A Phase I/II, Open Label Study of Ad-RTS-hIL-12, an Adenovirus Vector Engineered to Express hIL-12, in Combination With an Oral Activator Ligand, in Subjects With Unresectable Stage III or IV Melanoma
Phase: PHASE1
Conditions: Melanoma
Sponsor: Alaunos Therapeutics



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8.3 
CONCOMITANT THERAPY .................................................................................................................. 39 
8.4 
EVALUATION AND ASSESSMENT PROCEDURES .................................................................................. 39 
8.4.1 
Schedule of Assessments .............................................................................................................. 39 
8.4.2 
Safety Evaluations ........................................................................................................................ 40 
8.4.2.1 
Demographics and Medical History ................................................................................................... 40 
8.4.2.2 
Physical Examinations ....................................................................................................................... 40 
8.4.2.3 
ECOG Performance Status ................................................................................................................. 40 
8.4.2.4 
Height and Weight ............................................................................................................................. 40 
8.4.2.5 
Vital Signs .......................................................................................................................................... 40 
8.4.2.6 
Adverse Events .................................................................................................................................. 40 
8.4.2.7 
Pregnancy Testing .............................................................................................................................. 40 
8.4.2.8 
Hematology ........................................................................................................................................ 41 
8.4.2.9 
Serum Chemistry ............................................................................................................................... 41 
8.4.2.10 
Urinalysis ........................................................................................................................................... 41 
8.4.2.11 
Electrocardiogram (ECGs) ................................................................................................................. 41 
8.4.2.12 
Serum Tryptase .................................................................................................................................. 41 
8.4.2.13 
Immune Response Analyses .............................................................................................................. 41 
8.4.3 
INXN-1001 Pharmacokinetic Assessment ................................................................................... 42 
8.4.4 
Efficacy Assessments ................................................................................................................... 42 
8.4.5 
Assessments of Transgene Function, Immunological Activities and Biological Effects .............. 43 
8.4.5.1 
Transgene Function ............................................................................................................................ 43 
8.4.5.2 
Immunological Activities ................................................................................................................... 43 
8.4.5.3 
Other Biological Effects ..................................................................................................................... 43 
9. 
ADVERSE EVENTS ............................................................................................................................. 44 
9.1 
ADVERSE EVENT (AE) DEFINITION ................................................................................................... 44 
9.2 
EVALUATION OF ADVERSE EVENTS (AES) ........................................................................................ 44 
9.2.1 
Determination of Seriousness ....................................................................................................... 44 
9.2.1.1 
Serious Adverse Event (SAE) ............................................................................................................ 45 
9.2.1.2 
Non-Serious Adverse Event ............................................................................................................... 45 
9.2.2 
Determination of Severity ............................................................................................................. 45 
9.2.3 
Causality Assessments .................................................................................................................. 46 
9.3 
DOCUMENTING ADVERSE EVENTS (AES) .......................................................................................... 46 
9.4 
REPORTING SERIOUS ADVERSE EVENTS (SAES) ............................................................................... 47 
9.5 
SPONSOR AND INVESTIGATOR RESPONSIBILITY FOR REPORTING ADVERSE EVENTS (AES) ............... 48 
9.6 
FOLLOW-UP INFORMATION ................................................................................................................ 48 
9.7 
PREGNANCIES .................................................................................................................................... 48 
10. 
STATISTICAL PROCEDURES .......................................................................................................... 49 
10.1 
DETERMINATION OF SAMPLE SIZE ..................................................................................................... 49 
10.1.1 
Subject Randomization ................................................................................................................. 49 
10.1.2 
Populations for Analysis ............................................................................................................... 49 
10.2 
PROCEDURES FOR HANDLING MISSING, UNUSED, AND SPURIOUS DATA ........................................... 50 
10.3 
STATISTICAL METHODS ..................................................................................................................... 50 
10.3.1 
Baseline Characteristics ................................................................................................................ 50 
10.3.2 
Safety Analyses ............................................................................................................................ 50 
10.3.3 
Efficacy Analyses ......................................................................................................................... 51 
10.3.4 
Immunologic Responses ............................................................................................................... 51 
10.3.5 
INXN-1001 Pharmacokinetics ...................................................................................................... 51 
10.3.6 
Multi-Center Study ....................................................................................................................... 51 
10.3.7 
Adjustments for Covariates .......................................................................................................... 52 
10.4 
PROCEDURES FOR REPORTING DEVIATIONS TO ORIGINAL STATISTICAL ANALYSIS PLAN ................. 52 
11. 
STUDY ADMINISTRATION ............................................................................................................... 52 
11.1 
CASE REPORT FORMS AND SOURCE DOCUMENTATION ..................................................................... 52 
11.2 
GOOD CLINICAL PRACTICE STATEMENT ............................................................................................ 52 
11.3 
SPONSOR MONITORING ..................................................................................................................... 53 
11.4 
DURATION OF THE STUDY ................................................................................................................. 53 
11.5 
RECORDS RETENTION ........................................................................................................................ 54 

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11.6 
INSTITUTIONAL REVIEW BOARD ........................................................................................................ 54 
11.7 
CONFIDENTIALITY AND HIPAA ........................................................................................................ 54 
12. 
INFORMED CONSENT ....................................................................................................................... 55 
12.1 
FDA INFORMED CONSENT REQUIREMENTS ....................................................................................... 55 
12.2 
SUBJECT INFORMED CONSENT FORM ................................................................................................ 55 
13. 
PROTOCOL APPROVAL PAGE ....................................................................................................... 56 
14. 
REFERENCES ....................................................................................................................................... 57 
15. 
APPENDIX 1:  EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) PERFORMANCE 
STATUS .................................................................................................................................................. 60 
16. 
APPENDIX 2:  CYP450 3A4 INDUCERS, INHIBITORS AND SUBSTRATES ............................ 61 
17. 
APPENDIX 3:  SUGGESTED REGIMEN FOR HYDRATION, ANTIPYRETIC AND/OR 
ANALGESIC PROPHYLAXIS ............................................................................................................ 62 
18. 
APPENDIX 4:  IMMUNE-RELATED RESPONSE CRITERIA (IRRC) ........................................ 63 
19. 
APPENDIX 5:  PHASE I AND PHASE II GROUP 1......................................................................... 65 
 
 

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3. PROTOCOL SYNOPSIS 
Title 
A Phase I/II, Open Label Study of Ad-RTS-hIL-12, an Adenovirus 
Vector Engineered to Express hIL-12, in Combination with an Oral 
Activator Ligand, in Subjects with Unresectable Stage III or IV 
Melanoma 
Protocol Number 
ATI001-101  
Study Sponsor 
ZIOPHARM Oncology, Inc. 
Objectives 
The primary objective is to: 
• Evaluate the safety and tolerability of intratumoral injections of 
INXN-2001 (Ad-RTS-hIL-12) in combination with INXN-1001 
(activator ligand) in subjects with unresectable Stage III or IV 
melanoma.  
The secondary objectives are to: 
• 
Inform the selection of an INXN-1001 dose(s) and regimen for 
further study in combination with INXN-2001. 
• Assess preliminary anti-tumor activity according to RECIST 1.1 
criteria.   
• Assess anti-tumor response based on total measurable tumor burden. 
• Evaluate the immunological effect of study treatment in terms of 
cellular and humoral immune responses, as well as other biological 
activities in the injected tumor(s), tumor-involved draining lymph 
nodes (if accessible) and in the peripheral circulation.  
• Evaluate the extent of the uptake of INXN-2001 into tumor cells and 
tumor-infiltrating immune cells, and to assess adenovirus vector 
shedding in body fluids.  
• Assess the pharmacokinetics (PK) of INXN-1001 in subjects with 
unresectable stage III or IV melanoma. 
Clinical Phase 
I/II 
Study Drugs 
INXN-2001 (Ad-RTS-hIL-12) 
INXN-1001 (Oral Activator Ligand) 
Concurrent INXN-2001 and INXN-1001 dosing will be referred to as 
“study treatment” throughout this protocol. 
No. of Subjects 
Approximately 30 subjects  
(3 subjects per dose level cohort in Phase I and approximately 15 subjects 
enrolled in Phase II at a single dose level at or below the MTD), exclusive 
of replacement subjects or the addition of intermediate dose level cohorts, 
if any. 
Number of Centers 
Multi-center (approximately 8 to 12 centers) 

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Study Design 
Single-arm, open label, Phase I/II dose escalation study of intratumoral 
injections INXN-2001 and oral INXN-1001 in subjects with unresectable 
Stage III or IV melanoma.   
 
Table 1:  Study Design 
Study Part 
Cohorts 
Dose Regimen 
Phase I 
Dose Escalation  INXN-2001: 
  
INXN-1001: 5, 20, 100, 160 mg  
Phase II 
Group 1 
INXN-2001: 
  
INXN-1001: 160 mg daily for 7 consecutive 
days; 21-day cycle 
Group 2 
INXN-2001: 
 
INXN-1001: 160 mg every other day  for 14 
days; 28-day cycle 
In Phase I, four sequential dose escalation cohorts of INXN-1001 in 
combination with a fixed dose of INXN-2001 are planned (Table 1).  
Subject enrollment and dose escalation will proceed according to a 
standard 3+3 design. In each cycle, the subjects will be treated with one 
intratumoral injection of INXN-2001 in combination with 7 oral doses of 
INXN-1001.  No intrasubject dose escalation will be allowed.  
[Please refer to Appendix 5 for additional study design details for the 
Phase I and Phase II, Group 1 portions of this study.]  
In Phase II, approximately 15 additional subjects will be enrolled at a 
single dose level at or below the MTD. Phase II of the study will include 
two groups of subjects. Subjects enrolled in the Phase II portion of the 
study under Amendment 6 or prior will be enrolled into Group 1; subjects 
enrolled under Amendment 7 or later will be enrolled into Group 2. 
Subjects in Group 1 will be treated with one intratumoral injection of 
INXN-2001 in combination with oral doses of INXN-1001 given at 160 
mg daily for 7 consecutive days at the beginning of a 21-day cycle. 
Subjects in Group 2 will be treated with one intratumoral injection of 
INXN-2001 in combination with oral doses of INXN-1001 given at 160 
mg every other day for 14 days at the beginning of a 28-day cycle.  
Subjects may receive treatment for 6 cycles. 
Safety and tolerability will be assessed by the incidence and severity of 
adverse events as determined by NCI Common Terminology Criteria for 
Adverse Events (CTCAE) v4.03.  A Safety Review Committee (SRC) 
comprised of the Medical Monitor, Principal Investigators, and sponsor 
representatives, will be convened to review safety information and to 
decide upon dose escalation and further subject enrollment. 
The anti-tumor activity of study treatment will be assessed according to 
Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 guidelines.1 
Additional assessment of anti-tumor activity will be explored based on 
total measurable tumor burden.39 (Appendix 4) 
Immunological and biological markers of response will include 

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examinations of tumor biopsy samples, cytokine levels, peripheral blood 
mononuclear cells (PBMC) and antibody response to INXN-2001.  
Study Population 
The target population for this study is adult subjects with unresectable 
Stage III or IV melanoma for which is no alternative curative therapy 
exists. 
Inclusion Criteria:  
1. Males or females of all races ≥ 18 years of age, who have provided 
written informed consent prior to completing any study specific 
procedure. 
2. Unresectable Stage III or Stage IV melanoma arising from any site 
other than ocular melanoma. 
3. A minimum of 2 accessible lesions (shortest diameter ≥ 1 cm) or 
palpable tumor-involved lymph nodes (shortest diameter ≥ 1.5 cm). 
4. ECOG performance status of 0 or 1 (Appendix 1). 
5. Adequate bone marrow, liver, and renal function, as assessed by the 
following laboratory requirements: 
a. Hemoglobin ≥ 9 g/L 
b. Lymphocytes > 700/ mm3 
c. Neutrophils ≥ 1,500/ mm3 
d. Platelets ≥ 100,000/ mm3 
e. Serum creatinine ≤ 1.5 x ULN 
f. AST and ALT ≤ 2.5 x ULN. For subjects with documented 
liver metastases, ALT and AST ≤ 5×ULN 
g. Total bilirubin < 1.5 x ULN 
h. International Normalized Ratio (INR) and activated partial 
thromboplastin time [PTT] < 1.5 x ULN, if 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 no prior evidence of underlying 
abnormality in coagulation parameters, screening test results 
are in appropriate therapeutic range, and anticoagulation 
regimen is stable and closely monitored. 
6. An expected survival of at least 6 months. 
7. Male and female subjects must agree to use a highly reliable method 
of birth control (expected failure rate less than 5% per year) from the 
screening visit through 28 days after the last dose of study drug.  
Exclusion Criteria:  
 
1. Any prior anti-cancer therapy or investigational agent within 28 days 

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on Day 1 of a 4-week cycle.  The subjects will also receive a single oral 
dose of INXN-1001 every other day for 14 days starting on Day 1 of each 
cycle.  Subjects may receive up to 6 cycles of study treatment. 
INXN-2001 should be injected into a different lesion at each cycle.  If 
only 3 accessible lesions are present, the injections will be done in 
sequential rotation between 2 lesions.  If only 2 accessible lesions are 
present, then all injections will be into a single lesion.   
Note: One accessible lesion will not be injected since that lesion will be 
used to evaluate the systemic effect of INXN-2001.  If only 2 accessible 
lesions are present at screening and the single injected lesion can no 
longer support the injection volume at subsequent cycles, then the 
medical monitor should be contacted for a discussion. 
Route of 
Administration 
INXN-1001: Taken orally in a fed state (30 minutes after the start of a 
normal meal) and at least 4 hours before another meal. 
INXN-2001: Intratumoral injection on the first day of each cycle into one 
accessible tumor lesion or tumor-involved (palpable) draining lymph 
node when necessary.  Radiologically-guided injections are permitted 
under BL2 conditions. The injection should be administered 3 hours ± 30 
minutes after the first dose of INXN-1001.   
Duration of Subject 
Participation 
[Please refer to Appendix 5 for the study duration for subjects enrolled 
under the Phase I and Phase II, Group 1 portions of this study.] 
Phase II, Group 2 subjects’ participation in this study will last 
approximately 8 months, including: 
• 
30 day screening period. 
• 
6 cycles (24 weeks) of study treatment. 
• 
Post-Treatment Safety Assessment visit performed 28 days after the 
last dose of INXN-1001. 
• 
Follow-Up Tumor Assessment visit performed 35 ± 7 days after the 
Post-Treatment Safety Assessment visit. 
In addition, subjects who discontinue or complete study treatment in the 
absence of rapid clinical deterioration and without objective evidence of 
confirmed immune-related progressive disease (irPD) should continue to 
be followed until irPD has been confirmed or an alternate anti-cancer 
therapy has been initiated, whichever occurs first.   
Safety Evaluations 
Safety parameters will include serious adverse events (SAEs), adverse 
events (AEs), physical examinations, electrocardiograms (ECGs), vital 
signs, clinical laboratory evaluations, medical history, and 
prior/concomitant medications.  
Efficacy Evaluations  Efficacy will be evaluated as the objective tumor response according to 
RECIST v1.1 guidelines.1 Additional assessment of anti-tumor activity 
will be explored based on total measurable tumor burden.39 (Appendix 4) 

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Pharmacodynamic 
Evaluations 
Immunological and biological markers of response will include 
examinations of tumor biopsy samples, cytokine levels, peripheral blood 
mononuclear cells (PBMC) and antibody responses.  
Pharmacokinetic 
Evaluations 
INXN-1001 pharmacokinetics will be evaluated in all subjects during 
Cycle 1 only. 
Sample Size 
Determination 
No formal sample-size estimation was performed.  The choice of the 
number of subjects was based on the standard Phase I 3+3 inter-cohort 
dose escalation design in which 3 to 6 subjects are enrolled into each dose 
level cohort.  
In order to increase the ability to estimate the effect of the treatment on 
clinical response and to correlate with immunologic or other biologic 
markers, an additional number of subjects may be entered into the study 
after the initial safety evaluation has been completed.    Based on a review 
of available safety and clinical response data, the SRC may identify a 
single dose cohort to be expanded to a total of 15 evaluable subjects to 
better define the safety, tolerability and activity of the study treatment.  
Should a subject discontinue study treatment before receiving 3 cycles for 
reasons other than toxicity, another subject may be added to the dose 
cohort to provide a total of 3 or 6 subjects for full analysis.  
Given these considerations, a total of approximately 30 subjects may be 
enrolled into this study, including 3 subjects enrolled in each of the 4 
planned dose level cohorts and approximately 15 additional subjects 
enrolled at or below the MTD during the Phase II portion of the study.  
Additional subjects may also be enrolled as replacement subjects or to 
explore intermediate dose level cohorts. 

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4. TABLE 2.  SCHEDULE OF ASSESSMENTS 
Activity 
FOR ALL PHASE II GROUP 2 SUBJECTS  
Screening1 
ALL Cycles 
Post 
Treatment 
Safety 
Assessment 
Visit28 
Follow-Up 
Tumor 
Assessment 
Visit29 
Day -28 
to -7 
Day -6  
to -2 
Day 1 
Day 2 
Day 3 
OR  
Day 427 
Day 7 
Day 13 
Day 15  
28±3 days 
post-INXN-
1001 dose 
35±7 days 
after PTSA 
visit 
Clinical Assessments 
 
 
 
 
 
 
 
 
 
 
Informed Consent2 
X 
 
 
 
 
 
 
 
 
 
Medical/Cancer History3 
X 
 
 
 
 
 
 
 
 
X30 
Physical Exam4 
X 
X 
X 
 
 
 
X 
 
X 
 
ECOG PS5 
X 
 
X 
 
 
 
 
 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
 
 
 
 
 
X 
 
Vital Signs6 
X 
X 
X 
X 
X28 
X 
X 
X 
X 
 
Adverse Events7 
X 
 
 
 
 
 
 
 
X 
 
Concomitant Med.8  
X 
 
 
 
 
 
 
 
 
X 
Clinical Laboratory 
 
 
 
 
 
 
 
 
 
 
Pregnancy test9 
X 
 
X 
 
 
 
 
 
 
 
Hematology tests10 
X 
 
X22 
 
 
X 
 
X 
X 
 
Serum Chemistry tests11 
X 
 
X22 
 
 
X 
 
X 
X 
 
Urinalysis12 
X 
 
X22 
 
 
 
 
X 
X 
 
ECG13 
X 
 
X 
 
 
 
 
 
X 
 
Serum Tryptase14 
 
 
X 
 
 
Subject Registration15 
X 
 
 
 
 
 
 
 
 
 
Study Drug Administration 
 
 
 
 
 
 
 
 
 
 
Intratumoral INXN-200123 
 
 
X 
 
 
 
 
 
 
 
Oral INXN-100124 
 
 
X 
 
 
 
Verify Adherence to INXN-
1001 dosing25 
 
 
 
 
 
 
 
X 
 
 
Activity 
FOR ALL PHASE II GROUP 2 SUBJECTS 
Screening1 
Cycles 1, 3, and 6 ONLY 
Post 
Treatment 
Safety 
Assessment 
Visit28 
Follow-Up 
Tumor 
Assessment 
Visit29 
Day -28 
to -7 
Day -6 
to -2 
Day 1 
Day 2 
Day 3 
OR 
Day 427 
Day 7 
Day 13 
Day 15  
28±3 days 
post-INXN-
1001 dose 
35±7 days 
after PTSA 
visit 
Ab responses16  
 
X 
 
 
 
 
 
X 
X 
 
Cytokine profile17 
 
X 
 
 
X 
 
 
X 
X 
 
INXN-1001 PK26 
CYCLE 1 ONLY 
 
 
X 
X 
 
 
X 
 
 
 

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8. Concomitant medication information, including blood products, vitamins and other supplements 
will be collected for the time period beginning 28 days prior to the first dose of study drug, 
through the Follow-Up Tumor Assessment visit.   
9. Females of childbearing potential will have a serum pregnancy test at the Screening visit and a 
urine pregnancy test on the first day of each treatment cycle, prior to administration of 
INXN-1001.   
10. Hematology tests include: complete blood count and white blood cell count, differential white 
blood cell count, red blood cell count, hematocrit, hemoglobin, red blood cell indices, 
reticulocyte count, MCV (mean corpuscular volume) and platelet count. PTT (partial 
thromboplastin time) and INR (international normalized ratio) will also be evaluated. 
11. Serum chemistry tests include: aspartate transaminase (AST), alanine transaminase (ALT), 
lactate dehydrogenase (LDH), alkaline phosphatase (ALP), creatinine, total bilirubin, total 
protein, albumin, blood urea nitrogen, glucose, sodium, potassium, chloride, calcium, 
phosphorus and bicarbonate.   
12. 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. 
13. Standard, single 12-lead ECG at screening, 2½ to 3 hours after INXN-1001 dosing (prior to 
INXN-2001 injection) on Day 1 of each cycle, and at the Post-Treatment Safety Assessment 
visit.  
14. Serum tryptase level will be obtained upon the occurrence of a suspected injection and/or 
hypersensitivity reaction.  Otherwise, this test is not required at any other time. 
15. For subjects who meet inclusion and exclusion criteria. Centralized registration of eligible 
subjects will be completed according to a process defined by the sponsor.  
16. Blood sample for analysis of antibody responses to the adenovirus and/or the RTS  components, 
and antibodies to melanoma-associated antigens. Please refer to the laboratory manual for details 
regarding sample processing and shipment. 
17. Blood samples for cytokine profiling.  Please refer to the laboratory manual for details regarding 
sample processing and shipment.   
18. Appropriate cancer staging procedures should be performed during screening.  For the purpose 
of this clinical trial, the following imaging is expected at screening: 
a. CT of the chest, and CT (or MRI) of the abdomen and pelvis 
b. MRI (or CT) of the brain if brain metastasis are known or suspected  
c. CT or MRI of other anatomical regions as clinically indicated 
For subjects with measurable lesions, target lesions should be selected and measured as per 
RECIST 1.1 guidelines.  Lesions that will be/are injected with INXN-2001 and/or biopsied 
should not be selected as target lesions, but should be measured (if measureable).   
Disease sites are to be assessed throughout the study using the same method(s) used at 
screening.  Specific image acquisition guidelines will be provided by a central imaging 
laboratory.  Chest, abdomen, pelvis imaging is required for all follow-up imaging time points; 
images of the brain and other anatomical regions should be acquired on follow-up if positive at 
screening and as clinically indicated. 
NOTE: As a supplement to the standard RECIST v1.1 guidelines established to evaluate anti-
tumor responses to chemotherapeutic agents, anti-tumor response will be explored by measuring 
total tumor burden over time. (see Appendix 4) 
 

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26. FOR CYCLE 1 ONLY: Subjects will undergo an INXN-1001 pharmacokinetic (PK) assessment. 
Blood samples for INXN-1001 PK analysis should be obtained on the following days and time 
points: 
Day 1: Pre-dose (< 30 minutes prior to INXN-1001 dosing) 
1-2 hours post INXN-1001 dosing 
3-6 hours post INXN-1001 dosing 
Day 2: Pre-dose (< 30 minutes prior to INXN-1001 dosing) 
Day 13: 1-2 hours post INXN-1001 dosing 
3-6 hours post INXN-1001 dosing 
Day 15: Anytime >24 hours post-Day 13 INXN-1001 dose 
27. Blood pressure will be assessed at Cycle 1 and Cycle 2 Day 3 or 4 visit.  During Cycle 1 and 2, 
Day 3 or 4 visits are required.  For Cycles 3-6, Day 3 or 4 visits should be performed when 
feasible (eg, Monday through Friday).  
28. Post-Treatment Safety Assessment visit will be performed 28 ± 3 days after the last dose of 
INXN-1001 or at the time of early withdrawal from study treatment.   
29. A Follow-Up Tumor Assessment visit will be performed 35 ± 7 days after the Post-Treatment 
Safety Assessment visit.  This assessment is required for all subjects, including those with prior 
objective evidence of disease progression to ensure that more slowly declining tumor burden in 
response to therapy is not missed.   
Subjects without objective evidence of disease progression should continue to have tumor 
assessments performed at 8 -10 weeks intervals until irPD has been confirmed or an alternate 
anti-cancer therapy has been initiated, whichever occurs first. 
30. Interim cancer history information will include documentation of any new concomitant 
medications and any anti-cancer treatments received since the Post-Treatment Safety 
Assessment visit or previous tumor assessment.   

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5.4.3 Safety of Intratumoral injection of IL-12 genes  
In comparison with administration of recombinant IL-12 protein, injection of plasmids or 
adenovirus containing hIL-12 genes to cancer patients has proven to limit or abrogate the 
toxic effects of hIL-12, thus providing an effective way to provide this potent 
immunomodulatory cytokine.  This has been observed in Phase I and II clinical trials where 
IL-12 is delivered locally, IL-12 levels have been measured systemically in patient serum, 
and in the majority of these studies, increases in IL-12 serum levels post baseline have not 
been observed.31-33  Numerous studies have shown gene delivery of IL-12 to be well 
tolerated.  In a Phase I dose escalation trial using electroporation to administer plasmid DNA 
encoding hIL-12 into metastatic melanoma, minimal systemic toxicity and no IL-12-related 
adverse events were observed in subjects treated at several dose levels.34  Similarly, 
intratumoral injection of a plasmid DNA encoding human IL-12 (2 to 20 mg of total DNA) in 
subjects with melanoma was also well tolerated.35  Limited elevations in serum cytokines 
were observed after treatment.  Intra-peritoneal injection of hIL-12 plasmid DNA formulated 
in polyethyleneglycol-polyethyleneimine-cholesterol (PPC) given to women with 
chemotherapy-resistant recurrent ovarian cancer also was found to be generally safe and well 
tolerated. Low-grade fever and abdominal pain were the most common side effects.36 
Plasmid DNA was not detected in the patients’ serum samples and treatment-related 
increases in IFN-γ levels were observed only in pleural fluid but not in serum.  Similar 
findings have been obtained with intratumoral injection of adenoviral vectors encoding hIL-
12 at doses ranging from 2.5 x 1010 to 3 x 1012 viral particles, to subjects with advanced 
pancreatic, colorectal, or primary liver malignancies.31   Treatment was well tolerated and 
dose-limiting toxicity was not reached.  AEs were transient, with fever, malaise, sweating, 
and lymphopenia being the most common AEs observed.  No cumulative toxicity was 
observed.  All AEs were deemed to be related to injection of the virus and not to transgene 
expression.   
5.5 
RATIONALE FOR STUDY DESIGN AND DOSE SELECTION 
The objectives of this Phase I/II clinical trial are to assess the safety, objective response rate, 
and immunological and biological effects of intratumoral injections of INXN-2001 in 
combination with escalating dose levels of oral INXN-1001.  The dose escalation portion of 
the study (Phase I) uses a standard 3+3 design commonly used in Phase I studies of 
investigational anticancer therapies.  To provide an opportunity to monitor the safety of the 
combination therapy, there will be at least 7 days between the initiation of treatment for the 
sentinel (first) subject and additional subjects in all cohorts during the dose escalation stage 
of the study. Phase II will be enrolled (approximately 15 subjects) at or below the MTD and 
using two groups.  One group will receive an INXN-1001 daily for 7 days dosing regimen, 
and the other group will receive an every other day dosing regimen for 14 days to compare 
tolerability of INXN-1001 at the 160-mg dose.   
Phase I:  In each of six 21-day cycles, the subjects will receive one intratumoral injection of 
INXN-2001 in combination with 7 oral daily doses of INXN-1001.   
Phase II, Group 1:  In each of six 21-day cycles, the subjects will receive one intratumoral 
injection of INXN-2001 in combination with 7 oral daily doses of INXN-1001.   

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• Assess anti-tumor response based on total measurable tumor burden.   
• Evaluate the immunological effect of study treatment in terms of cellular and humoral 
immune responses, as well as other biological activities in the injected tumor(s), 
tumor-involved draining lymph nodes (if accessible) and in the peripheral circulation.  
• Evaluate the extent of the uptake of INXN-2001 into tumor cells and tumor-
infiltrating immune cells, and to assess adenoviral vector shedding in body fluids. 
• Assess the pharmacokinetics (PK) of INXN-1001 in subjects with unresectable stage 
III or IV melanoma.  
6.2 
STUDY DESIGN AND DOSE ESCALATION PROCEDURE 
6.2.1 Overall Study Design 
This is a single-arm, open label, Phase I/II dose escalation study of intratumoral injections of 
INXN-2001 and oral INXN-1001 in subjects with unresectable Stage III or IV melanoma.   
Phase I:  Four sequential dose escalation cohorts of INXN-1001 in combination with a fixed 
dose of INXN-2001 are planned.  Subject enrollment and dose escalation will proceed 
according to a standard 3+3 design.  Each subject will be treated for up to 6 treatment cycles, 
each 21 days in duration.  Previously enrolled subjects received 3 cycles under former 
versions of this protocol.  There will be at least 7 days between the initiation of treatment for 
the sentinel (first) subject and additional subjects in all cohorts during the dose escalation 
stage of the study.  In each cycle, subjects will be treated with one intratumoral injection of 
INXN-2001 in combination with 7 oral daily doses of INXN-1001.  No intrasubject dose 
escalation will be allowed.   
Phase II:  Approximately 15 subjects will be enrolled in Phase II at or below the MTD.  For 
Group 1, in each of six 21-day cycles, the subjects will receive one intratumoral injection of 
INXN-2001 in combination with 7 oral daily doses of INXN-1001.  For Group 2, in each of 
six 28-day cycles, the subjects will receive one intratumoral injection of INXN-2001 in 
combination with 7 oral doses of INXN-1001 administered every other day for 14 days.   
Safety and tolerability will be assessed by the incidence and severity of adverse events as 
determined by NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.03.  A 
SRC comprised of the Medical Monitor, Principal Investigators, and sponsor representatives, 
will be convened to review safety information and to decide upon dose escalation and further 
subject enrollment.  
The anti-tumor activity of study treatment will be assessed according to RECIST v1.1 
guidelines. Additional assessment of anti-tumor activity will be explored based on total 
measurable tumor burden.39 (Appendix 4) 
Immunological and biological markers of response will include examinations of tumor 
biopsy samples, cytokine levels, PBMCs and antibody response to INXN-2001.   

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6.2.2 Treatment Parameters and Duration 
All subjects will receive intratumoral injections of INXN-2001 
 
 
 
on Day 1 of each cycle.  The subjects will also receive an oral daily dose of 
INXN-1001 for 7 consecutive days (Phase I and Phase II Group 1) or every other day for 14 
days (Phase II Group 2) starting on Day 1 of each cycle.   
Subjects may receive up to 6 cycles of study treatment. Because tumor nodules may enlarge 
due to the anticipated induction of an inflammatory response, subjects with disease 
progression (per RECIST criteria) may still complete the 6 treatment cycles, unless the 
progression is clinically significant, eg, development of new metastases or an ECOG 
performance status that increases during study treatment to ≥ 2.   
6.2.3 Safety Review Committee (SRC) 
A SRC comprised of the Medical Monitor, Principal Investigators and sponsor 
representatives, will hold periodic teleconferences to evaluate the safety and treatment status 
of all subjects.  The SRC will review and assess the safety data at the completion of each 
dose cohort as described in Section 6.2.6, and at any other time as needed.  The SRC has the 
authority to recommend dose modifications for safety concerns. 
A written summary documenting the results and recommendations of each review will be 
provided to the Investigator(s) and maintained on file with the sponsor.  Additional sub-
Investigators and personnel may participate in reviews as indicated.   
In Phase I, following a cohort review, the SRC may recommend proceeding with enrollment 
in the next dose cohort, enrolling additional subjects in the current cohort, dropping back to a 
lower cohort, exploring an alternate dose level, or not enrolling any additional subjects.  The 
dose escalation and enrollment guidelines outlined in Section 6.2.6, as well as the study 
stopping rules outlined in Section 6.2.7, will be used as the basis for these assessments. 
In Phase II, Group 2, the DLT definitions in Section 6.2.4 will be utilized along with the 
criteria for de-escalation.  The SRC may recommend a dose reduction for subjects in Group 2 
if one or more DLT(s) are observed.   
While the SRC is expected to reach a consensus opinion regarding any premature 
discontinuation or significant modification of the study, the sponsor may independently stop 
the study. 
6.2.4 Definition and Management of Dose-Limiting Toxicity (DLT) 
Dose-limiting toxicity (DLT) is defined as: 
• Any injection site reaction that includes ulceration, necrosis, severe tissue damage or 
where operative intervention is required.  
• Any local or systemic injection reaction that has life-threatening consequences, 
requires urgent intervention or results in death.  

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• Any study drug-related ≥Grade 3 adverse event, except nausea and/or vomiting in 
subjects who did not receive optimal treatment with anti-emetics.  
Phase I and Phase II, Group 1:  If DLTs have been observed in >1 of the 3-6 subjects in a 
cohort during the first treatment cycle, the MTD will have been exceeded and further use of 
that dose will be discontinued in all subjects, and the next lower dose cohort will be assessed 
as to whether it meets the definition of the MTD. 
Phase II, Group 2: If an adverse event that meets the Phase I DLT definition is observed in 
>1 of the 3-6 subjects in Group 2 during the first treatment cycle, the SRC will convene to 
discuss reduction in dose and/or change to posology and the cohort will be expanded by 3 
subjects. The recommended Phase II dose will be the dosage and posology where ≤1 of 3 to 6 
subjects experiences an adverse event as described in the definition of DLT. 
The Medical Monitor should be immediately notified of any potential DLT.  Subjects will be 
withdrawn from study treatment if they experience an injection site reaction that meets DLT 
criteria or other Grade 3 toxicity related to study drug that, upon review of the SRC, is 
deemed to be a DLT.  If, however, the subject has experienced a substantial benefit from 
treatment and the SRC recommends continuation on the study, re-exposure to the 
experimental treatment may proceed at a lower dose of INXN-1001 on a case by case basis.  
Any subject who experiences a Grade 4 toxicity related to study treatment will be withdrawn 
from study. 
6.2.5 Definition of Maximum Tolerated Dose (MTD) and Recommended Phase II 
Dose (RP2D) 
The MTD will be defined as the highest dose of INXN-1001 studied in combination with 
INXN-2001 at which a DLT has been seen in a maximum of 1 in 6 subjects (< 33%) during 
the first treatment cycle.  Subsequent to Cycle 1, study drug-related adverse events that meet 
the DLT criteria will also be considered by the SRC and any previous determination of the 
MTD may be reconsidered.   
The recommended Phase II dose will be the dosage and posology where ≤1 of 3 to 6 subjects 
experiences an adverse event as described in the definition of DLT. 
6.2.6 Dose Escalation Procedure 
In Phase I, four sequential INXN-1001 dose escalation cohorts are planned, as described in 
Appendix 5.  Subject enrollment and dose escalation will proceed according to a standard 
3+3 design.  No intrasubject dose escalation will be allowed.  An intermediate dose level(s) 
of INXN-1001 may be explored after review of all available safety and activity data, as may 
be decided by the SRC. 
Approximately 15 subjects will be enrolled in Phase II at or below the MTD 
To increase the ability to estimate the effect of the treatment on clinical response and to 
correlate with immunologic or other biologic markers, an additional number of subjects may 
be entered into the study after the initial safety evaluation has been completed.   

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6.2.7 Study Stopping Rules 
Rules for stopping dose escalation due to DLTs observed during the first cycle of study 
treatment are outlined in Section 6.2.4.  In the event that a given dose is determined to have 
exceeded the MTD, then further use of that dose will be discontinued for all subjects as noted 
in Section 6.2.4.  Subsequent to Cycle 1, study drug-related adverse events that meet the 
DLT criteria will also be considered by the SRC and any previous determination of the MTD 
may be reconsidered. 
Stopping rules for toxicities that occur from Day 1, Cycle 2 through the Post-treatment 
follow-up visit will apply as follows:  
• If an adverse event can be definitely shown to be unrelated to study treatment (eg, 
motor vehicle accident, bee sting, elective surgery), that specific toxicity will not be 
considered in a stop vs. dose modification decision.  
• Recruitment in the current dose level will not be stopped for Grade 2 (NCI CTCAE 
v.4.03) non-dose limiting toxicities, irrespective of the number of events or number of 
subjects. 
• Recruitment in the current dose level will be stopped for any Grade 4 toxicity.  Upon 
occurrence, all data will be reviewed by the Investigator, the Investigator’s IRB as 
applicable, ZIOPHARM Medical and Regulatory Staff, and the SRC to determine if 
the study should proceed and if/what changes must be implemented.  
o For toxicity based on laboratory tests:  an abnormality related to study drug 
per investigator assessment must be confirmed (when appropriate) by repeat 
testing before qualifiying for review as above. 
• Subject enrollment into the study will be halted in the event of any study drug-related 
death.  In this case, subject enrollment will only resume following review and 
approval of the SRC.  
7. SUBJECT SELECTION 
The target population for this study is adult subjects with unresectable Stage III or IV 
melanoma for which there is no alternative curative therapy. 
7.1 
INCLUSION CRITERIA 
To be enrolled in the trial, each subject must satisfy all of the following inclusion criteria: 
1. Males or females of all races ≥ 18 years of age, who have provided written informed 
consent prior to completing any study specific procedure.  
2. Unresectable Stage III or Stage IV melanoma arising from any site other than ocular 
melanoma. 
3. A minimum of 2 accessible lesions (shortest diameter ≥1 cm) or palpable tumor-involved 
lymph nodes (shortest diameter ≥1.5 cm).   

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4. ECOG performance status of 0 or 1 (Appendix 1).  
5. Adequate bone marrow, liver, and renal function, as assessed by the following laboratory 
requirements: 
a. Hemoglobin ≥ 9 g/L 
b. Lymphocytes > 700/ mm3 
c. Neutrophils ≥ 1,500/ mm3  
d. Platelets ≥ 100,000/ mm3 
e. Serum creatinine ≤ 1.5 x ULN 
f. AST and ALT ≤ 2.5 x ULN. For subjects with documented liver metastases, 
ALT and AST ≤ 5×ULN 
g. Total bilirubin < 1.5 x ULN 
h. International Normalized Ratio (INR) and activated partial thromboplastin 
time [PTT] <1.5 x ULN, if 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 
no prior evidence of underlying abnormality in coagulation parameters, 
screening test results are in appropriate therapeutic range, and anticoagulation 
regimen is stable and closely monitored. 
6. An expected survival of at least 6 months.  
7. Male and female subjects must agree to use a highly reliable method of birth control 
(expected failure rate less than 5% per year) from the screening visit through 28 days 
after the last dose of study drug. 
7.2 
EXCLUSION CRITERIA 
Subjects will be excluded from enrolling in the trial if they meet any of the following 
exclusion criteria: 
1. Any prior anti-cancer therapy or investigational agent within 28 days prior to the first 
dose of study drug.   
NOTE: For Phase II ONLY, if subjects received ipilimumab, a 45-day washout period 
since last dose of ipilimumab is required. If subjects received other immunomodulating 
therapies (eg, anti-PD1 antibodies), the medical monitor should be contacted and an 
evaluation will be made. 
2. Clinically significant infection requiring systemic antibacterial, antifungal, or antiviral 
therapy within 2 weeks of the first dose of study drug.   
3. History of HIV infection.  
4. Active autoimmune disease requiring steroids (>10 mg prednisone or comparable) or 
other immunosuppressive therapy (eg, methotrexate, etc.).  

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5. Documented symptomatic brain metastases.  Screening for brain lesions by CT or MRI 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. 
6. Any medications that induce, inhibit or are substrates of CYP450 3A4 within 7 days prior 
to the first dose of study drug. 
7. Prior history of hematopoietic stem cell transplant or organ allograft.  
8. Other concurrent clinically active malignant disease, with the exception of other cancers 
of the skin.  
9. Females who are nursing or pregnant.  
10. Subjects who have a history of hypersensitivity that may relate to any component of the 
study drugs, eg to benzoic acid since INXN-1001 contains two benzene rings.   
11. Unstable or clinically significant concurrent medical condition that would, in the opinion 
of the investigator, jeopardize the safety of a subject and/or their compliance with the 
protocol. Examples include, but are not limited to, unstable angina, congestive heart 
failure, recent (within 2 months of screening) myocardial infarction, ongoing 
maintenance therapy for life-threatening ventricular arrhythmia, uncontrolled asthma, 
evidence of hepatic pathology due to or consistent with infection with a chronic hepatitis 
virus, uncontrolled major seizure disorder, or electrolyte imbalances. 
12. Local infection at site of injectable lesion requiring anti-infective therapy within 2 weeks 
of the first dose of study drug. 
7.3 
WITHDRAWAL OF SUBJECTS FROM STUDY TREATMENT AND/OR 
STUDY 
The investigator and/or the subject have the right to terminate the subject’s participation in 
the study at any time. Subjects who discontinue study drug should complete the Post-
Treatment Safety Assessment visit.   
A subject may withdraw (or be withdrawn) from the study treatment prematurely for any of 
the following reasons: 
• Principal investigator (PI) determines further participation is not in subject’s best 
interest. 
• Clinically significant disease progression. 
NOTE: In the absence of rapid clinical deterioration, disease progression should be 
confirmed by a repeat, consecutive assessment no less than 4 weeks from the date 
first documented to ensure that more slowly declining tumor burden in response to 
therapy is not missed. 
A subject MUST be withdrawn in the event of any of the following: 

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• Withdrawal of informed consent.  (Note: Any subject who wishes to withdraw from 
the study treatment may do so but will be counseled that follow-up for the effects of 
immunotherapy is strongly recommended.) 
• Any DLT meeting the withdrawal criteria described in Section 6.2.4. 
• Any treatment-related adverse event meeting withdrawal criteria as described in 
Section 8.2.6. 
• Substantial noncompliance with the requirements of the study. 
• Subjects with a confirmed positive pregnancy test (to be reported via pregnancy 
notification form). 
• Any intercurrent illness that would, in the judgement of the investigator, 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 with 
ongoing treatment-related adverse events in order to determine the outcome of the event.  
7.4 
REPLACEMENT OF SUBJECTS 
Subjects who are withdrawn from study treatment prior to completing Cycle 1 dosing for 
reasons other than toxicity may be replaced so that a full cohort of subjects completes Cycle 
1 safety evaluations.  In addition, should a subject discontinue study treatment before 
receiving 3 cycles for reasons other than toxicity, another subject may be added to that dose 
cohort so as to result in a total of at least three  subjects for full analysis. 
7.5 
PREMATURE TERMINATION OF STUDY/CLOSURE OF CENTER 
The sponsor has the right to close the study at any time, although this should occur only after 
mutual consultation between the sponsor and the investigators. The IRB/IEC must be 
informed. Should the study/center be closed prematurely, all study materials (completed, 
partially completed, and blank case report forms, study medication, etc) must be stored or 
disposed of according to the sponsor’s instructions. Events that may trigger premature 
termination of the study or closure of a center include, but are not limited to a new toxicity 
finding, results of any interim analysis, noncompliance with the protocol, change in 
development plans for the study drug, slow recruitment, or poor-quality data.   
8. TREATMENT PROCEDURES 
8.1 
SCREENING 
Principal investigators (PIs) at each site are responsible for maintaining a record of all 
subjects screened, including both those who enter the study and those who are excluded.  

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8.1.1 Informed Consent 
Each potential subject must sign a written, informed consent form (ICF) prior to performing 
any study specific screening procedure. 
8.1.2 Inclusion and Exclusion Criteria 
Inclusion and exclusion criteria will be reviewed for each potential subject and documented 
in the CRF.  
8.1.3 Registration of Subjects 
Centralized registration of subjects will be completed according to a process defined by the 
sponsor.  The sponsor will assign a subject specific identification number and note the dose 
cohort to which the subject is assigned. Once assigned, a subject’s identification number will 
not be reused. 
8.2 
STUDY DRUG  
8.2.1 Accountability and Dispensation 
The Principal Investigator (PI) must maintain accurate records accounting for the receipt and 
dispensation of the study drugs.   
The investigational materials are to be prescribed only by the PI or the sub-investigators 
named on the Form FDA 1572, and may only be dispensed by authorized personnel at the 
institution(s) listed therein.   
Under no circumstances will the PI allow investigational drug to be used other than as 
directed by the protocol.  
8.2.2 Handling and Storage  
Study drugs must be stored in a restricted access area under the storage conditions indicated 
on the product label or Investigator’s Brochure.   
All necessary precautions while handling potentially toxic compounds must be strictly 
followed.   
8.2.3 Treatment Regimen 
Each subject’s assigned INXN-1001 dose will be given orally daily for the first 7 consecutive 
days of each 21-day cycle (Phase I and Phase II Group 1).  For Phase II Group 2 the INXN-
1001 dose will be given orally every other day for 14 days of each 28-day cycle,    
INXN-2001 will be given as intratumoral injections of 
 
 
 in 0.5 mL 
per treatment.  Following Cycle 1, if no accessible lesion for INXN-2001 injection is present 
(eg, due to complete resolution), then INXN-2001 should be injected into a tumor-involved 

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8.2.5.3 Preparation and Administration of INXN-2001 
INXN-2001 will be supplied by the sponsor as single dose vials.  Information regarding the 
preparation of the INXN-2001 dose will be provided in the Pharmacy Manual.  
INXN-2001 
 
 
 will be administered as an intratumoral injection 3 
hours (± 30 minutes) after oral INXN-1001 dosing on Day 1 of each cycle.  INXN-2001 
should be injected into a different lesion at each cycle.   
If only 3 accessible lesions are present, the injections will be done in sequential rotation 
between 2 lesions.  If only 2 accessible lesions are present, then all injections will be into a 
single lesion.  If only 2 accessible lesions are present at screening and the single injected 
lesion can no longer support the injection volume at subsequent cycles, then the medical 
monitor should be contacted for a discussion. 
Note:  One accessible lesion will not be injected since that lesion will be used to evaluate the 
systemic effect of INXN-2001.  
The INXN-2001 intratumoral administration should be delivered by multiple injections with 
a fine needle (no finer than 27 gauge) directly into each quadrant of the lesion or tumor-
involved lymph node, at approximately 0.5 cm apart three dimensionally, to reach all aspects 
of the entire lesion.  Attention must be paid to adequately infiltrate the circumference of the 
tumor margins. Radiographically-guided injections are permitted under BL2 conditions.  A 
detailed description and photograph of physical location(s) of the injected tumor(s) and 
surrounding tissue, and any visible local reactions should be documented.  Lesions displaying 
signs of local infection should not be injected. 
Should the tumor selected for injection not support the entire INXN-2001 injection volume, 
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 lymph node of the injected tumor.  Following 
Cycle 1, if no accessible lesion for INXN-2001 injection is present (eg, due to complete 
resolution), then INXN-2001 should be injected into a draining lymph node of a previously 
accessible 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 INXN-2001 injection. The 
subject should be instructed to call the clinical site if any such reactions develop or don’t 
resolve within 24 to 48 hours. 
 
 

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8.2.6 Retreatment Criteria, Dose Delays and Modifications 
Subjects may receive up to 6 cycles of study drug treatment.  In order to receive each repeat 
treatment cycle, all treatment-related adverse events must have resolved to Grade 1 or 
baseline and the following laboratory criteria must be met:
• Hemoglobin ≥ 9 g/L 
• Lymphocytes > 700/ mm3 
• Neutrophils ≥ 1,500/ mm3  
• Platelets ≥ 100,000/ mm3 
• Serum creatinine ≤ 1.5 x ULN 
• AST and ALT ≤ 2.5 x ULN.  For 
subjects with documented liver 
metastases, ALT and AST ≤ 5×ULN 
• Total bilirubin < 1.5 x ULN 
• INR and PTT <1.5 x ULN, if not 
therapeutically anticoagulated.
Clinical laboratory tests drawn for analysis on Day 15 of each cycle may be used for 
determining if the retreatment criteria have been met, and must be reviewed by the 
investigator or designee prior to the next cycle of study drug administration.  Treatment 
delays to allow for recovery to acceptable levels are allowed at weekly intervals up to a 
maximum of 4 weeks. In the event that a treatment-related dose delay is necessary, then the 
next cycle of study treatment will be administered at the next lower INXN-1001 dose level.  
Subjects in the first dose cohort who do not meet the retreatment criteria will be discontinued 
from study treatment (ie, no dose reductions are permitted). 
Subjects who experience a DLT will be managed as described in Section 6.2.4.  Subjects who 
experience an injection site reaction should be managed as described in Section 8.2.7. 
Subjects who experience a treatment-related Grade 3 adverse event, other than nausea and/or 
vomiting in the absence of optimal treatment with anti-emetics, will be discontinued from 
study treatment.  If, however, the subject has experienced a substantial benefit from treatment 
and the SRC recommends continuation on the study, re-exposure to the experimental 
treatment may proceed on a case by case basis.   
Subjects who experienced a Grade 4 treatment-related adverse event at any time during study 
treatment must be discontinued from study treatment. 
8.2.7 Severity Grading and Management of Injection Site Reactions 
Injection of a biologic agent carries a potential risk of injection site reaction which is 
characterized as an intense reaction (usually immunologic) at or near the site of injection.  
Injection reactions will be graded according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03.  
Table 3 outlines the injection site reaction grading system, associated symptoms, and the 
recommended actions to be taken.  For any injection reaction, a serum tryptase level will be 
measured.  Reactions at the INXN-2001 injection site that occur within 24 hours after the 
injection and are attributed to INXN-2001 will be considered to be injection related AEs.  
 
 

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Table 3. 
Injection Site Reaction Severity Grading and Management 
CTCAE 
Grade 
Symptoms 
Course of Action 
1 
Tenderness with or without 
associated symptoms (eg, warmth, 
erythema, itching) 
No intervention required. 
2 
Pain; lipodystrophy; edema; 
phlebitis 
Proceed with further dosing cycles.   
 
3 
Ulceration or necrosis; severe tissue 
damage; operative intervention 
indicated 
Discontinue further study treatment and notify Medical 
Monitor.  Report and manage as DLT: see Section 6.2.4.  
If  toxicity meets seriousness criteria, immediately report as 
per SAE reporting procedures; see Section 9.4. 
4 
Life-threatening consequences; 
urgent intervention indicated 
Permanently discontinue study treatment and notify 
Medical Monitor.  Report and manage as DLT: see Section 
6.2.4.   
Defaults to “serious”.  Immediately report as per SAE 
reporting procedures; see Section 9.4.  
5 
Death 
Immediately notify Medical Monitor and report as per SAE 
reporting procedures; see Section 9.4. 
Discontinue further subject enrollment as per study stopping 
rules; see Section 6.2.7. 
 
As with all AEs, injection-related signs or symptoms which, in the Investigator’s judgment, 
are not related to immunologic reactions (eg, dyspepsia, urinary frequency, etc) should be 
recorded and graded as AEs according to NCI CTCAE v.4.03 criteria in the CRF.  Study 
stopping rules will not apply to a specific event if it is clearly unrelated to INXN-2001 
injection (eg, accidental trauma).  If an AE associated with injection cannot be definitely 
shown to be unrelated to INXN-2001, then study stopping rules will apply.   
8.2.8 Prophylactic Hydration, Antipyretic and/or Analgesic Administration 
The use of antipyretics and/or analgesics and aggressive hydration is allowed anytime during 
study treatment, as indicated, including prophylactic administration. 
Since fever and flu like symptoms are commonly experienced following adenoviral vector 
administration it is strongly recommended that subjects be treated with prophylactic oral 
hydration, antipyretic and/or analgesic medications prior to study drug administration. 
For those subjects who experience treatment related symptoms (eg, fever, headache, chills, 
dehydration, etc) during Cycle 1, prophylactic hydration, antipyretic and/or analgesic 
medications must be given prior to study drug administration in subsequent cycles. Please 
refer to Appendix 3 for a recommended regimen for the prophylactic hydration and 
administration of antipyretics and/or analgesics. 

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8.2.9 Disposition of Unused Study Drug 
All unused study drug should be destroyed on site in accordance with applicable site facility 
and US Occupational Safety and Health Administration (OSHA) procedures after a full 
accountability has been documented. Any on-site destruction of unused study drug must be 
documented and the records maintained in the Investigator’s study file.  
8.3 
CONCOMITANT THERAPY 
Concomitant medication information, including blood products, vitamins and other 
supplements, will be collected for the time period beginning 28 days prior to the first dose of 
study drug through the Post-Treatment Safety Assessment visit.  The following medications 
are or are not permitted: 
Permitted: 
• Subjects may receive standard treatments, including palliative and supportive care for 
any underlying illness with the exception of palliative radiotherapy which is NOT 
permitted. 
• Antidiarrheal therapy is permitted for study drug-induced diarrhea. 
• Antiemetics are permitted for study drug-induced nausea and vomiting. 
• Treatment with vitamin/mineral supplements is acceptable provided that they do not 
interfere with study endpoints, in the opinion of the investigator.  
Not Permitted: 
• Subjects may not receive medications, foods or drinks that induce, inhibit, or are 
substrates of the CYP450 3A4 pathway within 7 days prior to the first dose of study 
drug through 96 hours after their last dose of INXN-1001.  See Appendix 2 for 
examples. 
• Subjects may not receive any other investigational agent or anti-cancer therapy 
(chemotherapy, radiotherapy, etc) while receiving study treatment. 
8.4 
EVALUATION AND ASSESSMENT PROCEDURES 
8.4.1 Schedule of Assessments 
A tabular schedule of evaluations and procedures is provided in Table 2 (Schedule of 
Assessments).  

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8.4.3 INXN-1001 Pharmacokinetic Assessment 
Subjects will undergo an INXN-1001 pharmacokinetic (PK) assessment during Cycle 1 of 
their study treatment. Whole blood samples will be collected on Day 1, Day 2, Day 7, and 
Day 15 as defined in the Schedule of Assessments (see Table 2).  
8.4.4 Efficacy Assessments 
Appropriate cancer staging procedures should be performed during screening.  For the 
purpose of this clinical trial, the following imaging is expected at screening: 
a. CT of the chest, and CT (or MRI) of the abdomen and pelvis 
b. MRI (or CT) of the brain if brain metastasis are known or suspected  
c. CT or MRI of other anatomical regions as clinically indicated 
 
For subjects with measurable lesions, target lesions should be selected and measured as per 
RECIST 1.1 guidelines.1  Lesions that will be/are injected with INXN-2001 and/or biopsied 
should not be selected as target lesions, but should be measured (if measureable).   
For each subject, disease sites are to be assessed throughout the study using the same 
method(s) of assessment used at screening. Specific image acquisition guidelines will be 
provided by a central imaging laboratory.  Chest, abdomen, pelvis imaging is required for all 
follow-up imaging time points; images of the brain and other anatomical regions should be 
acquired on follow-up if positive at screening and as clinically indicated. 
All subjects will have tumor response assessments performed including Cycle 3 Day 13, the 
Post-Treatment Safety Assessment visit (28 ± 3 days following the last dose of INXN-1001) 
or at the time of early withdrawal from study treatment and again at the Follow-Up Tumor 
Assessment visit (35 ± 7 days following the Post-Treatment Safety Assessment visit).  The 
Investigator will evaluate each subject for response to therapy according to RECIST 1.1 
guidelines.1 Subjects without objective evidence of disease progression at the Follow-Up 
Tumor Assessment visit should continue to have tumor assessments performed at 8-10 week 
intervals until disease progression has been documented or an alternate anti-cancer therapy 
has been initiated, whichever occurs first. 
In addition to radiological imaging techniques, photographs of visible cutaneous lesions 
should also be obtained.  Digital photograph(s) with included measuring tape should be taken 
of all visible injected tumor(s) and non-injected tumors, and of any remaining visible local 
reactions in or around the injected lesion(s).  Any subject who has or develops vitiligo, 
should be documented the same way.  Details regarding photographic methodology will be 
provided in the Photography Operations Manual. 
As a supplement to the standard RECIST v1.1 guidelines established to evaluate anti-tumor 
responses to chemotherapeutic agents, the sponsor will be analyzing anti-tumor response by 
assessing total tumor burden over time. Please refer to Appendix 4 for a description of 
“immune-related Response Criteria” (irRC). 

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9. ADVERSE EVENTS 
9.1 
ADVERSE EVENT (AE) DEFINITION 
An adverse event is any untoward medical occurrence associated with the use of a drug in 
humans whether or not considered drug related.  Any worsening of a preexisting condition, 
which is temporally associated with the use of the study drug, is also an AE. 
Adverse events include: 
 
• Suspected adverse drug reactions; 
• Reactions from study drug overdose, abuse, withdrawal, sensitivity, or toxicity; 
• Significant changes or abnormalities when compared to baseline, in signs, symptoms, 
clinical laboratory results, or physiological testing. This includes any worsening of a 
preexisting condition temporally associated with the use of study drug; 
• Other untoward medical events, regardless of their relationship to the study drug, 
such as injury, events that require surgery, accidents, extensions of symptoms, or 
apparently unrelated illnesses. 
The following considerations apply when identifying an AE: 
• Anticipated day-to-day fluctuations of pre-existing conditions including the disease 
under study that do not represent a clinically significant exacerbation or worsening 
need not be considered adverse events.  
• In the event that a constellation of symptoms results in a confirmed diagnosis, the 
diagnosis (not the symptoms) should be recorded as the adverse event term. 
• If a diagnosis cannot be established, the symptoms should be recorded as the adverse 
event(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 (eg, increase in pain).  
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. 
9.2 
EVALUATION OF ADVERSE EVENTS (AEs) 
9.2.1 Determination of Seriousness 
The Investigator will determine the seriousness of an AE based on the following: 

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9.2.1.1 Serious Adverse Event (SAE) 
 An AE is considered an SAE if at least one of the following conditions applies: 
 
• Death: An AE that results in death during the active study period or within 30 days 
following Study Drug administration.  In addition, a reported death at any time post-
study that is thought to be related to Study Drug administration; 
• Life-threatening adverse event: An AE that places the patient, in the view of the 
 
Investigator, at immediate risk of death from the event as it occurred (ie, 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 patient into a hospital for at least a 24-hour 
stay. Hospitalizations for routine blood transfusions, hospitalization for an elective or 
diagnostic procedure, or surgery for a pre-existing condition that has not worsened, 
are not considered SAEs.  (Emergency Room visits that do not result with admission 
are not considered as SAEs); 
• A congenital anomaly/birth defect: A fixed, permanent impairment established at or 
before birth; 
• Important medical event: Events that may not result in death, be life-threatening, or 
require hospitalization may be considered SAEs when, based upon appropriate 
medical judgment, they jeopardize the patient and require medical or surgical 
intervention to prevent a life-threatening situation, hospitalization or death; 
• New Cancer: Occurrence or diagnosis of a new cancer during the trial is considered a 
serious adverse event. (This does not pertain to metastasis of current disease); 
• Any AE associated with an overdose of the study drug: An overdose of study drug is 
defined as an occurrence of administered dose exceeding that which is prescribed by 
the Investigator per protocol. 
9.2.1.2 Non-Serious Adverse Event 
Adverse events that do not fulfill the previous criteria are classified as non-serious AEs. 
9.2.2 Determination of Severity 
The severity of AEs will be assessed according to the NCI CTCAE, v. 4.03. If the AE is not 
defined in the NCI CTCAE, v. 4.03, the Investigator will determine the severity of an AE 
based on the following definitions: 
• Mild (Grade 1): The AE is noticeable to the patient, but does not interfere with 
routine activity. The AE does not require discontinuing administration or reducing the 
dose of the study drug. 
• Moderate (Grade 2): The AE interferes with routine activity, but responds to 
symptomatic therapy or rest. The AE may require reducing the dose, but not 

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discontinuing administration of the study drug. 
• Severe (Grade 3): The AE significantly limits the patient’s ability to perform routine 
activities despite symptomatic therapy. In addition, the AE leads to discontinuing 
administration or reducing the dose of the study drug. 
• Life Threatening (Grade 4): The AE requires discontinuing administration of the 
study drug. The patient is at immediate risk of death. 
• Death (Grade 5): The patient dies as a direct result of the complication or condition  
Adverse events should be reported using the maximum intensity of the event (eg, if a subject 
reported nausea lasting 3 days, one start date and stop date should be recorded along with the 
maximum intensity experienced for that event over that 3 day timeframe). 
9.2.3 Causality Assessments 
The Investigator will use medical consideration to determine the potential relationship of the 
AE to the study drugs based on his/her clinical judgment.  Assessment of causality will be 
based upon the following: 
• Alternative possible causes of the AE, including the subject’s underlying disease or 
co-morbid conditions, other drugs, other host and environmental factors; 
• The temporal sequence between the exposure to study drug and the AE; 
• Whether the clinical or laboratory manifestations of the AE are consistent with known 
actions or previously reported toxicity of the study drug (or similar drugs); 
• Whether the AE resolved or improved with decreasing the dose or stopping the study 
drug (ie, dechallenge); or recurred or worsened with re-exposure to the drug (ie, 
rechallenge). 
The relationship between the study drug and the AE will be described using one of the 
following categories: 
• Unrelated: Another factor is clearly the cause of the AE. 
• Possibly Related: There is a reasonable possibility that the study drug is the cause of 
the AE, including that the study drug and another factor(s) are equally likely as 
causes of the AE. 
• Related: The AE can be fully explained by the administration of study drug. 
9.3 
DOCUMENTING ADVERSE EVENTS (AES) 
All AEs (including SAEs) are to be accurately recorded on the Adverse Event page of the 
patient’s eCRF from the time the patient signs the informed consent until the post-treatment 
safety visit. Each event will be assessed for serious criteria, severity, and causality (See 
“Causality Assessments”). The date of onset, as well as the duration of the event will be 
recorded. In addition, treatments provided to the patient, actions taken with the study drugs, 
and the outcome of the AE will also be noted. 
 
 

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9.4 
REPORTING SERIOUS ADVERSE EVENTS (SAEs) 
Time Frame for Reporting 
 
SAEs must be reported to the Sponsor or Sponsor’s designee within 24 hours of becoming 
aware of the event (regardless of the initiation of any new anti-cancer therapy) including the 
following: 
• Any death or SAE experienced by the patient from the signing of informed consent to 
30 days after the last dose of study drug, regardless of relationship to study drug. 
• Any death or SAE that the Investigator becomes aware of, and believes to be study 
drug related, that occurs more than 30 days after the patient last received study drug. 
 
Study drug-related AEs/SAEs that are ongoing at the time of the Post-Treatment Safety 
Assessment visit should continue to be followed until resolution, return to baseline, or until 
they have stabilized or become chronic (and following consultation and agreement by the 
ZIOPHARM Medical Monitor). 
 
Information to be provided by the Investigator   
 
Within 24 hours of becoming aware of the SAE or patient death, the Investigator must notify 
the Sponsor or designee and transmit information to the Sponsor or designee. Information 
(initial and follow-up) should be provided on an electronic and/or paper SAE Report form 
signed and dated by the Investigator. The SAE Report form and copies of source documents 
(with patient identifiers redacted) will be transmitted electronically or 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 the form. The Investigator will 
provide all of the following information related to the event: 
 
• Investigator identification 
• Patient identification  (eg, patient number, initials, sex, age or date of birth) 
• Information regarding study drug administration (eg, start/stop date, dose and 
frequency ) 
• Description of event 
• Action taken with the study drugs 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 study drug (causality assessment) 

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9.5 
SPONSOR AND INVESTIGATOR RESPONSIBILITY FOR REPORTING 
ADVERSE EVENTS (AEs) 
All AEs 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 from the Sponsor to his/her IRB/IEC per agreements and local requirements. 
The Investigator must keep copies of all safety reports, including correspondence with 
ZIOPHARM and the IRB/IEC, in the study file.  
9.6 
FOLLOW-UP INFORMATION 
Appropriate diagnostic tests should be performed and therapeutic measures, as medically 
indicated, should be instituted. Appropriate consultation and follow-up evaluations should be 
carried out until the event has resolved, stabilized, returned to baseline, or is otherwise 
explained by the Investigator. 
 
Follow-up data concerning the SAE (ie, diagnostic test reports, hospital summaries, etc) must 
be promptly reported (within 24 hours of receipt) to the Sponsor or Sponsor’s designee, until 
resolution of the SAE. Should the FDA or National Regulatory Authorities require that the 
Sponsor submit additional data on the event, the Investigator will be asked to provide those 
data to the Sponsor in a timely fashion. 
 
Required Follow-up for Serious Adverse Events (SAEs) 
All treatment-related AEs/SAEs that are ongoing at the time of the Post-Treatment Safety 
visit will be followed until: 
• The event resolves, or 
• The event returns to baseline if a baseline value is available, or 
• The event stabilizes (and following consultation and agreement by the ZIOPHARM 
Medical Monitor), or 
• The event can be attributed to factors other than the study drug or other than study 
procedure. 
9.7 
PREGNANCIES 
Subjects who become pregnant during the study should immediately discontinue 
participation in the study. The Sponsor should be immediately notified. 
An initial Pregnancy Report form and a Pregnancy Outcome Form are to be completed by the 
Investigator or designee. The Pregnancy Report form and the completion guidelines will be 
provided in the investigator study files.  Please refer to the investigator study files for details 
on how to complete these forms. 

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10. STATISTICAL PROCEDURES  
Data from this study will be analyzed and included in a clinical study report that will be 
prepared after the last subject has completed the Post-Treatment Safety Assessment visit.  
Additional data collected from subjects who have not progressed by the Post-Treatment 
Safety Assessment visit and are continuing to be followed for tumor response at the time of 
the final data cut-off date will be presented in an addendum to the study report. 
10.1 DETERMINATION OF SAMPLE SIZE 
No formal sample-size estimation was performed.  The choice of the number of subjects was 
based on the standard Phase I 3+3 inter-cohort dose escalation design in which 3 to 6 subjects 
are enrolled into each dose level cohort. 
In order to increase the ability to estimate the effect of the treatment on clinical response and 
to correlate with immunologic or other biologic markers, an additional number of subjects 
may be entered into the study after the initial safety evaluation has been completed.  Based 
on a review of available safety and clinical response data, an additional 15 subjects may be 
enrolled in Phase II at a single dose level at or below the MTD.  Should a subject discontinue 
study treatment before receiving 3 cycles for reasons other than toxicity, another subject may 
be added to the dose cohort to provide a total of 3 or 6 subjects for full analysis.  
Given these considerations, a total of approximately 30 subjects may be enrolled into this 
study, including 6 subjects enrolled in each of the 4 planned dose level cohorts and 
approximately 15 additional subjects enrolled at a single dose level at or below the MTD.  
Additional subjects may also be enrolled as replacement subjects or to explore intermediate 
dose level cohorts, if any. 
10.1.1 Subject Randomization 
Not applicable. 
10.1.2 Populations for Analysis 
The following subject populations will be evaluated and used for presentation and analysis of 
the data: 
• Safety Population: All subjects who receive at least one INXN-1001 capsule or, in the 
event an injection of INXN-2001 is administered before an INXN-1001 capsule is 
taken, at least one injection of INXN-2001.  
• Activity Evaluable Population: All subjects who received at least 1 dose of INXN-
2001 and INXN-1001, and have at least 1 post-screening response evaluation. 

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10.2 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. 
10.3 STATISTICAL METHODS 
Categorical data will be summarized using counts and percentages based on non-missing 
values.  For continuous variables, the mean, median, standard deviation, minimum and 
maximum values will be presented. 
Data will be summarized by dose cohort based on the actual dose of INXN-1001 received on 
Day 1, Cycle 1.  For Phase II, data will be summarized based on group and dose regimen. 
10.3.1 Baseline Characteristics 
Demographic and baseline disease characteristic data will be summarized.  Data to be 
tabulated will include at least demographic features such as sex, age, and race, as well as 
disease-specific status and medical history. 
10.3.2 Safety Analyses 
The Safety Population will be used for the analyses of safety data based on the dose of 
INXN-1001 received. 
Safety evaluations will be based on the incidence, intensity, and type of AEs and SAEs.  
Clinically significant changes in the subjects’ physical examinations, vital signs, and ECG 
evaluations, and clinical manifestations relevant to abnormal laboratory values will be 
captured as AEs.  Safety will also be assessed based on medical history and 
prior/concomitant medications. 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA®) for 
the purpose of summarization.  All AEs occurring during the study will be included in by-
subject data listings.  Treatment-emergent events will be tabulated.  ‘Treatment-emergent’ is 
defined as any AE that occurs during or after administration of the first dose of study drug 
through the Post-Treatment Safety Assessment visit (28 days after the last INXN-1001 dose); 
any event after the first dose of study drug that is considered study drug-related regardless of 
the start date of the event; or any event that is present at baseline that worsens in intensity or 
is subsequently considered to be drug related by the investigator.  Deaths, SAEs, and AEs 
resulting in study discontinuation will be listed.   
Safety variables will be tabulated and presented by dose cohort.  Exposure to study drug and 
reasons for discontinuation of study treatment will be tabulated. 

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10.3.3 Efficacy Analyses 
The Activity Evaluable Population will be used for the analyses of efficacy data based on the 
dose of INXN-1001 received. 
Following completion of the study, best response will be determined for each subject in 
accordance with RECIST v.1.1 guidelines and the objective response rate presented for each 
dose cohort.  Progression-free survival and durability of response will be determined using 
Kaplan-Meier methodology. 
As a supplement to the standard RECIST v1.1 guidelines established to evaluate anti-tumor 
responses to chemotherapeutic agents, the sponsor will be analyzing anti-tumor response by 
assessing total tumor burden over time. Please refer to Appendix 4 for a description of 
“immune-related Response Criteria” (irRC). 
10.3.4 Immunologic Responses 
The trial will assess the immunological effects of each treatment cycle on the cellular and 
humoral immune responses in the peripheral circulation and in tumor biopsy specimens.  
Humoral immune responses (potential antibody production) to the adenovirus and/or the 
RTS  components as well as against melanoma antigens will be compared to baseline in 
serum samples, and cytokine profiling will also be performed by multiplex analysis.  Whole 
blood will be collected for flow and/or ELISPOT assays to test anti-tumor T lymphocyte 
responses against adenovirus and/or the RTS  components as well as against melanoma-
associated antigens.  Samples will also be screened for the relative percentages of 
mononuclear immune cell subpopulations.  At each time point, the change in immunologic 
response (CTL and Treg frequency in blood) from baseline and from the preceding time 
point will be correlated with the INXN-1001 dosage level. 
In addition, tumor punch biopsies or FNAs will be examined for genomic changes due to IL-
12 expression, presence of injected adenovirus and CTL frequency, Treg and MDSC 
frequency, and other immunological markers.  The change in each measure from baseline 
and from the preceding biopsy will be correlated with the INXN-1001 dose used in the each 
cohort. 
10.3.5 INXN-1001 Pharmacokinetics 
INXN-1001 PK parameters to be determined will include, but is not limited to, the maximum 
concentration (Cmax), time to maximum concentration (Tmax), half-life (t1/2), area-under-the-
concentration time curve (AUC), volume of distribution (Vd), and clearance (CL).  Where 
possible, descriptive statistics of the PK parameters will be provided; individual subject 
INXN-1001concentrations, actual sampling times, and PK parameters will be listed.   
10.3.6 Multi-Center Study 
Efficacy and safety data will be presented for each dose cohort pooled over all centers.   

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10.3.7 Adjustments for Covariates 
No adjustments for covariates will be made. 
10.4 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. 
11. STUDY ADMINISTRATION 
11.1 CASE REPORT FORMS AND SOURCE DOCUMENTATION 
For each subject, case report forms and corresponding source records will be kept and will 
include: 
• Drug treatment (dose and dates) 
• Concomitant drug therapies 
• Data from the Post-Treatment Safety Assessment 
• Toxicity records (clinical and autopsy dates, when available) 
• Other pertinent data 
Case report forms 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 CRF 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. The completed CRF must be promptly reviewed, signed, and dated by the investigator. 
It is the obligation of the investigator to review each page of the CRF. Case report 
completion may be delegated to other study personnel; however, the sponsor must be 
informed in writing of the name of such persons and the scope of their authority. 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. 
11.2 GOOD CLINICAL PRACTICE STATEMENT 
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 Harmonisation 
(ICH) Good Clinical Practice (GCP) guidelines, applicable regulatory requirements, and 
ZIOPHARM policies. 

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11.3 SPONSOR MONITORING 
After satisfactory receipt of all necessary regulatory paperwork, the sponsor’s monitor will 
arrange that all study material be delivered to the study site at a mutually convenient time. 
An initiation visit by ZIOPHARM and its monitoring personnel will be made. At this 
meeting, all personnel expected to be involved in the conduct of the study will undergo an 
orientation to include review of study protocol, instruction for CRF completion and overall 
responsibilities, including those for drug accountability and study file maintenance. 
Throughout the course of the study, the sponsor’s monitor will make frequent contact with 
the investigator. 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 (eg, 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 
12.6. The 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. 
11.4 DURATION OF THE STUDY 
The study is estimated to complete enrollment over 24 months. The estimated number of 
months to complete study visits for the last enrolled subject is approximately 9 months 
(assuming 6 treatment cycles).  Therefore, the total duration of this study is expected to be 
approximately 1.5 to 2.5 years. 
Each subject’s participation in this study will last approximately 8 months, including: 
• 30 day screening period. 
• 6 cycles (24 weeks) of study treatment. 
• Post-Treatment Safety Assessment visit performed 28 days after the last dose of 
INXN-1001.   
• Follow-Up Tumor Assessment visit performed 35 ± 7 days after the Post-Treatment 
Safety Assessment visit. 
In addition, subjects who discontinue or complete study treatment without objective evidence 
of disease progression should continue to be followed until disease progression has been 
documented or an alternate anti-cancer therapy has been initiated, whichever occurs first.  
The active study period refers to the study period from informed consent through the Post-
Treatment Safety Assessment visit.   

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11.5 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 two years following the date on which the test article is 
approved by FDA for marketing for the purposes that were investigated in the study. If no 
application is to be filed or if the application is not approved for such indication, the records 
must be stored for two additional years and then returned to ZIOPHARM. No records will be 
destroyed, but will be indefinitely stored. 
11.6 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 
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. 
11.7 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 representative, will be identified by subject number and study code. 
The written Informed Consent will also explain that for data verification purposes, authorized 
representatives of ZIOPHARM, a regulatory authority (FDA), and/or the IRB 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. 

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12. INFORMED CONSENT 
12.1 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. It 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 or 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 approval/favorable 
opinion in advance of use. 
12.2 SUBJECT INFORMED CONSENT FORM 
ZIOPHARM will provide a sample subject Informed Consent Form, for modification as 
appropriate by the investigator. 

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13. PROTOCOL APPROVAL PAGE 
 
A Phase I/II, Open Label Study of Ad-RTS-hIL-12, an Adenovirus Vector Engineered to 
Express hIL-12, in Combination with an Oral Activator Ligand, in Subjects  with 
Unresectable Stage III or IV Melanoma 
With the exception of a change intended to eliminate an immediate hazard to subjects, the 
study shall be conducted as described in the approved protocol. All deviations from the 
protocol will be documented in the CRF.  Any significant deviation or deviation related to 
dosing or safety evaluation will be reported to ZIOPHARM and documented in the CRF. 
I agree to the terms of this study protocol.  I will conduct the study according to the 
procedures specified herein, and according to principles of Good Clinical Practice and local 
regulations and requirements. 
 
 
Center Name:   ______________________________ 
 
 
Principal Investigator 
 
Print Name:  ______________________________ 
 
Signature: 
______________________________ 
 
Date:   
______________________________ 
 

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14. REFERENCES 
1. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-247. 
2. Korn E, Liu P, Lee S, et al.  Meta-Analysis of Phase II Cooperative Group Trials in Metastatic 
Stage IV melanoma to Determine Progression-Free and Overall Survival Benchmarks for Future 
Phase II Trials. J Clin Oncol.2008;26(4):527-534.   
3. Hodi FS, O'Day SJ, McDermott DF, et al.  Improved survival with ipilimumab in patients with 
metastatic melanoma.  N Engl J Med 2010;363(8):711-23. Epub 2010 Jun 5. 
4. Palli, SR, Kapitskaya, MZ, Kumar, MB, et al.  Improved ecdysone receptor-based inducible gene 
regulation system. European Journal of Biochemistry  2003;270:1308-1315. 
5. KumarP & Katakam A.  RheoSwitch™ System: a highly sensitive ecdysone receptor-based gene 
regulation system induced by synthetic small-molecule ligands. In Gene Transfer: Delivery and 
Expression of DNA and RNA b Ed. Friedmann, T. and Rossi, J., Cold Spring Harbor Laboratory 
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6. Anderson RD, Haskell RE, Xia H, et al.  Ad-RTS-hIL-1. A simple method for the rapid 
generation of recombinant adenovirus vectors. Gene Therapy. 2000;4:1034-1038. 
7. Karzenowski D, Potter DW, Padidam M, et al.  Inducible control of transgene expression with 
ecdysone receptor: gene switches with high sensitivity, robust expression, and reduced size. 
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8. Talor E, Timar J, et al.  Leukocyte interleukin, Injection (LI) treatment in advanced primary 
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Clin Oncol., 2004 ASCO Annual Meeting Proceedings (Post-meeting Edition).  2004;22:14S 
(July 15 Supplement), 2605. 
9. Tsung K, Meko JB, Peplinski GR, Tsung YL, Norton JA.  IL-12 induces T helper 1-directed 
antitumor response. J Immunol. 1997;158:3359-3365. 
10. Mosmann TR and Coffman RL.  TH1 and TH2 cells: different patterns of lymphokine secretion 
lead to different functional properties. Annu Rev Immunol. 1989;7:145-173.  
11. Trinchieri G.  Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that 
bridge innate resistance and antigen-specific adaptive immunity. Annu Rev Immunol. 
1995;13:251-76. 
12. Mailliard RB, Egawa S. et al. Complementary dendritic cell-activating function of CD8+ and 
CD4+ T-cells: helper role of CD8+ T-cells in the development of T helper type 1 responses J. 
Exp. Med. 2002;195:473-483. 
13. Brunda MJ, Luistro L, Warrier RR, et al. Antitumor and antimetastatic activity of interleukin 12 
against murine tumors. J Exp Med. 1993;178:1223-1230. 
14. Nastala CL, Edington HD, McKinney TG, et al.  Recombinant IL-12 administration induces 
tumor regression in association with IFN-gamma production. J Immunol. 1994;153: 1697-1706. 
15. Verbik DJ, Stinson WW, Brunda MJ, Kessinger A, Joshi SS.  In vivo therapeutic effects of 
interleukin-12 against highly metastatic residual lymphoma. Clin Exp Metastasis. 1996;14: 219-
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16. Zou JP, Yamamoto N, Fujii T, et al.  Systemic administration of rIL-12 induces complete tumor 
regression and protective immunity: response is correlated with a striking reversal of suppressed 
IFN-gamma production by anti-tumor T-cells. Int Immunol. 1995;7:1135-1145.  
17. Zhu S, Lee DA, Li S.  IL-12 and IL-27 sequential gene therapy via intramuscular electroporation 
delivery for eliminating distal aggressive tumors. J Immunol. 2010;184:2348-54.  
18. Robertson MJ, Cameron C, Atkins MB, et al.  Immunological effects of interleukin 12 
administered by bolus intravenous injection to patients with cancer. Clin Cancer Res. 1999;5:9-
16.  
19. Atkins MB, Robertson MJ, Gordon M, et al.  Phase I evaluation of intravenous recombinant 
human interleukin 12 in patients with advanced malignancies. Clin Cancer Res. 1997;3:409-17. 
20. Gollob JA, Mier JW, Veenstra K, et al.  Phase I trial of twice-weekly intravenous interleukin 12 
in patients with metastatic renal cell cancer or malignant melanoma: ability to maintain IFN-
gamma induction is associated with clinical response. Clin Cancer Res. 2000;6:1678-92.   
21. Lenzi R, Edwards R, June C, et al.  Phase II study of intraperitoneal recombinant interleukin-12 
(rhIL-12) in patients with peritoneal carcinomatosis (residual disease < 1 cm) associated with 
ovarian cancer or primary peritoneal carcinoma. J Transl Med. 2007;5:66. 
22. Alatrash G, Hutson TE, Molto L, et al. Clinical and immunologic effects of subcutaneously 
administered interleukin-12 and interferon alfa-2b: phase I trial of patients with metastatic renal 
cell carcinoma or malignant melanoma. J. Clin. Oncol. 2004;22:2891-900.   
23. Gollob JA, Veenstra KG, Parker RA, et al.  Phase I trial of concurrent twice-weekly recombinant 
human interleukin-12 plus low-dose IL-2 in patients with melanoma or renal cell carcinoma. J 
Clin Oncol. 2003;21:2564-73.   
24. Eisenbeis CF, Lesinski GB, Anghelina M, et al.  Phase I study of the sequential combination of 
interleukin-12 and interferon alfa-2b in advanced cancer: evidence for modulation of interferon 
signaling pathways by interleukin-12. J Clin Oncol. 2005;23:8835-44. 
25. Portielje JE, Gratama JW, van Ojik HH, Stoter G, Kruit WH.  IL-12: a promising adjuvant for 
cancer vaccination. Cancer Immunol Immunother. 2003;52:133-44.  
26. Van Herpen CM, Huijbens R, Looman M, et al.  Pharmacokinetics and immunological aspects of 
a phase Ib study with intratumoral administration of recombinant human interleukin-12 in 
patients with head and neck squamous cell carcinoma: a decrease of T-bet in peripheral blood 
mononuclear cells. Clin Cancer Res. 2003;9:2950-6. 
27. Leonard JP, Sherman ML, Fisher GL, et al. Effects of single-dose interleukin-12 exposure on 
interleukin-12-associated toxicity and interferon-gamma production. Blood. 1997;90:2541-8. 
28. Patel P, Young JG, Mautner V, et al. A phase I/II clinical trial in localized prostate cancer of an 
adenovirus expressing nitroreductase with CB1954 [correction of CB1984]. Mol Ther. 
2009;17(7):1292-9.  
29. Zhang S, Li Y, Li L, Zhang Y, Gao N, Zhang Z, Zhao H.  Phase I Study of Repeated 
Intraepithelial Delivery of Adenoviral p53 in Patients With Dysplastic Oral Leukoplakia. J Oral 
Maxillofac Surg. 2009;67(5):1074-82. 

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30. Shimada H, Matsubara H, Shiratori T, et al.  Phase I/II adenoviral p53 gene therapy for 
chemoradiation resistant advanced esophageal squamous cell carcinoma. Cancer Sci. 
2006;97(6):554-61. 
31. Sangro B, Mazzolini G, Ruiz J, et al.  Phase I trial of intratumoral injection of an adenovirus 
encoding interleukin-12 for advanced digestive tumors. J Clin Oncol. 2004;22: 1389–1397.  
32. Triozzi P, Allen KO, Carlisle RR, Craig M, LoBuglio AF, Conry RM.  Phase I study of the 
intratumoral administration of recombinant canarypox viruses expressing B7.1 and interleukin 12 
in patients with metastatic melanoma. Clin Cancer Res. 2005;11: 4168–4175 
33. Mazzolini, G., Alfaro, C., Sangro, B., et al.  Intratumoral injection of dendritic cells engineered to 
secrete interleukin-12 by recombinant adenovirus in patients with metastatic gastrointestinal 
carcinomas. J Clin Oncol. 2005;23:999-1010. 
34. Daud AI, DeConti RC, Andrews S, et al.  Phase I trial of interleukin-12 plasmid electroporation 
in patients with metastatic melanoma. J Clin Oncol. 2008;26:5896-903.  
35. Heinzerling L, Burg G, Dummer R, et al.  Intratumoral injection of DNA encoding human 
interleukin 12 into patients with metastatic melanoma: clinical efficacy. Hum Gene Ther. 
2005;16:35-48. 
36. Anwer K, Barnes MN, Fewell J, Lewis DH, Alvarez RD.  Phase-I clinical trial of IL-12 
plasmid/lipopolymer complexes for the treatment of recurrent ovarian cancer. Gene Ther. 
2010;17:360-9. 
37. US National Cancer Institute, Melanoma Treatment (PDQ®).  Accessed on 05APR2011: 
http://www.cancer.gov/cancertopics/pdq/treatment/melanoma/HealthProfessional/page4 
38. Nwanegbo E, Vardas E, Gao W, et al. Prevalence of neutralizing antibodies to adenoviral 
serotypes 5 and 35 in the adult populations of The Gambia, South Africa, and the United States. 
Clinical Diagnostic Lab Immunology. 2004;11(2), 351-357. 
39. Wolchok J, Hoos A, O’Day S, et al. Guidelines for the Evaluation of Immune Therapy Activity in 
Solid Tumors: Immune-Related Response Criteria. Clin Cancer Res. 2009;15, 7412-7420.  
40. Ziopharm Data Report No. WIL820001 
 
 
 
 
 
 

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15. APPENDIX 1:  EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS 
 
 
ECOG PERFORMANCE STATUSa 
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, e.g., light house work, office work. 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed 
or chair. 
5 
Dead. 
a 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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16. APPENDIX 2:  CYP450 3A4 INDUCERS, INHIBITORS AND SUBSTRATES 
Medications, foods and drinks which induce, inhibit or are substrates of the CYP450 3A4 
pathway include, but are not limited to, the following: 
Alfentanil 
Disopyramide (Norpace) 
Lopinavir (Kaletra) 
Ranolazine (Ranexa) 
Alfuzosin (Uroxatral) 
Donepezil (Aricept) 
Loratadine 
Repaglinide (Prandin) 
Almotriptan (Axert) 
Droperidol 
Lovastatin 
Rifabutin (Rimactane) 
Alprazolam 
Dutasteride (Avodart) 
Maraviroc (Selzentry) 
Rifampin 
Aminoglutethimide 
Ebastine (Kestine) 
Mefloquine (Lariam) 
Rifapentine 
Amlodipine (Norvasc) 
Efavirenz (Sustiva) 
Miconazole 
Ritonavir 
Amprenavir 
Eletriptan (Relpax) 
Midazolam 
Saquinavir 
Aprepitant (Emend) 
Eplerenone (Inspra) 
Mifepristone (Mifeprex) 
Sibutramine (Meridia) 
Astemizole 
Erythromycin 
Modafinil (Provigil) 
Simvastatin 
Atazanavir (Reyataz) 
Estazolam (ProSom) 
Nafcillin  
Sirolimus (Rapamune) 
Atorvastatin (Lipitor) 
Eszopiclone (Lunesta) 
Nefazodone 
Sildenafil 
Bepridil (Vascor) 
Ethosuximide (Zarontin) 
Nelfinavir 
Solifenacin (Vesicare) 
Bexarotene (Targretin) 
Felodipine 
Nevirapine 
St. John's wort 
Bosentan (Tracleer) 
Fentanyl (Sublimaze) 
Nevirapine (Viramune) 
Sufentanil (Sufenta) 
Bromocriptine (Parlodel) 
Finasteride (Proscar) 
Nicardipine (Cardene) 
Tacrolimus 
Budesonide (Entocort) 
Fluconazole 
Nifedipine (Adalat) 
Tadalafil (Cialis) 
Buprenorphine (Subutex) 
Fluoxetine 
Nimodipine (Nimotop) 
Tamsulosin (Flomax) 
Bupropion /(Buspar) 
Flurazepam (Dalmane) 
Nisoldipine (Sular) 
Telithromycin 
Carbamazepine (eg, Tegretol) 
Fluvoxamine 
Nitrendipine (Baypress) 
Teniposide (Vumon) 
Cerivastatin 
Fosamprenavir 
Oxcarbazepine 
Terfenadine 
Cevimeline (Evoxac) 
Fosamprenavir (Lexiva) 
Oxybutynin (Ditropan) 
Testosterone 
Chloramphenicol 
Fosphenytoin 
Oxycodone (Percodan) 
Tiagabine (Gabitril) 
Cilostazol (Pletal) 
Galantamine (Reminyl) 
Paricalcitol (Zemplar) 
Tinidazole (Tindamax) 
Cisapride 
Granisetron (Kytril) 
Phenobarbital 
Tipranavir (Aptivus) 
Clarithromycin 
Grapefruit juice 
Phenytoin 
Topiramate (Topamax) 
Clonazepam (Klonopin) 
Griseofulvin 
Pimozide (Orap) 
Triazolam 
Clopidogrel (Plavix) 
Halofantrine (Halfan) 
Pioglitazone 
Troleandomycin 
Colchicine 
Ifosfamide (Ifex) 
Posaconazole 
Vardenafil (Levitra) 
Conivaptan 
Indinavir 
Praziquantel (Biltricide) 
Verapamil 
Danazol 
Isoniazid 
Primidone 
Voriconazole 
Dapsone (Avlosulfon) 
Isradipine (DynaCirc) 
Propoxyphene 
Zafirlukast 
Darunavir (Prezista) 
Itraconazole 
Quazepam (Doral) 
Ziprasidone (Geodon) 
Dasatinib 
Ixabepilone (Ixempra) 
Quetiapine (Seroquel) 
Zolpidem (Ambien) 
Dasatinib (Sprycel) 
Ketoconazole (Nizoral) 
Quinacrine 
Zonisamide (Zonegran) 
Delavirdine 
Lapatinib (Tykerb) 
Quinidine 
Zopiclone (Imovane) 
Dihydroergotamine 
Levomethadyl (Orlaam) 
Quinine  
Diltiazem 
Loperamide (Imodium) 
Quinupristin 
 
 

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17. APPENDIX 3:  SUGGESTED REGIMEN FOR HYDRATION, ANTIPYRETIC 
AND/OR ANALGESIC PROPHYLAXIS 
Recombinant adenoviral vectors have the potential to elicit potent cellular and humoral immune 
responses in recipients. While the mechanism responsible for these effects is poorly understood, 
dehydration and transient low-grade fevers are common after systemic recombinant adenovirus vector 
administration and temperatures up to 104o F with chills and generalized malaise have been observed 
in first and/or subsequent treatment cycles.  
Dehydration may occur in the absence of adequate hydration prophylaxis.  Subjects must be 
instructed to maintain adequate oral hydration on and in between dosing days; sites must closely 
monitor subjects’ hydration status.  Oral hydration is of paramount importance after first injection of 
INXN-2001 through Cycle 2 because most toxicity has been observed during this time period.  
Because low grade fever is very likely to occur, prophylaxis with a non-steroidal anti-inflammatory 
agent (ibuprofen) or acetaminophen (if a subject cannot tolerate ibuprofen) is strongly recommended 
starting with Cycle 1.   
• 
Ibuprofen is available without a prescription in 200 mg tablets. Usually 800 mg every 6-8 hours 
will prevent and/or decrease fever. The lowest expected efficacious dose should be used.  
• 
Side effects of ibuprofen include nausea and vomiting, which may be prevented if the 
medication is taken with food. Rare side effects include diarrhea, constipation, heartburn, 
and stomach pain. People with stomach ulcers or kidney disease, and those with an aspirin 
allergy should avoid ibuprofen.  
• 
Common brand names of ibuprofen include Advil®, Motrin®, and Nuprin®.  
• 
Aspirin should be avoided as it may be toxic in large doses in adults. 
• 
While meta-analyses suggest that ibuprofen is a better anti-pyretic medication than 
acetaminophen, acetaminophen also prevents and or reduces a fever. It is available without a 
prescription in 325 mg or 500 mg tablets. Again, 1000 mg every 6-8 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 the same non-steroidal anti-inflammatory agents (eg, 
ibuprofen) or 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 ibuprofen or acetaminophen then a combination of 
both acetaminophen and ibuprofen may be needed to stop the fever.  If a fever does occur after 
administration of the adenoviral vector in any cycle then anti-pyretic prophylaxis should be used in all 
subsequent dose cycles. 

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18. APPENDIX 4:  IMMUNE-RELATED RESPONSE CRITERIA (irRC) 
Anti-tumor response based on total measurable tumor burden will be explored as a supplement to the 
standard RECIST v1.1 criteria established to evaluate anti-tumor responses to chemotherapeutic 
agents. Wolchok, et al maintain that by measuring total tumor burden over time this immune related 
response criteria (irRC) may prove to be a more sensitive means of evaluating antitumor response to 
immunotherapeutic agents. For the irRC, both index and measurable new lesions are taken into 
account (in contrast to conventional WHO criteria, which do not require the measurement of new 
lesions, nor do they include new lesion measurements in the characterization of evolving tumor 
burden). The following appendix describes the process of deriving the irRC overall response as 
defined by Wolchok et al.39 
At Baseline:  
• 
Identify a maximum of 15 index lesions (up to 5 lesions per organ, up to 10 visceral lesions 
and 5 cutaneous lesions). 
• 
Index lesions must be measurable; where measurable is defined as ≥5 x 5mm. 
• 
Calculate the sum of the products of the two largest perpendicular diameters (SPD) of all 
index lesions. 
• 
All remaining lesions are followed as non-index lesions. 
At Each Subsequent Assessment: (see Table 2, Schedule of Assessments)  
• 
Calculate the SPD of all index lesions. 
• 
Identify a maximum of 10 new, measurable lesions. 
• 
Measurable is defined as ≥5 x 5mm. 
• 
Up to 5 new lesions per organ. 
• 
Up to 10 new visceral lesions and 5 new cutaneous lesions. 
• 
Calculate the SPD of all new, measurable lesions. 
• 
Calculate the total tumor burden. 
• 
Tumor Burden = SPDindex lesions + SPDnew, measurable lesions 
At each tumor assessment after baseline the response in index and new, measurable lesions will be 
defined based on the change in tumor burden. Decreases in tumor burden will be assessed relative to 
baseline measurements (ie, the SPD of all index lesions at screening). 
The irRC overall response 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) with 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 with confirmation by a repeat, 
consecutive assessment no less than 4 weeks from the date first documented. 
• 
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) 
with confirmation by a repeat, consecutive assessment no less than 4 weeks from the 
date first documented. 

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Derivation of irRC Overall Response: 
 
 
Measurable 
Response 
 
Non-Measurable 
Response 
 
Overall 
Response 
 
 
Tumor Burdena 
 
Non-Index Lesions 
New, Non-Measurable Lesions 
 
Using irRC 
 
 
↓100% 
 
Absent 
Absent 
 
irCRb 
 
 
↓100% 
 
Stable 
Any 
 
irPRb 
 
 
↓100% 
 
Unequivocal Progression 
Any 
 
irPRb 
 
 
↓≥50% 
 
Absent/Stable 
Any 
 
irPRb 
 
 
↓≥50% 
 
Unequivocal Progression 
Any 
 
irPRb 
 
 
↓<50% to <25%↑ 
 
Absent/Stable 
Any 
 
irSD 
 
 
↓<50% to <25%↑ 
 
Unequivocal Progression 
Any 
 
irSD 
 
 
≥25%↑ 
 
Any 
Any 
 
irPDb 
 
a Decreases assessed relative to baseline and increases assessed relative to nadir, including measurable lesions only (≥5 × 5 mm). 
b Assuming response (irCR and irPR) and progression (irPD) are confirmed by a 2nd consecutive assessment at least 4 wks apart. 
 
In the absence of rapid clinical deterioration, irPD at the Post Treatment Safety Assessment visit 
should be confirmed by repeat scans at the Follow-Up Tumor Assessment to ensure that more slowly 
declining tumor burden in response to therapy is not missed. 
 
 

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19. APPENDIX 5:  PHASE I AND PHASE II GROUP 1  
Study Design for 
Phase I and Phase II 
Group 1 
Single-arm, open label, Phase I/II dose escalation study of intratumoral 
injections INXN-2001 and oral INXN-1001 in subjects with unresectable 
Stage III or IV melanoma.   
Table 1:  Study Design 
Study Part 
Cohorts 
Dose Regimen 
Phase I 
Dose Escalation  
INXN-2001: 
 
  
INXN-1001: 5, 20, 100, 160 mg  
Phase II 
Group 1 
INXN-2001: 
 
  
INXN-1001: 160 mg daily for 7 
consecutive days; 21-day cycle 
Group 2 
INXN-2001: 
 
 
INXN-1001: 160 mg every other day 
for 14 days; 28-day cycle 
In Phase I, four sequential dose escalation cohorts of INXN-1001 in 
combination with a fixed dose of INXN-2001 are planned (Table 1).  
Subject enrollment and dose escalation will proceed according to a 
standard 3+3 design.  Each subject will be treated for up to 6 treatment 
cycles, each of 21 days in duration.  Previously enrolled subjects received 
3 cycles under former versions of this protocol. There will be at least 7 
days between the initiations of treatment for the sentinel (first) subject 
and additional subjects in all cohorts during the dose escalation stage of 
the study.  In each cycle, the subjects will be treated with one intratumoral 
injection of INXN-2001 in combination with 7 oral doses of INXN-1001.  
No intrasubject dose escalation will be allowed.   
In Phase II, approximately 15 additional subjects will be enrolled at a 
single dose level at or below the MTD.  Phase II of the study will include 
two groups of subjects. Subjects enrolled in the Phase II portion of the 
study under Amendment 6 or prior will be enrolled into Group 1; subjects 
enrolled under Amendment 7 or later will be enrolled into Group 2. 
Subjects in Group 1 will be treated with one intratumoral injection of 
INXN-2001 in combination with oral doses of INXN-1001 given at 160 
mg daily for 7 consecutive days at the beginning of a 21-day cycle.  
Dose and Schedule 
During Phase I and 
Phase II Group 1 
Phase I:  All subjects will receive intratumoral injections of INXN-2001 
 
 on Day 1 of a 
3 week cycle.  The subjects will also receive a single daily oral dose of 
INXN-1001 for 7 consecutive days starting on Day 1 of each cycle.  
Subjects may receive up to 6 cycles of study treatment. 
Phase II Group 1:  All subjects will receive intratumoral injections of 
INXN-2001 
 
 
 
on Day 1 of a 3 week cycle.  The subjects will also receive a single oral 
dose of INXN-1001 for 7 consecutive days starting on Day 1 of each 
cycle. Subjects may receive up to 6 cycles of study treatment. 
 

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Dose Escalation 
Plan During Phase I 
Phase I:  Four sequential INXN-1001 dose escalation cohorts are planned, 
as described in Table 1.  Subject enrollment and dose escalation will 
proceed according to a standard 3+3 design.  No intrasubject dose 
escalation will be allowed.  An intermediate dose level(s) of INXN-1001 
may be explored after review of all available safety and activity data, as 
may be decided by the SRC.   
Initially, 3 subjects will be enrolled into each sequential dose cohort, 
beginning with the lowest planned INXN-1001 dose level.   
Dose escalation will not occur until the third subject in a cohort has 
completed the first treatment cycle (7 days of oral activator ligand 
followed by 14 days of observation).  Following this, a meeting of the 
SRC will be convened to review all reported ≥Grade 3 adverse events to 
determine if these meet dose-limiting toxicity (DLT) criteria. In addition, 
the SRC will review the overall occurrence of adverse events and relevant 
laboratory data in each cohort to determine whether the MTD has been 
reached.  Following this review, the SRC will advise on subject 
enrollment, dose escalation and/or cohort expansion using the following 
guidelines: 
a) If 0 of 3 subjects in a cohort experiences a DLT, then the next 
higher dose-level cohort may be enrolled. 
b) If 1 of 3 subjects in a cohort experiences a DLT, then up to 3 
additional subjects will be enrolled into that cohort. 
c) If >1 of 3-6 subjects in a cohort experience a DLT, then 
enrollment into that cohort will cease, and the previous dose-level 
will be explored as the maximum tolerated dose (MTD).  A total 
of 6 subjects will be enrolled into this lower-dose cohort, 
including previously enrolled subjects.  Using the same criteria, 
lower-dose cohorts will be explored as the MTD until ≤ 1 of 6 
subjects experience a DLT.   
d) Intermediate INXN-1001 dose levels may be recommended by 
the SRC (i) to advance the INXN-1001 dose in a smaller 
increment than originally planned, or (ii) to better determine the 
MTD.   The intermediate dose level(s) will not exceed the higher 
of either a dose level in which >1 of 3 or 6 subjects experienced a 
DLT or the highest planned dose level (ie, Cohort 4, 160 
mg/day).  If 160 mg is the MTD and pharmacokinetic data 
suggests that higher dose(s) of INXN-1001 are indicated, then 
additional dose cohorts may be explored following an approved 
amendment of this protocol. 

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Duration of Subject 
Participation 
During Phase I and 
Phase II Group 1 
Each subject’s participation in this study will last approximately 7 
months, including: 
• 
30 day screening period. 
• 
6 cycles (18 weeks) of study treatment. 
• 
Post-Treatment Safety Assessment visit performed 28 days after the 
last dose of INXN-1001. 
• 
Follow-Up Tumor Assessment visit performed 35 ± 7 days after the 
Post-Treatment Safety Assessment visit. 
In addition, subjects who discontinue or complete study treatment in the 
absence of rapid clinical deterioration and without objective evidence of 
confirmed irPD should continue to be followed irPD has been confirmed 
or an alternate anti-cancer therapy has been initiated, whichever occurs 
first.   
 
 
 

Protocol ATI001-101 
CONFIDENTIAL  
ZIOPHARM Oncology, Inc. 
Ad-RTS-hIL-12 
29 April 2013 
 
Page 68 of 69 
SCHEDULE OF ASSESSMENTS FOR SUBJECTS IN PHASE I AND PHASE II GROUP 1  
 
Activity 
FOR PHASE I AND PHASE II GROUP 1 SUBJECTS  
Screening1 
ALL Cycles 
Post 
Treatment 
Safety 
Assessment 
Visit28 
Follow-Up 
Tumor 
Assessment 
Visit29 
Day -28 
to -7 
Day -6  
to -2 
Day 1 
Day 2 
Day 3 
OR  
Day 427 
Day 7 
Day 13 
Day 15  
28±3 days 
post-INXN-
1001 dose 
35±7 days 
after PTSA 
visit 
Clinical Assessments 
 
 
 
 
 
 
 
 
 
 
Informed Consent2 
X 
 
 
 
 
 
 
 
 
 
Medical/Cancer History3 
X 
 
 
 
 
 
 
 
 
X30 
Physical Exam4 
X 
X 
X 
 
 
 
X 
 
X 
 
ECOG PS5 
X 
 
X 
 
 
 
 
 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
 
 
 
 
 
X 
 
Vital Signs6 
X 
X 
X 
X 
X28 
X 
X 
X 
X 
 
Adverse Events7 
X 
 
 
 
 
 
 
 
X 
 
Concomitant Med.8  
X 
 
 
 
 
 
 
 
 
X 
Clinical Laboratory 
 
 
 
 
 
 
 
 
 
 
Pregnancy test9 
X 
 
X 
 
 
 
 
 
 
 
Hematology tests10 
X 
 
X22 
 
 
X 
 
X 
X 
 
Serum Chemistry tests11 
X 
 
X22 
 
 
X 
 
X 
X 
 
Urinalysis12 
X 
 
X22 
 
 
 
 
X 
X 
 
ECG13 
X 
 
X 
 
 
 
 
 
X 
 
Serum Tryptase14 
 
 
X 
 
 
Subject Registration15 
X 
 
 
 
 
 
 
 
 
 
Study Drug Administration 
 
 
 
 
 
 
 
 
 
 
Intratumoral INXN-200123 
 
 
X 
 
 
 
 
 
 
 
Oral INXN-100124 
 
 
X 
 
 
 
Verify Adherence to INXN-
1001 dosing25 
 
 
 
 
 
 
 
X 
 
 
Activity 
FOR PHASE I AND PHASE II GROUP 1 SUBJECTS  
Screening1 
Cycles 1, 3, and 6 ONLY 
Post 
Treatment 
Safety 
Assessment 
Visit28 
Follow-Up 
Tumor 
Assessment 
Visit29 
Day -28 
to -7 
Day -6 
to -2 
Day 1 
Day 2 
Day 3 
& Day 
427 
Day 7 
Day 13 
Day 15  
28±3 days 
post-INXN-
1001 dose 
35±7 days 
after PTSA 
visit 
Ab responses16  
 
X 
 
 
 
 
 
X 
X 
 
Cytokine profile17 
 
X 
 
 
X 
 
 
X 
X 
 
INXN-1001 PK26 
 
 
X 
X 
 
 
X 
 
 
 

Protocol ATI001-101 
CONFIDENTIAL  
ZIOPHARM Oncology, Inc. 
Ad-RTS-hIL-12 
29 April 2013 
 
Page 69 of 69 
Activity 
FOR SUBJECTS IN PHASE 1 DOSE ESCALATION 
Screening1 
 
Cycles 1, 3, and 6 ONLY 
Post 
Treatment 
Safety 
Assessment 
Visit28 
Follow-Up 
Tumor 
Assessment 
Visit29 
Day -28 
to -7 
Day -6  
to -2 
Cycle 1 
Day 15±1 
Cycle 3 
Day 15±1 
Cycle 6 
Day 15±1 
28±3 days 
post-INXN-
1001 dose 
35±7 days 
after PTSA 
visit 
Tumor Response / 
Pharmacodynamics 
 
 
 
 
 
 
 
Imaging Studies/Tumor 
Assessment18 
X 
 
 
X 
 
X 
X 
Digital photography19 
X 
 
X 
 
X 
X 
X 
PBMC20  
 
X 
 
X 
 
X 
X 
Biopsy / FNA31  
 
X 
X 
X 
 
X 
X 
Tumor injected with 
INXN-2001 
 
 
FNA 
PBx 
FNA 
(optional) 
PBx 
PBx 
Non-Injected Tumor 
and/or Draining 
Lymph Node  
 
PBx 
FNA 
PBx 
FNA 
(optional) 
PBx 
PBx 
Normal Skin Tissue 
 
PBx or  
FNA 
 
 
 
PBx or  
FNA 
 
NOTE:  please refer to Table 2 Schedule of Assessments for description of all footnotes; footnote 31 
is detailed below 
31. Punch biopsies (PBx) or fine needle aspirate (FNA) samples of normal skin tissue, tumor(s) 
and/or associated tumor involved draining lymph nodes will be collected for in vivo assessment 
of transgene function and immunological activities, and other biological effects should be 
obtained at the time points indicated in the preceding table. Details of these procedures are 
described in the laboratory manual. 
PBx:  Punch biopsy (≥4 mm in diameter);   FNA: fine needle aspiration biopsy 
• 
At screening Day -6 to -2, punch biopsies should be obtained only after subject registration has 
been completed (i.e., after approval by sponsor for study participation) and before start of 
treatment.   
• 
Fine needle aspiration biopsies should be obtained on Day 15 after INXN-1001 administration. 
• 
Biopsies not required at Follow-Upup Tumor Assessment visit if ≤30 days since last biopsy. 
 

Protocol: ADA1001  
 
22 June 2011 
Confidential 
  
 
 
Page 1 of 5 
 
 
 
PROTOCOL AMENDMENT SUMMARY 
 
 
Protocol Title: 
A Phase I, Open Label Study of Ad-RTS-hIL-12, an 
Adenovirus Vector Engineered to Express hIL-12, in 
Combination with an Oral Activator Ligand, in Subjects  
with Unresectable Stage III or IV Melanoma 
Protocol Number: 
ADA1001 
Study Drugs: 
INXN-2001 (Ad-RTS-hIL-12) 
INXN-1001 (oral activator ligand)  
Date of Protocol: 
Original protocol: 21 April 2011 
Amendment 1: 22 June 2011 
 
 
 
 
 
 
 
 
 
 
NOTE TO INVESTIGATORS 
Amendment 1 dated 22 June 2011 will be used to conduct the study in place of any 
preceding version of this protocol.   
 
 
 
 
 
CONFIDENTIAL 

Protocol: ADA1001  
 
22 June 2011 
Confidential 
  
 
 
Page 3 of 5 
 
Section in 
Amended 
Protocol 
Revision 
Rationale for Change 
Synopsis, 
Objectives; 
Section 6.1, 
Objectives 
FROM: 
• 
Evaluate the extent of the uptake of INXN-2001 into tumor 
cells and tumor-infiltrating immune cells. 
TO: 
• 
Evaluate the extent of the uptake of INXN-2001 into tumor 
cells and tumor-infiltrating immune cells, and to assess 
adenovirus vector shedding in body fluids. 
Add a study objective and study 
procedures to assess adenovirus 
vector shedding in body fluids. 
 
Synopsis, No. 
of Subjects 
FROM:   
18 subjects (6 subjects per dose level cohort), exclusive of 
replacement subjects or the addition of intermediate dose level 
cohorts, if any. 
TO:  
24 subjects (6 subjects per dose level cohort and up to 6 additional 
subjects enrolled at a single dose level at or below the MTD), 
exclusive of replacement subjects or the addition of intermediate 
dose level cohorts, if any. 
Increase the number of subjects 
who may be enrolled such that a 
single dose cohort may be 
expanded to up to 12 evaluable 
subjects in order to better define 
the safety tolerability and 
preliminary antitumor activity of 
the study treatment. 
Synopsis, 
Sample Size 
Determination; 
Section 6.2.2, 
Dose 
Escalation 
Procedure; 
Section 10.1, 
Determination 
of Sample Size 
FROM: 
In order to increase the ability to estimate the effect of the treatment 
on clinical response and to correlate with immunologic or other 
biologic markers, an additional number of subjects may be entered 
into the study after the initial safety evaluation has been completed.  
If no DLTs are observed in any given cohort, additional subjects 
may be added such that 6 total evaluable subjects are studied at that 
dose level.  Should a subject discontinue study treatment before 
receiving three cycles for reasons other than toxicity, another 
subject may be added to the dose cohort so as to result in a total of 
6 subjects for full analysis. 
TO: 
In order to increase the ability to estimate the effect of the treatment 
on clinical response and to correlate with immunologic or other 
biologic markers, an additional number of subjects may be entered 
into the study after the initial safety evaluation has been completed.  
If no DLTs are observed in any given cohort, additional subjects 
may be added such that 6 total evaluable subjects are studied at that 
dose level. Based on a review of available safety and clinical 
response data, the Safety Evaluation Group may identify a single 
dose cohort to be expanded to a total of 12 evaluable subjects to 
better define the safety, tolerability and activity of the study 
treatment.  Should a subject discontinue study treatment before 
receiving three cycles for reasons other than toxicity, another 
subject may be added to the dose cohort so as to result in a total of 
6 subjects for full analysis. 
Increase the number of subjects 
who may be enrolled such that a 
single dose cohort may be 
expanded to up to 12 evaluable 
subjects in order to better define 
the safety tolerability and 
preliminary antitumor activity of 
the study treatment. 
Section 4, 
Table 2: 
Schedule of 
Assessments 
FROM: 
Day 8 
TO: 
Day 8 ± 1 day 
ADD: 
 ‘X’ for Physical Exam and Vital Signs within Day 8 column. 
Add Day 8 physical exam per 
regulatory reviewer request.   
Add visit window to allow 
flexibility in visit scheduling. 
 

 
 
 
 
PROTOCOL AMENDMENT SUMMARY 
 
 
Protocol Title: 
A Phase I, Open Label Study of Ad-RTS-hIL-12, an 
Adenovirus Vector Engineered to Express hIL-12, in 
Combination with an Oral Activator Ligand, in Subjects  
with Unresectable Stage III or IV Melanoma 
Protocol Number: 
ATI001-101 (formerly ADA1001) 
Study Drugs: 
INXN-2001 (Ad-RTS-hIL-12) 
INXN-1001 (oral activator ligand)  
Date of Protocol: 
Original protocol: 21 April 2011 
Amendment 1: 22 June 2011 
Amendment 2: 13 January 2012 
 
 
 
 
 
 
 
 
 
 
NOTE TO INVESTIGATORS 
Amendment 2 dated 13 January 2012 will be used to conduct the study in place of any 
preceding version of this protocol.   
 
 
 
 
 
CONFIDENTIAL 

 
Protocol: ATI001-101 (formerly ADA1001)  
 
13 JANUARY 2012 
Confidential 
  
 
 
Page 3 of 23 
 
Section in 
Amended 
Protocol 
Original Text/Section 
Revised Text/Section 
Rationale for Change 
Section 2 
Abbreviations 
 
Added: 
IEC 
Independent Ethics Committee 
PK 
Pharmacokinetics 
SRC 
Safety Review Committee 
Add new abbreviations used 
amended text. 
Section 3 Protocol 
Synopsis;  Protocol 
Number 
ADA1001 
ATI001-101 (formerly ADA1001) 
Update protocol number due 
to changes in ZIOPHARM's 
product numbering scheme. 
Section 3 Protocol 
Synopsis; 
Objectives 
 
Section 6.1 
Objectives 
The secondary objectives are to: 
 Determine the recommended Phase II dose of the oral 
activator ligand for use with intratumoral injections of 
INXN-2001. 
 To obtain preliminary anti-tumor activity according to 
RECIST 1.1 criteria.   
 Evaluate the immunological effect of study treatment in 
terms of cellular and humoral immune responses, as well as 
other biological activities in the injected tumor(s), tumor-
involved draining lymph nodes (if accessible) and in the 
peripheral circulation.  
 Evaluate the extent of the uptake of INXN-2001 into tumor 
cells and tumor-infiltrating immune cells, and to assess 
adenovirus vector shedding in body fluids. 
The secondary objectives are to: 
 
Inform the selection of an INXN-1001 dose(s) for further 
study in combination with INXN-2001. 
 
Assess preliminary anti-tumor activity according to 
RECIST 1.1 criteria.   
 
Assess anti-tumor response based on total measurable 
tumor burden. 
 
Evaluate the immunological effect of study treatment in 
terms of cellular and humoral immune responses, as well as 
other biological activities in the injected tumor(s), tumor-
involved draining lymph nodes (if accessible) and in the 
peripheral circulation.  
 
Evaluate the extent of the uptake of INXN-2001 into tumor 
cells and tumor-infiltrating immune cells, and to assess 
adenovirus vector shedding in body fluids.  
 
Assess the pharmacokinetics (PK) of INXN-1001 in 
subjects with unresectable stage III or IV melanoma. 
Clarify secondary objective 
for INXN-1001 dose selection 
for further study (may be 1 or 
more doses). 
Add an objective to assess 
total measureable tumor 
burden. 
Add an objective to assess 
INXN-1001 PK.  
Section 3 Protocol 
Synopsis; Study 
Drugs 
Not applicable. 
Added: 
Concurrent INXN-2001 and INXN-1001 dosing will be 
referred to as “study treatment” throughout this protocol. 
Define “study treatment” as 
used throughout protocol. 
Section 3 Protocol 
Synopsis; Number 
of Centers 
Multi-center (approximately 2 to 5 centers) 
Multi-center (approximately 5 to 10 centers) 
Update number of centers 
planned for participation. 

 
Protocol: ATI001-101 (formerly ADA1001)  
 
13 JANUARY 2012 
Confidential 
  
 
 
Page 4 of 23 
 
Section in 
Amended 
Protocol 
Original Text/Section 
Revised Text/Section 
Rationale for Change 
Section 3 Protocol 
Synopsis; 
Inclusion Criteria 
 
Section 7.1  
Inclusion Criteria 
 
Section 7.2  
Exclusion Criteria 
 
Inclusion Criteria: 
1. Males or females of all races ≥ 18 to ≤ 60 years of age, who 
have provided written informed consent prior to completing 
any study specific procedure. 
2. Unresectable Stage III or Stage IV melanoma arising from a 
cutaneous, mucosal, subungal or unknown primary site.  
5. Adequate bone marrow, liver, and renal function, as 
assessed by the following laboratory requirements: 
b. Lymphocytes > 1,000/ mm3  
6. An expected survival of at least approximately 6 months. 
 
Exclusion Criteria: 
1. Prior chemotherapy, immunotherapy, radiation therapy or 
any investigational agent within 30 days prior to the first 
dose of study drug. 
2. Active infection requiring systemic antibacterial, antifungal, 
or antiviral therapy within 2 weeks of the first dose of study 
drug.   
3. HIV-seropositive. 
6. Previous treatment with any anti-tumor gene therapy. 
Inclusion Criteria: 
1. Males or females of all races ≥ 18 years of age, who have 
provided written informed consent prior to completing any 
study specific procedure. 
2. Unresectable Stage III or Stage IV melanoma arising from 
any site other than ocular melanoma. 
5. Adequate bone marrow, liver, and renal function, as 
assessed by the following laboratory requirements: 
b. Lymphocytes > 700/ mm3  
6. An expected survival of at least 6 months. 
 
Exclusion Criteria: 
1. Any prior anti-cancer therapy or investigational agent 
within 28 days prior to the first dose of study drug. 
2. Clinically significant infection requiring systemic 
antibacterial, antifungal, or antiviral therapy within 2 
weeks of the first dose of study drug.   
3. History of HIV infection. 
6. Previous treatment with any anti tumor gene therapy. 
6. Any medications that induce, inhibit or are substrates of 
CYP450 3A4 within 7 days prior to the first dose of study 
drug. 
Revise eligibility criteria to 
increase the study population: 
 Remove upper age limit 
restriction 
 Simplify eligible melanoma 
primary sites of disease 
 Alleviate restriction on 
lymphocyte count per CDC 
standards 
 Remove restriction on prior 
gene therapy 
 
Clarify eligibility criteria to 
facilitate study conduct. 
 
  
Section 3 Protocol 
Synopsis; Dose 
and Schedule 
INXN-2001 should be injected into a different lesion at each 
cycle, and if the number of lesions is limited, the injections will 
be done in sequential rotation. One accessible lesion will not be 
injected since that lesion will be used to evaluate the systemic 
effect of INXN-2001. 
INXN-2001 should be injected into a different lesion at each 
cycle.  If only 3 accessible lesions are present, the injections 
will be done in sequential rotation between 2 lesions.  If only 2 
accessible lesions are present, then all injections will be into a 
single lesion.  Note: One accessible lesion will not be injected 
since that lesion will be used to evaluate the systemic effect of 
INXN-2001. 
Clarify INXN-2001 dosing 
when the number of 
accessible lesions is limited. 
Section 3 Protocol 
Synopsis; Dose 
Escalation Plan 
Three sequential dose escalation cohorts are planned, as 
described in Table 1. 
Four sequential INXN-1001 dose escalation cohorts are 
planned, as described in Table 1. 
 
A fourth dose cohort of 
INXN-1001 (160mg/day) was 
added in order to ensure the 

 
Protocol: ATI001-101 (formerly ADA1001)  
 
13 JANUARY 2012 
Confidential 
  
 
 
Page 5 of 23 
 
Section in 
Amended 
Protocol 
Original Text/Section 
Revised Text/Section 
Rationale for Change 
MTD is fully explored 
Section 3 Protocol 
Synopsis; Table 1 
Section 6.2.6  
Dose Escalation 
Procedure; Table 1 
(repeated)  
Not applicable. 
Added footnote: 
* Intermediate dose level(s) of INXN-1001 may be explored 
after review of all available safety and activity data, as may 
be decided by the SRC.   
Add informational footnote 
(repeated from text). 
Section 3 Protocol 
Synopsis;  Dose 
Escalation Plan 
 
Section 6.2.6  
Dose Escalation 
Procedure  
(formerly Section 
6.2.2)   
Dose escalation will not occur until the third subject in a cohort 
has completed the active treatment period (7 days of oral 
activator ligand) followed by 14 days of observation during the 
first treatment cycle.  Following this, a meeting of the Safety 
Evaluation Group will be convened to review all reported 
≥Grade 3 adverse events to determine if these meet dose-
limiting toxicity (DLT) criteria. In addition, the Safety 
Evaluation Group will review the overall occurrence of adverse 
events and relevant laboratory data in each cohort to determine 
whether the MTD has been reached and to decide upon further 
subject enrollment. 
Subject enrollment and dose escalation will proceed using the 
following guidelines: 
a) If 0 of 3 subjects in a cohort experiences a DLT, then the 
next higher dose-level cohort may be enrolled. 
b) If 1 of 3 subjects in a cohort experiences a DLT, then up to 
a total of 6 subjects will be enrolled. 
c) If >1 of 3-6 subjects in a cohort experience a DLT, then 
enrollment into that cohort will cease, and the previous 
dose-level will be explored as the maximum tolerated dose 
(MTD), and a total of 6 subjects will be enrolled into that 
cohort. Using the same criteria, lower-dose cohorts will be 
explored as the MTD until ≤ 1 of 6 subjects experiences a 
DLT.   
d) Once a dose-level has been presumptively defined as the 
MTD using the above criteria, intermediate doses may be 
explored to further define the MTD, provided that ≤ 1 of 6 
subjects experiences a DLT.    
Dose escalation will not occur until the third subject in a cohort 
has completed the first treatment cycle (7 days of oral activator 
ligand followed by 14 days of observation).  Following this, a 
meeting of the SRC will be convened to review all reported 
≥Grade 3 adverse events to determine if these meet dose-
limiting toxicity (DLT) criteria. In addition, the SRC will 
review the overall occurrence of adverse events and relevant 
laboratory data in each cohort to determine whether the MTD 
has been reached.  Following this review, the SRC will advise 
on subject enrollment, dose escalation and/or cohort expansion 
using the following guidelines: 
a) If 0 of 3 subjects in a cohort experiences a DLT, then the 
next higher dose-level cohort may be enrolled. 
b) If 1 of 3 subjects in a cohort experiences a DLT, then up to 
3 additional subjects will be enrolled into that cohort. 
c) If >1 of 3-6 subjects in a cohort experience a DLT, then 
enrollment into that cohort will cease, and the previous 
dose-level will be explored as the maximum tolerated dose 
(MTD).  A total of 6 subjects will be enrolled into this 
lower-dose cohort, including previously enrolled subjects.  
Using the same criteria, lower-dose cohorts will be 
explored as the MTD until ≤ 1 of 6 subjects experiences a 
DLT.   
d) Intermediate INXN-1001 dose levels may be recommended 
by the SRC (i) to advance the INXN-1001 dose in a 
smaller increment than originally planned, or (ii) to better 
determine the MTD.   The intermediate dose level(s) will 
not exceed the higher of either a dose level in which >1 of 
Clarify dose escalation 
procedure.   

 
Protocol: ATI001-101 (formerly ADA1001)  
 
13 JANUARY 2012 
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Page 6 of 23 
 
Section in 
Amended 
Protocol 
Original Text/Section 
Revised Text/Section 
Rationale for Change 
During the dose escalation stage of the study, the initiation of 
dosing for each subject in any given dose cohort will be 
staggered by a minimum of seven days.  However, subjects 
who will be enrolled after the MTD has been determined can 
be entered simultaneously. 
3 or 6 subjects experienced a DLT or the highest planned 
dose level (i.e., Cohort 3, 100 mg/day).   If 100 mg is the 
MTD and pharmacokinetic data suggests that higher 
dose(s) of INXN-1001 are indicated, then additional dose 
cohorts may be explored following an approved 
amendment of this protocol. 
Section 3 Protocol 
Synopsis; 
Definition of MTD 
 
 
The highest dose studied in which a DLT has been seen in less 
than 2 out of 6 subjects (< 33%) during the first treatment 
cycle.   
The highest dose of INXN-1001 studied in combination with 
INXN-2001 at which a DLT has been seen in less than 2 out of 
6 subjects (< 33%) during the first treatment cycle.  Subsequent 
to Cycle 1, study drug-related adverse events that meet the 
DLT criteria will also be considered by the SRC and any 
previous determination of the MTD may be reconsidered.   
Clarify MTD definition. 
Section 3 Protocol 
Synopsis;  
Definition of DLT 
Dose-limiting toxicity (DLT) is defined as the occurrence of 
any study drug-related ≥Grade 3 adverse event occurring 
during the first treatment cycle, except nausea and/or vomiting 
in subjects who did not receive optimal treatment with anti-
emetics. 
Dose-limiting toxicity (DLT) is defined as: 
 Any injection site reaction that includes phlebitis, ulceration, 
necrosis, severe tissue damage or where operative 
intervention is required.  
 Any local or systemic injection reaction that has life-
threatening consequences, requires urgent intervention or 
results in death.  
 Any study drug-related ≥Grade 3 adverse event, except 
nausea and/or vomiting in subjects who did not receive 
optimal treatment with anti-emetics. 
Clarify and expand DLT 
definition to include local and 
systemic reactions. 
Section 3 Protocol 
Synopsis; Duration 
of Subject 
Participation 
 
Section 11.4  
Duration of The 
Study 
Each subject's participation in this study will last 
approximately 4½ months, including: 
 30 day screening period. 
 3 cycles (9 weeks) of study treatment. 
 Post-treatment safety assessment visit performed 28 days 
after the last dose of INXN-1001. 
 
Each subject's participation in this study will last 
approximately 5½ months, including: 
 30 day screening period. 
 3 cycles (9 weeks) of study treatment. 
 Post-treatment safety assessment visit performed 28 days 
after the last dose of INXN-1001. 
 Follow-up tumor assessment visit performed 35 ± 7 days 
after the Post-treatment safety assessment visit. 
In addition, subjects who discontinue or complete study 
treatment in the absence of rapid clinical deterioration and 
without objective evidence of confirmed immune-related 
Add a Follow-up tumor 
assessment visit. 

 
Protocol: ATI001-101 (formerly ADA1001)  
 
13 JANUARY 2012 
Confidential 
  
 
 
Page 7 of 23 
 
Section in 
Amended 
Protocol 
Original Text/Section 
Revised Text/Section 
Rationale for Change 
disease progression (irPD) should continue to be followed until 
immune-related disease progression has been confirmed or an 
alternate anti-cancer therapy has been initiated, whichever 
occurs first. 
Section 3 Protocol 
Synopsis; Efficacy 
Evaluations 
Not applicable. 
Added: 
Additional assessment of anti-tumor activity will be explored 
based on total measurable tumor burden.39 (Appendix 4) 
Add central assessment of 
total tumor burden. 
Section 3 Protocol 
Synopsis; 
Pharmacokinetic 
Evaluations 
Not applicable. 
This row was added: 
Pharmacokinetic Evaluations  
INXN-1001 pharmacokinetics will be evaluated in all subjects 
during cycle one. 
Add INXN-1001 PK 
assessment. 
Section 3 Protocol 
Synopsis; Sample 
Size Determination 
 
Section 10.1  
Determination of 
Sample Size 
This Phase I trial is being conducted primarily to provide 
descriptive safety and tolerability evaluations of intratumoral 
injections of INXN-2001 in subjects with Stage III or IV 
melanoma.  No formal sample-size estimation was performed.  
The choice of the number of subjects was based on the standard 
Phase I 3 + 3 inter-cohort dose escalation design.  Therefore, 
the maximum planned sample size will be 18 subjects if 6 
subjects are assigned at each of the 3 dose levels.  However, 
additional subjects may be added if exploration of intermediate 
dose level(s) of INXN-1001 is warranted. 
In order to increase the ability to estimate the effect of the 
treatment on clinical response and to correlate with 
immunologic or other biologic markers, an additional number 
of subjects may be entered into the study after the initial safety 
evaluation has been completed.  In the event that the dose 
escalation phase does not result in 6 subjects in any given 
cohort, additional subjects may be added such that 6 total 
evaluable subjects are studied at that dose level.  Based on a 
review of available safety and clinical response data, the Safety 
Evaluation Group may identify a single dose cohort to be 
expanded to a total of 12 evaluable subjects to better define the 
safety, tolerability and activity of the study treatment.  Should a 
subject discontinue study treatment before receiving three 
cycles for reasons other than toxicity, another subject may be 
No formal sample-size estimation was performed.  The choice 
of the number of subjects was based on the standard Phase I 
3+3 inter-cohort dose escalation design in which 3 to 6 subjects 
are enrolled into each dose level cohort.  
In order to increase the ability to estimate the effect of the 
treatment on clinical response and to correlate with 
immunologic or other biologic markers, an additional number 
of subjects may be entered into the study after the initial safety 
evaluation has been completed.  In the event that the dose 
escalation phase does not result in 6 subjects in any given 
cohort, additional subjects may be added such that 6 total 
evaluable subjects are studied at that dose level.  Based on a 
review of available safety and clinical response data, the SRC 
may identify a single dose cohort to be expanded to a total of 
12 evaluable subjects to better define the safety, tolerability and 
activity of the study treatment.  Should a subject discontinue 
study treatment before receiving three cycles for reasons other 
than toxicity, another subject may be added to the dose cohort 
to provide a total of 3 or 6 subjects for full analysis.  
Given these considerations, a total of approximately 30 
subjects may be enrolled into this study, including 6 subjects 
enrolled in each of the 3 planned dose level cohorts and up to 6 
additional subjects enrolled at a single dose level at or below 
the MTD.  Additional subjects may also be enrolled as 
Clarify number of subjects 
planned for study. 

 
Protocol: ATI001-101 (formerly ADA1001)  
 
13 JANUARY 2012 
Confidential 
  
 
 
Page 8 of 23 
 
Section in 
Amended 
Protocol 
Original Text/Section 
Revised Text/Section 
Rationale for Change 
added to the dose cohort so as to result in a total of 6 subjects 
for full analysis. 
replacement subjects or to explore intermediate dose level 
cohorts, if any. 
Section 4, Table 2 
Schedule of 
Assessments 
Not applicable. 
Added procedures and visit  to table: 
Serum Tryptase 
INXN-1001 PK 
Follow-up Tumor Assessment Visit 
Add safety assessment (serum 
tryptase). 
Add INXN-1001 PK 
assessment. 
Add a Follow-up tumor 
assessment visit. 
Section 4, Table 2 
Schedule of 
Assessments; 
Footnotes 
Not applicable. 
New footnotes added: 
14. Serum tryptase level will be obtained upon the occurrence 
of a suspected injection and/or hypersensitivity reaction.  
Otherwise, this test is not required at any other time. 
23. FOR CYCLE 1 ONLY: Subjects will undergo an INXN-
1001 pharmacokinetic (PK) assessment. Blood samples for 
INXN-1001 PK analysis should be obtained on the 
following days and timepoints: 
Day 1: Pre-dose (< 30 minutes prior to INXN-1001 
dosing) 
 
1-2 hours post INXN-1001 dosing 
 
3-8 hours post INXN-1001 dosing 
Day 2: Pre-dose (< 30 minutes prior to INXN-1001 
dosing) 
Day 7: 1-2 hours post INXN-1001 dosing 
 
3-8 hours post INXN-1001 dosing 
Day 8 OR Day 9: anytime >24 hours post-Day 7 INXN-
1001 dose 
27. Day 1 clinical laboratory assessments may be performed 
within 2 days prior to the Day 1 clinic visit.  Clinical 
laboratory tests drawn for analysis on Day 15 of each cycle 
may be used for determining if the retreatment criteria have 
been met, and must be reviewed by the investigator or 
designee prior to the next cycle of study drug administration 
(see Section 8.2.6).   
30. A Follow-up tumor assessment visit will be performed 35 ± 
7 days after the Post-treatment safety assessment visit.  This 
Add safety assessment (serum 
tryptase). 
Add INXN-1001 PK 
assessment. 
Add cross reference to 
retreatment criteria (Section 
8.2.6). 
Add a Follow-up tumor 
assessment visit. 

 
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assessment is required for all subjects, including those with 
prior objective evidence of disease progression.   
 
Visit procedures will include a tumor response assessment 
per RECIST v1.1 guidelines (see footnote 16), digital 
photography of all visible tumors (see footnote 17), and 
documentation of any anti-cancer treatments received since 
the previous tumor assessment.   
 
Subjects without objective evidence of disease progression 
at the Follow-up tumor assessment visit should continue to 
have tumor assessments performed at 8-10 week intervals 
until disease progression has been documented or an 
alternate anti-cancer therapy has been initiated, whichever 
occurs first.    
31. Interim cancer history information will include 
documentation of any anti-cancer treatments received since 
the previous tumor assessment.   
Section 4, Table 2 
Schedule of 
Assessments; 
Footnotes 
7. AEs/SAEs will be collected after the start of INXN-1001 
dosing through the Post-treatment safety assessment visit.  
AEs/SAEs that occur after the subject has signed informed 
consent and prior to  INXN-1001 dosing will be entered 
into the medical history.  However, study drug-related 
AEs/SAEs that are ongoing at the time of the Post-
treatment safety assessment visit should continue to be 
followed until resolution, return to baseline, or until they 
have stabilized (and following consultation and agreement 
by the ZIOPHARM Medical Monitor). 
8. Concomitant medication information, including blood 
products, vitamins and other supplements will be collected 
for the time period beginning 28 days prior to the first dose 
of study drug, through the Post-treatment safety assessment 
visit.   
15. Appropriate cancer staging procedures should be performed 
during Screening, including chest and abdominal CT or 
MRI scans.  For subjects with measurable lesions, target 
lesions should be selected and measured as per RECIST 1.1 
guidelines.  Lesions that will be/are injected with INXN-
7. Monitoring and recording of adverse events (AEs) and 
serious adverse events (SAEs) will be conducted throughout 
the study.  AEs/SAEs that occur following informed 
consent until the Post-treatment safety assessment must be 
recorded on the AE CRF; AEs/SAEs that occur prior to 
informed consent should be added to the medical history 
CRF.  Study drug-related AEs/SAEs that are ongoing at the 
time of the Post-treatment safety assessment visit should be 
followed until resolution, return to baseline, they have 
stabilized (and following consultation and agreement by the 
ZIOPHARM Medical Monitor), or they can be attributed to 
other than the study drug or other than study conduct.  
SAEs considered to be related to study drug that occur 
beyond 30 days after the last dose must also be reported.   
 
In addition, all SAEs must be reported by the investigator or 
designee within 24 hours of becoming aware of the event, 
from the time of informed consent through 30 days after the 
last dose of study drug, regardless of the initiation of any 
new anti-cancer therapy.  SAEs considered to be related to 
study drug that occur beyond 30 days after the last dose 
Update Adverse Event 
sections to be consistent with 
changes made in other 
ZIOPHARM protocols. 
ConMeds will be collected 
through Follow-up tumor 
assessment visit. 
Revise for consistency within 
study protocol. 
Revise text for clarity. 
Add a Follow-up tumor 
assessment visit. 
Add INXN-1001 PK 
assessment. 
 

 
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2001 and/or biopsied should not be selected as target 
lesions, but should be measured (if measureable).   
 
Disease sites are to be assessed throughout the study using 
the same method(s) used at Screening.  All subjects will 
have tumor assessments performed within 2 weeks prior to 
the Post-treatment safety assessment visit.  The Investigator 
will evaluate response to therapy according to RECIST 1.1 
guidelines. Subjects who discontinue or complete study 
treatment without objective evidence of disease progression 
should continue to have tumor assessments performed at 8 
10 week intervals until disease progression has been 
documented or an alternate anti-cancer therapy has been 
initiated, whichever occurs first.  Details regarding response 
assessments will be provided in the investigator’s study 
files. 
21. FOR CYCLE 1 ONLY:  Optional sampling of body fluids 
may be performed to assess adenovirus vector shedding.  
Samples collected may include any or all of the following: 
whole blood, saliva and semen.  Please refer to the 
laboratory manual for details regarding sample collection, 
processing and shipment.  Note: Subjects may freely 
decline participating in all or any portion of this sampling 
without any effect on their study participation 
26. Post-treatment assessment visit is to be performed 28 ± 2 
days after the last dose of INXN-1001 or at the time of 
early withdrawal from study treatment.  
 
Subjects with ongoing study drug-related AEs/SAEs should 
continue to be followed until resolution, return to baseline, 
or until they have stabilized (and following consultation and 
agreement by the ZIOPHARM Medical Monitor).   
 
Subjects without objective evidence of disease progression 
should continue to have tumor assessments performed at 8 -
10 weeks intervals until disease progression has been 
documented or an alternate anti-cancer therapy has been 
initiated, whichever occurs first.   
 
must also be reported. 
8. Concomitant medication information, including blood 
products, vitamins and other supplements will be collected 
for the time period beginning 28 days prior to the first dose 
of study drug, through the Follow-up tumor assessment 
visit.   
 (15) 16. Appropriate cancer staging procedures should be 
performed during screening, including chest and abdominal 
CT or MRI scans. PET scans may be accepted in place of 
CT or MRI scans following consultation and agreement by 
the ZIOPHARM Medical Monitor. 
 
For subjects with measurable lesions, target lesions should 
be selected and measured as per RECIST 1.1 guidelines.  
Lesions that will be/are injected with INXN-2001 and/or 
biopsied should not be selected as target lesions, but should 
be measured (if measureable).   
 
Disease sites are to be assessed throughout the study using 
the same method(s) used at screening.  All subjects will 
have at least 2 tumor response assessments performed 
following the initiation of study treatment: 
• At the Post-treatment safety assessment visit (28 ± 3 
days following the last dose of INXN-1001) or at the 
time of early withdrawal from study treatment. 
• At the Follow-up tumor assessment visit (35 ± 7 days 
following the Post-treatment safety assessment visit).   
 
The Investigator will evaluate response to therapy 
according to RECIST v1.1 guidelines.  
 
NOTE: As a supplement to the standard RECIST v1.1 
guidelines established to evaluate anti-tumor responses to 
chemotherapeutic agents, anti-tumor response will be 
explored by measuring total tumor burden over time. (see 
Appendix 4)    
(21)22. 
FOR CYCLE 1 ONLY:  Subjects will be asked to 
provide samples of body fluids to assess any potential 
adenoviral vector shedding.  Samples collected may include 
any or all of the following: whole blood, saliva and semen.  

 
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Subjects will sign a consent form if they agree, but may 
freely decline to participate in all or any portion of this 
sampling without effect on their core study participation or 
prejudice to their future care.  Please refer to the laboratory 
manual for details regarding sample collection, processing 
and shipment.    
(26) 29. Post-treatment safety assessment visit will be 
performed 28 ± 3 days after the last dose of INXN-1001 or 
at the time of early withdrawal from study treatment.  Note: 
imaging studies performed for the tumor response 
assessment may be completed within 2 weeks prior to the 
Post-treatment safety assessment visit. 
 
Subjects with ongoing study drug-related AEs/SAEs should 
continue to be followed until resolution, return to baseline, 
or until they have stabilized (and following consultation and 
agreement by the ZIOPHARM Medical Monitor) , or they 
can be attributed to other than the study drug or other than 
study conduct.   
 
Subjects found to have residual viral particles or DNA in 
tissue or blood samples may be requested to return to the 
clinic at monthly intervals for further testing until clearance 
has been documented. 
Section 5.1 
Disease 
Background 
(Melanoma) 
…  Ipilimumab, an anti-CTLA-4 mono-clonal antibody used to 
overcome or reverse T cell suppression and thereby potentiate 
an antitumor T-cell response, was evaluated in a Phase III 
study in patients with unresectable Stage III and IV melanoma.  
The patients were randomized to receive ipilimumab plus 
gp100 (403 patients), ipilimumab alone (137 patients), or a 
gp100 vaccine alone (136 patients). The median overall 
survival with ipilimumab alone was 10.1 months (hazard ratio 
of 0.66 for death in comparison with gp100 alone-; p=0.003). 
The most common drug-related adverse events were immune 
related.  These occurred in approximately 60% of patients 
treated with ipilimumab and 32.5% in patients treated with 
gp100.  The frequency of Grade 3 and 4 immune-related events 
was 10 to 15% in the ipilimumab group.  These immune related 
adverse events most often affected the skin and the 
…  Ipilimumab, an anti-CTLA-4 mono-clonal antibody used to 
overcome or reverse T cell suppression and thereby potentiate 
an antitumor T-cell response, was approved by the FDA for 
treatment of unresectable Stage III and IV melanoma on the 
basis of a Phase III trial which demonstrated an improvement 
in median overall survival.  In that study, there were 14 deaths 
related to the study drugs and 7 were associated with immune 
related adverse events.3 Other immunotherapies for the 
treatment of melanoma are also in various stages of 
development, including OncoVEXGM-CSF, an oncolytic herpes 
simplex virus encoding GM-CSF. 
Informational update. 

 
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gastrointestinal tract (most commonly diarrhea) and also 
included hypophysitis and thyroiditis.  The immune related 
events required treatment with high doses of corticosteroids in 
order to control these clinically significant safety problems. 
There were 14 deaths related to the study drugs and 7 were 
associated with immune related adverse events.3   
6.2.2  Treatment 
Parameters and 
Duration 
(formerly Section 
6.2.3) 
All subjects will receive intratumoral injections of INXN-2001 
 
 
 on Day 1 of a 3-
week cycle.  The subjects will also receive a single daily oral 
dose of INXN-1001 for 7 consecutive days starting on Day 1 of 
each cycle.  The INXN-1001 dose assigned to any given 
subject will progress as per the dose escalation schedule above. 
INXN-2001 should be injected into a different lesion at each 
cycle, and if the number of lesions is limited, the injections 
should be done in sequential rotation. One accessible lesion 
will not be injected since that lesion will be used to evaluate the 
systemic effect of INXN-2001.  
Subjects may receive up to 3 cycles of study treatment. 
Because tumor nodules may enlarge due to the anticipated 
induction of an inflammatory response, subjects with disease 
progression (per RECIST criteria) may still complete the 3 
treatment cycles, unless the progression is clinically significant, 
e.g. the ECOG performance status increases during the protocol 
to ≥ 2.    
All subjects will receive intratumoral injections of INXN-2001 
 
 on Day 1 of a 3-
week cycle.  The subjects will also receive a single daily oral 
dose of INXN-1001 for 7 consecutive days starting on Day 1 of 
each cycle.  The INXN-1001 dose assigned to any given 
subject will be determined according to the dose escalation 
schedule (Section 6.2.6). 
Subjects may receive up to 3 cycles of study treatment. 
Because tumor nodules may enlarge due to the anticipated 
induction of an inflammatory response, subjects with disease 
progression (per RECIST criteria) may still complete the 3 
treatment cycles, unless the progression is clinically significant, 
e.g., development of new metastases or an ECOG performance 
status that increases during study treatment to ≥ 2.   
 
Clarify text. 
6.2.3  Safety 
Review Committee 
(SRC) 
 
(formerly Section 
6.2.4  Safety 
Evaluation Group) 
A Safety Evaluation Group comprised of the Medical Monitor, 
Principal Investigators and sponsor representatives, will hold 
periodic teleconferences to evaluate the safety and treatment 
status of all subjects. 
 
A SRC comprised of the Medical Monitor, Principal 
Investigators and sponsor representatives, will hold periodic 
teleconferences to evaluate the safety and treatment status of all 
subjects.  The SRC will review and assess the safety data at the 
completion of each dose cohort as described in Section 6.2.6, 
and at any other time as needed.   
The following data will be reviewed at each SRC meeting to 
determine whether to proceed to a subsequent cohort: physical 
examination and vital signs; medical history; complete blood 
count with differential; serum chemistry panel including 
alanine transaminase (ALT), aspartate transaminase (AST), 
alkaline phosphatase (ALP), and total bilirubin; lactate 
Clarify dose escalation 
procedure.  
Provide additional 
information regarding SRC 
review meetings and 
procedures. 

 
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dehydrogenase (LDH); albumin; serum tryptase level; ECG; 
cytokine levels; and adverse event and concomitant medication 
records.  Additional information will be reviewed as necessary.  
A written summary documenting the results and 
recommendations of each review will be provided to the 
Investigator(s) and maintained on file with the sponsor.  
Additional sub-Investigators and personnel may participate in 
reviews as indicated.   
Following a cohort review, the SRC may recommend 
proceeding with enrollment in the next dose cohort, enrolling 
additional subjects in the current cohort, dropping back to a 
lower cohort, exploring an alternate dose level, or not enrolling 
any additional subjects.  The dose escalation and enrollment 
guidelines outlined in Section 6.2.6, as well as the study 
stopping rules outlined in Section 6.2.7, will be used as the 
basis for these assessments. 
While the SRC is expected to reach a consensus opinion 
regarding any premature discontinuation or significant 
modification of the study, the sponsor may independently stop 
the study. 
6.2.4  Definition 
and Management 
of Dose-Limiting 
Toxicity (DLT) 
(formerly Section 
6.3) 
Dose-limiting toxicity (DLT) is defined as the occurrence of 
any study drug-related ?Grade 3 adverse events occurring 
during the first treatment cycle, except nausea and/or vomiting 
in subjects who did not receive optimal treatment with anti-
emetics.  
If DLTs have been observed in >1 of the 6 subjects in a cohort 
during the first treatment cycle, the MTD will have been 
exceeded and further use of that dose will be discontinued in all 
subjects, and the next lower dose cohort will be assessed as to 
whether it meets the definition of the MTD.   No further use of 
a dose of INXN-1001 above the MTD will be allowed.  
Subjects will be withdrawn from study treatment if they 
experience Grade 3 toxicity related to study drug that occurs 
after the initiation of treatment and that, upon review of the 
Safety Evaluation Group, is deemed to fit the definition of 
DLT.  If, however, the patient has experienced a substantial 
benefit from treatment and the Safety Evaluation Group 
Dose-limiting toxicity (DLT) is defined as: 
 Any injection site reaction that includes phlebitis, ulceration, 
necrosis, severe tissue damage or where operative 
intervention is required.  
 Any local or systemic injection reaction that has life-
threatening consequences, requires urgent intervention or 
results in death.  
 Any study drug-related ≥Grade 3 adverse event, except 
nausea and/or vomiting in subjects who did not receive 
optimal treatment with anti-emetics.  
If DLTs have been observed in >1 of the 3-6 subjects in a 
cohort during the first treatment cycle, the MTD will have been 
exceeded and further use of that dose will be discontinued in all 
subjects, and the next lower dose cohort will be assessed as to 
whether it meets the definition of the MTD.   
Clarify and expand DLT 
definition to include local and 
systemic reactions.  Add 
requirement that the Medical 
Monitor be notified of 
potential DLTs. 

 
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recommends continuation on the study, re-exposure to the 
experimental treatment may proceed on a case by case basis.  
Any subject who experiences a Grade 4 toxicity related to 
study drug will be withdrawn from study. 
 
The Medical Monitor should be immediately notified of any 
potential DLT.  Subjects will be withdrawn from study 
treatment if they experience an injection site reaction that 
meets DLT criteria or other Grade 3 toxicity related to study 
drug that, upon review of the SRC, is deemed to be a DLT.  If, 
however, the subject has experienced a substantial benefit from 
treatment and the SRC recommends continuation on the study, 
re-exposure to the experimental treatment may proceed at a 
lower dose of INXN-1001 on a case by case basis.  Any subject 
who experiences a Grade 4 toxicity related to study treatment 
will be withdrawn from study. 
6.2.5  Definition of 
Maximum 
Tolerated Dose 
(MTD)   
(formerly Section 
6.4) 
The MTD will be defined as the highest dose studied in which 
a DLT has been seen in less than 2 out of 6 subjects (< 33%) 
during the first treatment cycle.  After the MTD has been 
determined based on DLTs during the first treatment cycle 
within a cohort, the MTD will remain the same even if 
additional DLTs are determined during the second or third 
treatment cycle.  
The MTD will be defined as the highest dose of INXN-1001 
studied in combination with INXN-2001 at which a DLT has 
been seen in less than 2 out of 6 subjects (< 33%) during the 
first treatment cycle.  Subsequent to Cycle 1, study drug-related 
adverse events that meet the DLT criteria will also be 
considered by the SRC and any previous determination of the 
MTD may be reconsidered.   
Clarify MTD definition. 
Section 6.2.7  
Study Stopping 
Rules 
Not applicable. 
The following section was added: 
6.2.7  Study Stopping Rules 
Rules for stopping dose escalation due to DLTs observed 
during the first cycle of study treatment are outlined in Section 
6.2.6.  In the event that a given dose level cohort is determined 
to have exceeded the MTD, then further use of that dose will be 
discontinued for all subjects as noted in Section 6.2.4.  
Subsequent to Cycle 1, study drug-related adverse events that 
meet the DLT criteria will also be considered by the SRC and 
any previous determination of the MTD may be reconsidered. 
Stopping rules for toxicities that occur from Day 1, Cycle 2 
through the Post-treatment follow-up visit will apply as 
follows:  
 If an adverse event can be definitely shown to be unrelated 
to study treatment (e.g., motor vehicle accident, bee sting, 
elective surgery), that specific toxicity will not be 
considered in a stop vs. dose escalation decision.  
Clarify dose escalation 
procedure.   
Add study stopping rules to 
enhance subject safety. 

 
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 Recruitment in the current cohort will not be stopped for 
Grade 2 (NCI CTCAE v.4.03) non-dose limiting toxicities, 
irrespective of the number of events or number of subjects. 
 Recruitment in the current cohort will be stopped for any 
Grade 3 or 4 toxicity, unless the adverse event is clearly and 
incontrovertibly due to extraneous causes.  All data will be 
reviewed by the Investigator, the Investigator’s IRB, 
ZIOPHARM Medical and Regulatory Staff, and the SRC to 
determine if the study should proceed and if/what changes 
must be implemented.  
 In addition to stopping rules for dose escalation, patient 
enrollment into the study will be halted in the event of any 
study drug-related death.  In this case, patient enrollment 
will only resume following review and approval of the SRC. 
For toxicity grading based on laboratory tests, an abnormality 
must be confirmed (when appropriate) by repeat testing.   For 
any suspected injection and/or hypersensitivity reaction, a 
serum tryptase level will be measured. 
Section 7.3 
Withdrawal of 
Subjects from 
Study Treatment 
and/or Study 
A subject may withdraw (or be withdrawn) from the study 
treatment prematurely for any of the following reasons: 
 
Principal investigator (PI) determines further participation 
is not in subject’s best interest. 
 
Clinically significant disease progression. 
A subject may withdraw (or be withdrawn) from the study 
treatment prematurely for any of the following reasons: 
 
Principal investigator (PI) determines further participation 
is not in subject’s best interest. 
 
Clinically significant disease progression. 
NOTE: In the absence of rapid clinical deterioration, disease 
progression should be confirmed by a repeat, consecutive 
assessment no less than 4 weeks from the date first documented 
to ensure that more slowly declining tumor burden in response 
to therapy is not missed. 
Clarification for the need of a 
confirmatory progression 
scan. 
Section7.4  
Replacement of 
Subjects 
Subjects who are withdrawn from study treatment prior to 
completing Cycle 1 dosing for reasons other than toxicity may 
be replaced so that a full cohort of subjects completes Cycle 1 
safety evaluations.  In addition, should a subject discontinue 
study treatment before receiving three cycles for reasons other 
than toxicity, another subject may be added to that dose cohort 
Subjects who are withdrawn from study treatment prior to 
completing Cycle 1 dosing for reasons other than toxicity may 
be replaced so that a full cohort of subjects completes Cycle 1 
safety evaluations.  In addition, should a subject discontinue 
study treatment before receiving three cycles for reasons other 
than toxicity, another subject may be added to that dose cohort 
so as to result in a total of at least three  subjects for full 
Clarify that replacement of 
subjects also applies to 
cohorts of 3 subjects. 

 
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so as to result in a total of six subjects for full analysis. 
analysis. 
8.2.3  Treatment 
Regimen 
INXN-2001 will be given as intratumoral injections of 
 
 
 in 0.5 mL per treatment. If no 
accessible tumor is available, a tumor-involved draining lymph 
node will be injected. The injections will be administered on 
the first day of each cycle throughout the study.  
 
INXN-2001 will be given as intratumoral injections of 
 
in 0.5 mL per treatment.  
Following Cycle 1, if no accessible lesion for INXN-2001 
injection is present (e.g., due to complete resolution), then 
INXN-2001 should be injected into a draining lymph node of a 
previously accessible lesion.  The injections will be 
administered on the first day of each cycle throughout the 
study.  
Clarify INXN-2001 dosing 
when the number of 
accessible lesions is limited. 
8.2.5.3  
Preparation and 
Administration of 
INXN-2001 
INXN-2001 
 
 should be delivered 
by multiple injections with a fine needle (no finer than 27 
gauge) directly into each quadrant of the lesion or tumor-
involved lymph node, at approximately 0.5 cm apart three 
dimensionally, to reach all aspects of the entire lesion.  
Attention must be paid to adequately infiltrate the 
circumference of the tumor margins. The injection should be 
given 3 hours ± 30 minutes after the INXN-1001 dose.  A 
detailed description and photograph of physical location(s) of 
the injected tumor(s) and surrounding tissue, and any visible 
local reactions should be documented.   
Note:  One of the minimum of two accessible lesions (per the 
eligibility criteria) will not be injected as that lesion will be 
used to evaluate the systemic effect of INXN-2001.    
If ≥2 accessible lesions are present (not including the lesion 
that will not be injected), INXN-2001 will be injected into a 
different lesion at each cycle, to the extent feasible. If the 
number of lesions is limited, the injections will be done in 
sequential rotation. After the first cycle, should the accessible 
tumor not support the INXN-2001 injection volume, another 
tumor should be injected with the remaining volume to ensure 
that all subjects receive 
 
.  If an 
accessible lesion is not present, INXN-2001 will be injected 
into a draining lymph node of a previously accessible lesion. 
 
INXN-2001 
 
 will be administered 
as an intratumoral injection 3 hours (± 30 minutes) after oral 
INXN-1001 dosing on Day 1 of each cycle.  INXN-2001 
should be injected into a different lesion at each cycle.  If only 
3 accessible lesions are present, the injections will be done in 
sequential rotation between 2 lesions.  If only 2 accessible 
lesions are present, then all injections will be into a single 
lesion.   
Note:  One accessible lesion will not be injected since that 
lesion will be used to evaluate the systemic effect of INXN-
2001.  
The INXN-2001intratumoral administration should be 
delivered by multiple injections with a fine needle (no finer 
than 27 gauge) directly into each quadrant of the lesion or 
tumor-involved lymph node, at approximately 0.5 cm apart 
three dimensionally, to reach all aspects of the entire lesion.  
Attention must be paid to adequately infiltrate the 
circumference of the tumor margins. A detailed description and 
photograph of physical location(s) of the injected tumor(s) and 
surrounding tissue, and any visible local reactions should be 
documented.   
Should the tumor selected for injection not support the entire 
INXN-2001 injection volume, 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 
lymph node of the injected tumor.  Following Cycle 1, if no 
Clarify INXN-2001 dosing 
procedure. 

 
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accessible lesion for INXN-2001 injection is present (e.g., due 
to complete resolution), then INXN-2001 should be injected 
into a draining lymph node of a previously accessible lesion. 
Section 8.2.6  
Retreatment 
Criteria, Dose 
Delays and 
Modifications 
Subjects may receive up to 3 cycles of study drug treatment.  In 
order to receive each repeat treatment cycle, all treatment-
related adverse events must have resolved to Grade 1 or 
baseline.   
… 
Subjects who experience a DLT will be managed as described 
in Section 7.3. 
Subjects may receive up to 3 cycles of study drug treatment.  In 
order to receive each repeat treatment cycle, all treatment-
related adverse events must have resolved to Grade 1 or 
baseline and the following laboratory criteria must be met: 
 Hemoglobin ≥ 9 g/L 
 Lymphocytes > 700/ mm3 
 Neutrophils ≥ 1,500/ mm3  
 Platelets ≥ 100,000/ mm3 
 Serum creatinine ≤ 1.5 x ULN 
 AST and ALT ≤ 2.5 x ULN.  For subjects with documented 
liver metastases, ALT and AST ≤ 5×ULN. 
 Total bilirubin < 1.5 x ULN 
 INR and PTT <1.5 x ULN, if not therapeutically 
anticoagulated.  
Clinical laboratory tests drawn for analysis on Day 15 of each 
cycle may be used for determining if the retreatment criteria 
have been met, and must be reviewed by the investigator or 
designee prior to the next cycle of study drug administration.   
… 
Subjects who experience a DLT will be managed as described 
in Section 6.2.4.  Subjects who experience an injection site 
reaction should be managed as described in Section 8.2.7. 
Add retreatment criteria to 
enhance subject safety. 
Section 8.2.7  
Severity Grading 
and Management 
of Injection Site 
Reactions 
Not applicable. 
This section was added: 
8.2.7  Severity Grading and Management of Injection Site 
Reactions 
Injection of a biologic agent carries a potential risk of injection 
site reaction which is characterized as an intense reaction 
(usually immunologic) at or near the site of injection.  Injection 
reactions will be graded according to the National Cancer 
Add section addressing 
management and grading of 
potential injection site 
reactions as an additional 
safety measure. 

 
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Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03.  
Table 3 outlines the injection site reaction grading system, 
associated symptoms, and the recommended actions to be 
taken.  For any injection reaction, a serum tryptase level will be 
measured.  Reactions at the INXN-2001 injection site that 
occur within 24 hours after the injection and are attributed to 
INXN-2001 will be considered to be injection related AEs.  
< Table 3 > 
As with all AEs, injection-related signs or symptoms which, in 
the Investigator’s judgment, are not related to immunologic 
reactions (e.g., dyspepsia, urinary frequency, etc.) should be 
recorded and graded as AEs according to NCI CTCAE v.4.03 
criteria in the CRF.  Study stopping rules will not apply to a 
specific event if it is clearly unrelated to INXN-2001 injection 
(e.g. accidental trauma).  If a AE associated with injection 
cannot be definitely shown to be unrelated to INXN-2001, then 
study stopping rules will apply.   
8.2.8  Prophylactic 
Antipyretic and/or 
Analgesic 
Administration 
(formerly Section 
8.2.7  Prophylactic 
Acetaminophen 
Administration) 
Treatment-related fever during Cycle 1 may be treated with 
acetaminophen.   
It is recommended that subjects who experience treatment-
related fever during Cycle 1 be administered 700 mg (2 x 350 
mg) of acetaminophen prior to injection of INXN-2001 in 
subsequent cycles.  In addition, if the subject needs additional 
doses of acetaminophen, he/she should be instructed to take 
one or two 350 mg tablets every 6 hours as needed for 
symptoms (pain at injection site, fever, etc.).  If the subject 
needs to continue taking the acetaminophen for longer than two 
days, he/she should be instructed to contact the clinical site. 
The use of antipyretics and/or analgesics is allowed anytime 
during study treatment, as indicated, including prophylactic 
administration. 
Since fever and flu like symptoms are commonly experienced 
following adenoviral vector administration it is strongly 
recommended that subjects be treated with prophylactic 
antipyretic and/or analgesic medications prior to study drug 
administration. 
For those subjects who experience treatment related symptoms 
(e.g. fever, headache, chills, etc.) during Cycle 1, prophylactic 
antipyretic and/or analgesic medications must be given prior to 
study drug administration in subsequent cycles. Please refer to 
Appendix 3 for a recommended regimen for the prophylactic 
administration of antipyretics and/or analgesics. 
Clarify recommendation on 
the use of prophylactic 
medications. 
Section 8.2.9  
Disposition of 
Unused Study 
All unused study drug must be returned to the sponsor or 
destroyed on site in accordance with applicable site facility and 
US Occupational Safety and Health Administration (OSHA) 
procedures after a full accountability has been documented. 
All unused study drug should be destroyed on site in 
accordance with applicable site facility and US Occupational 
Safety and Health Administration (OSHA) procedures after a 
full accountability has been documented. Any on-site 
Clarify that unused study drug 
should be destroyed on site 
(rather than being returned to 

 
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Drug 
(formerly Section  
8.2.8)   
Any on-site destruction of unused study drug must be 
documented and the records maintained in the Investigator’s 
study file.  
destruction of unused study drug must be documented and the 
records maintained in the Investigator’s study file.  
the sponsor). 
Section 8.3  
Concomitant 
Therapy 
Permitted: 
 Subjects may receive standard treatments, including 
palliative and supportive care for any underlying illness. 
 Subjects should be cautioned to avoid, if possible, 
medications, foods or drinks that induce, inhibit, or are 
substrates of the CYP450 3A4 pathway.  See Appendix 2 
for examples. 
Not Permitted: 
 Subjects may not receive other investigational or approved 
cancer therapy (chemotherapy, etc.) while receiving study 
treatment. 
 
Permitted: 
 Subjects may receive standard treatments, including 
palliative and supportive care for any underlying illness with 
the exception of palliative radiotherapy which is NOT 
permitted. 
 Antidiarrheal therapy is permitted for study drug-induced 
diarrhea. 
 Antiemetics are permitted for study drug-induced nausea 
and vomiting. 
 Treatment with vitamin/mineral supplements is acceptable 
provided that they do not interfere with study endpoints, in 
the opinion of the investigator. 
Not Permitted: 
 Subjects may not receive medications, foods or drinks that 
induce, inhibit, or are substrates of the CYP450 3A4 
pathway within 7 days prior to the first dose of study drug 
through 96 hours after their last dose of INXN-1001.  See 
Appendix 2 for examples. 
 Subjects may not receive any other investigational agent or 
anti-cancer therapy (chemotherapy, radiotherapy, etc.) while 
receiving study treatment. 
Clarify that concurrent 
prophylactic radiotherapy is 
not permitted during study 
treatment. 
Prohibition of medications, 
foods or drinks that induce, 
inhibit, or are substrates of the 
CYP450 3A4. 
Section 8.4.2.6  
Adverse Events 
Monitoring and recording of adverse events (AEs) will be 
conducted throughout the study. AEs, including serious adverse 
events (SAEs), will be captured on the CRFs from the start of 
INXN-1001 dosing (Cycle 1, Day 1) through the Post-
treatment safety assessment visit. However, study drug-related 
AEs/SAEs that are ongoing at the time of the Post-treatment 
safety assessment visit should continue to be followed until 
resolution, return to baseline, or until they have stabilized (and 
following consultation and agreement by the ZIOPHARM 
Medical Monitor). Definitions, documentation, and reporting of 
Monitoring and recording of adverse events (AEs) and serious 
adverse events (SAEs) will be conducted throughout the study. 
AEs/SAEs that occur following the first dose of study drug 
until the Post-treatment safety assessment must be recorded on 
the AE CRF; AEs/SAEs that occur following informed 
consent, but prior to the first dose of study drug, should be 
added to the medical history CRF.  Study drug-related 
AEs/SAEs that are ongoing at the time of the Post-treatment 
safety assessment visit should continue to be followed until 
resolution, return to baseline, or until they have stabilized (and 
Update Adverse Event 
sections to be consistent with 
changes made in other 
ZIOPHARM protocols. 

 
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AEs are described in Section 10. 
following consultation and agreement by the ZIOPHARM 
Medical Monitor).  
In addition, all SAEs must be reported by the investigator or 
designee via a paper or electronic SAE Report form within 24 
hours of becoming aware of the event, from the time of 
informed consent through 30 days after the last dose of study 
drug, regardless of the initiation of any new anti-cancer 
therapy.  SAEs considered to be related to study drug that occur 
beyond 30 days after the last dose must also be reported.   
Definitions, documentation, and reporting of AEs and SAEs are 
described in Section 10. 
Section 8.4.2.12  
Serum Tryptase 
Not applicable. 
This section was added: 
8.4.2.12  Serum Tryptase 
A serum tryptase level will be obtained upon the occurrence of 
a suspected injection and/or hypersensitivity reaction.   
Add safety assessment (serum 
tryptase). 
Section 8.4.2.13 
Immune Response 
Analysis 
(formerly Section 
8.4.2.12)   
…  Serum IL-12 and IFN-γ will be assessed in as close to real 
time as possible for Day 1 through Day 4 timepoints, and 
clinically significant increases will be discussed by the Medical 
Monitor and Principal Investigator.   
…  One or more serum cytokines may be assessed in as close 
to real time as possible for one or more time points in a dosing 
cycle at the request of  the Medical Monitor or other sponsor 
representative(s). 
Remove requirement for "real 
time" cytokine analyses to 
facilitate study conduct. 
Section 8.4.2.14 
Adenovirus Vector 
Shedding 
(formerly Section 
8.4.2.13)   
Optional sampling of body fluids may be performed to assess 
adenoviral vector shedding.  Samples collected may include 
any or all of the following: whole blood, saliva and semen.  
Subjects may freely decline participating in all or any portion 
of this sampling without any effect on their study participation.  
 
Subjects will be asked to provide samples of body fluids to 
assess any potential adenoviral vector shedding.  Samples 
collected may include any or all of the following: whole blood, 
saliva and semen.  Subjects will sign a consent form if they 
agree, but may freely decline to participate in all or any portion 
of this sampling without effect on their core study participation 
or prejudice to their future care.   
Minor clarification of text. 
Section 8.4.3  
INXN-1001 
Pharmacokinetic 
Assessment 
Not applicable. 
This section was added: 
8.4.3  INXN-1001 Pharmacokinetic Assessment 
Subjects will undergo an INXN-1001 pharmacokinetic 
(PK) assessment during cycle one of their study 
treatment. Whole blood samples will be collected on Day 
1, Day 2, Day 7, and Day 8 or 9 as defined in the 
Add INXN-1001 PK 
assessment. 

 
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Schedule of Assessments (see Table 2).. 
Section 8.4.4 
Efficacy 
Assessments 
(formerly Section 
8.4.3)   
All subjects will have tumor assessments performed within 2 
weeks prior to the Post-treatment safety assessment visit.  The 
Investigator will evaluate each subject for response to therapy 
according to RECIST 1.1 guidelines.1 Subjects who 
discontinue or complete study treatment without objective 
evidence of disease progression should continue to be followed 
for response at 8 -10 weeks intervals until disease progression 
has been documented or an alternate anti-cancer therapy has 
been initiated, whichever occurs first. 
…  Details regarding response assessments and photographs 
will be provided in the investigator’s study files. 
All subjects will have tumor assessments performed within 2 
weeks prior to the Post-treatment safety assessment visit and 
again at the Follow-up tumor assessment visit.  The 
Investigator will evaluate each subject for response to therapy 
according to RECIST 1.1 guidelines.1 Subjects without 
objective evidence of disease progression at the Follow-up 
tumor assessment visit should continue to have tumor 
assessments performed at 8-10 week intervals until disease 
progression has been documented or an alternate anti-cancer 
therapy has been initiated, whichever occurs first. 
…  Details regarding photographic methodology will be 
provided in the Photography Operations Manual 
As a supplement to the standard RECIST v1.1 guidelines 
established to evaluate anti-tumor responses to 
chemotherapeutic agents, the sponsor will be analyzing anti-
tumor response by assessing total tumor burden over time. 
Please refer to Appendix 4 for a description of this “immune-
related Response Criteria” (irRC). 
Add a Follow-up tumor 
assessment visit. 
Clarification of provided 
reference materials. 
Addition of central 
assessment of Total tumor 
burden. 
Section 9 
Adverse Events 
Entire Section 
Entire Section 
Entire section replaced with 
new ZIOPHARM Template 
language. 
Section 10  
Statistical 
Procedures 
Data from this study will be analyzed and included in an 
interim report after the last subject has completed the Post-
treatment safety assessment visit.  Additional data collected 
from subjects who are assessed for tumor response every 8-10 
weeks will be provided as an addendum to the study report. 
 
Data from this study will be analyzed and included in a clinical 
study report that will be prepared after the last subject has 
completed the Post-treatment safety assessment visit.  
Additional data collected from subjects who have not 
progressed by the Post-treatment safety assessment visit and 
are continuing to be followed for tumor response at the time of 
the final data cut-off date will be presented in an addendum to 
the study report. 
Clarify text. 
Section 10.1.2  
Populations for 
Analysis 
 Activity Evaluable Population: All subjects in the Safety 
Population who have at least 1 post-baseline response 
evaluation. 
 Activity Evaluable Population: All subjects who received at 
least 1 dose of INXN-2001 and INXN-1001, and have at 
least 1 post-screening response evaluation. 
Clarify definition of Activity 
Evaluable Population 
 
Section 10.3  
Data will be summarized by dose cohort. 
Data will be summarized by dose cohort based on the actual 
Clarify text. 

 
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Statistical Methods 
dose of INXN-1001 received on Day 1, Cycle 1. 
Section 10.3.3 
Efficacy Analyses 
 
The Activity Evaluable Population will be used for the analyses 
of efficacy data based on the dose of INXN-1001 received. 
 
Following completion of the study, best response will be 
determined for each subject in accordance with RECIST v.1.1 
guidelines and the objective response rate presented for each 
dose cohort.  Progression-free survival and durability of 
response will be determined using Kaplan-Meier methodology. 
The Activity Evaluable Population will be used for the analyses 
of efficacy data based on the dose of INXN-1001 received. 
Following completion of the study, best response will be 
determined for each subject in accordance with RECIST v.1.1 
guidelines and the objective response rate presented for each 
dose cohort.  Progression-free survival and durability of 
response will be determined using Kaplan-Meier methodology. 
As a supplement to the standard RECIST v1.1 guidelines 
established to evaluate anti-tumor responses to 
chemotherapeutic agents, the sponsor will be analyzing anti-
tumor response by assessing total tumor burden over time. 
Please refer to Appendix 4 for a description of this “immune-
related Response Criteria” (irRC). 
Addition of central 
assessment of Total tumor 
burden. 
Section 10.3.5  
INXN-1001 
Pharmacokinetics 
Not applicable. 
This section was added: 
10.3.5  INXN-1001 Pharmacokinetics 
INXN-1001 PK parameters to be determined will include, but 
is not limited to, the maximum concentration (Cmax), time to 
maximum concentration (Tmax), half-life (t1/2), area-under-the-
concentration time curve (AUC), volume of distribution (Vd), 
and clearance (CL).  Where possible, descriptive statistics of 
the PK parameters will be provided; individual subject INXN-
1001concentrations, actual sampling times, and PK parameters 
will be listed.     
Add INXN-1001 PK 
assessment for subjects 
receiving medications relevant 
to CYP450 3A4. 

 
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Section 11.6  
Institutional 
Review Board 
This protocol and the study informed consent form must be 
reviewed and approved by the IRB or IEC prior to the start of 
the study and a copy of the approval letter supplied to 
ZIOPHARM. 
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. 
Add mention that review and 
approval of Institutional 
Biosafety Committee is also 
required, where applicable. 
Appendix 3 
SUGGESTED 
REGIMEN FOR 
ANTIPYRETIC 
AND/OR 
ANALGESIC 
PROPHYLAXIS 
Not applicable 
Entire new appendix 
Addition of a recommended 
antipyretic regimen in order to 
prophylax patients prior to 
dosing with INXN-1001 
Appendix 4 
IMMUNE-
RELATED 
RESPONSE 
CRITERIA (irRC) 
Not applicable 
Entire new appendix 
Description of the response 
criteria to be used to measure 
total tumor burden. 
 

 
 
PROTOCOL AMENDMENT SUMMARY 
 
 
Protocol Title: 
A Phase I, Open Label Study of Ad-RTS-hIL-12, an 
Adenovirus Vector Engineered to Express hIL-12, in 
Combination with an Oral Activator Ligand, in Subjects  
with Unresectable Stage III or IV Melanoma 
Protocol Number: 
ATI001-101 (formerly ADA1001) 
Study Drugs: 
INXN-2001 (Ad-RTS-hIL-12) 
INXN-1001 (oral activator ligand)  
Date of Protocol: 
Original protocol: 21 April 2011 
Amendment 1: 22 June 2011 
Amendment 2: 13 January 2012 
Amendment 3: 20 April 2012 
 
 
 
 
 
 
 
 
 
NOTE TO INVESTIGATORS 
Amendment 3 dated 20 April 2012 will be used to conduct the study in place of any 
preceding version of this protocol.   
 
 
 
 
 
CONFIDENTIAL 

 
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20 APRIL 2012 
Confidential 
  
 
 
Page 3 of 4 
 
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Section 4 Schedule 
of Assessments 
Table 2 Footnotes 
25.  The subject will be dispensed INXN-1001 for self-
administration on days 2 through 7.  The first INXN-1001 
dose will be given at the clinical site in a fasted state (at least 
2 hours after a meal, and at least 2 hours before a meal) and 
then the remaining 6 doses will be self-administered at the 
same time every day (±1 hour) in the fasted state.  Subjects 
should return bottles of INXN-1001 for reconciliations to 
determine extent of subject adherence to self-administration 
preferably on the Day 8 visit of each cycle.  Please refer to 
Section 8.2.5 for additional information. 
 
30. Subjects without objective evidence of disease progression 
should continue to have tumor assessments performed at 8 -10 
weeks intervals until immune-related disease progression 
(irPD) has been confirmed or an alternate anti-cancer therapy 
has been initiated, whichever occurs first. 
25.  The subject will be dispensed INXN-1001 for self-
administration on Days 2 through 7.  The first INXN-1001 
dose will be given at the clinical site in a fed state (30 
minutes after the start of a normal meal) and at least 4 
hours before another meal and then the remaining 6 doses will 
be self-administered at the same time every day (±1 hour) in 
the fed state.  Subjects should return bottles of INXN-1001 
for reconciliations to determine extent of subject adherence to 
self-administration preferably on the Day 7 visit of each cycle.  
Please refer to Section 8.2.5 for additional information. 
 
30. Subjects without objective evidence of disease progression 
should continue to have tumor assessments performed at 8 -10 
weeks intervals until immune-related progression of disease 
(irPD) has been confirmed or an alternate anti-cancer therapy 
has been initiated, whichever occurs first. 
Typographical correction of 
study days for INXN-1001 
self-administration and drug 
reconciliation. 
 
 
 
 
 
Improve readability. 
Section 5.3.2 
Preclinical 
Efficacy Studies 
with Ad-RTS-
mIL-12 
Figure 3 
 
Added axes labels: 
Days post tumor inoculation (x-axis) 
Tumor volume (mm3) (y-axis) 
Clarification of Figure.  
Section 5.5  
Rationale for 
Study Design and 
Dose Selection 
The objectives of this Phase I clinical trial are to assess the 
safety, objective response rate, and immunological and 
biological effects of intratumoral injections of INXN-2001 in 
combination with escalating dose levels of oral INXN-1001.  
The dose escalation portion of the study uses a standard 3+3 
design commonly used in Phase I studies of investigational 
anticancer therapies.  To provide an opportunity to monitor the 
safety of the combination therapy, there will be at least 7 days 
between the initiations of treatment for each subject in all 
cohorts during the dose escalation stage of the study.  
 
The objectives of this Phase I clinical trial are to assess the 
safety, objective response rate, and immunological and 
biological effects of intratumoral injections of INXN-2001 in 
combination with escalating dose levels of oral INXN-1001.  
The dose escalation portion of the study uses a standard 3+3 
design commonly used in Phase I studies of investigational 
anticancer therapies.  To provide an opportunity to monitor the 
safety of the combination therapy, there will be at least 7 days 
between the initiations of treatment for the sentinel (first) 
subject and additional subjects in all cohorts during the 
dose escalation stage of the study.  
 
Clarify 7 day period between 
treatment initiation of the 
sentinel (first) subject in a 
cohort and additional subjects 
in the cohort. 
Section 6.2.1 
Overall Study 
Four sequential dose escalation cohorts of INXN-1001 in 
combination with a fixed dose of INXN-2001 are planned.  
Four sequential dose escalation cohorts of INXN-1001 in 
combination with a fixed dose of INXN-2001 are planned.  
Clarify 7 day period between 
treatment initiation of the 

 
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Design 
Subject enrollment and dose escalation will proceed according 
to a standard 3+3 design.  Each subject will be treated for up to 
three treatment cycles, each of 21 days in duration.  There will 
be at least 7 days between the initiations of treatment for 
each subject in all cohorts during the dose escalation stage 
of the study.  In each cycle, subjects will be treated with one 
intratumoral injection of INXN-2001 in combination with 7 
oral daily doses of INXN-1001 (Table 1).  No intrasubject dose 
escalation will be allowed. 
 
Subject enrollment and dose escalation will proceed according 
to a standard 3+3 design.  Each subject will be treated for up to 
three treatment cycles, each of 21 days in duration.  There will 
be at least 7 days between the initiations of treatment for 
the sentinel (first) subject and additional subjects in all 
cohorts during the dose escalation stage of the study.  In 
each cycle, subjects will be treated with one intratumoral 
injection of INXN-2001 in combination with 7 oral daily doses 
of INXN-1001 (Table 1).  No intrasubject dose escalation will 
be allowed. 
 
sentinel (first) subject in a 
cohort and additional subjects 
in the cohort. 
Section 8.2.5.1 
Preparation and 
Administration of 
INXN-1001 
INXN-1001 capsules will be dispensed for subject oral dosing 
by the site pharmacy. The site must instruct the subject to take 
each dose in a fasted state (i.e. at least 2 hours following any 
food) and to not eat any food for at least 2 hours after each dose 
is taken. 
INXN-1001 capsules will be dispensed for subject oral dosing 
by the site pharmacy. The site must instruct the subject to take 
each dose in a fed state (30 minutes after the start of a 
normal meal) and to not eat any food for at least 4 hours after 
each dose is taken.  
 
 
 

 
 
PROTOCOL AMENDMENT SUMMARY 
 
 
Protocol Title: 
A Phase I/II, Open Label Study of Ad-RTS-hIL-12, an 
Adenovirus Vector Engineered to Express hIL-12, in 
Combination with an Oral Activator Ligand, in Subjects  
with Unresectable Stage III or IV Melanoma 
Protocol Number: 
ATI001-101 (formerly ADA1001) 
Study Drugs: 
INXN-2001 (Ad-RTS-hIL-12) 
INXN-1001 (oral activator ligand)  
Date of Protocol: 
Original protocol: 21 April 2011 
Amendment 1: 22 June 2011 
Amendment 2: 13 January 2012 
Amendment 3: 20 April 2012 
Amendment 4: 13 July 2012 
 
 
 
 
 
 
 
NOTE TO INVESTIGATORS 
Amendment 4 dated 13 July 2012 will be used to conduct the study in place of any 
preceding version of this protocol.   
 
 
 
 
 
CONFIDENTIAL 

 
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Rationale for Change 
duration.  There will be at least 7 days between the initiations 
of treatment for the sentinel (first) subject and additional 
subjects in all cohorts during the dose escalation stage of the 
study. 
during the dose escalation stage of the study.  In each cycle, the 
subjects will be treated with one intratumoral injection of 
INXN-2001 in combination with 7 oral daily doses of INXN-
1001.  No intrasubject dose escalation will be allowed.  
Approximately 15 additional subjects will be enrolled as an 
expansion cohort at a single dose level at or below the 
MTD. 
the study design to include an 
expansion cohort. 
Section 3 Protocol 
Synopsis, 
Exclusion Criteria 
1. 
Any prior anti-cancer therapy or investigational agent 
within 28 days prior to the first dose of study drug.   
. 
 
1. 
Any prior anti-cancer therapy or investigational agent 
within 28 days prior to the first dose of study drug.   
NOTE: For the expansion cohort ONLY, if subjects 
received ipilimumab, a 90-day washout period since 
last dose of ipilimumab is required. If subjects received 
other immunomodulating therapies (eg, anti-PD1 
antibodies), the medical monitor should be contacted 
and an evaluation will be made. 
Clarify washout period for 
subjects who have been 
administered 
immunomodulating therapies 
prior to enrollment on study. 
Section 3 Protocol 
Synopsis; Dose 
and Schedule 
INXN-2001 should be injected into a different lesion at each 
cycle.  If only 3 accessible lesions are present, the injections 
will be done in sequential rotation between 2 lesions.  If only 2 
accessible lesions are present, then all injections will be into a 
single lesion.  Note: One accessible lesion will not be injected 
since that lesion will be used to evaluate the systemic effect of 
INXN-2001 
INXN-2001 should be injected into a different lesion at each 
cycle.  If only 3 accessible lesions are present, the injections 
will be done in sequential rotation between 2 lesions.  If only 2 
accessible lesions are present, then all injections will be into a 
single lesion.  Note: One accessible lesion will not be injected 
since that lesion will be used to evaluate the systemic effect of 
INXN-2001.  If only 2 accessible lesions are present at 
screening and the single injected lesion can no longer 
support the injection volume at subsequent cycles, then the 
medical monitor should be contacted for a discussion. 
Clarify procedure for injecting 
lesions. 
Section 3 Protocol 
Synopsis; Dose 
Escalation Plan 
Not applicable. 
ADDED TEXT: 
e)  An additional 15 subjects will be enrolled as an 
expansion cohort at a single dose level at or below the 
MTD. 
Describe the modification to 
the study design to include an 
expansion cohort. 
Section 3 Protocol 
Synopsis; Sample 
Size Determination 
In order to increase the ability to estimate the effect of the 
treatment on clinical response and to correlate with 
immunologic or other biologic markers, an additional number 
of subjects may be entered into the study after the initial safety 
In order to increase the ability to estimate the effect of the 
treatment on clinical response and to correlate with 
immunologic or other biologic markers, an additional number 
of subjects may be entered into the study after the initial safety 
Sentence no longer relevant. 

 
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evaluation has been completed.  In the event that the dose 
escalation phase does not result in 6 subjects in any given 
cohort, additional subjects may be added such that 6 total 
evaluable subjects are studied at that dose level.  Based on a 
review of available safety and clinical response data, the SRC 
may identify a single dose cohort to be expanded to a total of 
12 evaluable subjects to better define the safety, tolerability and 
activity of the study treatment.  Should a subject discontinue 
study treatment before receiving three cycles for reasons other 
than toxicity, another subject may be added to the dose cohort 
to provide a total of 3 or 6 subjects for full analysis.  
Given these considerations, a total of approximately 30 
subjects may be enrolled into this study, including 6 subjects 
enrolled in each of the 3 planned dose level cohorts and up to 6 
additional subjects enrolled at a single dose level at or below 
the MTD.  Additional subjects may also be enrolled as 
replacement subjects or to explore intermediate dose level 
cohorts, if any. 
evaluation has been completed.    Based on a review of 
available safety and clinical response data, the SRC may 
identify a single dose cohort to be expanded to a total of 15 
evaluable subjects to better define the safety, tolerability and 
activity of the study treatment.  Should a subject discontinue 
study treatment before receiving 3 cycles for reasons other than 
toxicity, another subject may be added to the dose cohort to 
provide a total of 3 or 6 subjects for full analysis.  
Given these considerations, a total of approximately 27 
subjects may be enrolled into this study, including 3 subjects 
enrolled in each of the 4 planned dose level cohorts and 
approximately 15 additional subjects enrolled at a single dose 
level at or below the MTD.  Additional subjects may also be 
enrolled as replacement subjects or to explore intermediate 
dose level cohorts, if any. 
Section 3 Protocol 
Synopsis; Duration 
of Subject 
Participation 
Each subject’s participation in this study will last 
approximately 5½ months, including: 
 
30 day screening period. 
 
3 cycles (9 weeks) of study treatment. 
 
Post-treatment safety assessment visit performed 28 days 
after the last dose of INXN-1001. 
 
Follow-up tumor assessment visit performed 35 ± 7 days 
after the Post-treatment safety assessment visit. 
Each subject’s participation in this study will last 
approximately 7 months, including: 
 
30 day screening period. 
 
6 cycles (18 weeks) of study treatment. 
 
Post-treatment safety assessment visit performed 28 days 
after the last dose of INXN-1001. 
 
Follow-up tumor assessment visit performed 35 ± 7 days 
after the Post-treatment safety assessment visit. 
Update number of cycles 
subjects may receive to 6 
cycles. 
Section 4 Schedule 
of Assessments 
Table 2  
Cycles 1, 2 &3 
Assessments were rescheduled as follows: 
 
Cycles 1 – 6:  Clinical assessments, clinical laboratory, 
subject registration, study drug administration 
Cycles 1, 3, 6 only: assessments of  Ab responses, cytokine 
profile, Ad vector shedding 
Cycles 1, 3, 6 only Day 15 ± 1:  tumor 
response/pharmacodynamics including imaging studies, 
Revise assessments to include 
subjects who may be eligible 
to receive up to 6 cycles of 
therapy. 
 
 

 
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digital photography, biopsy/FNA, PBMC, plasma 
For Expansion cohort only: 
Cycles 1, 3, 6 only Day 7 ± 1:  tumor 
response/pharmacodynamics including imaging studies, 
digital photography, biopsy/FNA, PBMC, plasma 
Section 4 Schedule 
of Assessments 
table footnotes 
15.  For subjects who meet inclusion and exclusion criteria. 
Centralized registration of eligible subjects will be completed 
according to a process defined by the sponsor.  
Appropriate cancer staging procedures should be 
performed during screening, including chest and 
abdominal CT or MRI scans. PET scans may be accepted 
in place of CT or MRI scans following consultation and 
agreement by the ZIOPHARM Medical Monitor. 
For subjects with measurable lesions, target lesions 
should be selected and measured as per RECIST 1.1 
guidelines.  Lesions that will be/are injected with INXN-
2001 and/or biopsied should not be selected as target 
lesions, but should be measured (if measureable).   
Disease sites are to be assessed throughout the study using the 
same method(s) used at screening.  
 
All subjects will have at least 2 tumor response 
assessments performed following the initiation of study 
treatment: 
 
At the Post-treatment safety assessment visit 
(28 ± 3 days following the last dose of INXN-
1001) or at the time of early withdrawal from 
study treatment. 
 
At the Follow-up tumor assessment visit (35 ± 
7 days following the Post-treatment safety 
assessment visit).   
The Investigator will evaluate response to therapy 
according to RECIST v1.1 guidelines.  
  
15.  For subjects who meet inclusion and exclusion criteria. 
Centralized registration of eligible subjects will be completed 
according to a process defined by the sponsor.  
Appropriate cancer staging procedures should be 
performed during screening.  For the purpose of this 
clinical trial, the following imaging is expected at 
screening: 
a. 
CT of the chest, and CT (or MRI) of the 
abdomen and pelvis 
b. 
MRI (or CT) of the brain if brain metastasis 
are known or suspected  
c. 
CT or MRI of other anatomical regions as 
clinically indicated 
 
For subjects with measurable lesions, target lesions 
should be selected and measured as per RECIST 1.1 
guidelines.  Lesions that will be/are injected with INXN-
2001 and/or biopsied should not be selected as target 
lesions, but should be measured (if measureable).   
Disease sites are to be assessed throughout the study 
using the same method(s) used at screening.  Specific 
image acquisition guidelines will be provided by a 
central imaging laboratory.  Chest, abdomen, pelvis 
imaging is required for all follow-up imaging 
timepoints; images of the brain and other anatomical 
regions should be acquired on follow-up if positive at 
screening and as clinically indicated. 
All subjects will have at least 2 tumor response 
assessments performed following the initiation of study 
treatment: 
 
At the Post-treatment safety assessment visit 
Clarify text pertaining to 
imaging procedures as part of 
the study. 

 
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Section in 
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Revised Text/Section 
Rationale for Change 
(28 ± 3 days following the last dose of INXN-
1001) or at the time of early withdrawal from 
study treatment. 
 
At the Follow-up tumor assessment visit (35 ± 
7 days following the Post-treatment safety 
assessment visit).   
For subjects with measurable lesions, target lesions 
should be selected and measured as per RECIST 1.1 
guidelines.  Lesions that will be/are injected with 
INXN-2001 and/or biopsied should not be selected as 
target lesions, but should be measured (if 
measureable). 
 
Section 4 Schedule 
of Assessments 
table footnotes 
17.  Fine needle aspiration biopsies on Day 2 should be 
obtained 24 hours (± 4 hours) after INXN-2001 injection, 
which should also be after the Day 2 INXN-1001 
administration. 
18.  Blood sample for cellular immune response (PBMC) 
analyses to be collected at screening, Cycle 2 Day 15, and 
the Post-treatment safety assessment visit.  Please refer to 
the laboratory manual for details regarding sample 
processing and shipment. 
 
 
 
17.  Fine needle aspiration biopsies on Day 7 should be 
obtained 24 hours (± 4 hours) after INXN-2001 injection, 
which should also be after the Day 7 INXN-1001 
administration. 
18.  Blood sample for cellular immune response (PBMC) 
analyses to be collected at screening, Cycle 3 Day 7, the 
Post-treatment safety assessment visit, and Follow Up 
Tumor Assessment Visits.  Please refer to the laboratory 
manual for details regarding sample processing and 
shipment. 
22.  ADDED TEXT: 
A blood sample for PK assessment will also be obtained Cycle 
3 Day 7. 
29.  ADDED TEXT: 
Visit procedures will include: 
 
a tumor response assessment (see footnote 16), 
 
digital photography of all visible tumors (see 
footnote 17), 
 
PBx of injected and non-injected lesions (see 
footnote 18) 
 
PBMC collection (see footnote 19) 
 
documentation of any new concomitant 
medications since the Post-treatment safety 
Clarify the assessments 
occurring for Cycles 1 to 6 
and those pertaining to the 
expansion cohort. 

 
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Page 8 of 10 
 
Section in 
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Original Text/Section 
Revised Text/Section 
Rationale for Change 
Section 5.5 
Rationale for 
Study Design and 
Dose Selection 
The objectives of this Phase I/II clinical trial are to assess the 
safety, objective response rate, and immunological and 
biological effects of intratumoral injections of INXN-2001 in 
combination with escalating dose levels of oral INXN-1001.  
The dose escalation portion of the study uses a standard 3+3 
design commonly used in Phase I studies of investigational 
anticancer therapies.  To provide an opportunity to monitor the 
safety of the combination therapy, there will be at least 7 days 
between the initiation of treatment for the sentinel (first) 
subject and additional subjects in all cohorts during the dose 
escalation stage of the study. 
The objectives of this Phase I/II clinical trial are to assess the 
safety, objective response rate, and immunological and 
biological effects of intratumoral injections of INXN-2001 in 
combination with escalating dose levels of oral INXN-1001.  
The dose escalation portion of the study uses a standard 3+3 
design commonly used in Phase I studies of investigational 
anticancer therapies.  To provide an opportunity to monitor the 
safety of the combination therapy, there will be at least 7 days 
between the initiation of treatment for the sentinel (first) 
subject and additional subjects in all cohorts during the dose 
escalation stage of the study.  An expansion cohort will be 
enrolled (a total of 15 patients) at a single dose level at or 
below the MTD. 
 
Describe the modification to 
the study design to include an 
expansion cohort. 
Section 6.2 Study 
Design and Dose 
Escalation 
Procedure 
This is a single-arm, open label, Phase I dose escalation study 
of intratumoral injections of INXN-2001 and oral INXN-1001 
in subjects with unresectable Stage III or IV melanoma.   
Four sequential dose escalation cohorts of INXN-1001 in 
combination with a fixed dose of INXN-2001 are planned.  
Subject enrollment and dose escalation will proceed according 
to a standard 3+3 design.  Each subject will be treated for up to 
three treatment cycles, each of 21 days in duration.  There will 
be at least 7 days between the initiation of treatment for the 
sentinel (first) subject and additional subjects in all cohorts 
during the dose escalation stage of the study.  In each cycle, 
subjects will be treated with one intratumoral injection of 
INXN-2001 in combination with 7 oral daily doses of INXN-
1001 (Table 1).  No intrasubject dose escalation will be 
allowed. 
This is a single-arm, open label, Phase I/II dose escalation 
study of intratumoral injections of INXN-2001 and oral INXN-
1001 in subjects with unresectable Stage III or IV melanoma.   
Four sequential dose escalation cohorts of INXN-1001 in 
combination with a fixed dose of INXN-2001 are planned.  
Subject enrollment and dose escalation will proceed according 
to a standard 3+3 design.  Each subject will be treated for up to 
6 treatment cycles, each of 21 days in duration.  Previously 
enrolled subjects received 3 cycles under former versions of 
this protocol.  There will be at least 7 days between the 
initiation of treatment for the sentinel (first) subject and 
additional subjects in all cohorts during the dose escalation 
stage of the study.  In each cycle, subjects will be treated with 
one intratumoral injection of INXN-2001 in combination with 
7 oral daily doses of INXN-1001 (Table 1).  No intrasubject 
dose escalation will be allowed.  Approximately 15 subjects 
will be enrolled as an expansion cohort at a single dose level 
at or below the MTD. 
Modify the number of cycles 
that subjects are eligible to 
receive from 3 to 6 cycles. 
Describe the modification to 
the study design to include an 
expansion cohort. 
Section 6.2.6 Dose 
Escalation 
Procedure 
Not applicable. 
ADDED TEXT: 
e)  Approximately 15 subjects will be enrolled as an 
expansion cohort at a single dose level at or below the 
MTD.   
 
Describe the modification to 
the study design to include an 
expansion cohort. 

 
Protocol: ATI001-101 (formerly ADA1001) Amendment 4  
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Page 9 of 10 
 
Section in 
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Revised Text/Section 
Rationale for Change 
Section 6.2.7  
Study Stopping 
Rules 
For toxicity grading based on laboratory tests, an abnormality 
must be confirmed (when appropriate) by repeat testing.   For 
any suspected injection reaction and/or hypersensitivity 
reaction, a serum tryptase level will be measured. 
For toxicity grading based on laboratory tests, an abnormality 
must be confirmed (when appropriate) by repeat testing.   For 
any suspected injection reaction and/or hypersensitivity 
reaction, a serum tryptase level will be measured. 
 
 
Section 7.2 
Exclusion Criteria 
1. 
Any prior anti-cancer therapy or investigational agent 
within 28 days prior to the first dose of study drug.   
 
1. 
Any prior anti-cancer therapy or investigational agent 
within 28 days prior to the first dose of study drug.   
NOTE: For the expansion cohort ONLY, if subjects 
received ipilimumab, a 90-day washout period since 
last dose of ipilimumab is required. If subjects received 
other immunomodulating therapies (eg, anti-PD1 
antibodies), the medical monitor should be contacted 
and an evaluation will be made. 
 
Clarify washout period for 
subjects who have been 
administered 
immunomodulating therapies 
prior to enrollment on study. 
Section 8.2.5.3  
Preparation and 
Administration of 
INXN-2001 
INXN-2001 
 
 will be administered 
as an intratumoral injection 3 hours (± 30 minutes) after oral 
INXN-1001 dosing on Day 1 of each cycle.  INXN-2001 
should be injected into a different lesion at each cycle.  If only 
3 accessible lesions are present, the injections will be done in 
sequential rotation between 2 lesions.  If only 2 accessible 
lesions are present, then all injections will be into a single 
lesion.   
INXN-2001 
 
 will be administered 
as an intratumoral injection 3 hours (± 30 minutes) after oral 
INXN-1001 dosing on Day 1 of each cycle.  INXN-2001 
should be injected into a different lesion at each cycle.  If only 
3 accessible lesions are present, the injections will be done in 
sequential rotation between 2 lesions.  If only 2 accessible 
lesions are present, then all injections will be into a single 
lesion.  If only 2 accessible lesions are present at screening 
and the single injected lesion can no longer support the 
injection volume at subsequent cycles, then the medical 
monitor should be contacted for a discussion. 
 
Clarify procedure for injecting 
lesions. 
Section 8.4.2.13  
Immune Response 
Analyses 
Blood samples will be collected from the subjects at specified 
visits to evaluate the potential antibody and cellular immune 
response to INXN-2001 (adenovirus and, RTS  components) 
and melanoma-associated antigens.  The AdVeGFP infectivity 
blocking type assay will be used to detect an antibody response 
to the adenoviral vector.38 Antibody response to the RTS  
components may be assessed by western blot and/or enzyme-
linked immunosorbent assay (ELISA).  Plasma and/or serum 
cytokine levels (e.g., IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IFN-
γ, etc. will be assayed using multiplex and/or ELISA 
Blood samples will be collected from the subjects at specified 
visits to evaluate the potential antibody and cellular immune 
response to INXN-2001 (adenovirus and, RTS
components) 
and melanoma-associated antigens.  Antibody response to the 
RTS  components may be assessed by western blot and/or 
enzyme-linked immunosorbent assay (ELISA).  Plasma and/or 
serum cytokine levels (eg, IL-12, IFN-γ, etc.. will be assayed 
using multiplex and/or ELISA methodology.   
Describe the modification to 
the study design to include an 
expansion cohort. 

 
Protocol: ATI001-101 (formerly ADA1001) Amendment 4  
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Page 10 of 10 
 
Section in 
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methodology.   
Section 10.1 
Determination of 
Sample Size 
In order to increase the ability to estimate the effect of the 
treatment on clinical response and to correlate with 
immunologic or other biologic markers, an additional number 
of subjects may be entered into the study after the initial safety 
evaluation has been completed.  In the event that the dose 
escalation phase does not result in 6 subjects in any given 
cohort, additional subjects may be added such that 6 total 
evaluable subjects are studied at that dose level.  Based on a 
review of available safety and clinical response data, the SRC 
may identify a single dose cohort to be expanded to a total of 
12 evaluable subjects to better define the safety, tolerability and 
activity of the study treatment.  Should a subject discontinue 
study treatment before receiving three cycles for reasons other 
than toxicity, another subject may be added to the dose cohort 
to provide a total of 3 or 6 subjects for full analysis. 
In order to increase the ability to estimate the effect of the 
treatment on clinical response and to correlate with 
immunologic or other biologic markers, an additional number 
of subjects may be entered into the study after the initial safety 
evaluation has been completed.  Based on a review of available 
safety and clinical response data, an additional 15 subjects 
may be enrolled as an expansion cohort at a single dose 
level at or below the MTD.  Should a subject discontinue 
study treatment before receiving 3 cycles for reasons other than 
toxicity, another subject may be added to the dose cohort to 
provide a total of 3 or 6 subjects for full analysis. 
 
Section 11.4 
Duration of the 
Study 
The study is estimated to complete enrollment within 12 
months. The estimated number of months to complete study 
visits for the last enrolled subject is approximately 4½ months 
(assuming 3 treatment cycles).  Therefore, the total duration of 
this study is expected to be approximately 1 to 2 years. 
Each subject’s participation in this study will last 
approximately 5½ months, including: 
 
 
Not applicable 
The study is estimated to complete enrollment within 12 
months. The estimated number of months to complete study 
visits for the last enrolled subject is approximately 7 months 
(assuming 6 treatment cycles).  Therefore, the total duration of 
this study is expected to be approximately 1.5 to 2.5 years. 
Each subject’s participation in this study will last 
approximately 7 months, including: 
 
ADDED TEXT: 
The active study period refers to the study period from 
informed consent through the Post Treatment Safety 
Assessment visit.   
 
Clarify the definition of the 
study period. 
 

 
 
PROTOCOL AMENDMENT SUMMARY 
 
 
Protocol Title: 
A Phase I/II, Open Label Study of Ad-RTS-hIL-12, an 
Adenovirus Vector Engineered to Express hIL-12, in 
Combination with an Oral Activator Ligand, in Subjects  
with Unresectable Stage III or IV Melanoma 
Protocol Number: 
ATI001-101 (formerly ADA1001) 
Study Drugs: 
INXN-2001 (Ad-RTS-hIL-12) 
INXN-1001 (oral activator ligand)  
Date of Protocol: 
Original protocol:  21 April 2011 
Amendment 1:       22 June 2011 
Amendment 2:       13 January 2012 
Amendment 3:       20 April 2012 
Amendment 4:       13 July 2012 
Amendment 5:       28 September 2012 
 
 
 
NOTE TO INVESTIGATORS 
Amendment 5 dated 28 September 2012 will be used to conduct the study in place of 
any preceding version of this protocol.   
 
 
 
 
 
CONFIDENTIAL 

 
Protocol: ATI001-101 (formerly ADA1001) Amendment 5 
28 SEPTEMBER 2012 
Confidential 
  
 
 
Page 3 of 6 
 
Section in Amended 
Protocol 
Revised Text/Section 
Rationale for Change 
 
17. Digital photograph(s) of all visible injected tumor(s) and non-
injected tumors, and of any visible local reactions in or 
around the injected lesion(s).  Photographs are required at 
screening, Cycle 1 Day 7 or 15, Cycle 6 Day 7 or 15, PTSA 
and FUTA visits and ad hoc as the investigator deems 
necessary. For any subject who has or develops vitiligo, this 
should be documented the same way.  Details regarding 
photographic methodology will be provided in the 
Photography Operations Manual. 
18. Fine needle aspiration biopsies should be obtained on Day 7 
should be obtained 24 hours (± 4 hours) after INXN 2001 
injection, which should also be after the Day 7 INXN-1001 
administration. 
 
24. Intratumoral INXN-2001 
 
 
 injection should be 
given 3 hours ± 30 minutes after the INXN-1001 dose.  
Lesions displaying signs of local infection should not be 
injected.  Subjects must be adequately hydrated on each day 
of study drug administration.  Subjects should be instructed 
to maintain good oral hydration on dosing days.  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 INXN-2001 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.  Please refer to Section 8.2.5 for 
additional information.  
25. The subject will be dispensed INXN-1001 for self-
administration on Days 2 through 7.  Subjects must be 
adequately hydrated on each day of study drug 
administration.  Subjects should be instructed to maintain 
good oral hydration on dosing days.  The first INXN-1001 
Clarify photography 
assessment timing 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clarify lesions displaying 
signs of localized infection 
are not to be injected. 
 
Indicate that adequate 
hydration is required during 
study drug administration. 

 
Protocol: ATI001-101 (formerly ADA1001) Amendment 5 
28 SEPTEMBER 2012 
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Page 5 of 6 
 
Section in Amended 
Protocol 
Revised Text/Section 
Rationale for Change 
Section 8.2.5.3  
Preparation and 
Administration of 
INXN-2001 
The INXN-2001intratumoral administration should be delivered by 
multiple injections with a fine needle (no finer than 27 gauge) directly 
into each quadrant of the lesion or tumor-involved lymph node, at 
approximately 0.5 cm apart three dimensionally, to reach all aspects of 
the entire lesion.  Attention must be paid to adequately infiltrate the 
circumference of the tumor margins. A detailed description and 
photograph of physical location(s) of the injected tumor(s) and 
surrounding tissue, and any visible local reactions should be 
documented.  Lesions displaying signs of local infection should not be 
injected. 
Clarify lesions displaying 
signs of localized infection 
are not to be injected. 
 
Section 8.4.2.5 
Vital Signs 
Vital signs will include blood pressure, pulse, temperature, and 
respiration.  Subject’s blood pressure is to be monitored closely with 
hydration as needed to prevent hypotension for up to 72 hours after 
administration of INXN-1001.  Blood pressure assessment is required 
on Day 4 for Cycle 1 and Cycle 2. 
 
Include instruction to 
monitor blood pressure 
following INXN-1001 
administration.  
Section 8.4.4 
Efficacy 
Assessments 
Appropriate cancer staging procedures should be performed during 
screening.  including chest and abdominal CT or MRI scans.  PET 
scans may be accepted in place of CT or MRI scans following 
consultation and agreement by the ZIOPHARM Medical Monitor.  
For the purpose of this clinical trial, the following imaging is 
expected at screening: 
a. 
CT of the chest, and CT (or MRI) of the abdomen and 
pelvis 
b. MRI (or CT) of the brain if brain metastasis are known 
or suspected  
c. 
CT or MRI of other anatomical regions as clinically 
indicated 
 
Language updated to clarify 
tumor response assessment 
at Post-Treatment Safety 
Assessment visit, and to 
match footnote 16 in 
Schedule of Assessments 

 
Protocol: ATI001-101 (formerly ADA1001) Amendment 5 
28 SEPTEMBER 2012 
Confidential 
  
 
 
Page 6 of 6 
 
Section in Amended 
Protocol 
Revised Text/Section 
Rationale for Change 
For subjects with measurable lesions, target lesions should be selected 
and measured as per RECIST 1.1 guidelines.1  Lesions that will be/are 
injected with INXN-2001 and/or biopsied should not be selected as 
target lesions, but should be measured (if measureable).   
For each subject, disease sites are to be assessed throughout the study 
using the same method(s) of assessment used at screening. Specific 
image acquisition guidelines will be provided by a central imaging 
laboratory.  Chest, abdomen, pelvis imaging is required for all follow-
up imaging timepoints; images of the brain and other anatomical 
regions should be acquired on follow-up if positive at screening and as 
clinically indicated. 
All subjects will have at least 2 tumor response assessments performed 
within 2 weeks prior at to the Post-Treatment Safety Assessment visit 
(28 ± 3 days following the last dose of INXN-1001) or at the time of 
early withdrawal from study treatment and again at the Follow-Up 
Tumor Assessment visit (35 ± 7 days following the Post-treatment 
safety assessment visit). 
Section 11.4 
Duration of the 
Study 
Each subject’s participation in this study will last approximately 7 
months, including: 
• 
30 day screening period. 
• 
6 cycles (918 weeks) of study treatment. 
 
Corrected typo 
 

 
 
PROTOCOL AMENDMENT SUMMARY 
 
 
Protocol Title: 
A Phase I/II, Open Label Study of Ad-RTS-hIL-12, an 
Adenovirus Vector Engineered to Express hIL-12, in 
Combination with an Oral Activator Ligand, in Subjects  
with Unresectable Stage III or IV Melanoma 
Protocol Number: 
ATI001-101 (formerly ADA1001) 
Study Drugs: 
INXN-2001 (Ad-RTS-hIL-12) 
INXN-1001 (oral activator ligand)  
Date of Protocol: 
Original protocol:  21 April 2011 
Amendment 1:       22 June 2011 
Amendment 2:       13 January 2012 
Amendment 3:       20 April 2012 
Amendment 4:       13 July 2012 
Amendment 5:       26 September 2012 
Amendment 6:       01 March 2013 
 
 
 
 
NOTE TO INVESTIGATORS 
Amendment 6 dated 01 March 2013 will be used to conduct the study in place of any 
preceding version of this protocol.   
 
 
 
 
 
CONFIDENTIAL 

Protocol: ATI001-101 (formerly ADA1001) Amendment 6 
01 MARCH 2013 
Confidential 
  
 
 
Page 2 of 8 
 
1. Tabular Summary of Revisions Implemented in the Amended Protocol 
Section in 
Amended Protocol Revised Text/Section 
Rationale for Change 
Title Page, Page 
Headings and 
Footers 
Amendment 6:  01 March 2013 
Updated Protocol 
Amendment 
Global 
Corrections in grammar, style 
Clarity and accuracy 
Section 3  
Protocol Synopsis 
Exclusion Criteria 
Revised text: 
1. Any prior anti-cancer therapy or investigational agent 
within 28 days prior to the first dose of study drug.   
NOTE: For the expansion cohort ONLY, if subjects 
received ipilimumab, a 90 45-day washout period since last 
dose of ipilimumab is required. If subjects received other 
immunomodulating therapies (eg, anti-PD1 antibodies), the 
medical monitor should be contacted and an evaluation will 
be made. 
 
 
Revised wash-out period 
from last dose of 
ipilimumab from 90 days 
to 45 days 
Section 3 
Protocol Synopsis 
Route of 
Administration 
Added text: 
INXN-1001: Taken orally in a fed state (30 minutes after the 
start of a normal meal) and at least 4 hours before another meal. 
INXN-2001: Intratumoral injection on the first day of each 
cycle into one accessible tumor lesion or tumor-involved 
(palpable) draining lymph node when necessary.  
Radiologically-guided injections are permitted under BL2 
conditions. The injection should be administered 3 hours ± 30 
minutes after the first dose of INXN-1001.   
 
Clarify that 
radiographically-guided 
injections are permitted  
if available 

Protocol: ATI001-101 (formerly ADA1001) Amendment 6 
01 MARCH 2013 
Confidential 
  
 
 
Page 4 of 8 
 
Section in 
Amended Protocol Revised Text/Section 
Rationale for Change 
in vivo assessment of transgene function and 
immunological activities, and other biological effects 
should be obtained at the time points indicated in the 
preceding table. Details of these procedures are described 
in the laboratory manual. 
PBx:  Punch biopsy (≥4 mm in diameter);   FNA: fine 
needle aspiration biopsy 
• 
At screening Day -6 to -2, punch biopsies should 
be obtained only after subject registration has been 
completed (i.e., after approval by sponsor for study 
participation) and before start of treatment.   
• 
Fine needle aspiration biopsies should be obtained 
on Day 7 after INXN 1001 administration. 
• 
Biopsies not required at Follow up Tumor 
Assessment visit if ≤30 days since last biopsy. 
24. 
Intratumoral INXN-2001 (1.0 x 1012 vp) injection 
should be given 3 hours ± 30 minutes after the INXN-1001 
dose.  Lesions displaying signs of local infection should not be 
injected.  Subjects must be adequately hydrated on each day of 
study drug administration, and .  Subjects should must be 
instructed to maintain good oral hydration on dosing days.  
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 INXN-2001 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.  Please refer to Section 8.2.5 for 

 
 
PROTOCOL AMENDMENT SUMMARY 
 
 
Protocol Title: 
A Phase I/II, Open Label Study of Ad-RTS-hIL-12, an 
Adenovirus Vector Engineered to Express hIL-12, in 
Combination with an Oral Activator Ligand, in Subjects  
with Unresectable Stage III or IV Melanoma 
Protocol Number: 
ATI001-101  
Study Drugs: 
INXN-2001 (Ad-RTS-hIL-12) 
INXN-1001 (oral activator ligand)  
Date of Protocol: 
Original protocol:  29 April 2011 
Amendment 1:       22 June 2011 
Amendment 2:       13 January 2012 
Amendment 3:       20 April 2012 
Amendment 4:       13 July 2012 
Amendment 5:       26 September 2012 
Amendment 6:       01 February 2013 
Amendment 7:       29 April 2013 
 
 
 
NOTE TO INVESTIGATORS 
Amendment 7 dated 29 April 2013 will be used to conduct the study in place of any 
preceding version of this protocol.   
 
 
 
CONFIDENTIAL 

Protocol: ATI001-101 Amendment 7 
 
29 APRIL 2013 
Confidential 
Page 3 of 24 
Section in 
Amended Protocol Revised or Deleted Text/Section 
Rationale for Change 
Section 3  
Protocol Synopsis 
No. of Subjects 
Added text: 
Approximately 30 subjects  
(3 subjects per dose level cohort in Phase I and approximately 15 subjects enrolled 
in an expansion cohort Phase II at a single dose level at or below the MTD), 
exclusive of replacement subjects or the addition of intermediate dose level 
cohorts, if any 
Update study design and 
clarify Phases 
Section 3  
Protocol Synopsis 
Study Design 
Added table: 
Table 1:  Study Design 
Study Part 
Cohorts 
Dose Regimen 
Phase I 
Dose 
Escalation  
INXN-2001: 
 
  
INXN-1001: 5, 20, 100, 160 mg  
Phase II 
Group 1 
INXN-2001: 
 
  
INXN-1001: 160 mg daily for 7  
consecutive days; 21-day cycle 
Group 2 
INXN-2001: 
 
 
INXN-1001: 160 mg every other day   
for 14 days; 28-day cycle 
Added/revised text: 
In Phase I, four sequential dose escalation cohorts of INXN-1001 in combination 
with a fixed dose of INXN-2001 are planned (Table 1).  Subject enrollment and 
dose escalation will proceed according to a standard 3+3 design.  Each subject will 
be treated for up to 6 treatment cycles, each of 21 days in duration.  Previously 
enrolled subjects received 3 cycles under former versions of this protocol. There 
will be at least 7 days between the initiations of treatment for the sentinel (first) 
subject and additional subjects in all cohorts during the dose escalation stage of the 
study.  In each cycle, the subjects will be treated with one intratumoral injection of 
INXN-2001 in combination with 7 oral daily doses of INXN-1001.  No 
intrasubject dose escalation will be allowed.  
[Please refer to Appendix 5 for additional study design details for the Phase I 
Update study design and 
revise descriptions of the 
study Phases 

Protocol: ATI001-101 Amendment 7 
 
29 APRIL 2013 
Confidential 
Page 4 of 24 
Section in 
Amended Protocol Revised or Deleted Text/Section 
Rationale for Change 
portion of this study.]  
In Phase II, approximately 15 additional subjects will be enrolled as an expansion 
cohort at a single dose level at or below the MTD. Phase II of the study will 
include two groups of subjects. Subjects enrolled in the Phase II portion of the 
study under Amendment 6 or prior will be enrolled into Group 1; subjects enrolled 
under Amendment 7 or later will be enrolled into Group 2. 
Subjects in Group 1 will be treated with one intratumoral injection of INXN-2001 
in combination with oral doses of INXN-1001 given at 160 mg daily for 7 
consecutive days at the beginning of a 21-day cycle. Subjects in Group 2 will be 
treated with one intratumoral injection of INXN-2001 in combination with oral 
doses of INXN-1001 given at 160 mg every other day for 14 days at the beginning 
of a 28-day cycle.  Subjects may receive treatment for 6 cycles. 
Section 3  
Protocol Synopsis 
Inclusion Criteria 
3. A minimum of 2 accessible nonvisceral lesions (shortest diameter ≥ 1 cm) 
or palpable tumor-involved lymph nodes (shortest diameter ≥ 1.5 cm). 
Revise  text for clarity 
Section 3 
Protocol Synopsis 
Dose and Schedule 
Deleted text: 
All subjects will receive intratumoral injections of INXN 2001 
 
 
 
 on Day 1 of a 3 week cycle.  The subjects 
will also receive a single daily oral dose of INXN 1001 for 7 consecutive days 
starting on Day 1 of each cycle.  Subjects may receive up to 6 cycles of study 
treatment. 
 
Added text: 
Phase II, Group 2:  All subjects will receive intratumoral injections of INXN-2001 
 
 on Day 1 of a 4-week 
cycle.  The subjects will also receive a single oral dose of INXN-1001 every other 
day for 14 days starting on Day 1 of each cycle.  Subjects may receive up to 6 
cycles of study treatment. 
 
Update study design and 
revise descriptions of the 
study Phases 
Section 3 
Protocol Synopsis 
Dose Escalation Plan 
The Dose Escalation Plan, Definition of MTD, and Definition of DLT Sections 
were deleted from the Synopsis and added to Appendix 5 
Modified to simplify the 
protocol 

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Definition of MTD 
 
Definition of DLT 
Section 3 
Protocol Synopsis 
Duration of Subject 
Participation 
Revised text: 
Each Phase II, Group 2 subjects’ participation in this study will last approximately 
9 8 months, including: 
• 
30 day screening period. 
• 
6 cycles (18 24 weeks) of study treatment. 
• 
Post-Treatment Safety Assessment visit performed 28 days after the last dose 
of INXN-1001. 
• 
Follow-Up Tumor Assessment visit performed 35 ± 7 days after the Post-
Treatment Safety Assessment visit. 
In addition, subjects who discontinue or complete study treatment in the absence 
of rapid clinical deterioration and without objective evidence of confirmed 
immune-related disease progressionve disease (irPD) should continue to be 
followed until immune-related disease progression (irPD) has been confirmed or 
an alternate anti-cancer therapy has been initiated, whichever occurs first. 
Update study design, revise 
descriptions of the study 
Phases and duration of 
subject participation 
Section 3 
Protocol Synopsis 
Sample Size 
Determination 
Revised text: 
Given these considerations, a total of approximately 30 subjects may be enrolled 
into this study, including 3 subjects enrolled in each of the 4 planned dose level 
cohorts and approximately 15 additional subjects enrolled at a single dose level at 
or below the MTD during the Phase II portion of the study.  Additional subjects 
may also be enrolled as replacement subjects or to explore intermediate dose level 
cohorts, if any. 
Update study design and 
revise descriptions of the 
study Phases 
Section 4  
Table 2 
Schedule of 
Assessments and 
Footnotes 
 
Assessments included are for all Phase II Group II subjects; Phase I and 
Phase II Group I Schedule of Assessments are now located in Appendix 5 
 
• 
Day 3 &OR Day 4 
• 
Day 8 OR Day 913 
• 
Day 15 ± 2 days 
 
 
Clarify Study visits and 
Assessments; simplify 
schedule 

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• 
Oral INXN-1001 Day 1 – Day 714 
• 
Cytokine profile:  added Day 3 
• 
PK: deleted Day 3 
• 
Deleted Ad Vector Shedding 
• 
Deleted FNA 
• 
Footnote numbering has changed 
Footnotes: 
6. Vital signs include blood pressure, pulse, temperature, and respirations.  
On Day 1 of each cycle, vital signs will be recorded prior to INXN-1001 
dosing and hourly for the first two hours after INXN-2001 dosing.  Blood 
pressure is to be monitored closely to prevent hypotension for up to 72 
hours after administration of INXN-1001.  Blood pressure assessment is 
required on Day 3 or Day 4 for Cycle 1 and Cycle 2. Subjects must be 
instructed to maintain adequate oral hydration on and in between dosing 
days; sites must closely monitor subjects’ hydration status.  Oral 
hydration is of paramount importance during the first 72 hours after first 
injection of INXN-2001 because most toxicity has been observed during 
this time period.   
7. Monitoring and recording of adverse events (AEs) and serious adverse 
events (SAEs) will be conducted throughout the study.  AEs/SAEs that 
occur following informed consent until the Post-Treatment Safety 
Assessment must be recorded on the AE CRF; AEs/SAEs that occur prior 
to informed consent should be added to the medical history CRF.  Study 
drug related AEs/SAEs that are ongoing at the time of the Post Treatment 
Safety Assessment visit should be followed until resolution, return to 
baseline, they have stabilized (and following consultation and agreement 
by the ZIOPHARM Medical Monitor), or they can be attributed to other 
than the study drug or other than study conduct.  SAEs considered to be 
related to study drug that occur beyond 30 days after the last dose must 
also be reported.   
8. In addition, all SAEs must be reported by the investigator or designee 
within 24 hours of becoming aware of the event, from the time of 

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informed consent through 30 days after the last dose of study drug, 
regardless of the initiation of any new anti-cancer therapy.  SAEs 
considered to be related to study drug that occur beyond 30 days after the 
last dose must also be reported. 
10. Hematology tests include: complete blood count and white blood cell 
count, differential white blood cell count, red blood cell count, 
hematocrit, hemoglobin, red blood cell indices, reticulocyte count, MCV 
(mean corpuscular volume) and platelet count. PTT (partial 
thromboplastin time) and INR (international normalized ratio) will also 
be evaluated. 
16. Serum Blood sample for analysis of antibody responses to the adenovirus 
and/or the RTS components, and antibodies to melanoma-associated 
antigens. Please refer to the laboratory manual for details regarding 
sample processing and shipment. 
17. Blood samples for cytokine profiling.  Please refer to the laboratory 
manual for details regarding sample processing and shipment. 
18. For subjects with measurable lesions, target lesions should be selected 
and measured as per RECIST 1.1 guidelines.  Lesions that will be/are 
injected with INXN-2001 and/or biopsied should not be selected as target 
lesions, but should be measured (if measureable).   
Disease sites are to be assessed throughout the study using the same 
method(s) used at screening.  Specific image acquisition guidelines will 
be provided by a central imaging laboratory.  Chest, abdomen, pelvis 
imaging is required for all follow-up imaging time points; images of the 
brain and other anatomical regions should be acquired on follow-up if 
positive at screening and as clinically indicated. 
All subjects will have at least 2 tumor response assessments performed 
following the initiation of study treatment: 
At the Post Treatment Safety Assessment visit (28 ± 3 days following the 
last dose of INXN 1001) or at the time of early withdrawal from study 
treatment. 
At the Follow Up Tumor Assessment visit (35 ± 7 days following the 

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Post-Treatment Safety Assessment visit).   
19. Digital photograph(s) of all visible injected tumor(s) and non-injected 
tumors, and of any visible local reactions in or around the injected 
lesion(s).  Photographs are required at screening, Cycle 1 Day 7 or 1513, 
Cycle 6 Day 7 or 1513, PTSA and FUTA visits and ad hoc as the 
investigator deems necessary. 
20. For Phase II:  blood samples for cellular immune response (PBMC) 
analyses are to be collected at screening, Cycle 3 Day 13, the Post-
Treatment Safety Assessment, and Follow-Up Tumor Assessment visits.  
Please refer to the laboratory manual for details regarding sample 
processing and shipment. NOTE: If a subject is off-study before Cycle 3, 
then a blood sample will be obtained at the PTSA visit. 
24. The first INXN-1001 dose will be given on Day 1 at the clinical site in a 
fed state (30 minutes after the start of a normal meal) and at least 4 hours 
before another meal and then the remaining 6 doses will be self-
administered every other day at the same time (±1 hour) in the fed state.  
Subjects must be adequately hydrated on each day of study drug 
administration, and must be instructed to maintain good oral hydration on 
and between dosing days.  Oral hydration is of paramount importance 
through Cycle 2 following injection of INXN-2001 because most toxicity 
has been observed during this time period. Study sites must verify 
compliance with INXN-1001 dosing on Days 5, 11, and 13.  Subjects 
should return bottles of INXN-1001 for reconciliations to determine 
extent of subject adherence to self-administration preferably on the Day 
15 visit of each cycle.  Please refer to Section 8.2.5 for additional 
information. 
26. FOR CYCLE 1 ONLY: Subjects will undergo an INXN-1001 
pharmacokinetic (PK) assessment. Blood samples for INXN-1001 PK 
analysis should be obtained on the following days and time points: 
Day 1: Pre-dose (< 30 minutes prior to INXN-1001 dosing) 
1-2 hours post INXN-1001 dosing 
3-8 6 hours post INXN-1001 dosing 
Day 2: Pre-dose (< 30 minutes prior to INXN-1001 dosing) 

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Day 713:1-2 hours post INXN-1001 dosing 
3-8 6 hours post INXN-1001 dosing 
Day 8 OR Day 915: anytime >24 hours post-Day 713 INXN-1001 dose 
Plasma samples will be obtained for determining levels of INXN-1001, IL-12 
and interferon-gamma for subjects in the dose escalation cohorts on 
Cycle 3 Day 15, and for subjects in the expansion cohort on Cycle 3 
Day 7. 
27. Blood pressure will be assessed at Cycle 1 and Cycle 2 Day 3 or 4 visit.  
During Cycle 1 and 2, Day 3 or 4 visits are required.  For Cycles 3-6, Day 
3 or Day 4 visits should be performed when feasible (eg, Monday through 
Friday). 
28. Post- Treatment Safety Assessment visit will be performed 28 ± 3 days 
after the last dose of INXN-1001 or at the time of early withdrawal from 
study treatment.  Note: imaging studies performed for the tumor response 
assessment may be completed within 2 weeks prior to the Post-Treatment 
Safety Assessment visit. 
Subjects with ongoing study drug-related AEs/SAEs should continue to 
be followed until resolution, return to baseline, or until they have 
stabilized (and following consultation and agreement by the ZIOPHARM 
Medical Monitor), or they can be attributed to other than the study drug or 
other than study conduct.  Subjects found to have residual viral particles 
or DNA in tissue or blood samples may be requested to return to the 
clinic at monthly intervals for further testing until clearance has been 
documented. 
29. A Follow-Up Tumor Assessment visit will be performed 35 ± 7 days after 
the Post-Treatment Safety Assessment visit.  This assessment is required 
for all subjects, including those with prior objective evidence of disease 
progression to ensure that more slowly declining tumor burden in 
response to therapy is not missed.   
Visit procedures will include: 
• 
a tumor response assessment (see footnote 16), 
• 
digital photography of all visible tumors (see footnote 17), 

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treated for up to 6 treatment cycles, each of 21 days in duration.  Previously 
enrolled subjects received 3 cycles under former versions of this protocol.  There 
will be at least 7 days between the initiation of treatment for the sentinel (first) 
subject and additional subjects in all cohorts during the dose escalation stage of the 
study.  In each cycle, subjects will be treated with one intratumoral injection of 
INXN-2001 in combination with 7 oral daily doses of INXN-1001 (Table 1).  No 
intrasubject dose escalation will be allowed.   
Phase II:  Approximately 15 subjects will be enrolled as anin expansion 
cohortPhase II at a single dose level at or below the MTD.  For Group 1, in each of 
six 21-day cycles, the subjects will receive one intratumoral injection of 
INXN-2001 in combination with 7 oral daily doses of INXN-1001.  For Group 2, 
in each of six 28-day cycles, the subjects will receive one intratumoral injection of 
INXN-2001 in combination with 7 oral doses of INXN-1001 administered every 
other day for 14 days.   
 
Section 6.2.2 
Treatment Parameters 
and Duration 
Revised text: 
 
All subjects will receive intratumoral injections of INXN-2001 
 
 
 
 on Day 1 of a 3-week each cycle.  The subjects will also 
receive a single dailyan oral daily dose of INXN-1001 for 7 consecutive days 
(Phase I and Phase II Group 1) or every other day for 14 days (Phase II Group 2) 
starting on Day 1 of each cycle.  The INXN-1001 dose assigned to any given 
subject will be determined according to the dose escalation schedule (Section 
6.2.6). 
Update study design and 
revise descriptions of the 
study Phases; revise dosing 
regimen 
Section 6.2.3 Safety 
Review Committee 
(SRC) 
Revised text: 
 
A SRC comprised of the Medical Monitor, Principal Investigators and sponsor 
representatives, will hold periodic teleconferences to evaluate the safety and 
treatment status of all subjects.  The SRC will review and assess the safety data at 
the completion of each dose cohort as described in Section 6.2.6, and at any other 
time as needed.  The SRC has the authority to recommend dose modifications for 
safety concerns. 
The following data will be reviewed at each SRC meeting to determine whether to 
Simplify language and 
clarify the role of the SRC 
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proceed to a subsequent cohort: physical examination and vital signs; medical 
history; complete blood count with differential; serum chemistry panel including 
alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase 
(ALP), and total bilirubin; lactate dehydrogenase (LDH); albumin; serum tryptase 
level; ECG; cytokine levels; and adverse event and concomitant medication 
records.  Additional information will be reviewed as necessary.  A written 
summary documenting the results and recommendations of each review will be 
provided to the Investigator(s) and maintained on file with the sponsor.  Additional 
sub-Investigators and personnel may participate in reviews as indicated.   
In Phase I, Ffollowing a cohort review, the SRC may recommend proceeding with 
enrollment in the next dose cohort, enrolling additional subjects in the current 
cohort, dropping back to a lower cohort, exploring an alternate dose level, or not 
enrolling any additional subjects.  The dose escalation and enrollment guidelines 
outlined in Section 6.2.6, as well as the study stopping rules outlined in Section 
6.2.7, will be used as the basis for these assessments. 
In Phase II, Group 2, the DLT definitions in Section 6.2.4 will be utilized along 
with the criteria for de-escalation.  The SRC may recommend a dose reduction for 
subjects in Group 2 if one or more DLT(s) are observed. 
Section 6.2.4 
Definition and 
Management of Dose-
limiting Toxicity 
(DLT) 
Added text: 
Phase I and Phase II, Group 1:  If DLTs have been observed in >1 of the 3-6 
subjects in a cohort during the first treatment cycle, the MTD will have been 
exceeded and further use of that dose will be discontinued in all subjects, and the 
next lower dose cohort will be assessed as to whether it meets the definition of the 
MTD.   
Phase II, Group 2: If an adverse event that meets the Phase I DLT definition is 
observed in >1 of the 3-6 subjects in Group 2 during the first treatment cycle, the 
SRC will convene to discuss reduction in dose and/or change to posology and the 
cohort will be expanded by 3 subjects. The recommended Phase II dose will be the 
dosage and posology where ≤1 of 3 to 6 subjects experiences an adverse event as 
described in the definition of DLT. 
Update study design and 
revise descriptions of DLT 
for Phase II Group 2 
Section 6.2.5 
Definition of 
Maximum Tolerated 
Revised text: 
The MTD will be defined as the highest dose of INXN-1001 studied in 
combination with INXN-2001 at which a DLT has been seen in a maximum of less 
Update study design and 
revise descriptions of MTD 
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Dose (MTD) and 
Recommended Phase 
II Dose (RP2D) 
than 2 out1 of in 6 subjects (< 33%) during the first treatment cycle.  Subsequent 
to Cycle 1, study drug-related adverse events that meet the DLT criteria will also 
be considered by the SRC and any previous determination of the MTD may be 
reconsidered. 
The recommended Phase II dose will be the dosage and posology where ≤1 of 3 to 
6 subjects experiences an adverse event as described in the definition of DLT. 
Section 6.2.6 
Dose Escalation 
Procedure 
Revised text: 
In Phase I, Ffour sequential INXN-1001 dose escalation cohorts are planned, as 
described in Table 1Appendix 5.  Subject enrollment and dose escalation will 
proceed according to a standard 3+3 design.  No intrasubject dose escalation will 
be allowed.  An intermediate dose level(s) of INXN-1001 may be explored after 
review of all available safety and activity data, as may be decided by the SRC. 
 
Approximately 15 subjects will be enrolled in Phase II at or below the MTD. 
 
In order to increase the ability to estimate the effect of the treatment on clinical 
response and to correlate with immunologic or other biologic markers, an 
additional number of subjects may be entered into the study after the initial safety 
evaluation has been completed.   
 
Moved text: 
The remaining text from this Section was moved to Appendix 5. 
 
Update study design and 
revise descriptions of the 
study Phases 
Section 6.2.7 
Study Stopping Rules 
Revised text: 
Rules for stopping dose escalation due to DLTs observed during the first cycle of 
study treatment are outlined in Section 6.2.4.  In the event that a given dose level 
cohort is determined to have exceeded the MTD, then further use of that dose will 
be discontinued for all subjects as noted in Section 6.2.4.  Subsequent to Cycle 1, 
study drug-related adverse events that meet the DLT criteria will also be 
considered by the SRC and any previous determination of the MTD may be 
reconsidered. 
Stopping rules for toxicities that occur from Day 1, Cycle 2 through the Post-
Clarify study stopping rules 
that apply in Phase II 

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treatment follow-up visit will apply as follows:  
• 
If an adverse event can be definitely shown to be unrelated to study 
treatment (eg, motor vehicle accident, bee sting, elective surgery), that 
specific toxicity will not be considered in a stop vs. dose escalation 
modification decision.  
• 
Recruitment in the current cohort dose level will not be stopped for Grade 
2 (NCI CTCAE v.4.03) non-dose limiting toxicities, irrespective of the 
number of events or number of subjects. 
• 
Recruitment in the current cohort dose level will be stopped for any 
Grade 3 or 4 toxicity, unless the adverse event is clearly and 
incontrovertibly due to extraneous causes.  Upon occurrence, aAll data 
will be reviewed by the Investigator, the Investigator’s IRB as applicable, 
ZIOPHARM Medical and Regulatory Staff, and the SRC to determine if 
the study should proceed and if/what changes must be implemented.  
o 
For toxicity based on laboratory tests:  an abnormality related to 
study drug per investigator assessment must be confirmed (when 
appropriate) by repeat testing and related to study drug per 
investigator before qualifiying for review as above. 
• 
In addition to stopping rules for dose escalation, sSubject enrollment into 
the study will be halted in the event of any study drug-related death.  In 
this case, subject enrollment will only resume following review and 
approval of the SRC.  
For toxicity grading based on laboratory tests, an abnormality must be confirmed 
(when appropriate) by repeat testing. 
 
Section 7.1 
Inclusion Criteria 
Deleted text: 
 
3.  A minimum of 2 accessible nonvisceral lesions (shortest diameter ≥1 cm) or 
palpable tumor-involved lymph nodes (shortest diameter ≥1.5 cm).   
Clarify/revise inclusion 
criteria 

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Section 8.2.3 
Treatment Regimen 
Added text: 
 
Each subject’s assigned INXN-1001 dose will be given orally daily for the first 7 
consecutive days of each 21 day cycle (Phase I and Phase II Group 1).  For Phase 
II Group 2 the INXN-1001 dose will be given orally every other day for 14 days of 
each 28 day cycle,   
 
Oral hydration is of paramount importance during the first 72 hours afterthrough 
Cycle 2 following injection of INXN-2001 
 
 Blood pressure should be monitored Cycle 1 and 
2 Days 1, 2, 3 or 4, and regularly thereafter.  
 
Update study design and 
revise descriptions of the 
study Phases; revise dosing 
regimen 
Section 8.2.5 
Preparation and 
Administration of 
Study Drug 
Deleted text: 
A combination of two investigational medications will be evaluated for safety, 
tolerability, efficacy, and biological effects in this trial. The small molecule INXN-
1001 will be administered as oral capsules to subjects once daily, for seven 
consecutive days, in combination with an intratumoral injection of INXN-2001 (on 
Day 1 of each cycle). For each treatment cycle, INXN-2001 dosing will occur 3 
hours ± 30 minutes after the first dose of INXN-1001. 
 
Revise to align with dosing 
regimen 
Section 8.2.5.2 
Monitoring of Subject 
Adherence and 
Managing Missed 
INXN-1001 Doses 
Subjects should be instructed not to make up for missed doses.  to make up for a 
missed dose by taking the dose the following day, and then continuing with dosing 
as scheduled (eg, if the dose on Day 3 is missed, dosing should occur on Day 4 and 
then continue as scheduled on Days 5, 7, 9 etc). Capsules that for any reason were 
not taken during a prior day should not be taken but left in the container. 
Clarify instructions for  
how to continue after 
missing a dose with every 
other day dosing 
Section 8.2.7  
Severity Grading and 
Management of 
Injection Site 
Reactions 
Added text: 
Table 3. Injection Site Reaction Severity Grading and Management 
CTCA
E 
Grade 
Symptoms 
Course of Action 
1 
Tenderness with or 
without associated 
No intervention required. 
Update language for 
clarification 

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symptoms (eg, warmth, 
erythema, itching) 
2 
Pain; lipodystrophy; 
edema; phlebitis 
Proceed with further dosing cycles.   
 
3 
Ulceration or necrosis; 
severe tissue damage; 
operative intervention 
indicated 
Discontinue further study treatment and 
notify Medical Monitor.  Report and 
manage as DLT: see Section 6.2.4.  
If  toxicity meets seriousness criteria, 
immediately report as per SAE reporting 
procedures; see Section 9.4. 
4 
Life-threatening 
consequences; urgent 
intervention indicated 
Permanently discontinue study treatment 
and notify Medical Monitor.  Report and 
manage as DLT: see Section 6.2.4.   
Defaults to “serious”.  Immediately 
report as per SAE reporting procedures; 
see Section 9.4.  
5 
Death 
Immediately notify Medical Monitor and 
report as per SAE reporting procedures; 
see Section 9.4. 
Discontinue further subject enrollment as 
per study stopping rules; see Section 
6.2.7. 
Section 8.2.8 
Prophylactic 
Hydration, Antipyretic 
and/or Analgesic 
Administration 
The use of antipyretics and/or analgesics and aggressive hydration is allowed 
anytime during study treatment, as indicated, including prophylactic 
administration. 
Since fever and flu like symptoms are commonly experienced following 
adenoviral vector administration it is strongly recommended that subjects be 
treated with prophylactic oral hydration, antipyretic and/or analgesic medications 
prior to study drug administration. 
Add prophylactic hydration 
along with prophylactic 
antipyretics and/or 
analgesics  

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For those subjects who experience treatment related symptoms (eg, fever, 
headache, chills, dehydration, etc) during Cycle 1, prophylactic hydration, 
antipyretic and/or analgesic medications must be given prior to study drug 
administration in subsequent cycles. Please refer to Appendix 3 for a 
recommended regimen for the prophylactic administration of antipyretics and/or 
analgesics. 
Section 8.4.2.6 
Adverse Events 
Deleted text: 
.  Study drug-related AEs/SAEs that are ongoing at the time of the Post-Treatment 
Safety Assessment visit should continue to be followed until resolution, return to 
baseline, or until they have stabilized (and following consultation and agreement 
by the ZIOPHARM Medical Monitor).  
In addition, all SAEs must be reported by the investigator or designee within 24 
hours of becoming aware of the event, from the time of informed consent through 
30 days after the last dose of study drug, regardless of the initiation of any new 
anti-cancer therapy.  SAEs considered to be related to study drug that occur 
beyond 30 days after the last dose must also be reported. 
Deleted redundant text 
Section 8.4.2.8 
Hematology 
Added text: 
Hematology tests include: complete blood count and white blood cell count, 
differential white blood cell count, red blood cell count, hematocrit, hemoglobin, 
red blood cell indices, reticulocyte count, MCV (mean corpuscular volume) and 
platelet count. PTT (partial thromboplastin time) and INR (international 
normalized ratio) will also be evaluated. 
Clarify red blood cell 
indices 
Section 8.4.2.14 
Adenovirus Vector 
Shedding 
Deleted text: 
Subjects will be asked to provide samples of body fluids to assess any potential 
adenoviral vector shedding.  Samples collected may include any or all of the 
following: whole blood, saliva and semen.  Subjects will sign a consent form if 
they agree, but may freely decline to participate in all or any portion of this 
sampling without effect on their core study participation or prejudice to their future 
Delete adenoviral shedding 
as an assessment 

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care. 
Section 8.4.3 
INXN-1001 
Pharmacokinetic 
Assessment 
Revised text: 
Whole blood samples will be collected on Day 1, Day 2, Day 7, and Day 8 or 9 15 
as defined in the Schedule of Assessments (see Table 2). 
Align PK with new dosing 
regimen 
Section 8.4.4 
Efficacy Assessments 
Revised text: 
All subjects will have at least 2 tumor response assessments performed including 
Cycle 3 Day 13, the Post-Treatment Safety Assessment visit (28 ± 3 days 
following the last dose of INXN-1001) or at the time of early withdrawal from 
study treatment and again at the Follow-Uup Ttumor Aassessmentup tumor 
assessment visit (35 ± 7 days following the Post-Treatment Safety Assessment 
visit). 
Align efficacy assessments 
with revised study design 
Section 8.4.5.1  
Transgene Function 
Deleted text: 
FNAs of the tumor(s) and/or associated tumor involved draining lymph nodes will 
be collected for genomic analysis and IHC.   
FNAs are no longer being 
collected as part of the 
study 
Section 8.4.5.3 
Other Biological 
Effects 
Deleted text: 
Tumor biopsies and FNAs will also be assessed for changes in the frequency of 
apoptotic tumor cells and for other biologic effects of the treatment, such as 
change in tumor vasculature as a result of induction of IL-12 and other cytokines 
in the tumor microenvironment. 
FNAs are no longer being 
collected in the study 
Section 9.2.3 
Causality Assessments 
Deleted text: 
The Investigator will use medical consideration to determine the potential 
relationship of the AE to the study drugs based on his/her clinical judgment.  For 
SAEs, the Sponsor will provide a separate assessment of causality.  The 
Investigator’s assessment and/or the Sponsor’s assessment will be considered for 
expedited reporting of SAEs per relevant regulatory requirements.   
Revise safety language for 
clarity 

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Section 9.4  
Reporting Serious 
Adverse Events 
Revised text: 
 
SAEs must be reported to the Sponsor or Sponsor’s designee immediately within 
24 hours of becoming aware of the event (regardless of the initiation of any new 
anti-cancer therapy) including the following: 
• 
Any death or SAE experienced by the patient from the signing of 
informed consent to 30 days after the last dose of study drug, regardless 
of relationship to study drug. 
• 
Any death or SAE that the Investigator becomes aware of, and believes to 
be study drug related, that occurs more than 30 days after the patient last 
received study drug. 
 
Study drug-related AEs/SAEs that are ongoing at the time of the Post-Treatment 
Safety Assessment visit should continue to be followed until resolution, return to 
baseline, or until they have stabilized or become chronic (and following 
consultation and agreement by the ZIOPHARM Medical Monitor). 
 
In addition to the above information, the Investigator must provide, for each event 
term, an assessment of the following: 
• 
Severity of the SAE/intensity 
• 
Relationship to the study drug (causality assessment) 
Revise safety language for 
clarity 
Section 10.3 
Statistical Methods 
Added text: 
Data will be summarized by dose cohort based on the actual dose of INXN-1001 
received on Day 1, Cycle 1.  For Phase II, data will be summarized based on group 
and dose regimen. 
Update statistical 
considerations for revised 
study design 
Section 11.4 
Duration of the Study 
Revised text: 
The study is estimated to complete enrollment within 12 over 24 months. The 
estimated number of months to complete study visits for the last enrolled subject is 
approximately 78 months (assuming 6 treatment cycles).  Therefore, the total 
duration of this study is expected to be approximately 1.5 to 2.5 years. 
Each subject’s participation in this study will last approximately 78 months 
Update to align with dosing 
regimen and cycle length 

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Rationale for Change 
Section 17 
Appendix 3 
Added/revised text: 
 
Recombinant adenoviral vectors have the potential to elicit potent cellular and 
humoral immune responses in recipients. While the mechanism responsible for 
these effects is poorly understood, dehydration and transient low-grade fevers are 
common after systemic recombinant adenovirus vector administration and 
temperatures up to 104o F with chills and generalized malaise have been observed 
in first and/or subsequent treatment cycles.  
Dehydration may occur in the absence of adequate hydration prophylaxis.  
Subjects must be instructed to maintain adequate oral hydration on and in between 
dosing days; sites must closely monitor subjects’ hydration status.  Oral hydration 
is of paramount importance after first injection of INXN-2001 through Cycle 2 
  
Because low grade fever is very likely to occur, prophylaxis with a non-steroidal 
anti-inflammatory agent (ibuprofen) or acetaminophen (if a subject cannot tolerate 
ibuprofen) is strongly recommended starting with Cycle 1.   
• 
Ibuprofen is available without a prescription in 200 mg tablets. Usually 1 2 
tablets 800 mg every 4-6-8 hours will prevent and/or decrease fever. The 
lowest expected efficacious dose should be used.  
• 
Side effects of ibuprofen include nausea and vomiting, which may be 
prevented if the medication is taken with food. Rare side effects include 
diarrhea, constipation, heartburn, and stomach pain. People with 
stomach ulcers or kidney disease, and those with an aspirin allergy 
should avoid ibuprofen.  
• 
Common brand names of ibuprofen include Advil®, Motrin®, and 
Nuprin®.  
• 
Aspirin should be avoided as it may be toxic in large doses in adults. 
• 
While meta-analyses suggest that ibuprofen is a better anti-pyretic medication 
than acetaminophen, acetaminophen also prevents and or reduces a fever. It is 
available without a prescription in 325 mg or 500 mg tablets. Again, 1 2 
tablets 1000 mg every 4 6-8 hours should be used to eliminate fever. The 
Update with language about 
hydration and its 
importance during 
treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
Update doses of antipyretics 
to be used 

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Section in 
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Rationale for Change 
maximum dose of acetaminophen in adults should not exceed 4 grams in a 24 
hour period. 
Deleted Text: 
If you choose not to institute prophylactic anti-pyretic therapy on Cycle1, Day 1 
then a subject should be instructed in how to treat fever if it occurs following viral 
vector injection. 
Section 19  
Appendix 5 
Added text: 
Sections of protocol synopsis referring to the Phase I and Phase II, Group 1 have 
been moved to Appendix 5. 
Simplify the protocol by 
moving information about 
completed Phase/groups to 
the Appendix