or b) 
together with a first- or second-line anti-HER2 antibody therapy  in  HER2-positive 
(HER2+) subjects as defined  by Section 12.4.2. 
Requested by principal investigator and 
site staff 
Secondary Objective 
and Primary Endpoints 
(pages 2, 8, 35, 73) 
Secondary Objectives, deleted “To explore the biologic/immunologic effects of 
treatment on levels of the following cytokines in serum: interleukin-12 (IL-12), 
interleukin-10 (IL-10), and interferon-gamma (IFN–γ)” and “To explore the effect of 
treatment on tumor infiltration by effector cells and immune suppressor elements” 
and replaced them with “To compare radiographic responses by irRC with 
conventional reporting by RECIST” and “To explore the impact of treatment on 
tumor and serum immune biomarkers” 
Requested by principal investigator and 
site staff 
Study Design (page 2 - 3) 
Study Design language changed from “This is a single-arm pilot, single-center study 
to examine the safety, tolerability and preliminary efficacy of providing one cycle of 
Ad-RTS-hIL-12 immunotherapy following achievement of SD or PR on standard 
treatment as first- or second-line therapy in breast cancer subjects. The patient 
population will include patients with locally advanced or metastatic breast cancer of 
Requested by principal investigator and 
site staff 
 
 


Ad-RTS-hIL-12 (INXN-2001) + Veledimex (INXN-1001) 
ZIOPHARM Oncology, Inc. 
Protocol ATI001-203 – Amendment 1 
 
Final:  05 November 2014 
Confidential 
 
 
 
 
 
Page 3 of 10 
Section in Amended 
Protocol 
Revised or Deleted Text/Section 
Rationale for Change 
all subtypes. The safety of this therapy and the preliminary evidence of efficacy will 
guide further studies. Patients will be required to have SD or PR after completion of a 
minimum of 12 weeks on standard therapy.  Subjects who have progressive disease 
(PD) or a CR after the standard therapy are not eligible for the study.  Following entry 
into the trial, patients will go on a treatment holiday from the standard therapy and 
enter an immunotherapy phase of treatment” to “This is a single-arm, single-center 
study to examine the safety, tolerability and preliminary efficacy of one cycle of 
Ad-RTS-hIL-12 immunotherapy in women with advanced breast cancer and 
pre-study SD or PR after completion of a minimum 12 week course of standard 
first- or second-line chemotherapy. The patient population will include patients 
with locally advanced or metastatic breast cancer of all subtypes. The safety of 
this therapy and the preliminary evidence of efficacy will guide further studies. 
Subjects who have progressive disease (PD) or a CR after the standard therapy 
are not eligible for the study.  Following entry into the trial, patients will go on a 
treatment holiday from chemotherapy and enter an immunotherapy phase of 
treatment.  Continuation of HER2-targeted antibody therapy is permitted 
during this immunotherapy phase for women with HER2+ disease.” 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Design (page 3) 
Study Design language changed from “Radiographic PD at week 6 must be 
confirmed at least 4 weeks later.” To “Radiographic PD at week 6 must be confirmed 
at least 4 weeks later, either at week 12 or earlier if clinically necessitated.” 
Requested by principal investigator and 
site staff 
Study Design (page 3) 
Study Design language specified from standard therapy to “chemotherapy” and 
changed anti-HER2 therapy to anti-HER 2 “antibody therapy” 
Requested by principal investigator and 
site staff 
Pages 3, 6, 12, 36, 44, 46 
and 54 
“The first dose of veledimex followed 3 hours ± 30 minutes later by an intratumoral 
injection of Ad-RTS-hIL-12” to 3 hours ± 3 hours 
Requested by principal investigator and 
site staff 
Study Design (page 3) 
Study Design, deleted “A post-treatment safety assessment visit will be conducted 28 
days after the last dose of veledimex.” 
Requested by principal investigator and 
site staff to lessen burden for patients 
Study Design (pages 3 
and 37) 
Study Design, changed “The primary endpoint is safety/tolerability, defined as the 
proportion of patients who are able to complete 12 weeks on study without a Grade 3 
or higher toxicity” to “The primary endpoint is safety/tolerability, defined as the 
Requested by principal investigator and 
site staff 


Ad-RTS-hIL-12 (INXN-2001) + Veledimex (INXN-1001) 
ZIOPHARM Oncology, Inc. 
Protocol ATI001-203 – Amendment 1 
 
Final:  05 November 2014 
Confidential 
 
 
 
 
 
Page 4 of 10 
Section in Amended 
Protocol 
Revised or Deleted Text/Section 
Rationale for Change 
proportion of patients who are able to complete 12 weeks on study without Grade 3 or 
higher toxicity as defined by Section 12.4.2. 
Study Design (pages 3 
and 37) 
Study Design, changed “Additional secondary endpoints are the ORR, the DCR and 
the proportion of subjects who experience an improvement from a baseline tumor 
status from SD to PR/CR or from PR to CR, biologic/immunologic effects of 
treatment on levels of the cytokines in serum and the effect of treatment on tumor 
infiltration by immune cells. Biological markers of response (biomarkers) in serum 
will include various cytokines; for example, IL-12, IL-10 and interferon-gamma 
(IFN-γ).  Additionally, immunocytochemistry will be performed on core or punch 
biopsy or fine needle aspiration (FNA) of the tumor and/or associated tumor-involved 
draining lymph nodes. Cellular infiltration by effector cells and immune suppressor 
elements will be evaluated using antibodies to various cluster of differentiation (CD) 
antigens, including CD3, CD4, CD8, CD25, FOX-P3, and CD56. In addition, blood 
for tumor markers such as CA 15-3 and CEA will be collected on day 1 and at 6 and 
12 weeks after the start of immunotherapy” to “Additional secondary endpoints are 
the ORR, the DCR and the proportion of subjects who experience an 
improvement from a baseline tumor status from SD to PR/CR or from PR to 
CR. Disease responses by RECIST versus irRC will be explored. The effect of 
treatment on serum biomarkers [including IL-12, IL-10 and interferon-gamma 
(IFN-γ)] and tumoral immune cell subtypes (including CD8+ effector cells and T-
regulatory cells) will also be explored.” 
Requested by principal investigator and 
site staff 
Exclusion Criteria 
(pages 5 and 39) 
Exclusion #6 changed from “History of prior malignancy, unless the prior 
malignancy was diagnosed and definitively treated ≥ 5 years previously and showed 
no subsequent evidence of recurrence; adequately treated basal cell or squamous cell 
skin cancer or carcinoma in situ of the cervix, low grade thyroid  are permitted  to 
“An active, second potentially life-threatening cancer, adequately treated basal 
cell or squamous cell skin cancer or carcinoma in situ of the cervix, low grade 
thyroid are permitted.” 
Requested by principal investigator and 
site staff 
Safety Assessments 
(page 7) 
Safety Assessments changed from “Subjects who experience drug-related Grade 3 
AEs during the first 7 days of oral dosing with veledimex will interrupt further 
dosing. Subjects who experience drug-related Grade 4 AEs during the first 7 days of 
oral dosing with veledimex will discontinue therapy.  The decision as to whether 
Requested by principal investigator and 
site staff 


Ad-RTS-hIL-12 (INXN-2001) + Veledimex (INXN-1001) 
ZIOPHARM Oncology, Inc. 
Protocol ATI001-203 – Amendment 1 
 
Final:  05 November 2014 
Confidential 
 
 
 
 
 
Page 5 of 10 
Section in Amended 
Protocol 
Revised or Deleted Text/Section 
Rationale for Change 
subjects who experience severe or serious treatment-related adverse events will 
remain on study will be made by the investigator in conjunction with the Sponsor” to 
“Subjects who experience drug-related Grade 3 AEs during the first 7 days of oral 
dosing with veledimex will interrupt/discontinue further dosing at the discretion of 
the investigator. Subjects who experience drug-related Grade 4 AEs during the first 
7 days of oral dosing with veledimex will discontinue therapy.  The decision as to 
whether subjects who experience severe or serious treatment-related adverse events 
will remain on study will be made by the investigator in conjunction with the Sponsor 
Medical Monitor.” 
Efficacy Assessments 
(page 7) 
Efficacy Assessments changed from “Biologic/immunologic assessments will be 
performed using serum samples obtained at days 1, 3, 7, as well as tumor biopsies, 
preferably core biopsy (punch or FNA biopsy accepted in the absence of the core 
biopsy), taken on days 1 and 7 following initiation of immunotherapy” to 
“Biologic/immunologic assessments will be performed using serum samples obtained 
at screening, days 1, 3, 8, and weeks 6 and 12.  Tumor biopsies will be obtained by 
interventional radiology prior to the intra-tumoral vector injection and again at 
6 weeks.” 
Requested by principal investigator and 
site staff 
Study Schema (page 10) 
Updated Study Schema to match the Schedule of Study Procedures 
Requested by principal investigator and 
site staff 
Schedule of Study 
Procedures (page 11) 
Updated Schedule of Study Procedures 
Requested by principal investigator and 
site staff 
Overall Study Design 
(page 36) 
Overall Study Design, Changed from “This is a pilot single-arm, single-center study 
to examine the safety, tolerability and preliminary efficacy of providing one cycle of 
Ad-RTS-hIL-12 immunotherapy following achievement of SD or PR on standard 
treatment as first- or second-line therapy in breast cancer subjects” to “This is a 
single-arm, single-center phase 1b/II study to examine the safety, tolerability and 
preliminary efficacy of providing one cycle of Ad-RTS-hIL-12 immunotherapy 
following achievement of SD or PR on standard first- or second-line chemotherapy 
in breast cancer subjects.”  Also changed, “Subjects who have PD or a CR after the 
standard therapy are not eligible for the study.  Following entry into the trial, patients 
Requested by principal investigator and 
site staff 


Ad-RTS-hIL-12 (INXN-2001) + Veledimex (INXN-1001) 
ZIOPHARM Oncology, Inc. 
Protocol ATI001-203 – Amendment 1 
 
Final:  05 November 2014 
Confidential 
 
 
 
 
 
Page 6 of 10 
Section in Amended 
Protocol 
Revised or Deleted Text/Section 
Rationale for Change 
will go on a treatment holiday from the standard therapy and enter an immunotherapy 
phase of treatment to “Subjects who have PD or a CR after the standard 
chemotherapy are not eligible for the study.  Following entry into the trial, patients 
will go on a treatment holiday from the standard chemotherapy and enter an 
immunotherapy phase of treatment.” 
Overall Study Design 
(page 36) 
Overall Study Design, changed from “For subjects with HER2- disease, the Ad-RTS-
hIL-12 immunotherapy is intended to be given as a chemotherapy break, for example, 
to avoid intolerable or undesirable toxicity of the standard therapy.  Ad-RTS-hIL-12 
immunotherapy must be started within 4 weeks of stopping the pre-study standard 
therapy. Subjects with HER2+ disease will receive the Ad-RTS-hIL-12 
immunotherapy in conjunction with first- or second-line anti-HER2 therapy, ie, 
subjects may continue anti-HER2-directed therapy during the study period” to “For 
subjects with HER2- disease, the Ad-RTS-hIL-12 immunotherapy is intended to be 
given as a chemotherapy holiday, for example, to avoid intolerable or undesirable 
toxicity of the standard therapy.  Ad-RTS-hIL-12 immunotherapy must be started 
within 4 weeks of stopping the pre-study standard therapy. Subjects with HER2+ 
disease will receive the Ad-RTS-hIL-12 immunotherapy in conjunction with first- or 
second-line anti-HER2 antibody therapy, ie, subjects may continue anti-HER2-
directed antibody therapy during the study period.”   
Requested by principal investigator and 
site staff 
Inclusion Criteria (pages 
4 and 38) 
Inclusion # 3, and 7, changed therapy to “chemotherapy” 
Requested by principal investigator and 
site staff 
Exclusion Criteria (page 
5 and 41) 
Exclusion #15, changed “International normalized ration (INR) and activated partial 
thromboplastin time (aPTT) <1.5 × ULN” to “International normalized ration 
(INR) and activated partial thromboplastin time (aPTT) >1.5 × ULN” 
Requested by principal investigator and 
site staff 
Section 5.4 (page 45) 
Section 5.4, changed “Study drug container(s) with any remaining capsules should be 
returned to the study staff on Day 7” to “Study drug container(s) with any remaining 
capsules should be returned to the study staff on Day 8” 
Requested by principal investigator and 
site staff 
Section 6.1 (page 46) 
Section 6.1, changed “If another tumor is not available, then the remaining volume 
should be injected into a draining, pathologic lymph node of the injected tumor” to 
“If another tumor is not available, then the remaining volume should be injected into 
a draining, pathologic lymph node of the injected tumor if possible” 
Requested by principal investigator and 
site staff 


Ad-RTS-hIL-12 (INXN-2001) + Veledimex (INXN-1001) 
ZIOPHARM Oncology, Inc. 
Protocol ATI001-203 – Amendment 1 
 
Final:  05 November 2014 
Confidential 
 
 
 
 
 
Page 7 of 10 
Section in Amended 
Protocol 
Revised or Deleted Text/Section 
Rationale for Change 
Section 6.5 (page 47) 
Section 6.5, changed “The decision as to whether subjects who experience severe or 
serious treatment-related adverse events will remain on study will be made by the 
investigator in conjunction with the Sponsor” to “The decision as to whether subjects 
who experience serious treatment-related adverse events will remain on study will be 
made by the investigator in conjunction with the Sponsor Medical Monitor” 
Requested by ZIOPHARM Safety and 
Medical Monitor for clarity 
Section 6.7 (page 47) 
Section 6.7, added “Subjects who experience drug-related Grade 3 AEs during 
the first 7 days of oral dosing with veledimex will interrupt/discontinue further 
dosing at the discretion of the investigator. Subjects who experience drug-related 
Grade 4 AEs during the first 7 days of oral dosing with veledimex will 
discontinue therapy.  The decision as to whether subjects who experience severe 
or serious treatment-related adverse events will remain on study will be made by 
the investigator in conjunction with the Sponsor Medical Monitor.” 
Requested by ZIOPHARM Medical 
Monitor for clarity 
Section 7.1 (page 49) 
Section 7.1, added “HER-directed therapies in patients with HER2+ disease” 
Requested by principal investigator and 
site staff 
Section 7.2 (page 49) 
Section 7.2 changed “Any other investigational agent or anticancer therapy 
(chemotherapy, radiotherapy, etc) while receiving study treatment” to “Any other 
investigational agent or anticancer therapy (chemotherapy, radiotherapy, including 
corticosteroids, etc) while receiving study treatment” 
Requested by ZIOPHARM Medical 
Monitor for clarity 
Section 8.3.1.5 (page 51) 
Section 8.3.1.5, changed “Females of childbearing potential will have a serum 
pregnancy test at the screening visit and a urine or serum pregnancy test on Day 1” to 
“Females of childbearing potential will have a serum pregnancy test at the screening 
visit within 14 days of dosing and a urine pregnancy test at Day 1.” 
Requested by principal investigator and 
site staff 
 
Pages 58 - 65 
Pages 58-65, updated assessments and visits to reflect the Schedule of Study 
Procedures 
 
Requested by principal investigator and 
site staff 
Section 9.2.1 (page 60) 
Section 9.2.1, changed “In the current study, the baseline measurement will be based 
on the scans and measurements taken at the end of the pre-study standard therapy, as 
submitted by the investigator” to “In the current study, the baseline measurement will 
be based on the scans and measurements taken at the end of the pre-study standard 
Requested by principal investigator and 
site staff 


Ad-RTS-hIL-12 (INXN-2001) + Veledimex (INXN-1001) 
ZIOPHARM Oncology, Inc. 
Protocol ATI001-203 – Amendment 1 
 
Final:  05 November 2014 
Confidential 
 
 
 
 
 
Page 8 of 10 
Section in Amended 
Protocol 
Revised or Deleted Text/Section 
Rationale for Change 
chemotherapy, as submitted by the investigator” 
Section 10.1 (page 65) 
Section 10.1, changed “Any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product that does not necessarily 
have a causal relationship the treatment” to “Any untoward medical occurrence in a 
patient or clinical investigation subject administered a pharmaceutical product that 
does not necessarily have a causal relationship to the treatment” 
Grammatical Correction 
Section 10.2 (page 65) 
Section 10.2, changed “Progression of disease is not itself an AE; however, the 
presenting sign or symptom of the disease progression should be documented as an 
AE (e.g. increase in pain)” To “Progression of disease is not itself an AE; however, 
the presenting sign or symptom of the disease progression should be documented as 
an AE (e.g. pleural effusion).” 
Requested by ZIOPHARM Safety and 
Medical Monitor for clarity 
Section 10.7 (page 70) 
Section 10.7, changed from “The SAE Report form is provided in the investigator 
study files. A DLT specific form will be used to report DLTs and is also provided in 
the investigator files.  Please refer to the investigator study files for instructions on 
how to complete these forms” to “The SAE Report form is provided in the 
investigator study files. Please refer to the investigator study files for 
instructions on how to complete this form.” Also deleted all occurrences of “DLT” 
Requested by ZIOPHARM Safety for 
clarity 
Section 10.10 (page 71) 
Section 10.10, changed “The Sponsor should be immediately notified” to “The 
Sponsor must be immediately notified” 
Requested by ZIOPHARM Safety for 
clarity 
Section 11.1 (page 72) 
Section 11.1, changed from “Immunologic markers will be examined in core biopsy 
(punch or FNA biopsy accepted in the absence of the core biopsy) taken on days 1 
and 7. Biopsies will be by evaluated by immunocytochemistry for evidence of tumor 
infiltration by effector cells such as T cells and their subsets, as well as immune 
suppressor elements, such as T-regulatory cells and myeloid-derived suppressor cells, 
and other immunological markers.  Antibodies to be used in the 
immunocytochemistry analysis may include, but are not limited to those against 
cluster of differentiation (CD) antigens CD3, CD4, CD8, CD25, FOX-P3, and CD56, 
and CD45RO” to “Soluble factors, such as cytokines, chemokines, soluble 
receptors, and antibodies to tumor antigens will be characterized and quantified 
Requested by principal investigator and 
site staff 


Ad-RTS-hIL-12 (INXN-2001) + Veledimex (INXN-1001) 
ZIOPHARM Oncology, Inc. 
Protocol ATI001-203 – Amendment 1 
 
Final:  05 November 2014 
Confidential 
 
 
 
 
 
Page 9 of 10 
Section in Amended 
Protocol 
Revised or Deleted Text/Section 
Rationale for Change 
by immunoassays in serum. Analyses may include, but are not necessarily 
limited to serum IL-12, IL-10, and IFN-γ. The proportion of specific lymphocyte 
subsets and expression levels of T cell co-stimulatory markers in peripheral 
blood mononuclear cell (PBMC) preparations will be quantified by flow 
cytometry. Analyses may include, but not necessarily be limited to, the 
proportion of T, B, and NK cells, proportion of memory and effector T cell 
subsets, and expression levels of PD-1, PDL1, ICOS, and Ki67.” 
Section 11.2 (page 72) 
Section 11.2, changed from “Immunologic markers will be examined in core biopsy 
(punch or FNA biopsy accepted in the absence of the core biopsy) taken on days 1 
and 7” to “Immunologic markers will be examined in core biopsy (punch or FNA 
biopsy accepted in the absence of the core biopsy) taken on day 1 and at week 6.” 
Requested by principal investigator and 
site staff 
Section 12.1 (page 73) 
Section 12.2, changed from “This sample size will allow us to estimate an overall 
progression rate with a maximum 95% exact confidence interval half-width of 0.16” 
to “This sample size will allow us to estimate an overall progression rate at 12 weeks 
with a maximum 95% exact confidence interval half-width of 0.16.  This is based on 
an exact binomial calculation and is an estimate.  However, analysis of 
progression-free survival will be conducted using Kaplan-Meier methods.” 
Requested by principal investigator and 
site staff 
Section 12.4.2 (page 74) 
Section 12.4.2, changed from “Deaths, SAEs, and AEs resulting in study 
discontinuation will be listed” to “Deaths, SAEs, and AEs resulting in patient 
discontinuation will be listed” 
Requested by ZIOPHARM Medical 
Monitor for clarity 
Section 12.4.3.2 (page 
75) 
Section 12.4.3.2, changed “The proportion failed by 12 weeks is denoted as the 
progression rate and is derived based on the sum of progression events, death events 
and subjects who discontinue the trial due to an AE” to “The proportion failed by 12 
weeks is denoted as the progression rate survival and is derived based on the sum of 
progression events, death events and subjects who discontinue the trial due to an AE” 
Requested by ZIOPHARM Statistician 
for clarity 
Section 12.4.3.3 (page 
76) 
Section 12.4.3.3, changed “Proportion of subjects who are progression free at Week 
12 (proportion failed) by 12 weeks after the start of immunotherapy” to “Proportion 
of subjects who have 12-week progression free survival (proportion failed) after the 
start of immunotherapy.” 
Requested by ZIOPHARM Statistician 
for clarity 


Ad-RTS-hIL-12 (INXN-2001) + Veledimex (INXN-1001) 
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Protocol ATI001-203 – Amendment 1 
 
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Confidential 
 
 
 
 
 
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Section in Amended 
Protocol 
Revised or Deleted Text/Section 
Rationale for Change 
Appendix 16.2 
Appendix 16.2, Added “NOTE: This is not a complete list of CYP450 3A4 
substrates, inhibitors and inducers.  To use a drug of unclear CYP450 3A4 
status, please contact the ZIOPHARM medical monitor.” 
Requested by ZIOPHARM Medical 
Monitor for clarity 
Pages 89 and 91 
Added “Fosaprepitant (Emend)” 
 
Requested by ZIOPHARM Medical 
Monitor for clarity 
 
 




















PROTOCOL: ATI001-203 
                                                         Confidential                                                              16 MAY 2016  
 
 
Page 10 of 17 
 
Section 4.4 
FROM: 
A subject may withdraw (or be withdrawn) from the study treatment 
prematurely for any of the following reasons: 
• The investigator determines further participation is not in subject’s 
best interest (for example, 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: 
• Withdrawal of informed consent 
• 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 if 
withdrawal occurs before 12 weeks.   
• Any treatment-related AE(s) that meet withdrawal criteria 
• Substantial noncompliance with study requirements 
• Confirmed positive pregnancy test 
• Any intercurrent illness that would, in the judgement of the 
investigator or Sponsor’s medical monitor, affect assessments of 
clinical status to a significant degree and require discontinuation of 
protocol therapy 
Every effort should be made to follow subjects who withdraw from 
study treatment for ongoing treatment-related AEs. 
 
TO:  
A subject may discontinue study treatment prematurely for any of the 
following reasons: 
• The investigator determines further participation is not in subject’s 
best interest (for example, subject experiences rapid clinical 
deterioration in the absence of confirmed disease progression) 
• Subject has confirmed disease progression  
 
A subject MUST discontinue study treatment in the event of any of the 
following: 
• Subject request to end study treatment 
• Any treatment-related AE(s) that meet withdrawal criteria 
• Substantial noncompliance with study requirements 
• Confirmed positive pregnancy test 
• Any intercurrent illness that would, in the judgement of the 
investigator or Sponsor’s medical monitor, affect assessments of 
clinical status to a significant degree and require discontinuation of 
protocol therapy 
 
A subject MUST be withdrawn from the study in the event of any of 
the following: 
• Withdrawal of informed consent for the study 
• The Ad-RTS-hIL-12 injection was not received 
NOTE: Any subject receiving veledimex will be included in the safety 
analysis group even if the Ad-RTS-hIL-12 injection was not received. 
Every effort should be made to follow subjects who withdraw from 
study treatment for ongoing treatment-related AEs until resolved, no 
resolution is expected, or the study has ended. 
Updated to clarify key 
differences between treatment 
discontinuation and study 
withdrawal and expected 
follow-up for AEs. 















SAP_001.pdf: 


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VERSION CONTROL 
Version 
Date 
Draft 1 
07 June 2017 
 
 




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Page 4 of 21 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................ 1 
VERSION CONTROL .................................................................................................................... 2 
SIGNATURE PAGE ....................................................................................................................... 3 
TABLE OF CONTENTS ................................................................................................................ 4 
1. 
LIST OF ABBREVIATIONS ...................................................................................... 6 
2. 
PURPOSE ..................................................................................................................... 8 
3. 
PRIMARY OBJECTIVES ........................................................................................... 9 
4. 
SECONDARY OBJECTIVES ................................................................................... 10 
5. 
STUDY DESIGN ....................................................................................................... 11 
5.1. 
Endpoints: ................................................................................................................... 11 
5.1.1. 
Primary Endpoint ........................................................................................................ 11 
5.1.2. 
Secondary Endpoints .................................................................................................. 11 
5.2. 
Overall Study Design ................................................................................................. 11 
5.3. 
Safety monitoring ....................................................................................................... 12 
5.4. 
Sample size ................................................................................................................. 12 
6. 
STATISTICAL METHODS ...................................................................................... 13 
6.1. 
Protocol Deviations .................................................................................................... 13 
6.2. 
Analysis Populations .................................................................................................. 13 
6.3. 
Data Handling Conventions ....................................................................................... 13 
7. 
SUBJECT DISPOSITION .......................................................................................... 15 
8. 
BASELINE DEMOGRAPHIC CHARACTERISTICS ............................................. 16 
8.1. 
Demography ............................................................................................................... 16 
8.2. 
Medical History .......................................................................................................... 16 
8.3. 
Previous and Concomitant Medication ...................................................................... 16 
9. 
SAFETY ..................................................................................................................... 17 
9.1. 
Study Drug Exposure ................................................................................................. 17 
9.1.1. 
Ad-RTS-hIL-12 .......................................................................................................... 17 
9.1.2. 
Veledimex ................................................................................................................... 17 
9.2. 
Adverse Events ........................................................................................................... 17 
9.3. 
Laboratory Evaluations` ............................................................................................. 17 
9.4. 
Vital signs ................................................................................................................... 18 
9.5. 
ECGs ........................................................................................................................... 18 


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9.6. 
Body weight ................................................................................................................ 18 
9.7. 
Physical exam ............................................................................................................. 18 
9.8. 
ECOG Performance Status ......................................................................................... 18 
10. 
EFFICACY ................................................................................................................. 19 
10.1. 
Progression rate .......................................................................................................... 19 
10.2. 
Disease Control Rate .................................................................................................. 19 
10.3. 
Tumor response rate by irRC ..................................................................................... 20 
10.4. 
Progression-Free Survival (PFS) at Week 12 ............................................................. 20 
10.5. 
Tumor and Serum Immune Biomarkers ..................................................................... 20 
11. 
REFERENCES ........................................................................................................... 21 
 
 
 
 
 


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1. 
LIST OF ABBREVIATIONS 
Abbreviation 
Meaning 
AE 
Adverse event 
ATC 
Anatomical Therapeutic Chemical 
Bpm 
Beats per minute 
ºC 
Degrees Celsius 
CR 
Complete response 
CRF 
Case Report Form 
CT 
Computed tomography 
CV 
Coefficient of variation 
CTC, CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
Disease control rate 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ºF 
Degrees Fahrenheit 
HER2 
Human epidermal growth factor receptor 2 
irCR 
Complete disappearance of all lesions (whether measurable or not, and no 
new lesions) confirmation by a repeat, consecutive assessment no less than 
4 weeks from the date first documented 
irDCR 
Immune-related Disease Control Rate 
irORR 
Immune-related Overall Response Rate 
irPD 
Increase in tumor burden ≥25% relative to nadir (minimum recorded tumor 
burden) confirmation by a repeat, consecutive assessment no less than 4 
weeks from the date first documented 
 
irPR 
Decrease in tumor burden ≥ 50% relative to baseline confirmed by a 
consecutive assessment at least 4 weeks after first documentation 
irRC 
Immune-Related Response Criteria 
irSD 
Not meeting criteria for irCR or irPR, in absence of irPD 
MedDRA 
Medical Dictionary for Regulatory Activities 
mmHg 
Millimeter(s) of mercury 
N 
Number of observations 
n 
Number of subjects 
NCI 
National Cancer Institute 
ORR 
Objective response rate 


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Abbreviation 
Meaning 
OS 
Overall Survival 
PD 
Progressive Disease 
PFS 
Progression-Free Survival 
PR 
Partial response 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SD 
Stable Disease 
Std dev 
Standard Deviation 
SPD 
Sum of perpendicular diameters 
SRC 
Safety review committee 
TEAE 
Treatment-emergent adverse event 
Vp 
Viral particles 
WHO 
World Health Organization 


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2. 
PURPOSE 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, summary tables, and 
figures that will be produced, and the statistical methodologies that will be used, are complete and 
appropriate to allow valid conclusions regarding the study objectives.   


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3. 
PRIMARY OBJECTIVES 
• To evaluate the safety and tolerability of one cycle of Ad-RTS-hIL-12 immunotherapy a) 
following a first-, second-, or third-line standard treatment in HER2-negative (HER2-) subjects, 
or b) together with a first-, second-, or third-line anti-HER2 antibody therapy in HER2-positive 
(HER2+) subjects as defined by Section 12.4.2 in the protocol. 


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4. 
SECONDARY OBJECTIVES 
• To estimate the progression rate at 12 weeks after the start of one cycle of Ad-RTS-hIL-12 
immunotherapy  
• To evaluate the overall response rate (ORR), defined as the rate of complete response (CR) plus 
the rate of partial response (PR) at 12 weeks following the start of Ad-RTS-hIL-12 
immunotherapy  
• To evaluate the disease control rate (DCR), defined as the proportion of subjects who have a 
CR, PR, or stable disease at 12 weeks following the start of one cycle of Ad-RTS-hIL-12 
immunotherapy 
• To evaluate the number of subjects whose baseline tumor status (stable disease or PR) 
improves to PR or better at 12 weeks following the start of Ad-RTS-hIL-12 immunotherapy 
• To compare radiographic responses by irRC with conventional reporting by RECIST 
• To explore the impact of treatment on tumor and blood immune biomarkers 


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5. 
STUDY DESIGN 
5.1. 
Endpoints: 
5.1.1. 
Primary Endpoint  
The primary endpoint is the safety assessment of Ad-RTS-hIL-12 immunotherapy  
a) following a first-, second-, or third-line standard treatment in HER2- subjects, or b) together with a 
first-, second-, or third-line anti-HER2 antibody therapy in HER2+ subjects as defined by 
Section 12.4.2.   
5.1.2. 
 Secondary Endpoints  
Secondary endpoints are as follows:  
• The proportion failed by 12 weeks is denoted as the progression rate survival and is derived 
based on the sum of progression events, death events, and subjects who discontinue the 
trial due to an Adverse event (AE). 
• The ORR, defined as the rate of CR plus the rate of PR at 12 weeks following the start of 
Ad-RTS-hIL-12 immunotherapy 
• The DCR, defined as the proportion of subjects who have a CR, PR, or stable disease at 
12 weeks following the start of one cycle of Ad-RTS-hIL-12 immunotherapy 
• The number of subjects whose baseline tumor status (stable disease or PR) improves to PR 
or better at 12 weeks following the start of Ad-RTS-hIL-12 immunotherapy  
• The radiographic responses by irRC with conventional reporting by RECIST 
• Tumor and serum immune biomarkers 
5.2. 
Overall Study Design  
This is a single-arm, single-center Phase Ib/II study to examine the safety, tolerability, and preliminary 
efficacy of providing one cycle of Ad-RTS-hIL-12 immunotherapy following achievement of stable 
disease or PR on standard first-, second-, or third-line chemotherapy in breast cancer subjects.  The 
subject population includes subjects with locally advanced or metastatic breast cancer of all subtypes.  
The safety of this therapy and the preliminary evidence of efficacy will guide further studies.  Subjects 
are required to be in stable disease or PR after completion of a minimum of 12 weeks on standard 
chemotherapy.  Subjects who have progressive disease (PD) or a CR after standard chemotherapy are 
not eligible for the study.  Following entry into the trial, subjects will go on a treatment holiday from 
the standard chemotherapy and enter an immunotherapy phase of treatment.   
Scans will be conducted 6 and 12 weeks after the start of Ad-RTS-hIL-12 immunotherapy for 
determination of tumor response.  Radiographic PD at Week 6 must be confirmed at least 4 weeks 
later, either at Week 12 or earlier if clinically necessitated.  In cases of slow tumor growth, the 
investigator may wait until confirmation of PD at 12 weeks to resume chemotherapy.  In cases of 
unequivocal progression, the investigator may resume chemotherapy prior to 12 weeks and the subject 
will be considered as treatment failure at 12 weeks.   
Upon completion of Week 12, subjects who are considered to have stable disease or better will enter 
long-term follow-up for up to an additional 36 weeks.  In the long-term follow-up period, scans will be 
performed at 18, 24, 36, and 48 weeks until a radiographic response of PD is confirmed. 


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The assessment of response will be based on Response Evaluation Criteria in Solid Tumors (RECIST) 
v1.1 using tumor measurements from contrast-enhanced computed tomography (CT).  Tumor response 
will also be assessed by Immune-Related Response Criteria (irRC) (Wolchok et al, 2009).  Eligible 
subjects will also be asked to consent to allow ZIOPHARM to obtain scans and tumor measurements 
taken both a) prior to initiating the prestudy standard chemotherapy and b) after a minimum of 
12 weeks of prestudy standard chemotherapy, and not more than 4 weeks prior to study enrollment, in 
order to confirm their stable disease or PR study entry status.  
For subjects with HER2- disease, the Ad-RTS-hIL-12 immunotherapy is intended to be given as a 
chemotherapy holiday, for example, to avoid intolerable or undesirable toxicity of the standard 
therapy.  Ad-RTS-hIL-12 immunotherapy must be started within 4 weeks of stopping the prestudy 
standard chemotherapy.   
Subjects with HER2+ disease will receive Ad-RTS-hIL-12 immunotherapy in conjunction with first-, 
second-, or third-line anti-HER2 antibody therapy, i.e., subjects may continue anti-HER2-directed 
antibody therapy during the study period.  Anti-HER2 antibody therapy will be administered according 
to the manufacturer’s recommendations.  Subjects with HER2+ breast cancer who continue the anti-
HER2 antibody therapy need to recover from any anti-HER2-related AE/serious adverse event (SAE), 
i.e., the event must have resolved to Grade 1 or baseline, before starting Ad-RTS-hIL-12 
immunotherapy. 
The Ad-RTS-hIL-12 immunotherapy cycle is a 21-day cycle comprised of investigational product 
administration on Days 1 through 7 followed by rest on Days 8 through 21.  On Day 1, enrolled 
subjects will receive the first dose of veledimex followed 3 hours ± 3 hours later by an intratumoral 
injection of Ad-RTS-hIL-12.  The veledimex will continue to be given once daily on Days 2 through 7.   
The safety evaluation will be based on the occurrence of related, treatment refractory Grade 3 and 4 
AEs within 21 days following the start of Ad-RTS-hIL-12 immunotherapy.  A post-treatment safety 
assessment visit will be conducted on Day 21. 
Immunologic biomarkers of response in blood and tumor will also be explored. 
Full details of the study design can be found in the protocol. 
5.3. 
Safety monitoring 
A safety review committee (SRC) will convene after every 5th subject with HER2- disease has 
completed the Ad-RTS-hIL-12 immunotherapy cycle (i.e., after each subject has completed 21 days on 
study).  The SRC will also convene after the first 5 subjects with HER2+ disease have completed the 
Ad-RTS-hIL-12 immunotherapy cycle. The SRC will consist of the investigator, medical monitor, and 
other appropriate Sponsor representatives.  The SRC will review all available safety information 
(AEs/SAEs, laboratory parameter data, ECG, etc.).  Tolerability will be evaluated separately for 
subjects with HER2- and HER2+ disease.   
5.4. 
Sample size 
A maximum of 40 subjects will be treated.  Because this patient population is heterogeneous, it is 
difficult to define a threshold for a clear null and alternative hypothesis.  This sample size will allow us 
to estimate an overall progression rate at 12 weeks with a maximum 95% exact confidence interval 
half-width of 0.16.  This is based on an exact binomial calculation and is an estimate.  However, 
analysis of progression-free survival will be conducted using Kaplan-Meier methods. 


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6. 
STATISTICAL METHODS 
This study is designed to evaluate the safety and tolerability of one cycle of Ad-RTS-hIL-12 
immunotherapy a) following a first-, second-, or third-line standard treatment in HER2- subjects, or b) 
together with a first-, second-, or third-line anti-HER2 antibody therapy in HER2+ subjects, thus the 
safety and efficacy analyses will be performed by HER2 status and overall. 
6.1. 
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.  
No subject will be removed from any analysis population because of a protocol deviation. 
Important protocol deviations include (but are not limited to): 
• 
Deviation from inclusion/exclusion criteria 
• 
Withdrawal criteria met during the study but subject was not withdrawn 
• 
Prohibited concomitant medications. 
Important protocol deviations will be identified prior to database lock.  Protocol deviations will be 
listed and summarized by type.  
6.2. 
Analysis Populations 
The following subject populations will be evaluated and used for presentation and analysis of the data:  
• The safety population will comprise all subjects who have received either the injection of 
Ad-RTS-hIL-12 or any doses of veledimex 
• The veledimex-treated population will comprise subjects who have received the injection of 
Ad-RTS-hIL-12 and at least one dose of veledimex 
• The veledimex-evaluable population will comprise subjects who have received the injection of 
Ad-RTS-hIL-12 and all 7 doses of veledimex 
6.3. 
Data Handling Conventions 
SAS version 9.1.3 or higher will be utilized for all listings and tables. 
All listings will be ordered by HER2 status and subject number.  Listings will present all available 
data. 
Tables will summarize data for each HER2 status group and overall. 
Summary statistics will be provided for continuous variables (e.g., age).  Unless otherwise stated, this 
will consist of the number of subjects with a non-missing value of the variable (n), mean, standard 
deviation (std dev), median, minimum, and maximum.  The same number of decimal places as in the 
raw data will be presented when reporting the minimum and maximum, 1 more decimal place than in 
the raw data will be presented when reporting the mean and median, and 2 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).  Unless otherwise stated, 
this will consist of the number of subjects with a response in a particular category and the percentage 


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of the total number of subjects in that particular 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 1 decimal place. 
No imputations for missing or partial data will be made. 
Unless otherwise specified, baseline is the last observation before the first administration of study 
drug.  


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7. 
SUBJECT DISPOSITION 
Study eligibility, inclusion and exclusion criteria, HER2 status, and population assignment will be 
listed.  
The number and percent of subjects who discontinue from the study will be summarized by reason for 
discontinuation, HER2 status group, and overall.  
The number and percentage of subjects in each analysis population will be tabulated. 
Important protocol deviations will be summarized and listed. 


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8. 
BASELINE DEMOGRAPHIC CHARACTERISTICS 
8.1. 
 Demography 
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. 
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 0.4536 
Demographics will be listed and tabulated using descriptive statistics. 
8.2. 
 Medical History 
Details of prior cancer treatment (chemo-, and immuno-therapies, radiation therapy, surgeries), current 
primary cancer diagnosis, initial diagnosis of breast cancer, diagnosis of metastatic disease and current 
disease status will be listed.  Time in months since initial diagnosis, grading and type at time of initial 
diagnosis, and at grading, pathology and HER genotype types at Screening will be tabulated. 
Prior cancer treatment information will be tabulated.  This will include whether the subject had any 
previous treatment, treatment type, and the best response from previous treatment. 
8.3. 
 Previous and Concomitant Medication 
Concomitant medications recorded during the study will be coded using the WHO-Drug version March 
2016.  Details of concomitant medications will be listed. 
Medications will be tabulated according to whether they were being taken prestudy and/or during the 
study.  Medications received in the period preceding consent (~28 days) in addition to those ongoing at 
Screening will be captured in the Case Report Form (CRF).  Concomitant medications are any that 
were being taken on or after the first dose of study medication until completion of veledimex dosing.  
If the start and stop dates of the concomitant medications do not clearly define the period(s) during 
which a medication was taken, it will be assumed to have been a concomitant medication. 
Previous and concomitant medications will be tabulated by preferred term and ATC term 2. 
Non-pharmacological concomitant measures (e.g., procedures) will be listed. 


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9. 
SAFETY 
Safety evaluations will be based on the incidence, intensity, and type of AEs and SAEs.  Clinically 
significant changes in the subject’s physical examinations, vital signs, ECG evaluations, and abnormal 
laboratory values will be captured as AEs.  AEs, laboratory test results, ECG findings, and vital signs 
will be tabulated and presented for all subjects in the study, as well as by HER2 status group and 
CYP450 3A4 drug interacting use.  Exposure to study drug and reasons for discontinuation of study 
treatment will be tabulated. 
9.1. 
Study Drug Exposure 
Details of study drug administration and dose modifications will be listed.   
9.1.1. 
Ad-RTS-hIL-12 
Total volume received, number of sites, and whether the dose was modified will be tabulated. 
9.1.2. 
Veledimex 
Full details of each dose and dose modifications will be listed.  
The number of doses received will be tabulated. Data will reflect date and mg of veledimex taken, % 
compliance (dose held by PI/Sponsor), % compliance (missed dose). 
9.2. 
Adverse Events 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA®) Version 18.1 
or higher for purposes of summarization.  All AEs occurring during the study will be included in data 
listings, presented by subject. 
Treatment-emergent adverse events (TEAEs) will be summarized.  Adverse events will be regarded as 
TEAEs if they occur during or after administration of the first dose of study drug (either veledimex or 
Ad-RTS-hIL-12) through the evaluation period for safety (in 6 weeks after first dose), regardless of the 
relationship to study drug.  In addition, any event present at baseline that worsens in intensity or is 
subsequently considered to be drug related by the investigator will be considered a TEAE. 
Summaries of all TEAEs, treatment-related TEAEs, and all SAEs will be tabulated by System Organ 
Class, Preferred Term, severity, and HER2 status group.  For summaries of events, percentages will be 
calculated from the total number of events per group/dose cohort.  For summaries of subjects, 
percentages will be calculated from the total number of subjects per group/dose cohort.  Where a 
subject has multiple adverse events in a System Organ Class / Preferred Term, only the most severe 
will be included in summaries.  
In addition to the full listing of all AEs, separate listings for AEs, leading to death, and AEs leading to 
study discontinuation will be presented. 
9.3. 
Laboratory Evaluations` 
All laboratory parameters will be converted to conventional units, usually SI units, for the purposes of 
summary.  Listings will present the data in the original unit collected, as well as the converted value in 
conventional units.  A separate listing will present all units used for data collection, along with the 
corresponding units and conversion factors.   


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Absolute values and change from baseline in clinical laboratory parameters will be summarized by 
visit and HER2 status group.  The incidence of normal and abnormal (subdivided into ‘not clinically 
significant’ and ‘clinically significant’) laboratory values will be tabulated by visit and HER2 status 
group. 
Pregnancy test data will be listed only. 
9.4. 
Vital signs 
Details of vital signs will be listed. 
Vital signs parameters include systolic and diastolic blood pressure (mmHg), heart rate (bpm), 
respiratory rate (breaths/minute), and temperature (ºC). 
The conversion for temperature is as follows: 
 
 
 
Temperature (ºC) = (Temperature (ºF) – 32) x 5/9 
Absolute values and changes from baseline for vital sign parameters will be summarized by visit and 
HER2 status. 
9.5. 
ECGs 
Heart Rate (bpm), PR Interval (ms), QRS complex duration (ms), RR interval (ms), QT interval (ms) 
and QTc interval (ms) will be summarized for absolute values and changes from baseline (Screening 
visit) by visit and HER2 status group. 
Overall electrocardiogram (ECG) finding categories will be summarized by visit and HER2 status 
group. 
9.6. 
 Body weight 
Body weight (kg) will be summarized for absolute values and changes from baseline by visit, HER2 
status group, and overall. 
9.7. 
Physical exam 
Results of the targeted neurological exam will be listed and summarized by HER2 status group. 
Physical examination data will be listed. 
9.8. 
ECOG Performance Status 
Results of the Eastern Cooperative Oncology Group (ECOG) Performance Status will be listed and 
will be summarized as a categorical variable by visit, HER2 status group, and overall. 


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10. 
EFFICACY 
The tumor response will be assessed by RECIST v1.1 and irRC.  Full details concerning the use of 
RECIST v.1.1 may be found in the Appendix 16.3 in the protocol and for irRC can be referred to the 
Section 9.2.2.7 in the protocol. 
10.1. 
Progression rate 
The proportion failed by 12 weeks is denoted as the progression rate, and is derived based on the sum 
of progression events, death events, and subjects who discontinue the trial due to an AE.  
The progression rate will be summarized by HER2 status group and overall for the evaluable 
population.  
An exact 2-sided 95% confidence interval for the proportion of subjects who failed treatment by 
12 weeks will also be presented by visit and overall (based on the best response).  
Objective Response Rate Tumor response following the start of Ad-RTS-hIL-12 immunotherapy will 
be assessed using RECIST v1.1.  Overall response at Week 12 is based on the totality of the responses 
for target and non-target lesions, as shown in the table below: 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
The ORR is defined as the percentage of subjects who have CR or PR at 12 weeks. The ORR will be 
summarized by HER2 status group and overall. An exact 2-sided 95% confidence interval will also be 
presented by HER2 status and overall.  
For this calculation, responders are defined as those experiencing a CR or a PR.  Non-responders are 
those either with stable or progressive disease.  Those subjects who cannot be assessed will be treated 
as non-responders for the purposes of deriving the percentage of responders and confidence intervals. 
In addition, the number of subjects whose baseline tumor status (stable disease or PR) improves to PR 
or better at 12 weeks following the start of Ad-RTS-hIL-12 immunotherapy with RECIST v1.1 will be 
listed and summarized by HER2 status and overall. 
10.2. 
Disease Control Rate 
The DCR is the proportion of subjects who have a CR, PR, or stable disease at 12 weeks following the 
start of Ad-RTS-hIL-12 immunotherapy using RECIST v1.1. 
The DCR will be summarized by HER2 status group and overall.  An exact 2-sided 95% confidence 
interval will also be presented.  


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For this calculation, responders are defined as those experiencing a CR, PR, or stable disease.  
Non-responders are defined as those with PD.  Those subjects that cannot be assessed will be treated as 
non-responders for the purposes of deriving the percentage of responders and confidence intervals. 
10.3. 
Tumor response rate by irRC 
The tumor response by irRC is based on the sum of the 2 largest perpendicular diameters (SPD) of all 
index lesions at baseline to provide the total tumor burden. At each subsequent tumor assessment, the 
SPD of the index lesions and of new, measurable lesions (≥ 5 × 5 mm; up to 5 new lesions per organ:  
5 new cutaneous lesions and 10 visceral lesions) are added together to provide the total tumor burden. 
The overall response according to the irRC is derived from time-point response assessments (based on 
tumor burden) as follows: 
• irCR:  complete disappearance of all lesions (whether measurable or not, and no new lesions) 
confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first 
documented 
• irPR:  decrease in tumor burden ≥ 50% relative to baseline confirmed by a consecutive 
assessment at least 4 weeks after first documentation 
• irSD:  not meeting criteria for irCR or irPR, in absence of irPD 
• irPD:  increase in tumor burden ≥ 25% relative to nadir (minimum recorded tumor burden) 
confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first 
documented 
irORR and irDCR by irRC will be analyzed the same way as described above for tumor response using 
RECIST v1.1. 
10.4. 
Progression-Free Survival (PFS) at Week 12 
This is defined as the proportion of subjects who have 12-week progression-free survival after the start 
of Ad-RTS-hIL-12 immunotherapy.  The PFS rate at Week 12 will be summarized by HER2 status 
group and overall.  
An exact 2-sided 95% confidence interval will also be presented by HER2 status and overall. 
10.5. 
Tumor and Serum Immune Biomarkers 
Change and percent change from baseline in collected tumor and blood immune biomarkers will be 
summarized by visit, by HER2 status, and overall.