Clinical trial NCT03754933
Conditions: Recurrent Head and Neck Cancer
Keywords: Fludarabine Adenovirus Head & neck squamous cell carcinoma
Sponsor: GeoVax, Inc.
Start date: 2019-02-11; Completion date: 2024-12-31
Enrollment: 10 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Primary Objective: The primary objective of the study is to evaluate the safety of repeat administration of a dose level of Ad/PNP plus fludarabine phosphate (F-araAMP) which demonstrated anti-tumor activity in patients with advanced head and neck cancer in a completed phase I study.

Secondary Objective: The secondary objective is to evaluate the antitumor activity of repeat administration of Ad/PNP plus F-araAMP.

FDA Office of Orphan Drugs Division is a source of funding for the overall project.

Detailed description:
1. Mechanism of action. The study drug, Ad/PNP-F-araAMP (Fludarabine phosphate) consists of a nonreplicating adenoviral vector expressing the E. coli purine nucleoside phosphorylase (PNP) injected intratumorally followed by intravenous administration of F-araAMP. This combination generates 2-fluoroadenine (F-Ade) within the tumor resulting in focal chemotherapeutic activity.

   F-araAMP is an agent that is rapidly cleaved by plasma phosphatases to fludarabine, which is the primary circulating form of the drug and has activity against certain hematological malignancies, but not against solid tumors such as head and neck squamous cell carcinoma (HNSCC). Fludarabine (F-araA) is an adenosine analog and substrate for E. coli PNP, which cleaves the glycosidic bond of F-araA to generate F-Ade. The F-Ade metabolite has shown pronounced activity against human tumor xenografts in mice.

   Many refractory tumors are refractory precisely because they have a very low growth fraction, i.e., a relatively small percentage of tumor cells dividing at any particular point in time. In nonclinical studies, significant in vivo antitumor activity has been demonstrated by F-Ade generation from F-araAMP in tumors in which 2.5 to 10% of cells express the E. coli PNP gene. In addition, anti-tumor effect was seen in patients with advanced solid tumors (melanoma and head and neck cancer) in the higher dose cohorts during a Phase 1 study (see next section).
2. Tumor response with Ad/PNP-F-araAMP in Phase 1 Study. The safety and efficacy of Ad/PNP-F-araAMP has been evaluated in a Phase 1 study, PNP-001 (NCT01310179). Four escalating dose levels were evaluated in 10 subjects with head and neck cancer and 2 subjects with melanoma; clinical activity was observed at the highest dose levels following 3 intratumoral injections of Ad/PNP over 2 days and IV F-araAMP phosphate over 3 days. The overall response rate (CR+PR) was approximately 67% in the 2 highest dose cohorts, Cohorts 3 and 4. Results suggest a dose response effect. The duration of response in the injected tumor was limited, with 4 of 5 responding tumors having disease progression of the injected lesion prior to last follow-up on Day 56, suggesting that repeat administration should be evaluated. Ad/PNP + F-araAMP was well tolerated. No subject experienced a dose-limiting toxicity and none of the subjects discontinued study treatment. Overall, the activity and safety profile of Ad/PNP seen in the Phase 1 study supports further clinical evaluation of repeat administration of Ad/PNP (IT) and F-araAMP phosphate infusion for patients with HNSCC.
3. Purpose of the Study. Based upon the tumor response seen with a single administration of the two highest dose levels of Ad/PNP-F-araAMP in the Phase 1 study (NCT01310179), PNP plans to investigate the safety and assess anti-tumor activity of repeat cycles of injection of Ad/PNP + F-araAMP in patients with advanced head and neck cancer. Subjects in the study will have RECIST 1.1 measurable HNSCC which is amenable to local injection for which there is no effective curative or palliative treatment option. This study population was selected since results from this Phase 1/2 trial are intended to support the safety of repeat dosing in further clinical investigation.
4. Study Design. The trial is designed as a single-arm study to evaluate the safety of repeat cycles of Ad/PNP and F-araAMP in patients with recurrent HNSCC with tumor(s) accessible for injection. Ad/PNP will be injected intratumorally twice on Day 1 and once on Day 2 followed by infusion of F-araAMP daily on Days 3, 4, and 5. Subjects will receive repeat administration of Ad/PNP-F-araAMP every 4 weeks (i.e., each cycle) for 5 cycles or until injected tumor progresses, unacceptable toxicity occurs, no tumor is present for injection, or patient death. Tumor response in the injected tumor(s) will be assessed by physical examination as well as by radiographic imaging. All subjects will be monitored for adverse events during study participation.

Arms: arm 1: Ad/PNP + fludarabine phosphate, 5 cycles
Interventions: intervention 1: Ad/PNP intervention 2: Fludarabine Phosphate
Intervention descriptions: intervention 1: Ad/PNP is a replication defective adenoviral vector expressing E. coli Purine Nucleoside Phosphorylase intervention 2: Fludarabine phosphate is an anticancer agent currently used for treatment of patients with chronic lymphocytic leukemia.

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL 
GeoVax, Inc. 
Ad/PNP-F-araAMP 
Protocol No. PNP-002 
V4.0 06 May 2022 
Phase 1/2, Open-label Study Evaluating the Safety of  
Repeat Administration of Ad/PNP-F-araAMP (Ad/PNP 
Administered Intratumorally with Co-administration of 
Fludarabine Phosphate Intravenously) in Subjects with Recurrent, 
Local Head and Neck Cancer 
Protocol No. PNP-002 
Version 04, 06 May 2022 
IND Sponsor 
GeoVax, Inc. 
1900 Lake Park Drive Suite 380 
Smyrna, GA 30080 
Phone: (678) 384-7220 
Fax: (678) 384-7283 
 www.geovax.com 
Sponsor Contact: 
Kelly T. McKee, Jr., MD, MPH 
Email: kmckee@geovax.com 
Contract Research Organization: 
CATO SMS, Ltd. 
2000 Centregreen Way, Suite 300 
Cary, NC 27513 
Coordinating Investigator: 
A. Dimitrios Colevas, M.D.
Phone: (650) 724-9707
Fax: (650) 498-5800 
Email: colevas@stanford.edu 


CONFIDENTIAL 
GeoVax, Inc. 
 
Ad/PNP-F-araAMP 
Protocol No. PNP-002 
V4.0 06 May 2022 
 
 
 
Page 2 
Document History 
Amendment Date 
Notes 
Version 1 Date: July 2016 
During the protocol development phase with the 
investigator and collaborator- never submitted to the Stanford 
Institutional Review Board (IRB) 
Version 2 Date: 8.7.2017 
Initial IRB/SRC Submission 
Version 2 Date: 10.6.2017 
SRC Edits 
Version 2 Date: 11.16.2017 
SRC Pre-Comments 
Version 02 Date: 05 September 2018 
Clarify enrollment numbers; adverse event (AE) reporting criteria and 
instructions 
Version 03 Date: 28 February 2019 
Revision includes: 
- 
Removal of requirement for emergency equipment beyond usual 
resources 
Version 04 Date: 06 May 2022 
 
Revision includes: 
- 
Addition of “Statement of Compliance”, “Sponsor’s Approval”, and 
“Investigator’s Agreement” sections  
- 
Coordinating center changed to GeoVax, Inc. and study changed to 
a multisite study with accompanying edits to the Safety Monitoring 
Committee Charter and sections in the protocol regarding the Safety 
Monitoring Committee 
- 
Clarification of Inclusion/Exclusion Criteria: patients with 
histologically or cytologically confirmed diagnosis of recurrent 
cancer of the head and neck region for whom there is no curative 
treatment option; for the purposes of trial eligibility, head and neck 
cancer shall include, in addition to head and neck squamous cell 
carcinoma (HNSCC), cutaneous squamous cell primary sites and 
squamous cell carcinoma of unknown primary presenting with neck 
lymph nodal disease, as well as nasopharyngeal carcinoma, and 
salivary gland tumors; patients with resolved side effects can receive 
treatment earlier than 4 weeks after latest chemotherapy dose 
- 
Removal of Section 2.6 Correlative Studies Background since there 
were no correlative studies 
- 
Removal of “Description of Study Drug” Section 4.1 since this text 
was referenced in “Description of Study Drug” Section 5.1. 
- 
Edits to study calendar: extension of screening period window; 
adjustments to pharmacokinetic collection and vitals timepoints, 
removal of projected study completion timelines;  
- 
Moved the first paragraph describing how tumor response will be 
assessed from Section 12.6 Assessment of Efficacy Measures to 
Section 10.3.5 Response Review 
- 
Clarified responsibilities of Sponsor and Contract Research 
Organization (CRO) in Section 11.9 Study Monitoring and Auditing 
- 
Clarification of endpoints and alignment of terminology with Food 
and Drug Administration (FDA) guidance and industry standards   
- 
Clarification of the Statistical Consideration section and added a 
description of study power 
- 
Minor grammatical and typographical updates throughout to 
improve clarity and readability 
- 
Miscellaneous edits to promote consistency 


CONFIDENTIAL 
GeoVax, Inc. 
 
Ad/PNP-F-araAMP 
Protocol No. PNP-002 
V4.0 06 May 2022 
 
 
 
Page 3 
STATEMENT OF COMPLIANCE 
The study will be conducted in compliance with this clinical study protocol, Good Clinical 
Practices (GCP) as outlined by International Conference for Harmonisation (ICH) E6(R2), and all 
applicable local and national regulatory requirements. Enrollment at any clinical study site may 
not begin prior to that site receiving approval from the ethics committee of record for the protocol 
and all materials provided to potential participants. 
Any amendments to the protocol or changes to the consent document will be approved before 
implementation of that amendment. Reconsent of previously enrolled participants may be 
necessary depending on the nature of the amendment. 
The Principal Investigator will ensure that changes to the study plan as defined by this protocol 
will not be made without prior agreement from the Sponsor and documented approval from the 
ethics committee of record, unless such a change is necessary to eliminate an immediate hazard to 
the study participants. 
All personnel involved in the conduct of this study have completed Human Subjects Protection 
and GCP Training as outlined by their governing institution. 
 
 


CONFIDENTIAL
GeoVax, Inc.
Ad/PNP-F-araAMP
Protocol No. PNP-002
V4.0 06 May 2022
Page 4
Title
Phase 1/2, Open-label Study Evaluating the Safety of Repeat Administration of Ad/PNP-F-
araAMP (Ad/PNP Administered Intratumorally with Co-administration of Fludarabine 
Phosphate Intravenously) in Subjects with Recurrent, Local Head and Neck Cancer
Protocol Number
PNP-002
Version Number
04
Version Date
06 May 2022
responsible personnel as indicated in the signature table below.
Medical Representative
Name:
Title:
Signature:
Date:
Kelly McKee, MD, MPH
Chief Medical Officer 
Coordinating Investigator 
Name:
Title:
Signature:
Date:
A. Dimitrios Colevas, MD
Professor of Medicine,
Stanford University


CONFIDENTIAL 
GeoVax, Inc. 
 
Ad/PNP-F-araAMP 
Protocol No. PNP-002 
V4.0 06 May 2022 
 
 
 
Page 5 
INVESTIGATOR’S AGREEMENT 
I have read the protocol, appendices, and accessory materials related to Study [insert number] and 
agree to the following: 
• To conduct this study as described by the protocol and any accessory materials 
• To protect the rights, safety, and welfare of the participants under my care 
• To provide oversight to all personnel to whom study activities have been delegated 
• To control all investigational products provided by the Sponsor and maintain records of the 
disposition of those products 
• To conduct the study in accordance with all applicable local and national regulations, the 
requirements of the ethics committee of record for my clinical site, and Good Clinical Practices 
as outlined by ICH E6(R2). 
• To obtain approval for the protocol and all written materials provided to participants prior to 
initiating the study at my site 
• To obtain informed consent – and updated consent in the event of new information or 
amendments – from all participants enrolled at my study site prior to initiating any 
study‑specific procedures or administering investigational products to those participants 
• To maintain records of each subject’s participation and all data required by the protocol 
 
Name 
Title 
Institution 
[Insert last name, first name] 
 
[Insert title (at institution)] 
[Insert address] 
 
 
Signature 
Date 
 
 
 
[DD Month YYYY] 
 
 


CONFIDENTIAL 
GeoVax, Inc. 
 
Ad/PNP-F-araAMP 
Protocol No. PNP-002 
V4.0 06 May 2022 
 
 
 
Page 6 
TABLE OF CONTENTS 
 
Page 
 
STATEMENT OF COMPLIANCE .............................................................................................................................. 3 
SPONSOR’S APPROVAL ............................................................................................................................................ 4 
INVESTIGATOR’S AGREEMENT ............................................................................................................................. 5 
PROTOCOL SYNOPSIS .............................................................................................................................................. 9 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................................................ 14 
1. 
OBJECTIVES.............................................................................................................................................. 16 
1.1 
Primary Objective ......................................................................................................................................... 16 
1.2 
Secondary Objectives .................................................................................................................................... 16 
2. 
BACKGROUND .......................................................................................................................................... 17 
2.1 
Advanced Head and Neck Cancer ................................................................................................................. 17 
2.2 
Description of Ad/PNP-F-araAMP ............................................................................................................... 18 
2.3 
Tumor Response with Ad/PNP-F-araAMP in Phase 1 Study ........................................................................ 18 
2.4 
Purpose of the Study ..................................................................................................................................... 19 
2.5 
Study Design ................................................................................................................................................. 20 
3. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES ............................................... 21 
3.1 
Inclusion Criteria ........................................................................................................................................... 21 
3.2 
Exclusion Criteria .......................................................................................................................................... 22 
3.3 
Informed Consent Process ............................................................................................................................. 23 
3.4 
Subject Withdrawal ....................................................................................................................................... 23 
4. 
TREATMENT PLAN ................................................................................................................................. 25 
4.1 
Dose and Dose Rationale .............................................................................................................................. 25 
4.2 
Administration of Ad/PNP-F-araAMP per Cycle.......................................................................................... 25 
4.3 
Dose Modification ......................................................................................................................................... 27 
4.4 
Expected Adverse Events .............................................................................................................................. 28 
4.4.1 
Infection Prophylaxis .................................................................................................................... 29 
4.5 
Stopping Rules .............................................................................................................................................. 29 
4.6 
Drug Accountability ...................................................................................................................................... 30 
4.7 
Concomitant Medications .............................................................................................................................. 30 
4.8 
Criteria for Removal from Study ................................................................................................................... 31 
5. 
INVESTIGATIONAL AGENT/DEVICE/PROCEDURE INFORMATION ........................................ 32 
5.1 
Description of Study Drug ............................................................................................................................ 32 
5.2 
Availability .................................................................................................................................................... 32 
5.3 
Agent Ordering .............................................................................................................................................. 33 


CONFIDENTIAL 
GeoVax, Inc. 
 
Ad/PNP-F-araAMP 
Protocol No. PNP-002 
V4.0 06 May 2022 
 
TABLE OF CONTENTS (continued) 
 
Page 
 
 
 
Page 7 
5.4 
Agent Accountability .................................................................................................................................... 33 
6. 
DOSE MODIFICATIONS .......................................................................................................................... 34 
7. 
ADVERSE EVENTS AND REPORTING PROCEDURES .................................................................... 35 
7.1 
Adverse Event ............................................................................................................................................... 35 
7.2 
Serious Adverse Event .................................................................................................................................. 35 
7.3 
Assessment of Causality ................................................................................................................................ 36 
7.4 
Severity of the Adverse Event ....................................................................................................................... 37 
7.5 
Safety Monitoring and Reporting .................................................................................................................. 37 
7.5.1 
Monitoring of Adverse Events ...................................................................................................... 37 
7.5.2 
Recording and Reporting Adverse Events and Serious Adverse Events ...................................... 38 
7.5.3 
Safety Monitoring Committee ...................................................................................................... 39 
8. 
CORRELATIVE/SPECIAL STUDIES ..................................................................................................... 40 
9. 
STUDY CALENDAR .................................................................................................................................. 43 
9.1 
Study Procedures Table ................................................................................................................................. 43 
9.2 
Study Procedures ........................................................................................................................................... 45 
9.2.1 
Visit 1 (Day -30 to 0, Screening and Baseline Laboratory Values) .............................................. 45 
9.2.2 
Visits 2 and 3 (Days 1 and 2 of Intratumoral Administration of Ad/PNP) ................................... 46 
9.2.3 
Visit 4 (Day 3, First infusion of F-araAMP) ................................................................................. 47 
9.2.4 
Visits 5 and 6 (Days 4 and 5) ........................................................................................................ 48 
9.2.5 
Visit 7 (Days 14 ± 2)..................................................................................................................... 48 
9.2.6 
Visit 8 (Day 28 ± 3 of the Last Cycle) .......................................................................................... 49 
9.2.7 
Visit 9 or Termination Visit (Day 56 ± 3 of the Last Cycle) ........................................................ 49 
9.3 
Description of Evaluations ............................................................................................................................ 50 
9.3.1 
Laboratory Evaluations ................................................................................................................. 50 
9.3.2 
Physical Examination ................................................................................................................... 50 
9.3.3 
Medical History ............................................................................................................................ 51 
9.3.4 
Tumor Response ........................................................................................................................... 51 
9.3.5 
Radiographic Imaging .................................................................................................................. 52 
9.4 
Tumor Biopsies ............................................................................................................................................. 52 
10. 
MEASUREMENTS ..................................................................................................................................... 53 
10.1 
Primary Outcome Measure ............................................................................................................................ 53 
10.2 
Secondary Outcome Measure ........................................................................................................................ 53 
10.3 
Primary and Secondary Outcome Measures-Discussion: .............................................................................. 53 
10.3.1 
Relevant Subset ............................................................................................................................ 54 
10.3.2 
Measurement Definition ............................................................................................................... 54 
10.3.3 
Measurement Methods .................................................................................................................. 55 
10.3.4 
Measurement Time Points ............................................................................................................ 55 
10.3.5 
Response Review .......................................................................................................................... 55 
11. 
REGULATORY CONSIDERATIONS ..................................................................................................... 56 
11.1 
Institutional Review of Protocol .................................................................................................................... 56 


CONFIDENTIAL 
GeoVax, Inc. 
 
Ad/PNP-F-araAMP 
Protocol No. PNP-002 
V4.0 06 May 2022 
 
TABLE OF CONTENTS (continued) 
 
Page 
 
 
 
Page 8 
11.2 
Safety Monitoring Plan ................................................................................................................................. 56 
11.3 
Informed Consent and HIPAA Authorization ............................................................................................... 57 
11.4 
Subject Confidentiality .................................................................................................................................. 57 
11.5 
Adherence to Reporting Requirements ......................................................................................................... 58 
11.6 
Records .......................................................................................................................................................... 58 
11.7 
Protocol Approval and Amendments ............................................................................................................ 59 
11.8 
Closure of the Study ...................................................................................................................................... 59 
11.9 
Study Monitoring and Auditing .................................................................................................................... 60 
11.10 
Documentation of Study Findings ................................................................................................................. 60 
12. 
STATISTICAL CONSIDERATIONS ....................................................................................................... 61 
12.1 
Sample Size ................................................................................................................................................... 61 
12.2 
Assessment of Safety Measures .................................................................................................................... 62 
12.3 
Adverse Events .............................................................................................................................................. 62 
12.4 
Clinical Laboratory Results ........................................................................................................................... 62 
12.5 
Vital Signs and Physical Examination .......................................................................................................... 63 
12.6 
Assessment of Efficacy Measures ................................................................................................................. 63 
13. 
REFERENCES ............................................................................................................................................ 65 
APPENDICES ............................................................................................................................................................. 66 
 
 
 


CONFIDENTIAL 
GeoVax, Inc. 
 
Ad/PNP-F-araAMP 
Protocol No. PNP-002 
V4.0 06 May 2022 
 
 
 
Page 9 
PROTOCOL SYNOPSIS 
Title 
Phase 1/2, Open-label Study Evaluating the Safety of Repeat Administration of Ad/PNP-F-
araAMP (Ad/PNP Administered Intratumorally with Co-administration of Fludarabine 
Phosphate Intravenously) in Subjects with Recurrent, Local Head and Neck Cancer 
Study Objectives 
The primary objective of the study is to evaluate the safety of repeat administration of a dose 
level of Ad/PNP-F-araAMP that demonstrated anti-tumor activity in patients with advanced head 
and neck cancer in the completed Phase 1 study. 
 
The secondary objective of the study is to evaluate the anti-tumor activity of repeat 
administration of Ad/PNP-F-araAMP. 
Study Design 
The study is an open-label, multisite, Phase 1/2 study evaluating the safety and anti-tumor activity 
of Ad/PNP-F-araAMP in subjects with recurrent cancer of the head and neck region who have 
relapsed following curative treatment and without additional potentially curative treatment 
options. The study is designed to evaluate repeat administration (up to 5 cycles) of a single dose 
level of Ad/PNP administered intratumorally followed by intravenous (IV) F-araAMP. 
Sample Size and Duration of Study 
It is anticipated that approximately 10 to 20 subjects will be enrolled into the study in order to 
have 10 subjects evaluable for efficacy. Each subject will be followed for ~ 60 days following 
their last dose of study medication. Based on the patient population, it is anticipated that the study 
will require 36 to 48 months to be completed. 
Study Population 
Inclusion Criteria 
1. 
Provided Informed Consent 
2. 
Age ≥ 18 years 
3. 
Patients with histologically or cytologically confirmed diagnosis of recurrent cancer of the 
head and neck region for whom there is no curative treatment option. For the purposes of 
trial eligibility, cancers of the head and neck shall include, in addition to head and neck 
squamous cell carcinoma (HNSCC), cutaneous squamous cell primary sites and squamous 
cell carcinoma of unknown primary presenting with neck lymph nodal disease, as well as 
nasopharyngeal carcinoma, and salivary gland tumors. 
4. 
All standard or approved treatment options that would provide substantive palliation must 
have failed, been exhausted, or patient not eligible for them (for example neuropathy, 
nephropathy, or hearing loss precluding the use of cisplatin). 
5. 
Tumor mass (primary tumor and/or lymphadenopathy) measurable by Response Evaluation 
Criteria in Solid Tumors (RECIST) 1.1 and technically suitable for intratumoral injections 
(otolaryngologist will determine feasibility). Patients with nodal disease (or metastatic 
disease) that is needle accessible are eligible. Patients with additional tumors (including 


CONFIDENTIAL 
GeoVax, Inc. 
 
Ad/PNP-F-araAMP 
Protocol No. PNP-002 
V4.0 06 May 2022 
 
PROTOCOL SYNOPSIS (continued) 
 
 
 
 
Page 10 
distant metastatic disease) beyond the intratumoral injection accessible tumor(s) that are not 
accessible for intratumoral injection are eligible ONLY if the patient has no other treatment 
option for the metastatic disease and treatment of local disease may provide the patient 
some benefit or palliation. 
6. 
Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. 
7. 
In the judgment of the Investigator, the patient has recovered sufficiently from any previous 
significant therapy side effects or toxicities prior to Ad/PNP administration. 
8. 
Absolute neutrophil count [ANC] ≥ 1,500 cells/µl; hemoglobin ≥ 9 g/dl, platelets ≥ 
100,000/µl. 
9. 
Serum creatinine ≤ 1.5 mg/dl, or calculated creatinine clearance ≥ 60 ml/min. 
10. Bilirubin ≤ upper limit normal [ULN], alanine aminotransferase [ALT] ≤ 1.5 x ULN and/or 
aspartate aminotransferase [AST] ≤ 1.5 x ULN, alkaline phosphatase ≤ 2.5 x ULN. 
11. Prothrombin time (PT)/international normalized ratio (INR) ≤ 1.5 x ULN. 
12. Activated partial thromboplastin (aPTT) time ≤ 1.5 x ULN. 
13. Female patients must have a negative urine or serum pregnancy at screening (pregnancy 
test is not required for patients with bilateral oophorectomy and/or hysterectomy or for 
those patients who are > 1 year postmenopausal). 
14. All patients of reproductive potential must agree to use a medically acceptable form of 
contraception (e.g., hormonal birth control, double-barrier method) or abstinence. 
 
Exclusion Criteria 
1. 
Prior history or current diagnosis of leukemia. 
2. 
Have received any gene therapy products or oncolytic viral therapy. 
3. 
Receiving allopurinol. 
4. 
Received an investigational drug within 30 days prior to first injection of Ad/PNP. 
5. 
Received radiation treatment < 4 weeks prior to first injection of Ad/PNP and does not have 
any RECIST 1.1 evaluable lesions that are outside the radiation field. (If the patient has 
RECIST 1.1 evaluable lesions outside the radiation field then they can be included.) 
6. 
Received chemotherapy (systemic anticancer treatment) < 4 weeks prior to first injection 
of Ad/PNP and has not recovered from all the related side effects. (If the patient has 
recovered from all related side effects or has reached a new baseline, then they may begin 
receiving treatment at sooner than 4 weeks). 
7. 
Have significant baseline neuropathy (> Grade 2 based on Common Terminology Criteria 
for Adverse events [CTCAE] v5.0). 
8. 
Uncontrolled intercurrent disease (e.g., diabetes, hypertension, thyroid disease, active 
infection). 
9. 
Had within 6 months prior to enrollment: myocardial infarction (MI), cerebral vascular 
accident (CVA), uncontrolled congestive heart failure (CHF), significant liver disease, 
unstable angina. 
10. Fever (temperature > 38.1°C orally). 


CONFIDENTIAL 
GeoVax, Inc. 
 
Ad/PNP-F-araAMP 
Protocol No. PNP-002 
V4.0 06 May 2022 
 
PROTOCOL SYNOPSIS (continued) 
 
 
 
 
Page 11 
11. Receiving chronic systemic corticosteroids (> 3 weeks) or any chronic immunosuppressive 
medications within 14 days prior to first injection of Ad/PNP. Subjects receiving short 
courses of corticosteroids are considered eligible for the study. 
12. Receiving anticoagulants other than those to maintain patency of venous lines. 
13. Women who are pregnant or breast feeding 
14. Known history of human immunodeficiency virus (HIV) infection. No requirement for 
testing. 
 
Study Drug and Administration 
• 
2 x 1011 viral particle (VP) x 3 over 2 days per cycle (total up to: 3 x 1012 Ad/PNP over 5 
cycles) intratumorally, followed by: 
• 
25 mg/m2 F-araAMP daily x 3 days (total: 75 mg/m2 per cycle) intravenously, over 
approximately 30 minutes 
Endpoints 
The primary endpoint is safety with repeat cycles of treatment. Safety measures include adverse 
events (AE) and laboratory parameters. 
 
Anti-tumor response will also be assessed for injected tumors and overall as determined by 
RECIST v.1.1. Efficacy assessments include: 
• 
Objective response rate (ORR), defined as the percentage of patients with a best overall 
response (BOR) of a complete response (CR) or a partial response (PR). BOR is the best 
response achieved during the 5 cycles of treatment, for injected tumors and overall as 
determined by RECIST v.1.1.  
• 
Durable response rate defined as a BOR of CR or PR for injected tumors and overall as 
determined by RECIST v.1.1 persisting for at least 4 weeks. 
• 
Time to response (TTR) defined as time from first intratumoral injection to date of first 
response value of CR or PR for injected tumors and overall as determined by RECIST v.1.1. 
• 
Overall survival (OS) defined as time from first intratumoral injection to date of progression 
or death for any cause, whichever occurs first. 
• 
Progression free survival (PFS) defined as time from first intratumoral injection to date of 
progression or death for any cause, whichever occurs first. 
• 
Duration of response (DOR) defined as time from first documentation of CR or PR for 
injected tumors and overall as determined by RECIST v.1.1 until disease progression or 
death for any cause, whichever occurs first 
 
RECIST as applied here will be version 1.1. Efficacy will be assessed in the population of 
subjects who receive three intratumoral administrations of Ad/PNP and any infusion of 
F-araAMP. 
 


CONFIDENTIAL 
GeoVax, Inc. 
 
Ad/PNP-F-araAMP 
Protocol No. PNP-002 
V4.0 06 May 2022 
 
PROTOCOL SYNOPSIS (continued) 
 
 
 
 
Page 12 
Statistical Methods 
The study is a Phase 1/2 safety study; no formal hypotheses or sample size estimates will be 
generated. The study will enroll 10 to 20 subjects to achieve 10 subjects evaluable for efficacy; 
this number of subjects is sufficient to assess preliminary safety and activity to guide design of 
subsequent clinical studies.  
 
A total of 10 to 20 subjects in the safety population provides sufficient precision to rule out a 
treatment-related serious adverse event (SAE) rate of 38.5% or more using a one-sided 80% 
upper confidence limit. With 10 subjects evaluable for efficacy, there is 83% power to reject a 
null hypothesis ORR of 10% or less when the alternative hypothesis ORR is at least 40% using 
a one-sided exact binomial test with a target alpha level of 10% (actual alpha is 7%). 
 
Descriptive statistics (number and percentage of subjects) will be used to summarize BOR, ORR, 
and durable response rate. 95% Clopper-Pearson confidence intervals will also be provided. OS, 
PFS, DOR, and TTR will be analyzed based on Kaplan-Meier methods; Kaplan-Meier curves 
will be plotted over time. The number and percentage of subjects identified to have had an event 
and those who were censored will be displayed. The median time to event and its corresponding 
95% CI will also be produced. A listing of response for subjects will be provided. 
Duration of Study Participation 
Each subject will participate for approximately 180 days. 
 


CONFIDENTIAL 
GeoVax, Inc. 
 
Ad/PNP-F-araAMP 
Protocol No. PNP-002 
V4.0 06 May 2022 
 
 
 
Page 13 
 
SCHEMA 
 
DLT = Dose-limiting toxicity; IV = intravenously; PD = progressive disease, VP = viral particle;  


CONFIDENTIAL 
GeoVax, Inc. 
 
Ad/PNP-F-araAMP 
Protocol No. PNP-002 
V4.0 06 May 2022 
 
 
 
Page 14 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin 
AST 
Aspartate aminotransferase 
BOR 
Best overall response 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CBER 
Center for Biologics Evaluation and Research (of the FDA) 
CFR 
Code of Federal Regulations 
CHF 
Congestive heart failure 
CLL 
Chronic lymphocytic leukemia 
Cr 
Creatinine 
CR 
Complete response 
CRF 
Case report form 
CRT 
Chemoradiation treatment 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CVA 
Cerebral vascular accident 
CXR 
Chest X-ray 
dL 
Decaliter 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
DOR 
Duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
F-Ade 
Fluoroadenine 
F-araA 
Fludarabine 
F-araAMP 
Fludarabine phosphate  
(F-) ATP 
(2-F-) adenosine triphosphate 
5-FU 
5-fluorouracil 
FDA 
Food and Drug Administration 
G-CSF 
Granulocyte colony-stimulating factor 
GCP 
Good clinical practice 
GM-CSF 
Granulocyte-macrophage colony-stimulating factor 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
HNSCC 
Head and neck squamous cell carcinoma 
HPLC 
High performance liquid chromatography 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IV 
Intravenous(ly) 
kg 
Kilogram 
LC/MS 
Liquid chromatography/mass spectrometry 
LD 
Longest diameter 
mg 
Milligram 
MI 
Myocardial infarction 
mL 
Milliliter 
MRI 
Magnetic resonance imaging 
NCI 
National Cancer Institute 
NOAEL 
No-observable-adverse effect-level 


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GeoVax, Inc. 
 
Ad/PNP-F-araAMP 
Protocol No. PNP-002 
V4.0 06 May 2022 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS (continued) 
 
 
Page 15 
OBA/NIH 
Office of Biotechnology Activities/National Institutes of Health 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression free survival 
PI 
Principal Investigator 
PJP 
Pneumocystis jiroveci 
PNP 
Purine Nucleoside Phosphorylase 
PR 
Partial response 
PT 
Prothrombin time 
R/M 
Recurrent and/or metastatic 
RNA 
Ribonucleic acid 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SD 
Stable disease 
SMC 
Safety Monitoring Committee 
SMX 
Sulfamethoxazole 
TEAE 
Treatment-emergent adverse event 
TMP 
Trimethoprim 
TTR 
Time to response 
ULN 
Upper limit of normal 
VP 
Viral particle 
µl 
Microliter 
 


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GeoVax, Inc. 
 
Ad/PNP-F-araAMP 
Protocol No. PNP-002 
V4.0 06 May 2022 
 
 
 
Page 16 
1. 
OBJECTIVES 
1.1 
Primary Objective 
The primary objective of the study is to evaluate the safety of repeat administration of a dose level 
of Ad/PNP-F-araAMP that demonstrated anti-tumor activity in patients with advanced head and 
neck cancer in the completed Phase 1 study. 
1.2 
Secondary Objectives 
The secondary objective is to evaluate the anti-tumor activity of repeat administration of Ad/PNP- 
F-araAMP. 
 
 


CONFIDENTIAL 
GeoVax, Inc. 
 
Ad/PNP-F-araAMP 
Protocol No. PNP-002 
V4.0 06 May 2022 
 
 
 
Page 17 
2. 
BACKGROUND 
2.1 
Advanced Head and Neck Cancer 
More than half of patients with head and neck squamous cell carcinoma (HNSCC) have 
locoregionally advanced cancer and approximately 10% have metastatic disease at the time of their 
initial diagnosis. Patients with resectable disease who receive adjuvant chemoradiation treatment 
(CRT) following surgery have a 5-year recurrence rate of 20%. Although some patients with 
recurrent disease can be salvaged with surgery or radiation therapy, the majority are incurable and 
are treated palliatively with systemic therapy. Patients with recurrent and/or metastatic (R/M) 
HNSCC receiving first- line chemotherapy for recurrent disease have a median overall survival 
(OS) of ~7 months. The prognosis for patients with R/M HNSCC when first-line chemotherapy 
fails for recurrent disease is dismal, with median OS of < 6 months [1]. 
The most common non-targeted, first-line treatment approach for R/M HNSCC in patients who 
are not candidates for surgery or radiation treatment is a platinum-containing agent (cisplatin, 
carboplatin) combined with either 5-fluorouracil (5-FU) or taxane (paclitaxel, docetaxel). 
Response rates and OS in HNSCC following platinum-based dual agent chemotherapy are low, 
i.e., response rates are about 20-30% and median OS between 6.5 and 8.0 months, across several 
studies [2]. Addition of cetuximab improves response marginally; in a Phase 3 study of R/M 
HNSCC patients receiving platinum-based chemotherapy and 5-FU, the median OS was prolonged 
from 7.4 months with chemotherapy alone to 10.1 months with addition of cetuximab. Median 
progression free survival (PFS) was also increased from 3.3 months to 5.6 months [3]. It should 
be noted that subjects in the study were in good general condition and had good organ function. 
However, not all patients are able to tolerate the intensive triple-drug chemotherapy regimen and 
are offered alternative therapies, e.g., dual therapy with platinum + taxane followed by 
monotherapy with cetuximab [4]. 
There are limited treatment options for patients with R/M HNSCC whose tumor fails to respond 
or recurs following first-line salvage treatment. Often, treatment of these patients is limited to 
therapy with non-cross-resistant agents such as cetuximab, methotrexate, nivolumab, or a taxane 
with an overall response rate reported to be less than 20%. Treatment options are further limited 
by poor performance status and patient tolerance. Therefore, patients with recurrent HNSCC for 
whom platinum-based treatments and cetuximab treatments fail represent a population in need of 
novel therapeutic approaches. 


CONFIDENTIAL 
GeoVax, Inc. 
 
Ad/PNP-F-araAMP 
Protocol No. PNP-002 
V4.0 06 May 2022 
 
 
 
Page 18 
2.2 
Description of Ad/PNP-F-araAMP 
The study drug, Ad/PNP-F-araAMP consists of a non-replicating adenoviral vector expressing the 
Escherichia. coli purine nucleoside phosphorylase (PNP) injected intratumorally followed by 
intravenous (IV) administration of F-araAMP. This combination generates fluoroadenine (F-Ade) 
within the tumor resulting in focal chemotherapeutic activity. 
F-araAMP is an agent that is rapidly cleaved by plasma phosphatases to fludarabine, which is the 
primary circulating form of the drug and has activity against certain hematological malignancies, 
but not against solid tumors such as HNSCC. F-araA is an adenosine analog and substrate for 
E. coli PNP, which cleaves the glycosidic bond of F-araA to generate F-Ade. The F-Ade 
metabolite has shown pronounced activity against human tumor xenografts in mice. 
F-Ade is converted to 2-F-adenosine triphosphate (F-ATP), which interferes with enzymatic 
reactions involving ATP and rapidly results in cell death. F-Ade has been shown to inhibit RNA 
and protein synthesis, two functions important to cellular metabolism regardless of the 
proliferative state of the cell (dividing versus quiescent). In contrast to toxins produced by first 
generation suicide gene therapy strategies such as ganciclovir monophosphate or 5-FU, F-Ade 
impairs one or more enzymes unrelated to DNA synthesis and kills tumor cells that are not actively 
proliferating. Many refractory tumors are refractory precisely because they have a very low growth 
fraction, i.e., a relatively small percentage of tumor cells dividing at any particular point in time. In 
nonclinical studies, significant in vivo anti-tumor activity has been demonstrated by F-Ade 
generation from F-araAMP in tumors in which 2.5 to 10% of cells express the E. coli PNP gene. 
In addition, anti-tumor effect was seen in patients with advanced solid tumors (melanoma and head 
and neck cancer) in the higher dose cohorts in a Phase 1 study. 
2.3 
Tumor Response with Ad/PNP-F-araAMP in Phase 1 Study 
The safety and efficacy of Ad/PNP-F-araAMP has been evaluated in a Phase 1 study, PNP-001. 
Four escalating dose levels were evaluated in 10 subjects with head and neck cancer and 2 subjects 
with melanoma; clinical activity was observed at the highest dose levels following 3 IT injections 
of Ad/PNP over 2 days and IV F-araAMP phosphate over 3 days [5]. The overall response rate 
(complete response [CR] + partial response [PR]) was 66.7% in the 2 highest dose cohorts, Cohorts 
3 and 4, versus 33.3% in Cohort 1, and 0% in Cohort 2; these results suggest a dose response 
effect. The duration of response (DOR) in the injected tumor was limited, with 4 of 5 responding 


CONFIDENTIAL 
GeoVax, Inc. 
 
Ad/PNP-F-araAMP 
Protocol No. PNP-002 
V4.0 06 May 2022 
 
 
 
Page 19 
tumors having disease progression of the injected lesion prior to last follow-up on Day 56, 
suggesting that repeat administration should be evaluated. 
Ad/PNP + F-araAMP was well tolerated. No subject experienced a dose-limiting toxicity (DLT) 
and none of the subjects discontinued study treatment. There was no evidence for an increased 
incidence of treatment-emergent adverse events (TEAEs), treatment-related adverse events (AEs), 
serious adverse events (SAEs), or Grade 3 or 4 TEAEs across dose cohorts. The most frequently 
reported TEAEs were those associated with the intratumoral injection site, primarily injection site 
pain (91.7%). The incidence of these events did not increase with dose, and most were mild or 
moderate in intensity. However, the single subject who experienced the most significant injection 
site pain (Grade 3, requiring subsequent pretreatment with local anesthetic) was in Cohort 4. Pain 
with subsequent Ad/PNP injection in this subject was managed with local lidocaine pre-injection 
and did not lead to discontinuation of study treatment. 
Overall, the activity and safety profile of Ad/PNP seen in the Phase 1 study supports further clinical 
evaluation of repeat administration of Ad/PNP (intratumorally) and F-araAMP phosphate infusion 
for patients with recurrent cancer of the head and neck region. 
2.4 
Purpose of the Study 
Based upon the tumor response seen with a single administration of the two highest dose levels of 
Ad/PNP-F-araAMP in the Phase 1 study, GeoVax plans to investigate the safety and assess 
anti-tumor activity of repeat cycles of injection of Ad/PNP + F-araAMP in patients with advanced 
head and neck cancer. The 2 x 1011 viral particle (VP)/injection was selected since there was no 
difference in tumor activity between the 1011 and 1012 VP dose levels in Phase 1 testing, and since 
the total cumulative dose (3.0 x 1012 VP) will be equivalent to the dose of Ad/PNP that was well 
tolerated in Cohort 4 of the Phase 1 trial (3 x 1012 VP). Subjects in the study will have Response 
Evaluation Criteria in Solid Tumors (RECIST) 1.1 measurable recurrent cancer of the head and neck 
region which is amenable to local injection for which there is no curative treatment option. This 
study population was selected since results from this Phase 1/2 trial are intended to support the 
safety of repeat dosing in further clinical investigations. 


CONFIDENTIAL 
GeoVax, Inc. 
 
Ad/PNP-F-araAMP 
Protocol No. PNP-002 
V4.0 06 May 2022 
 
 
 
Page 20 
2.5 
Study Design 
The trial is designed as a single-arm study to evaluate the safety of repeat cycles of Ad/PNP and 
F-araAMP in patients with recurrent cancer of the head and neck region with tumor(s) accessible 
for injection. 
Ad/PNP will be injected intratumorally twice on Day 1 and once on Day 2 followed by 25 mg/m2 
per infusion F-araAMP daily on Days 3, 4, and 5 infused over approximately 30 minutes. The 
25 mg/m2 F- araAMP dose level is the same as that evaluated in the two highest cohorts in the 
Phase 1 study. Subjects will receive repeat administration of Ad/PNP-F-araAMP every 4 weeks 
(i.e., each cycle) for 5 cycles or until injected tumor progresses, unacceptable toxicity occurs, no 
tumor is present for injection, or patient death. 
Tumor response in the injected tumor(s) will be assessed by physical examination (tumor 
measurement using ruler or calipers, if tumor can be assessed by palpation) as well as by 
radiographic imaging (magnetic resonance imaging [MRI] or computed tomography [CT] scan). 
The same methods to assess the injected tumor(s) will be used at baseline and subsequent time 
points. 
Subjects will be assessed for safety frequently, including Day 14 of each cycle. Subjects will be 
assessed 4 weeks after completion of the last or fifth cycle. During the study, subjects will be 
monitored for AEs including signs of infection, and changes in hematological or chemistry 
parameters (see Study Procedures Table). 
The Safety Monitoring Committee (SMC) will review accumulating safety data (i.e., AE reporting, 
reactions to study drug, deaths, etc.) at time intervals specified in the SMC Charter and at any other 
time when it is determined by the SMC or GeoVax that such a review is warranted.  
 
 


CONFIDENTIAL 
GeoVax, Inc. 
 
Ad/PNP-F-araAMP 
Protocol No. PNP-002 
V4.0 06 May 2022 
 
 
 
Page 21 
3. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
Subjects must fulfill the following eligibility criteria. 
3.1 
Inclusion Criteria 
1. 
Provided Informed Consent 
2. 
Age ≥ 18 years 
3. 
Patients with histologically or cytologically confirmed diagnosis recurrent cancer of the head 
and neck region for whom there is no curative treatment option. For the purposes of trial 
eligibility, cancers of the head and neck region shall include, in addition to HNSCC, cutaneous 
squamous cell primary sites and squamous cell carcinoma of unknown primary presenting 
with neck lymph nodal disease, as well as nasopharyngeal carcinoma, and salivary gland 
tumors. 
4. 
All standard or approved treatment options that would provide substantive palliation must 
have failed, been exhausted, or patient not eligible for them (for example neuropathy, 
nephropathy, or hearing loss precluding the use of cisplatin) 
5. 
Tumor mass (primary tumor and/or lymphadenopathy) measurable by RECIST 1.1 and 
technically suitable for intratumoral injections (otolaryngologist will determine feasibility). 
Patients with nodal disease (or metastatic disease) that is needle accessible are eligible. 
Patients with additional tumors (including distant metastatic disease) beyond the intratumoral 
injection accessible tumor(s) that are not accessible for intratumoral injection are eligible 
ONLY if the patient has no other treatment option for the metastatic disease and treatment of 
local disease may provide the patient some benefit or palliation. 
6. 
Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. 
7. 
In the judgment of the investigator, the patient has recovered sufficiently from any previous 
significant therapy side effects or toxicities prior to Ad/PNP administration. 
8. 
Absolute neutrophil count [ANC] ≥ 1,500 cells/µl; hemoglobin ≥ 9 g/dl, platelets ≥ 100,000/µl. 
9. 
Serum creatinine ≤ 1.5 mg/dl, or calculated creatinine clearance ≥ 60 ml/min. 


CONFIDENTIAL 
GeoVax, Inc. 
 
Ad/PNP-F-araAMP 
Protocol No. PNP-002 
V4.0 06 May 2022 
 
 
 
Page 22 
10. Bilirubin ≤ upper limit normal [ULN], alanine aminotransferase [ALT] ≤ 1.5 x ULN and/or 
aspartate aminotransferase [AST] ≤ 1.5 x ULN, alkaline phosphatase ≤ 2.5 x ULN. 
11. Prothrombin time (PT)/international normalized ratio (INR) ≤ 1.5 x ULN. 
12. Activated partial thromboplastin (aPTT) time ≤ 1.5 x ULN. 
13. Female patients must have a negative urine or serum pregnancy at screening (pregnancy test 
is not required for patients with bilateral oophorectomy and/or hysterectomy or for those 
patients who are > 1 year postmenopausal). 
14. All patients of reproductive potential must agree to use a medically acceptable form of 
contraception (e.g., hormonal birth control, double-barrier method) or abstinence. 
3.2 
Exclusion Criteria 
1. 
Prior history or current diagnosis of leukemia. 
2. 
Have received any gene therapy products or oncolytic viral therapy. 
3. 
Receiving allopurinol. 
4. 
Received an investigational drug within 30 days prior to first injection of Ad/PNP. 
5. 
Received radiation treatment < 4 weeks prior to first injection of Ad/PNP and does not have 
any RECIST 1.1 evaluable lesions that are outside the radiation field. (If the patient has 
RECIST 1.1 evaluable lesions outside the radiation field then they can be included.) 
6. 
Received chemotherapy (systemic anticancer treatment) < 4 weeks prior to first injection of 
Ad/PNP and have not recovered from all the related side effects. (If the patient has recovered 
from all related side effects or has reached a new baseline, then they may begin receiving 
treatment at sooner than 4 weeks). 
7. 
Have significant baseline neuropathy (> Grade 2 based on Common Terminology Criteria for 
Adverse Events [CTCAE] v5.0) 
8. 
Uncontrolled intercurrent disease (e.g., diabetes, hypertension, thyroid disease, active 
infection) 


CONFIDENTIAL 
GeoVax, Inc. 
 
Ad/PNP-F-araAMP 
Protocol No. PNP-002 
V4.0 06 May 2022 
 
 
 
Page 23 
9. 
Had within 6 months prior to enrollment: myocardial infarction (MI), cerebral vascular 
accident (CVA), uncontrolled congestive heart failure (CHF), significant liver disease, 
unstable angina. 
10. Fever (temperature > 38.1oC orally). 
11. Receiving chronic systemic corticosteroids (> 3 weeks) or any chronic immunosuppressive 
medications within 14 days prior to first injection of Ad/PNP. Subjects receiving short courses 
of corticosteroids are considered eligible for the study. 
12. Receiving anticoagulants other than those to maintain patency of venous lines. 
13. Women who are pregnant or breast feeding. 
14. History of human immunodeficiency virus (HIV) infection. No requirement for testing. 
3.3 
Informed Consent Process 
All participants must be provided a consent form describing the study with sufficient information 
for participants to make an informed decision regarding their participation. Participants must sign 
the Institutional Review Board (IRB) approved informed consent prior to participation in any study 
specific procedure. The participant must receive a copy of the signed and dated consent document. 
The original signed copy or certified copy of the consent document must be retained in the medical 
record and research file. This signed consent form present in the medical record shall be considered 
documentation that the GCP informed consent process has been completed. 
3.4 
Subject Withdrawal 
While subjects are encouraged to complete all study evaluations, they may withdraw from the 
study at any time and for any reason. Subjects receiving chemotherapy (other than F-araAMP) or 
radiation therapy will be removed from the study. Participation is voluntary, and declining to 
participate will involve no penalty, or loss of benefits to which the participant is otherwise entitled. 
The subject will be encouraged to maintain contact with the investigator and report any serious 
AEs experienced for the entire study period. Individuals who withdraw early from treatment will 
be asked to complete Day 56 (of the last treatment cycle) study visit evaluations. 
Subjects who withdraw or complete the study are not eligible to re-enter or be treated in the study 
again. Subjects who drop out following administration of study agent will not be replaced. 


CONFIDENTIAL 
GeoVax, Inc. 
 
Ad/PNP-F-araAMP 
Protocol No. PNP-002 
V4.0 06 May 2022 
 
 
 
Page 24 
Screen failures will include participants who consented and entered into the screening process 
appropriately, but subsequently did not meet the entry criteria and did not receive study drug. The 
investigator will maintain a screening log that documents the subject number, subject initials, and 
reason(s) for screen failure. No data other than reason for screen failure and basic screening data 
will be collected on Screen Failures. Participants who fail screening will not be followed for safety 
or activity of study drug, and no other study procedures will be performed. Screen failures will be 
replaced. 
 
 


CONFIDENTIAL 
GeoVax, Inc. 
 
Ad/PNP-F-araAMP 
Protocol No. PNP-002 
V4.0 06 May 2022 
 
 
 
Page 25 
4. 
TREATMENT PLAN 
4.1 
Dose and Dose Rationale 
The dose selected for evaluation with repeat administration has been chosen based upon tumor 
response and safety of the vector (Ad/PNP) and prodrug (F-araAMP) seen with single 
administration of this dose level in the completed Phase 1 study. With each cycle the subject will 
receive a total dose of 6 x 1011 VP Ad/PNP followed by a total dose of 75 mg/m2 F-araAMP. 
4.2 
Administration of Ad/PNP-F-araAMP per Cycle 
With each cycle, subjects will receive 3 intratumoral administrations of 2.0 X 1011 VP Ad/PNP over 
2 days followed by 3 daily infusions of 25 mg/m2 F-araAMP in the outpatient clinic or in-hospital 
at the discretion of the investigator. The physician or a designee trained to do the injections by the 
Principal Investigator (PI) will administer intratumoral Ad/PNP during each cycle. The outpatient 
unit is staffed with medical personnel to treat emergency and non-emergency medical events. 
Ad/PNP will be given via direct intratumoral injection three times over 2 days. If needed, the 
investigator may utilize radiologic guidance (e.g., ultrasound) to assist in the injection of Ad/PNP. 
Two intratumoral administrations will be given on Day 1 and one intratumoral administration on 
Day 2. The first administration will occur on the morning of Day 1 and the subject monitored 
closely for 1 hour for acute injection-related events. Approximately 3-6 hours after the first 
administration, the subject will receive the second intratumoral administration on Day 1. The third 
intratumoral administration will be given on the morning of Day 2. 
Vials of Ad/PNP will be thawed and prepared for injection by the investigational pharmacy 
according to the Preparation of Investigational Product Instructions. In the Phase 1 study, Ad/PNP 
was administered intratumorally in a 0.5 ml volume (~2 x 1011 VP/ml or ~2 x 1012 VP/ml); both 
dose levels showed activity and were well tolerated. In the Phase 1/2 study, 2 x 1011 VP will be 
administered in volumes up to 5 ml (4 x 1010 VP/ml) so that vector can be dispersed more 
effectively throughout needle-assessable tumor tissue. 
The volume of vector injected into each tumor will be according to tumor volume. All measurable 
tumors that are accessible for intratumoral injection will be identified and treated for each enrolled 
subject 


CONFIDENTIAL 
GeoVax, Inc. 
 
Ad/PNP-F-araAMP 
Protocol No. PNP-002 
V4.0 06 May 2022 
 
 
 
Page 26 
Subjects will receive a total of 2 x 1011 VP Ad/PNP per injection (3 injections per cycle) distributed 
across the injected tumors and volume of vector will vary dependent upon estimated tumor volume 
using the tumor’s two dimensions measured by calipers as described in the Operating Procedure - 
Injection of Investigational Product into the Tumors of Human Subjects. For example, for a subject 
with 3 tumors of 1.5 ml, 3 ml, and 5 ml size each, 2 x1011 VP Ad/PNP will be suspended in 3.5 mL 
and tumors injected with 0.5 mL, 1.0 mL, and 2.0 mL, respectively. If the tumor mass is very large 
or the total volume for all discreet tumors exceeds 16 ml, a portion of the tumor mass or certain 
discrete tumors will be selected by the physician and injected with 5 ml of Ad/PNP. The same 
tumors will be injected with each administration of 5 ml Ad/PNP. 
Lesion Volume 
Injection Volume 
> 16 ml 
5.0 mL 
12 ml to 16 ml 
4.0 mL 
8 ml to 12 ml 
3.0 mL 
4 ml to 8 ml 
2.0 mL 
2 ml to 4 ml 
1.0 mL 
Less than 2 ml 
0.5 ml 
 
 
Using aseptic technique, the Ad/PNP solution will be injected percutaneously with injection at 
multiple sites within the tumor to achieve thorough infiltration. A subcutaneous injection of local 
anesthetic may be used, if desired. 
Approximately 24 to 36 hours following the third administration of Ad/PNP into the tumor 
(Day 3), subjects will receive 25 mg/m2 F-araAMP daily for 3 days. F-araAMP will be prepared 
and administered intravenously over approximately 30 minutes per the package insert. Subjects 
who do not receive all three administrations of Ad/PNP will not receive F-araAMP; all subjects 
will be assessed for safety at the scheduled study visits. Subjects who do not receive all three full 
doses of Ad/PNP may be eligible to receive subsequent doses of F-araAMP at the discretion of the 
investigator. 
In this study, each 5-day course of treatment will commence every 28 days +/- 3 days and subjects 
will receive up to 5 cycles of Ad/PNP-F-araAMP. The 28-day interval complies with the 
recommended dosing schedule between courses of F-araAMP used to treat hematological 
malignancies. Treatment will be discontinued prior to 5 cycles in the event of injected tumor 
progression (and/or the investigator determines the patient may no longer stand to benefit from further 


CONFIDENTIAL 
GeoVax, Inc. 
 
Ad/PNP-F-araAMP 
Protocol No. PNP-002 
V4.0 06 May 2022 
 
 
 
Page 27 
treatment) or if there is no tumor present for injection. In the event that treatment is discontinued, the 
subject should complete the Day 28 and Day 56 visits of the last treatment cycle. 
Subjects will be monitored for clinical safety events and changes in laboratory parameters 
throughout the study period. Subjects who experience a CR before the next cycle will not receive 
treatment but will continue to be followed during the study period. Subjects whose tumors achieve 
a CR but then recur during the study period may resume treatment with Ad/PNP-F-araAMP up to 
the maximum allowed 5 total cycles. 
No formal follow-up visits are planned following the end of the study period (Day 56 of the last 
treatment cycle). However, the Investigational New Drug (IND) Sponsor may request follow-up 
information from the investigator on tumor status in subjects who have stable disease (SD), PR, or 
CR at completion of their study participation. 
4.3 
Dose Modification 
Based on monitoring of efficacy signal from subjects completing treatment, if no anti-tumor activity 
and no DLTs are observed, GeoVax may increase the dose of vector administered 5-fold from to  
2 x 1011 VP/dose to 1 x 1012 VP/dose, which was the high dose of vector used in the Phase 1 clinical 
trial. DLTs will be determined based on the incidence and intensity of AEs and SAEs assessed as 
being at least possibly related to Ad/PNP-F-araAMP and occurring up to 28 days after initiation 
of dosing on Cycle 1 Day 0. Formal approval from the Food and Drug Administration (FDA), IRB, 
and other regulatory offices as needed will be obtained prior to initiating an increase of vector 
dose. No serious toxicities were detected with this dose of vector (1 x 1012 VP/dose) in the earlier 
Phase 1 trial. 
The total dose of F-araAMP per cycle is lower than that recommended to treat patients with 
hematological malignancies. Subjects who experience greater than Grade 2 neurotoxicity should 
be discontinued from treatment and followed for safety. The investigator may decrease the dose 
of F-araAMP to 15 mg/m2 or delay administration based on evidence of high grade (CTCAE v5.0 
Grade 3 or higher) hematologic or nonhematologic toxicity not recovered to baseline by day 1 of 
each subsequent cycle, with the exception of isolated lymphopenia, which will not require a dose 
reduction. Subjects who require further reduction in F-araAMP in the judgment of the investigator, 
based upon recurrent high grade AEs not resolved by day 1 of the subsequent cycle should be 
discontinued from treatment and followed for safety. Growth factor support is not to be used 
prophylactically in this study. 


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GeoVax, Inc. 
 
Ad/PNP-F-araAMP 
Protocol No. PNP-002 
V4.0 06 May 2022 
 
 
 
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4.4 
Expected Adverse Events 
Local injection site reactions have been reported in clinical studies evaluating other non-replicating 
adenoviral vectors injected intratumorally. The Phase 1 study evaluated two dose levels of Ad/PNP 
(1011 VP/dose in Cohorts 1-3 and approximately 1012 VP/dose in Cohort 4) and 3 dose levels of 
F-araAMP (5, 15, and 25 mg/m2 in Cohorts 1, 2, and 3, respectively and 25 mg/m2 in Cohort 4). 
Among the 12 subjects in the study, the most frequently reported TEAEs were injection site pain 
(11 subjects, 91.7%) and fatigue (8 subjects, 66.7%). Injection site pain was reported in all but 
1 subject receiving 1011 VP/dose + 15 mg/m2 F-araAMP. The event was assessed as treatment- 
related in 10 subjects (83.3%); most reports were Grade 1 or 2 in severity. All Grade ≥3 events in 
our Phase I study were assessed as unrelated to study treatment, with the exception of 1 report of 
injection site pain as noted in this section. One subject receiving 1012 VP/dose experienced severe 
(Grade 3) injection site pain on Day 1 that was assessed as definitely related to Ad/PNP injection. 
The subject went on to complete the study receiving lidocaine injection prior to injection of 
Ad/PNP. Other injection site reactions included injection site discharge (4 subjects receiving either 
1011 or 1012 VP/dose, 33.3%); injection site erythema, hemorrhage, and pruritus (2 subjects each 
receiving 1011 VP/dose, 16.7%), and injection site paresthesia (1 subject receiving 1012 VP/dose, 
8.3%). All of these events were reported in only 1 subject within a cohort and all were assessed as 
Grade 1 or 2 in severity; most were reported as treatment-related. 
F-araAMP is a purine analog used to treat patients with chronic lymphocytic leukemia (CLL). 
Besides being an anti-tumor agent against lymphoid malignancies, F-araAMP has 
immunosuppressant activity and is incorporated in preparatory regimens for allogeneic bone 
marrow transplantation. 
When administered in cycles of the standard 25 mg/m2 five-day course, F-araAMP induces 
myelosuppression (neutropenia, thrombocytopenia and anemia). Other commonly reported AEs 
include fever and chills, infection (including opportunistic infections), nausea and vomiting, 
malaise, fatigue, anorexia, and weakness. Life-threatening autoimmune hemolytic anemia has 
been reported in patients receiving F-araAMP. Objective weakness, agitation, confusion, visual 
disturbances, and coma have occurred in CLL patients treated with F-araAMP at the recommended 
dose. A high incidence of opportunistic infections, including Pneumocystis jirovecii pneumonia 
has been seen in CLL patients, especially those with a substantial history of steroid or alkylator 
use. Reactivations of latent viral infections such as VZV (herpes zoster), Epstein-Barr virus and 
JC virus (progressive multifocal leukoencephalopathy) have been reported in patients treated with 
F-araAMP. Additional information concerning drug related effects reported with F-araAMP are 


CONFIDENTIAL 
GeoVax, Inc. 
 
Ad/PNP-F-araAMP 
Protocol No. PNP-002 
V4.0 06 May 2022 
 
 
 
Page 29 
described more fully in the package insert. It is unknown at this point whether any of these 
toxicities will be more or less pronounced when F-araAMP is given in conjunction with the 
Ad/PNP with repeat administration. 
The toxicity attributable to intratumorally generated F-Ade with repeat injection is unknown. 
Based on results from a nonclinical study, systemic exposure to levels of F-Ade higher than 
expected in this study may cause myelosuppression and/or elevation in liver enzymes. Review of 
the safety and laboratory data from the Phase 1 clinical study showed that 2 of the 12 subjects 
experienced Grade ≥ 3 lymphopenia (neither were assessed as definitely related to study treatment) 
and no subject had elevation in liver enzymes. One of the two subjects with Grade ≥ 3 lymphopenia 
received 5 mg/m2 F-araAMP and the other received 25 mg/m2 F-araAMP daily for 3 days. Neither 
subject experienced a serious infection. 
Two subjects experienced a serious infection. One subject developed a bacteremia related to a 
central intravenous line and another had a chronic wound over the tumor being injected. There 
were no reports of opportunistic infections. 
4.4.1 
Infection Prophylaxis 
Although the dose regimen of F-araAMP is shorter than that used to treat hematological 
malignancy, there remains a potential risk for Pneumocystis jiroveci (PJP) infection with repeat 
cycles. Consequently, all subjects will receive prophylaxis antibiotic treatment, e.g., one double- 
strength trimethoprim (TMP)/sulfamethoxazole (SMX) (i.e., 160 TMP/800 SMX) three times a 
week. Prophylaxis will start prior to Day 1 of the first cycle and continue for 8 weeks following 
the last infusion of F-araAMP. Alternative acceptable prophylactic treatment may be used and 
should be recorded. 
Additional prophylactic antibiotic therapy may be initiated in subjects with clinically relevant 
reduction in white blood cell counts per the investigator’s assessment. 
4.5 
Stopping Rules 
All study agent administration will stop if any of the following events occur during the study: 
• 
Death attributed to study drug; 
• 
Serious systemic anaphylactic tumor injection reaction; 


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• 
Serious rare reactions to F-araAMP, such as blindness or coma. 
The FDA, Office of Biotechnology Activities/National Institutes of Health (OBA/NIH), IRB and 
SMC will be notified immediately if one of these AEs occurs and a comprehensive review of the 
safety data will be conducted prior to resumption of dosing. In addition, findings from the review 
will be relayed to and discussed between the SMC and Sponsor (GeoVax). Should the SMC and 
GeoVax agree to stop the study, GeoVax will inform all investigational sites and the appropriate 
regulatory bodies of the decision to stop the study at all sites. 
4.6 
Drug Accountability 
The investigator will be responsible for dispensing and accounting of Ad/PNP provided by the 
IND Sponsor. The investigator will also be responsible for documentation of lot numbers, dose 
and administration of Ad/PNP-F-araAMP given during the study. Under no circumstances will the 
investigator supply vector to other investigators, allow vector to be used other than directed by this 
protocol, or destroy or dispose of vector in any other manner without prior authorization from the 
IND Sponsor. 
Any residual vector must be returned to the investigational pharmacy for disposition. The site’s 
Investigational Pharmacy will dispose of all unopened or partially used vials of Ad/PNP at the end 
of the study. Please see the Pharmacy Manual for full and current details. 
4.7 
Concomitant Medications 
All medications taken at the time of study entry will be recorded. Any changes in concomitant 
medication, including additions, discontinuations, and dose changes, occurring during study 
participation will be recorded. 
The following concomitant treatments are permitted during the study: 
• 
All supportive measures (including antiemetics, red blood cell transfusions, antibiotics) 
consistent with optimal patient care will be given throughout the study and should be 
documented in the case report form (CRF). 
• 
Colony-stimulating factors and erythropoietin may be used during the study if clinically 
indicated according to the American Society Clinical Oncology guidelines. However, 


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neither granulocyte colony-stimulating factor (G-CSF) nor granulocyte-macrophage 
colony-stimulating factor (GM-CSF) will be used prophylactically in this study. 
The following concomitant treatments are not permitted during the study: 
• 
Allopurinol 
• 
No systemic anticancer agent other than the study drug 
• 
Palliative radiation therapy (if a subject has need for palliative radiation, they will be 
removed from the study) 
• 
Subjects that develop symptomatic pleural effusion/pericardial effusion will be taken off 
study, and treated with standard therapies 
• 
No other investigational therapies or devices will be allowed during study participation. 
4.8 
Criteria for Removal from Study 
Treatment will be stopped and patients will be removed from study due to unacceptable AEs, 
withdrawal of consent, or non-compliance. 
 
 


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5. 
INVESTIGATIONAL AGENT/DEVICE/PROCEDURE INFORMATION 
5.1 
Description of Study Drug 
Study drug for administration to the subjects consists of the vector Ad/PNP for intratumoral 
administration and F-araAMP for intravenous administration. 
F-araAMP (fludarabine phosphate) is licensed as a treatment for hematological malignancies but 
lacks efficacy to treat solid tumors. In the nonclinical studies, administration of the Ad/PNP vector 
intratumorally alone had little or minimal activity on tumor size. F-araAMP is being administered 
as a prodrug where subsequent generation of F-Ade within tumor cells transfected with the vector 
is expected to have local anti-tumor effect on the solid tumor. Commercial F-araAMP (fludarabine 
phosphate) available from the site’s formulary will be used in this study. 
The vector, Ad/PNP, is manufactured by the biologicals manufacturing division of Sigma-Aldrich, 
SAFC Pharma (Carlsbad, CA). 
Ad/PNP will be supplied as a liquid formulation in vials containing 2 x 1011 VP/100 µl in 20 mM 
Tris (pH 8.0), 25 mM NaCl, 2.5% Glycerol and should be stored at less than -60o C. Dilutions of 
the vector in sterile normal saline USP will be made immediately prior to use. Following dilution, 
the investigational pharmacy will send the vector to the clinic on ice for administration. Vector 
should be administered as soon as possible after dilution and must be used within 6 hours of thaw. 
The vector will be administered percutaneously via injection into the tumor mass. A subcutaneous 
injection of local anesthetic may be used, if desired. 
5.2 
Availability 
Ad/PNP for this project will be furnished by GeoVax, Inc. (Smyrna, GA). Commercially sourced 
F-araAMP will be used for this study. 
 
 


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5.3 
Agent Ordering 
Orders for Ad/PNP will be placed with GeoVax by the study team after approval to proceed has 
been granted by the IRB and Investigational Pharmacy. Ad/PNP will be transported on dry ice by 
overnight courier to the site’s investigational pharmacy. 
5.4 
Agent Accountability 
Each investigator will be responsible for dispensing and accounting of Ad/PNP provided by the 
IND Sponsor. The investigator will also be responsible for documentation of lot numbers, dose 
and administration of Ad/PNP-F-araAMP given during the study. Under no circumstances will the 
investigator supply vector to other investigators, allow vector to be used other than directed by this 
protocol, or destroy or dispose of vector in any other manner without prior authorization from the 
IND Sponsor. 
Any residual vector must be returned to the investigational pharmacy for disposition. The site’s 
Investigational Pharmacy will dispose of all unopened or partially used vials of Ad/PNP at the end 
of the study. Please see the Pharmacy Manual for full and current details. 
 
 


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6. 
DOSE MODIFICATIONS 
See Section 4.3 for dose modifications of Ad/PNP and F-araAMP. 
 
 


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7. 
ADVERSE EVENTS AND REPORTING PROCEDURES 
7.1 
Adverse Event 
An adverse event (AE) is any unfavorable and unintended diagnosis, symptom, sign (including an 
abnormal laboratory finding), syndrome or disease which either occurs during the study, having 
been absent at baseline, or, if present at baseline, appears to worsen. For this study, only abnormal 
laboratory findings with clinical significance as determined by the PI are considered AEs. 
A TEAE is defined as an AE with onset occurring at any time point after the first intratumoral 
administration of Ad/PNP. A TEAE also may be a continuing AE reported prior to the date of the 
first dose of study drug, which worsens in severity after the first administration of Ad/PNP. 
Disease progression is not an AE (non-serious or serious), although signs and symptoms thereof 
may be reportable as AEs. 
7.2 
Serious Adverse Event 
A SAE (experience) is defined (21CFR312.32) as any adverse experience that suggests a 
significant hazard, contraindication, side effect, or untoward medical occurrence that: 
• 
Results in death, 
• 
Is life-threatening (Note: the term “life-threatening” refers to an event in which the subject 
was at risk of death at the time of the event rather than to an event which hypothetically 
might have caused death if it were more severe.), 
• 
Requires (or prolongs) hospitalization, 
• 
Causes persistent or significant disability/incapacity, 
• 
Results in congenital anomalies or birth defects, or 
• 
Important Medical Event Requiring Medical or Surgical Intervention to Prevent Serious 
Outcome. 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately life- 


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threatening or result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed in the above definition. These should be 
considered serious. 
Pregnancy is not considered an AE. However, the medical outcome of an elective or spontaneous 
abortion, stillbirth or congenital anomaly is considered an SAE and must be reported to the Sponsor 
within 24 hours of the site becoming aware of the event. The study investigator will make every 
effort to obtain permission to follow the outcome of the pregnancy and report the condition of the 
fetus or newborn to the Sponsor. 
Any pregnancy which occurs during this clinical trial must be treated as a SAE with regard to the 
reporting timeline. Any pregnancy must be followed until conclusion of the pregnancy (delivery 
or termination). Administration of study drug will be discontinued in a subject who becomes 
pregnant. The subject will be asked to complete safety evaluations through Study Day 56 of the 
subject’s last cycle (no follow-up imaging studies for the purposes of this study will be obtained). 
If a male subject reports a pregnancy of his spouse or significant other within Day 56 of last study 
treatment, every effort will be made to obtain data regarding the outcome of this pregnancy. 
Pregnancies must be reported using the paper Pregnancy Form. All pregnancies must be followed 
up until delivery or termination of pregnancy and until final outcome, using the paper Pregnancy 
Follow-Up Form. Reporting of both the initial pregnancy and the outcome must be done via e-mail 
to GeoVax_PV@cato-sms.com. 
7.3 
Assessment of Causality 
The relatedness of an AE to the study drug is the best estimate of the investigator at the time of the 
reporting of the causal relationship between the study drug and an AE. 
The following study drug relationships will be used for this clinical study: 
Unrelated: There is no temporal relationship between the event and the administration of the study 
drug, and/or the event is clearly due to the subject’s medical condition, other therapies, or accident. 
Possibly Related: There is some temporal relationship between the event and the administration 
of the study drug and the event is unlikely to be explained by the participant’s medical condition 
or other therapies. 


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Probably Related: The temporal relationship between the event and the administration of the 
study drug is compelling, and the participant’s medical condition or other therapies cannot explain 
the event. 
Definitely Related: The temporal relationship between the event and the administration of the 
study drug is compelling, the participant’s medical condition or other therapies cannot explain the 
event and the event follows a known or suspected response pattern to the medication. 
The categories of Definitely, Probably, and Possibly are considered study drug related. 
7.4 
Severity of the Adverse Event 
Adverse events will be graded per National Cancer Institute (NCI) CTCAE v5) 
(http://evs.nci.nih.gov/ftp1/CTCAE/about.html). 
• 
Mild (Grade 1) 
• 
Moderate (Grade 2) 
• 
Severe (Grade 3) 
• 
Life –Threatening (Grade 4) 
• 
Fatal (Grade 5) 
7.5 
Safety Monitoring and Reporting 
7.5.1 
Monitoring of Adverse Events 
All subjects will be monitored closely for AEs during study participation. Subjects who discontinue 
prematurely from the study will be encouraged to return for assessment of safety and their 
physician contacted to obtain follow-up safety information. 
The investigator will monitor subjects for the occurrence of AEs throughout their participation in 
the study and record all observed AEs in the CRF. 


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Adverse events spontaneously reported by the subject and/or in response to an open question from 
study personnel or revealed by observation, physical examination, or other diagnostic procedures 
are to be recorded in the study specific worksheets. Any clinically relevant deterioration in 
laboratory assessments or other clinical findings, as assessed by the investigator, is considered an 
adverse event and must be recorded on the appropriate pages of the CRF. Whenever possible, 
symptoms should be grouped as single syndrome or diagnosis. The investigator should specify the 
date of onset, maximal intensity, corrective therapy given, outcome, and his/her assessment of 
causality (i.e., whether the adverse event was related to the study drug) (Section 7.3). 
From signing of informed consent through initiation of study treatment, only SAEs considered 
related to study procedure(s) should be recorded. After initiation of study treatment (Day 1) through 
Day 56 of the subject’s last treatment cycle, all adverse events regardless of seriousness or 
relationship to study drug should be recorded. 
Serious adverse events considered related to prophylactic antibiotic treatment (and not suspected 
to be related to study treatment) are expected AEs. They should be collected but are not subject to 
expedited reporting. 
Any AE that is not resolved by the end of the study and considered to be potentially related to 
study drug or was the cause for the subject’s withdrawal will be followed as clinically indicated 
until its resolution, or if non-resolving, until considered stable. 
7.5.2 
Recording and Reporting Adverse Events and Serious Adverse Events 
The investigator must provide the IND Sponsor and monitoring team appropriate information 
concerning any findings suggesting significant hazards, contraindications, side effects or 
precautions pertinent to the safety of the study drug. The investigator will instruct subjects prior 
to administration of study drug to report any physical changes or new symptoms that they notice 
during the course of the study. 
Non-serious AEs and SAEs related only to prophylactic antibiotics will be reported annually to 
FDA and NIH Office of Science Policy via an Annual Report (by IND Holder GeoVax) and to 
IRB via Continuing Review (by clinical study team). 
The PI must report all SAEs and deaths, whether or not considered related to study treatment, 
immediately (within 24 hours of knowledge of event) to GeoVax. 


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For Serious Adverse Events/Pregnancy, please send completed report form to GeoVax_PV@cato-
sms.com or fax to 919-361-2536 
In the event of a SAE, the investigator must report: 
• 
Treatment regimen (dosing frequency, combination therapy) 
• 
Protocol description (and number, if assigned) 
• 
Description of event, severity, treatment, and outcome, if known 
• 
Supportive laboratory results and diagnostics 
• 
Investigator’s assessment of the relationship of the adverse event to each investigational 
product and suspect medication 
The PI should report any follow-up information as it becomes available. 
Adverse events meeting the IRB definition of ‘Unanticipated Problem’ will be reported to the IRB 
within 10 working days of investigator determination event meets reporting requirements, or 
within 5 working days for deaths or life-threatening experiences. 
Adverse events deemed serious and related to study drug or study procedures (regardless of 
expectedness) will be reported to any applicable oversite board at the site within 5 working days 
of knowledge of event. 
Adverse events deemed serious, unexpected (i.e., not described in the protocol, Investigator’s 
Brochure or informed consent documents) and related to study drug must be reported to GeoVax 
using the SAE Report Form within 24 hours of knowledge of event at contact information listed 
above. The Sponsor is responsible for reporting any event meeting IND Safety Reporting criteria 
to FDA. SAEs considered related to antibiotic treatment are considered expected. 
7.5.3 
Safety Monitoring Committee 
The SMC will meet and review safety data (i.e., adverse events reporting, reactions to study drug, 
deaths, etc.) and protocol deviations at time intervals specified in the SMC Charter and at any other 
time when it is determined by the SMC or GeoVax that such a review is warranted. The SMC will 
be comprised of, at a minimum, a Sponsor representative, medical monitor (SMC facilitator), and 


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investigative site designees from each participating site. Only the investigative site designees will 
be voting members of the SMC. SMC voting members will be experienced professionals in 
evaluating safety and efficacy data derived from oncology clinical trials. The medical monitor and 
Sponsor representative will be part of the SMC but will not be voting members. Observers without 
voting rights are also allowed to join the SMC meetings. All SMC recommendations will be 
documented and communicated to GeoVax and the investigators at each study site. Following their 
review, the SMC will recommend whether or not dosing may continue or the need for 
modifications to the protocol and/or safety monitoring.  
In addition, an ad hoc SMC meeting can be planned on initiative from the Medical 
Monitor/Sponsor based on the regular surveillance of the safety data and/or upon request from an 
investigator. The SMC may recommend stopping the study at any time that an unacceptable type 
and/or frequency of AEs is observed.  
8. 
CORRELATIVE/SPECIAL STUDIES 
Special studies to assess safety and efficacy of Ad/PNP with F-araAMP are planned and will be 
conducted by collaborators at Emory University (with IRB approval at that institution) or 
outsourced to commercial organizations specializing in testing of this sort. These studies are 
described in Section 9.1 (Procedures Table) as well as Sections 9.2 and 9.3, and include: 1) blood 
samples for adenovirus, 2) urine for adenovirus, 3) blood samples for antibody against adenovirus, 
4) F-Ade plasma level, and 5) tumor biopsy for studies of PNP activity, histochemistry, tumor 
growth fraction, and adenoviral distribution. Samples will be shipped to Emory or commercial site 
with the same strict attention to patient confidentiality described throughout the protocol. Please 
also see Section 10. 
Methods regarding tumor biopsy and analysis, as well as serum F-Ade to be arranged by 
investigators at Emory or designated subcontractor are described below: 
1) 
Measurement of E. coli PNP activity. Approximately 50 mg of tumor tissue will be 
obtained using a 3 mm dermal punch from the injected tumor site on day 3 just prior to 
treatment with F-araAMP. This timing coincides with robust transgene expression observed 
in our preclinical studies and will allow us to ascertain E. coli PNP activity at the beginning 
of F-araAMP treatment. Tissue samples will be immediately frozen and stored at -80°C. 
Crude extracts will be prepared and incubated with 50 mM potassium phosphate, 100 µM 
6-methylpurine-2’-deoxyriboxide (MeP-dR, a standardized E. coli PNP substrate), and 


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100 mM HEPES buffer (pH 7.4) at a concentration of tumor lysate that results in a linear 
reaction over the incubation period. The formation of 6- methylpurine will be monitored using 
reverse phase high performance liquid chromatography (HPLC). Care will be taken to 
thoroughly homogenize samples in order to release PNP enzyme. 
2) 
Metabolism of F-araAMP. An important measurement to evaluate effectiveness of vector 
delivery is to quantify active metabolites in tumor tissue following F-araAMP treatment, with 
the goal to determine levels of F-Ade produced from F-araAMP by E. coli PNP. F-Ade in 
tumor tissues is activated by purine metabolic enzymes to F-Ade - containing nucleotides 
(primarily F-ATP) and incorporated into RNA, which is responsible for cell killing action of 
F-Ade. For this measurement, tumor tissue will be obtained using a dermal punch from the 
tumor site one hour after the final F-araAMP treatment on Day 5. We have shown in mouse 
tumor xenografts that F-Ade metabolites are retained in tumor parenchyma for prolonged 
periods (t½ greater than 24 hours) and obtaining tumor samples one hour after the final 
injection of F-araAMP should allow for an assessment of F-Ade tumor levels attributable to 
cumulative administration of prodrug. Because cellular nucleotides rapidly degrade during 
extraction of tumor tissue, we plan to measure total F-Ade levels by treating the extract with 
RNase and phosphatases (in the presence of immucillin, a potent E. coli PNP inhibitor) to 
degrade all F-Ade nucleotides to 2-fluoro-adenosine (F-Ado). We will utilize an liquid 
chromatography/mass spectrometry (LC/MS) method to measure both F-Ade and F-Ado. 
Since tumor cells may also contain F-araA nucleotides, we will configure a parallel LC/MS 
method to measure F-araA. Please note that investigators in this project have access to LC/MS 
protocols specifically for analysis of nucleoside and related compounds, and over 20 years’ 
experience with measurements of this type. 
3) 
Plasma levels of F-Ade. It will be important to determine the extent to which F-Ade escapes 
into the general circulation, and we will monitor systemic release of the compound. Plasma 
samples will be obtained after F-araAMP injection on Days 3 and 5, and analyzed for F-Ade, 
F-Ado, and F-araA using LC/MS procedures familiar to our laboratories. In our Phase 1 study, 
no F-Ade was measurable in plasma with an LC/MS assay of sufficient sensitivity to detect 
F-Ade at levels approximately 100-fold below the no-observable-adverse effect-level 
(NOAEL) in rats given the compound daily for 7 days. 
4) 
Tumor growth fraction and effects on the stem cell compartment, and evidence for PNP 
protein expression. Tumor punch biopsies obtained above will also be studied by 
histochemistry for markers of active cell cycling (e.g., Ki67) or the tumor stem cell 


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compartment (e.g., SOX2, Nanog, Oct-4, CD44+/CD24+). Comparisons will be made to 
original (pretreatment) tumor sections. We will also use the biopsy samples to evaluate levels 
of PNP expression and adenoviral localization by immunohistochemistry with antibodies to 
the transgene uniquely available in our laboratory. A portion of each biopsy (e.g., 10%) will 
be placed in RNA-later for analysis of the same antigens by RT- PCR. 
 


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9. 
STUDY CALENDAR 
9.1 
Study Procedures Table 
Enrolled subjects will follow the schedule of evaluations provided below. 
 
 
Cycles 1-5 (28-day cycles)12 
Cycle 5 or last 
cycle 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Day 
Screen 
-30 to 0 
1 
2 
3 
4 
5 
14± 2 
28 ±3 
56 ±3 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
Physical examination1 
X 
X 
 
 
 
 
 
 
 
Vital Signs16 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inspect injected tumor 
site(s) 
 
 
X 
X 
X 
X 
X 
X 
X 
Performance Status 
X 
X 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
X 
CXR (If no chest CT) 
X 
 
 
 
 
 
 
 
 
Chemistries2 
X 
X8 
 
 
 
 
X 
X 
X 
Hematology3 
X 
X8 
 
 
 
 
X 
X 
X 
CD4/CD8 T-cell 
subsets 
X 
 
 
X11 
 
 
 
 
X
11 
Urine analysis 
X 
 
 
 
 
 
 
 
X 
Serum pregnancy 
X 
 
 
 
 
 
 
 
 
PT/aPTT 
X 
 
 
 
 
 
 
 
 
CT scan/MRI4  
X 
 
 
 
 
 
X 
 
(X) 
Physical measurement of 
tumor size5 
X 
X 
 
 
 
X 
X 
X 
X 
Blood samples for 
Adenovirus6 
 
X 
X 
 
 
 
 
 
 
Urine for adenovirus6 
 
X 
X 
 
 
 
 
 
 
F-Ade plasma level 
 
 
 
X9 
 
X9 
 
 
 
Blood sample for 
antibody to adenovirus 
 
X10 
 
 
 
 
 
X10 
 
Intratumoral 
administration Ad/PNP7 
 
X 
X 
 
 
 
 
 
 
PJP Prophylaxis13 
 
X 
 
 
 
 
 
 
X 
Tumor Biopsy14 
 
 
 
X 
 
X 
X 
 
 
Infusion of F-araAMP 
 
 
 
X 
X 
X 
 
 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
Medications15 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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1. 
A thorough physical examination will be done at screen and second study visit; system-oriented examination 
will be conducted as needed on other visits. Weight and height should be recorded at baseline. Injected tumor 
will be examined at each visit. 
2. 
Chemistries include: Na+, K+, CO2, Cl, glucose, Mg++, Ca++, blood urea nitrogen (BUN), creatinine (Cr), 
phosphorus, albumin, alkaline phosphatase, ALT, AST, total bilirubin, total protein. 
3. 
Hematology values include CBC with differential and platelet count. 
4. 
CT or MRI Imaging is to be done in all subjects at Screen and at Visit 7 of the first, second (if PD after first 
cycle), third, and last cycle. Subjects with CR, PR, or SD in the injected tumor at Day 14 of the fifth or last cycle 
will have imaging on Day 56. 
5. 
For injected tumors palpable on physical examination, tumor size is to be assessed by physical measurement 
(ruler or calipers), if possible. 
6. 
Samples will be collected prior to the first administration of Ad/PNP on Day 1 and 2 (+/-1 hour) hours after the 
third administration on Day 2 of the first and third cycle.   
7. 
Ad/PNP will be administered intratumorally three times: two administrations 3-6 hours apart on Day 1 and 1 
administration early (morning) on Day 2. Subjects will be monitored continuously for 1 hour after each 
administration. 
8. 
Blood sample to be drawn and routine chemistry and hematology results reviewed by the Clinical Investigator 
prior to administration of study drug. 
9. 
Draw two blood samples for F-Ade: one prior to F-araAMP infusion and one 15-30 minutes after infusion of F-
araAMP on Days 3 and 5 of the first and third cycle. 
10. Blood sample for antibody to be drawn prior to first administration of Ad/PNP on the first and third cycle, and 
Day 28 of the last cycle. 
11. Blood sample to be drawn prior to first infusion of F-araAMP on the first cycle and Day 56 of the last cycle. 
12. Evaluations on Visit 2 through 7 are to be done for each 28-day cycle. 
13. Prophylaxis for Pneumocystis jiroveci (PJP) extends pre-dose dose on Day 1 of cycle 1 through Day 56 following 
the last cycle. This will be one double-strength trimethoprim (TMP)/sulfamethoxazole (SMX) (i.e., 160 
TMP/800 SMX) three times a week. 
14. Biopsy of injected tumor will be done on Days 3 and 5 of the first cycle and on Day 14 of the third cycle. 
15. Medications will be recorded at screening and any change in medications will be recorded at study visits. 
16. Vital signs will be recorded at 30 +/- 15 min, and 60 +/- 15 minutes following each administration 
 
 


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9.2 
Study Procedures 
Subjects screened and enrolled will follow schedule of evaluations provided at the beginning of 
this protocol. The following evaluations will be performed: 
9.2.1 
Visit 1 (Day -30 to 0, Screening and Baseline Laboratory Values) 
The following evaluations and tests will be performed: Preliminary Screening: 
• 
Obtain written informed consent 
• 
Medical history including current medication 
• 
Assessment of performance status 
• 
Physical examination 
• 
Record vital signs 
Complete screening if entry criteria are met on preliminary screening: 
• 
Electrocardiogram (ECG) 
• 
Chest X-ray if no chest CT. Chest radiograph within two weeks prior to screening may be 
used 
• 
Blood samples for: Hematology, CD4/CD8 T-cell subsets, Chemistry, PT/aPTT 
• 
Serum pregnancy test in women of childbearing potential 
• 
Urine analysis 
• 
Assessment of tumor with CT scan or MRI 
 
 
 


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For injected tumors palpable on physical examination, measurement with calipers or rulers, if 
possible, with photo documentation. 
During each 28-Day Cycle of Ad/PNP-F-araAMP: 
The following tests and evaluations scheduled on Visits 2 through 7 are to be done during each 
treatment cycle. Up to five treatment cycles are planned in the study. At each clinic visit, any 
change in concomitant medication or adverse events will be recorded. 
Note that Day 28 of a cycle is Day 1 of the next repeat cycle. Tests and evaluations to be done on 
Day 1 of each cycle (i.e., Visit 2) should be conducted prior to study drug administration unless 
otherwise noted. 
9.2.2 
Visits 2 and 3 (Days 1 and 2 of Intratumoral Administration of Ad/PNP) 
Subjects may receive intratumoral administrations in the clinic or hospital (in-patient) at the 
discretion of the investigator. 
The following tests and evaluations will be performed: 
• 
Physical exam (Day 1 only) or examination of injected tumor site(s) (Day 2 only). 
• 
Record vital signs. 
• 
Record performance status on Day 1 of cycle. 
• 
For injected tumors palpable on physical examination, measurement with calipers or rulers, 
if possible, with photo documentation (Day 1). 
• 
Obtain blood sample for hematology and chemistry prior to first administration of Ad/PNP 
on Day 1 of cycle. 
• 
Obtain blood sample for antibody to adenovirus prior to the first administration of Ad/PNP 
on Day 1 of the first and third cycle. 
• 
Obtain blood samples for measurement of adenovirus level prior to first administration of 
Ad/PNP on Day 1 and 2 hours after the third administration of Ad/PNP on Day 2 of the 
first and third cycle. 


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• 
Obtain urine sample for testing adenovirus prior to first administration of Ad/PNP on Day 1 
and 2 (+/-1 hour) hours after the third administration of Ad/PNP on Day 2 of the first and 
third cycle. 
• 
Give two administrations of Ad/PNP intratumorally 3-6 hours apart on Day 1 and one 
administration early (morning) on Day 2. Following each intratumoral administration the 
subject will be observed closely for tumor injection reactions or other acute safety events. 
Vital signs will be recorded at 30 +/- 15 min, and 60 +/- 15 minutes following each 
administration. Non-hospitalized subjects will be discharged from the clinic after 1 hour of 
observation as long as the investigator considers them clinically stable. 
• 
Initiate PJP prophylaxis (Day 1). 
• 
Record any AEs. 
• 
Record any change in medications. 
9.2.3 
Visit 4 (Day 3, First infusion of F-araAMP) 
Subjects may receive F-araAMP daily in the clinic or as in-patients at the discretion of the 
investigator. 
• 
Examination of injected tumor site(s). 
• 
Record vital signs. 
• 
Obtain blood specimen prior to infusion of F-araAMP for: 
– 
CD4/CD8 T-cell counts (first cycle only) 
• 
Obtain tumor biopsy, first cycle only. 
• 
Administer F-araAMP intravenously over approximately 30 minutes. 
• 
Blood specimen for F-Ade plasma level prior to and 15 - 30 minutes following infusion of 
F- araAMP in the first and third cycle. 
• 
Record any AEs. 
• 
Record any change in medications. 


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9.2.4 
Visits 5 and 6 (Days 4 and 5) 
• 
Examination of injected tumor site(s). 
• 
Record vital signs. 
• 
For injected tumors palpable on physical examination, measurement with calipers or rulers, 
if possible (Day 5). 
• 
Administer F-araAMP intravenously over approximately 30 minutes. 
• 
Draw blood for F-Ade plasma level prior to and 15-30 minutes following infusion of 
F-araAMP on Day 5 in the first and third cycle. 
• 
Obtain tumor biopsy, Day 5 of first cycle only. 
• 
Record any AEs. 
• 
Record any change in medications. 
9.2.5 
Visit 7 (Days 14 ± 2) 
• 
Record vital signs 
• 
Examination of injected tumor site(s) 
• 
For injected tumors palpable on physical examination, measurement with calipers or rulers, 
if possible 
• 
Obtain blood specimen for hematology and chemistry parameters 
• 
Assessment of tumor with CT scan or MRI on first, second (if PD after first cycle), third 
and last cycle. 
• 
Obtain tumor biopsy, third cycle only. 
• 
Record any AEs. 
• 
Record any change in medications. 


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Following Visit 7 of the Last Cycle 
9.2.6 
Visit 8 (Day 28 ± 3 of the Last Cycle) 
• 
Examination of injected tumor site(s) 
• 
Record vital signs 
• 
Record any new or resolution of adverse events 
• 
Record any change in medications 
• 
For injected tumors palpable on physical examination, measurement with calipers or rulers, 
if possible 
• 
Blood specimen for: 
– 
Hematology 
– 
Chemistry 
– 
Antibody to adenovirus (last cycle) 
9.2.7 
Visit 9 or Termination Visit (Day 56 ± 3 of the Last Cycle) 
• 
Examination of injected tumor site(s) 
• 
Record vital signs 
• 
Record any new or resolution of adverse events 
• 
Record any change in medications 
• 
For injected tumors palpable on physical examination, measurement with calipers or rulers, 
if possible 
• 
ECG 
• 
Obtain blood specimen for: 
– 
Hematology 
– 
Chemistry 


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– 
CD4/CD8 T-cell counts 
• 
Urine analysis 
• 
MRI or CT scan for subjects who had CR, PR, or SD following last cycle 
9.3 
Description of Evaluations 
9.3.1 
Laboratory Evaluations 
Hematology values include complete blood count (CBC) with differential and platelet count. CD4 
and CD8 T-cell subsets will be obtained at baseline and at specified time points following infusion 
of F-araAMP. 
Chemistry values include Na+, K+, CO2, Cl, glucose, magnesium (Mg++), calcium (Ca++), blood 
urea nitrogen (BUN), creatinine (Cr), phosphorus, albumin, alkaline phosphatase, ALT, AST, total 
bilirubin, total protein. 
Blood samples for F-Ade plasma measurement will be drawn prior to and 15-30 minutes after 
infusion of F-araAMP (See Study Procedures Table) F-Ade plasma levels will be measured by 
HPLC mass spectrometry. Blood and urine samples will be collected prior to the first 
administration and 2 hours after the third administration of Ad/PNP (See Study Procedures Table) 
samples will be stored and assayed for adenovirus following study completion. 
Blood samples for antibody to adenovirus will also be collected prior to the first administration of 
Ad/PNP on the first and third cycle, and Day 28 of the last cycle. 
9.3.2 
Physical Examination 
Vital signs include blood pressure, respiration, heart rate, and temperature. A full physical 
examination will be done at screening and at the second study visit. At other time points in the 
study a physical that includes symptom directed examination (in addition to examination of 
tumor(s)) will be conducted as determined by the study clinician. The subject’s height and weight 
will be recorded at baseline. 
Injected tumors will be examined at each study visit. For injected tumors palpable on examination, 
the tumor will be measured with ruler or calipers (if possible) and assessed for any changes as 


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specified in the study as shown in the Study Procedures Table. The injection site(s) will be 
examined for local reactions to the injection. 
9.3.3 
Medical History 
A complete medical history includes age, race, and/or ethnicity, past or current treatments 
including surgical, radiation treatment, and chemotherapy. Current or past illnesses, current 
medications, and use of tobacco and alcohol will be recorded at baseline. 
9.3.4 
Tumor Response 
For this study, response will focus on the injected tumor(s) and be based on criteria according to 
those in RECIST v1.1.[6] In addition, overall tumor response will be assessed according to 
RECIST 1.1 criteria. 
The following criteria will be used to define response in injected tumor(s): 
• 
Complete Response (CR): Disappearance of the injected tumor(s). 
• 
Partial Response (PR): At least a 30% decrease in the longest diameter (LD) of the injected 
tumor(s), taking as reference the smallest LD. 
• 
Progression (PD): At least a 20% increase in the LD of the injected lesion(s), taking as 
reference the smallest LD recorded on study (this includes the baseline LD if that is the 
smallest on study). Note: appearance of one or more new lesions will be considered 
progression in assessing overall tumor response. 
• 
Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to quality for PD taking as reference the smallest LD while on study. 
Target tumors accessible for needle injection on physical examination will be injected. Size of the 
injected tumor masses will be measured with ruler or calipers, as possible, and it is preferable if 
the same practitioner measures using the same technique at each visit. 


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9.3.5 
Radiographic Imaging 
Lesions will also be assessed qualitatively using MRI or CT scan with the site’s available MRI 
and CT techniques. The same imaging technique will be used for all evaluations. The target lesions 
and injected tumors for intratumoral administration will be assessed radiographically at baseline 
and within 2 weeks of Ad/PNP-F-araAMP on the first, third, and last cycle (and during the second 
cycle for those showing PD). In subjects who have CR, PR or SD on imaging 2 weeks after the last 
drug administration, follow-up imaging will be obtained again approximately 6 weeks later. 
Non-neck tumor sites may be followed by conventional CT/MRI. 
9.4 
Tumor Biopsies 
A sample of tumor tissue will be obtained on three occasions from one of the injected tumors: 
Days 3 and 5 of the first cycle and on Day 14 of the third cycle. Biopsies will be evaluated by a 
number of tests intended to investigate the mechanism of tumor cell clearance including PNP 
expression, F-araAMP cleavage, and immunohistochemistry. 
In the event that more than one tumor was injected with Ad/PNP and the biopsied tumor has CR, 
then a tissue sample may be obtained from an alternate injected tumor. 
 
 


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10. 
MEASUREMENTS 
10.1 
Primary Outcome Measure 
Title: 
The primary objective of the study is to evaluate the safety of repeat administration of a dose level 
of Ad/PNP-F-araAMP that demonstrated anti-tumor activity in patients with advanced head and 
neck cancer in the Phase 1 study. 
Timeframe: 
Primary outcome will be evaluated on a longitudinal basis and at study completion. The study is 
expected to require 36-48 months. 
Safety Issue: 
Studies conducted here are intended to evaluate safety. 
10.2 
Secondary Outcome Measure 
Title: 
The secondary objective of the study is to evaluate the anti-tumor activity of repeat administration 
of Ad/PNP-F-araAMP. 
Timeframe: 
Secondary outcome will be evaluated on a longitudinal basis and at study completion. 
Safety Issue: 
N/A, please see above 
10.3 
Primary and Secondary Outcome Measures-Discussion: 
Primary Outcome Measurements for this study are directed towards safety and will be evaluated 
by: medical history, physical examination, vital signs, inspection of tumor site, performance status, 


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EKG, chest X-ray (CXR), blood chemistry, hematology, CD4/CD8 T-cell counts, urinalysis, 
PT/PTT, blood sample for adenovirus, urine for adenovirus, F-Ade plasma level, blood sample for 
antibody against adenovirus, and monitoring adverse events. Additional detail regarding these 
endpoints is furnished in Section 9.1, 9.2, and 9.3. 
Secondary Outcome Measurements are directed towards efficacy and will include: Objective 
response rate (ORR), defined as the percentage of patients with a best overall response (BOR) of 
a complete response (CR) or a partial response (PR). BOR is the best response achieved during 
the 5 cycles of treatment, for injected tumors and overall, as determined by RECIST v.1.1. Other 
measurements will include: 
• 
Durable response rate defined as a BOR of CR or PR for injected tumors and overall, as 
determined by RECIST v. 1.1 persisting for at least 4 weeks. 
• 
Time to response (TTR) defined as time from first intratumoral injection to date of first 
response value of CR or PR for injected tumors and overall, as determined by RECIST 
v.1.1. 
• 
Overall survival (OS) defined as time from first intratumoral injection to date of 
progression or  death for any cause, whichever occurs first. 
• 
Progression free survival (PFS) defined as time from first intratumoral injection to date of 
progression or death for any cause, whichever occurs first. 
• 
Duration of response (DOR) defined as time from first documentation of CR or PR for 
injected tumors and overall, as determined by RECIST v.1.1 until disease progression or 
death for any cause, whichever occurs first. 
10.3.1 
Relevant Subset 
N/A 
10.3.2 
Measurement Definition 
Please see below. 


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10.3.3 
Measurement Methods 
Primary outcome measurement methods will include clinical evaluation (physical examination, 
medical history, performance status, vital signs, evaluation of tumor site for evidence of tissue 
injury) by investigators conducting the study (or their designees). Laboratory and additional 
parameters (EKG, CXR, blood chemistry, hematology, CD4/CD8 T-cell counts, urine analysis, 
PT/PTT, etc.) will be measured according to standard hospital/clinic procedures, and as detailed 
in Section 7 of this document. 
Secondary outcome measurement methods are defined in Sections 9.3.4 and 9.3.5 and will be 
performed according to RECIST 1.1. 
Special Studies include 
Blood samples for adenovirus, urine for adenovirus, F-Ade plasma level, blood sample for antibody 
against adenovirus, tumor biopsy for studies of PNP activity, histochemistry, growth fraction, and 
adenoviral distribution. Specific studies are described in Section 8. 
10.3.4 
Measurement Time Points 
Please see Section 9.1, Tabular Summary, for information regarding time points at which each 
outcome measure will be assessed. 
10.3.5 
Response Review 
The study is designed primarily to evaluate safety with repeat treatment cycles, although the 
anti-tumor effect of Ad/PNP-F-araAMP will be assessed. For this study, response will focus 
primarily on the injected tumor(s) as the target lesion(s). Any observed effect on non-injected 
tumors and overall tumor response will also be assessed and recorded. Efficacy response results 
for injected tumors, non-injected tumors, and overall will be reported separately. Although we will 
evaluate response of the total tumor burden, only the injected mass will be used to primarily define 
efficacy. Because there is a possibility of immune-mediated anti-tumor benefit, we will also 
evaluate total tumor burden.  
Response (CR, PR, SD, PD) is based on RECIST v1.1 (http://www.ctep.info.nih.gov v1.1). [6]  


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11. 
REGULATORY CONSIDERATIONS 
11.1 
Institutional Review of Protocol 
The protocol, the proposed informed consent, and all forms of participant information related to 
the study (e.g. advertisements used to recruit participants) will be reviewed and approved by the 
IRB. Any changes made to the protocol will be submitted as a modification and will be approved 
by the IRB prior to implementation.  
The investigator will ensure that all necessary approvals are obtained from the hospital or other 
institution at which he or she will conduct the clinical study. A copy of the original IRB approval 
for the protocol and the Informed Consent form must be forwarded to the Sponsor or their 
representative before subject enrollment can begin. The investigator will retain copies of any and 
all correspondence with the IRB, and the Institution will make them available for review by the 
Sponsor’s representative or the FDA upon request. The investigator must inform the IRB of all 
protocol amendments and of serious or unexpected adverse events occurring during the study 
which are likely to affect the safety of the subjects or conduct of the study. The investigator must 
transmit in writing IRB approval to the Sponsor or representative. 
The investigator or designee will notify the IRB when the study is placed on “hold”, completed, 
or closed to further subject enrollment. 
11.2 
Safety Monitoring Plan 
Trial safety will be monitored and reviewed by the SMC as described in the SMC Charter. The 
Sponsor, GeoVax, will coordinate among all study sites to monitor safety (i.e., AE reporting, 
reactions to study drug, deaths, etc.). GeoVax will be responsible for reporting these AEs, 
unanticipated problems, and other relevant data to the FDA and to all study sites.  
The SMC will regularly review AE reporting associated with the research to ensure the protection 
of human subjects. Results of the SMC audit will be communicated to the Sponsor, GeoVax, the 
IRB, and the appropriate regulatory authorities at the time of continuing review, or in an expedited 
fashion, as needed. If the SMC and GeoVax agree to stop the study, GeoVax will inform the 
regulatory authorities and all the investigational sites of the decision to stop the study.  


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11.3 
Informed Consent and HIPAA Authorization 
The investigator will be responsible for obtaining from every subject prior to his/her participation 
in the study a written Informed Consent signed and dated in accordance with U.S. federal 
regulations (21CFR 50 and 21CFR 312.60) and Health Insurance Portability and Accountability 
Act (HIPAA) authorization to use and disclose protected health information (PHI). Subjects, their 
relatives, guardians or, if necessary, legal representatives must be given ample opportunity to 
inquire about details of the study. 
The IRB must approve the Informed Consent. The written Informed Consent and HIPAA 
Authorization will be obtained after the investigator has provided to the subjects a full explanation, 
both verbally and in writing, of the purpose, risks and discomforts involved. The original signed 
and dated copy of the Informed Consent and HIPAA Authorization must be maintained in the 
institution’s records. The names of subjects enrolled during the study will be considered 
confidential. 
11.4 
Subject Confidentiality 
Individual subject medical information obtained as a result of this study is considered confidential 
and disclosure to third parties, other than those cited below, is prohibited. Subject confidentiality 
will be further ensured by utilizing subject identification code numbers for all reports. Subject 
names will not be supplied in the IND Sponsor data. Study findings stored on a computer will be 
maintained in accordance with local data protection laws. 
In compliance with regulatory guidelines regarding the monitoring of clinical studies and in 
fulfillment of the investigator’s obligations to the IND Sponsor, it is required that data generated 
as a result of the study be available for inspection, on request, by personnel from the IND Sponsor 
and regulatory agencies. These will include all study-relevant documentation, including medical 
histories to verify eligibility, laboratory test results to verify transcription accuracy, treatment and 
diagnostic reports, admission/discharge summaries for hospital admissions occurring while the 
subject is on study, and autopsy reports (if available) for deaths occurring during or in temporal 
proximity to the study. 
As part of the required content of the informed consent, participants must be informed that their 
records will be reviewed by the monitoring team, IND Sponsor, and regulatory agencies. Should 
access to medical record require a separate waiver or authorization, it is the investigator’s 


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responsibility to obtain such permission from the subject in writing before the subject is entered 
into the study. 
11.5 
Adherence to Reporting Requirements 
Within a reasonable time following completion of the study, a final study report will be written, 
reviewed by the IND Sponsor or designee, and submitted to FDA. 
11.6 
Records 
The FDA requires that an investigator retains records for a period of two years following the date 
a New Drug Application or Product License Application is approved for the drug for the indication 
for which it is being investigated; or, if no application or license is to be filed or, if the application 
or license is not approved for such indication, until two (2) years after the investigation is 
discontinued (21CFR 312.62). 
The investigator should ensure that the following records are maintained: 
• 
Signed informed consent documents for all subjects 
• 
Patient identification code list and enrollment log 
• 
Record of all communications between the investigator and the IRB 
• 
Record of all communication between the investigator, monitoring team, and the Sponsor 
• 
List of subinvestigators and other appropriately qualified persons to whom the investigator 
has delegated significant study-related duties, together with their roles in the study and their 
signatures 
• 
Copies of CRFs and of documentation of corrections for all subjects 
• 
Pharmacy files containing copies of the record of use for the study drug, instructions for 
completion of these records, and the Investigator’s Brochure 
• 
All other source documents (subject medical records, laboratory records, etc.) 


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• 
Investigator files containing copies of the documents required for the initiation of the study 
(executed form FDA 1572, signed Investigator’s Agreement, Curricula Vitae for the 
investigator, copy of the IRB approval of the protocol and Informed Consent forms). Note: 
Scanned documents are acceptable as source materials. 
11.7 
Protocol Approval and Amendments 
Before the start of the study, the investigator will submit the clinical study protocol, informed 
consent document, and any other appropriate documents to the IRB with a cover letter listing the 
documents submitted, the dates of issue, and the site (or region or area of jurisdiction, as 
applicable) for which approval is sought. The IND Sponsor will submit the protocol and 
appropriate documents to the FDA and OBA/NIH in accordance with legal requirements. 
The investigator will notify the IRB of all protocol amendments and administrative changes, in 
accordance with the site’s requirements. The Sponsor or designee will notify the FDA and 
OBA/NIH of all protocol amendments and administrative changes in accordance with legal 
requirements. Amendments must be evaluated to determine whether the informed consent 
document should be revised. 
The investigator must keep a record of all communication with the IRB and, if applicable, between 
the coordinating investigator and the IRB. This also applies to any communication between the 
investigator (or coordinating investigator, if applicable) and the IND Sponsor or its designee. 
11.8 
Closure of the Study 
The study must be closed at the site upon completion. Furthermore, the IND Sponsor or the 
investigator has the right to close a study site at any time. As far as possible, premature closure 
should occur after mutual consultation. The IRB should be notified when the study is completed 
or terminated. The IND Sponsor will notify FDA and OBA/NIH when the study is completed or 
terminated including the reason for premature termination. 
At the end of the study, all study drug must be returned, disposed of, or retained as directed by the 
Sponsor. 


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11.9 
Study Monitoring and Auditing 
The Sponsor/Contract Research Organization (CRO) will monitor study conduct in accordance 
with industry standards, best practice, and all applicable regulations and may summarize various 
aspects of the study for SMC review. 
11.10 
Documentation of Study Findings 
Each investigational site will collect and compile clinical data for patients enrolled at their site(s) 
using the electronic data capture platform. All protocol-required information collected during the 
study must be entered by the investigator, or designated representative, in the CRF. Paper charts 
in the form of printouts of the electronic medical record will be kept at the investigational site for 
each subject enrolled and stored in a locked office with limited access for only research staff. Details 
of CRF completion and correction will be explained to the investigator. If the investigator 
authorizes other persons to make entries in the CRF, the names, positions, signatures, and initials 
of these persons must be supplied to the Sponsor. 
The investigator or designated representative should complete the CRF pages as soon as possible 
after information is collected, preferably on the same day that a study subject is seen for an 
examination, treatment, or any other study procedure. 
 
 


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12. 
STATISTICAL CONSIDERATIONS 
12.1 
Sample Size 
This study is an open-label, multisite, Phase 1/2 study evaluating the safety of repeat 
administration of a single dose level Ad/PNP-F-araAMP in subjects with head and neck cancer 
and who have failed or exhausted all standard or approved therapies. No formal sample size 
estimation will be conducted. Approximately 10 to 20 subjects will be enrolled into the study in 
order to have 10 subjects evaluable for efficacy; this number of subjects is sufficient to assess 
preliminary safety and activity to guide design of subsequent clinical studies. This study is to be 
conducted at Stanford University, Emory University, and Thomas Jefferson University. 
A total of 10 to 20 subjects in the safety population provides sufficient precision to rule out a 
treatment-related SAE rate of 38.5% or more using a one-sided 80% upper confidence limit as per 
the following table: 
Safety Population N 
N of Events 
Observed Proportion of 
Events 
One-sided 80% Upper 
Confidence Limit 
10 
2 
0.2000 
0.38094 
11 
2 
0.1818 
0.35005 
12 
2 
0.1667 
0.32382 
13 
3 
0.2308 
0.38397 
14 
3 
0.2143 
0.35917 
15 
3 
0.2000 
0.33735 
16 
4 
0.2500 
0.38452 
17 
4 
0.2353 
0.36388 
18 
4 
0.2222 
0.34528 
19 
5 
0.2632 
0.38418 
20 
5 
0.2500 
0.36646 
 
 
With 10 subjects evaluable for efficacy, there is 83% power to reject a null hypothesis ORR of 
10% or less when the alternative hypothesis ORR is at least 40% using a one-sided exact binomial 
test with a target alpha level of 10% (actual alpha is 7%). The null hypothesis is rejected if 3 or 
more responses are observed (i.e., observed ORR is at least 30%) and is considered sufficient 
evidence of efficacy to warrant further study of the treatment.  
An alternative hypothesis ORR of at least 40% in this study with five cycles of therapy is 
considered reasonable based on the published phase I results, where 66.7% of subjects in the higher 
dosing cohorts achieved a BOR of CR or PR with a single cycle of treatment.  


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12.2 
Assessment of Safety Measures 
The primary endpoint of the study is safety which will be assessed on clinical examination and 
measurement of laboratory parameters. 
All subjects who receive a dose of Ad/PNP-F-araAMP will be included in the safety analysis 
population. Each subject will be followed for safety for ~ 60 days following their final study dose. 
All safety assessments including adverse events, clinical laboratory evaluations, and vital signs 
will be summarized with descriptive statistics, where appropriate, and listed in the data listings 
using Medical Dictionary for Regulatory Activities (MedDRA) terms. We consider the repeat 
administration of Ad/PNP-F-araAMP safe if the one-sided 80% upper confidence limit of the 
percentage of subjects in the safety population experience treatment-related Serious Adverse 
Events as defined in Section 7.2. For example, if 2 of 10 subjects experience a treatment related 
SAE, then the one-sided 80% upper confidence limit is 38.1% and the repeat administration of 
Ad/PNP-F-araAMP is considered safe. 
12.3 
Adverse Events 
All AEs will be coded by system organ class (SOC) and preferred term using MedDRA v25.0. 
Summary tables for treatment emergent adverse events will include number of occurrences of 
events by SOC, and numbers and percentages of subjects experiencing adverse events by SOC and 
preferred term. If a subject has more than one AE which codes to the same preferred term, the 
subject will be counted only once for that preferred term. Similarly, if a subject has more than one 
AE within an SOC category, the subject will be counted only once in that SOC category. Summary 
tables to be generated include: summary of AEs, relationship of AEs to study drug, severity of 
AEs, AEs leading to study drug discontinuation and serious AEs. Data listings will be provided 
for AEs, AEs leading to study drug discontinuation, and serious AEs. 
12.4 
Clinical Laboratory Results 
Results of laboratory tests from hematology and chemistry evaluations that are outside of the 
reference range will be flagged and displayed in the summary tables. Descriptive statistics (e.g., 
number of subjects, mean, standard deviation, minimum, maximum, median and interquartile) for 
hematology and serum chemistry measurements will be calculated for each time point. The same 
descriptive statistics will be generated for these changes from baseline for each measurement. A 


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spaghetti plot will visually track selected measurements over time for each patient. Baseline is 
defined as the last measurable value prior to dosing on Day 1. All clinical laboratory data will be 
provided in the data listing. 
12.5 
Vital Signs and Physical Examination 
Descriptive statistics (e.g., number of subjects, mean standard deviation, minimum, maximum, 
and median) of vital sign measurements for systolic and diastolic blood pressure, heart rate, 
respiratory rate, and body temperature will be calculated for each measurement. Baseline is defined 
as the last measurable value prior to dosing on Day 1. All vital signs will be provided in the data 
listing.  Physical examination of individual subjects will be presented in the data listings. No 
summary tables will be provided. 
12.6 
Assessment of Efficacy Measures 
Response (CR, PR, SD, PD) is based on the Response Evaluation Criteria in Solid Tumors 
(RECISThttp://www.ctep.info.nih.gov v1.1) [6] and defined in Sections 9.3.4 and 10. 
Efficacy assessments include: 
• 
ORR is defined as the percentage of patients with a BOR of CR or PR.  BOR is the best 
response achieved during the 5 cycles of treatment, as per Section 9.3.4 for injected tumors 
and overall as determined by RECIST v.1.1.  
• 
Durable response rate is defined as a BOR of CR or PR as per Section 9.3.4 for injected 
tumors and overall as determined by RECIST v. 1.1 persisting for at least 4 weeks. 
• 
TTR is defined as time from first intratumoral injection to date of first response value of 
CR or PR for injected tumors as per Section 9.3.4 and overall as determined by RECIST 
v.1.1. 
• 
OS is defined as time from first intratumoral injection to date of progression or death for 
any cause, whichever occurs first. 
• 
PFS is defined as time from first intratumoral injection to date of progression or death for 
any cause, whichever occurs first. 


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GeoVax, Inc. 
 
Ad/PNP-F-araAMP 
Protocol No. PNP-002 
V4.0 06 May 2022 
 
 
 
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• 
DOR is defined as time from first documentation of CR or PR for injected tumors as per 
Section 9.3.4 and overall, as determined by RECIST v.1.1.until disease progression or 
death for any cause, whichever occurs first. 
Efficacy will be assessed in the population of subjects who receive three intratumoral 
administrations of Ad/PNP and any infusion of F-araAMP. 
Descriptive statistics (number and percentage of subjects) will be used to summarize BOR, ORR, 
and durable response rate. 95% Clopper-Pearson confidence intervals will also be provided. OS, 
PFS, DOR, and TTR will be analyzed based on Kaplan-Meier methods; Kaplan-Meier curves will 
be plotted over time. The number and percentage of subjects identified to have had an event and 
those who were censored will be displayed. The median time to event and its corresponding 95% 
CI will also be produced. A listing of response for subjects will be provided. 
 


CONFIDENTIAL 
GeoVax, Inc. 
 
Ad/PNP-F-araAMP 
Protocol No. PNP-002 
V4.0 06 May 2022 
 
 
 
Page 65 
13. 
REFERENCES 
1. 
Machiels JPH, et al., Rationale and design of LUX-Head & Neck 1: A randomised, Phase III 
trial of afatinib versus methotrexate in patients with recurrent and/or metastatic head and neck 
squamous cell carcinoma who progressed after platinum-based therapy. BMC Cancer 2014. 
14:473. 
2. 
Fury MG and Pfister DG. Current recommendations for systemic therapy of recurrent and/or 
metastatic head and neck squamous cell cancer. JNCCN, 2011. 9: 681-690. 
3. 
Vermorken JB, et al., Platinum-based chemotherapy plus cetuximab in head and neck cancer. 
N Engl J Med, 2008. 359:1116-27. 
4. 
Peron J, et al., An effective and well-tolerated strategy in recurrent and/or metastatic head and 
neck cancer is successive lines of active chemotherapeutic agents. BMC Cancer, 2014. 
15:504. 
5. 
Rosenthal EL, et al., Phase I dose-escalating trial of Escherichia coli purine nucleoside 
phosphorylase and F-araAMP gene therapy for advanced solid tumors. Ann Oncol, 2015. 
26:1481-7. 
6. 
Eisenhauer EA, et al., New response evaluation criteria in solid tumors: Revised RECIST 
guideline (version 1.1). European J Cancer, 2009. 45: 228-247. 
 


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GeoVax, Inc. 
 
Ad/PNP-F-araAMP 
Protocol No. PNP-002 
V4.0 06 May 2022 
 
 
 
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APPENDICES 


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GeoVax, Inc. 
 
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Protocol No. PNP-002 
V4.0 06 May 2022 
 
 
 
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Appendix A: Participant Eligibility Checklist 
A Participant Eligibility Checklist must be completed in its entirety for each subject prior to 
registration. The completed, signed, and dated checklist must be retained in the patient’s study file 
and the study’s Regulatory Binder. 
The study coordinator, treating physician and an independent reviewer must verify that the 
participant’s eligibility is accurate, complete, and legible in source records. A description of the 
eligibility verification process should be included in the EPIC or other electronic medical record 
progress note. 
Protocol Title: 
Phase 1/2, Open-label Study Evaluating the Safety of Repeat Administration 
of Ad/PNP-F-araAMP (Ad/PNP Administered Intratumorally with 
Co-administration of F-araAMP Phosphate Intravenously) in Subjects with 
Recurrent, Local Head and Neck Cancer 
 
 
 
II. 
Subject Information: 
Subject Name/ID: 
Gender: 
Male 
Female 
 
 
 
III. Study Information: 
SRC Approved IRB Approved Contract signed 
 
 


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Ad/PNP-F-araAMP 
Protocol No. PNP-002 
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IV. Inclusion/Exclusion Criteria 
Inclusion Criteria 
(From IRB approved 
protocol) 
Yes 
No 
Supporting 
Documentation* 
1. Provided Informed Consent 
 
 
 
2. Age ≥ 18 years. 
 
 
 
3. Patients with histologically or cytologically 
confirmed diagnosis of recurrent cancer of the 
head and neck region for whom there is no 
curative treatment option. For the purposes of 
trial eligibility, cancers of the head and neck 
region shall include, in addition to head and neck 
squamous cell carcinoma (HNSCC), cutaneous 
squamous cell primary sites and squamous cell 
carcinoma of unknown primary presenting with 
neck lymph nodal disease, as well as 
nasopharyngeal carcinoma and salivary gland 
tumors. 
 
 
 
4. All standard or approved treatment options that 
would provide substantive palliation must have 
failed, been exhausted, or patient not eligible for 
them (for example neuropathy, nephropathy, or 
hearing loss precluding the use of cisplatin). 
 
 
 
5. Tumor 
mass 
(primary 
tumor 
and/or 
lymphadenopathy) measurable by Response 
Evaluation Criteria in Solid Tumors (RECIST) 
1.1 and technically suitable for intratumoral 
injections (otolaryngologist will determine 
feasibility). Patients with nodal disease (or 
metastatic disease) that is needle accessible are 
eligible. Patients with additional tumors 
(including distant metastatic disease) beyond 
the intratumoral injection accessible tumor(s) 
that are not accessible for intratumoral injection 
are eligible ONLY if the patient has no other 
treatment option for the metastatic disease and 
treatment of local disease may provide the 
patient some benefit or palliation. 
 
 
 
6.  Eastern Cooperative Oncology Group (ECOG) 
performance status of ≤ 2. 
 
 
 
7.  In the judgment of the Investigator, the patient 
has recovered sufficiently from any previous 
significant therapy side effects or toxicities prior 
to Ad/PNP administration. 
 
 
 


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GeoVax, Inc. 
 
Ad/PNP-F-araAMP 
Protocol No. PNP-002 
V4.0 06 May 2022 
 
 
 
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Inclusion Criteria 
(From IRB approved 
protocol) 
Yes 
No 
Supporting 
Documentation* 
8.  Absolute neutrophil count [ANC] ≥ 1,500 
cells/µl; hemoglobin ≥ 9 g/dl, platelets ≥ 
100,000/µl. 
 
 
 
9.  Serum creatinine ≤ 1.5 mg/dl, or calculated 
creatinine clearance ≥ 60 ml/min. 
 
 
 
10.  Bilirubin ≤ upper limit normal [ULN], alanine 
aminotransferase [ALT] ≤ 1.5 x ULN and/or 
aspartate aminotransferase [AST] ≤ 1.5 x ULN, 
alkaline phosphatase ≤ 2.5 x ULN. 
 
 
 
11.  Prothrombin 
time 
(PT)/international 
normalized ratio (INR) ≤ 1.5 x ULN. 
 
 
 
12.  Activated partial thromboplastin (aPTT) time ≤ 
1.5 x ULN. 
 
 
 
13.  Female patients must have a negative urine or 
serum pregnancy at screening (pregnancy test 
is not required for patients with bilateral 
oophorectomy and/or hysterectomy or for those 
patients who are > 1 year postmenopausal) 
 
 
 
14.  All patients of reproductive potential must 
agree to use a medically acceptable form of 
contraception (e.g., hormonal birth control, 
double-barrier method) or abstinence. 
 
 
 
 
 
 


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GeoVax, Inc. 
 
Ad/PNP-F-araAMP 
Protocol No. PNP-002 
V4.0 06 May 2022 
 
 
 
Page 70 
Exclusion Criteria 
(From IRB approved 
protocol) 
Yes 
No 
Supporting 
Documentation* 
1.  Prior history or current diagnosis of leukemia. 
 
 
 
2.  Have received any gene therapy products or 
oncolytic viral therapy. 
 
 
 
3.  Receiving allopurinol. 
 
 
 
4.  Received an investigational drug within 30 days 
prior to first injection of Ad/PNP. 
 
 
 
5.  Received radiation treatment < 4 weeks prior to first 
injection of Ad/PNP and does not have any RECIST 
1.1 evaluable lesions that are outside the radiation 
field. (If the patient has RECIST 1.1 evaluable lesions 
outside the radiation field then they can be included). 
 
 
 
6.  Received 
chemotherapy 
(systemic 
anticancer 
treatment) < 4 weeks prior to first injection of 
Ad/PNP and have not recovered from all the related 
side effects. (If the patient has recovered from all 
related side effects or has reached a new baseline, 
then they may begin receiving treatment at sooner 
than 4 weeks). 
 
 
 
7.  Have significant baseline neuropathy (> Grade 2 
based on Common Terminology Criteria for 
Adverse Events [CTCAE] v5.0). 
 
 
 
8.  Uncontrolled intercurrent disease (e.g., diabetes, 
hypertension, thyroid disease, active infection). 
 
 
 
9.  Had within 6 months prior to enrollment: myocardial 
infarction (MI), cerebral vascular accident (CVA), 
uncontrolled congestive heart failure (CHF), 
significant liver disease, unstable angina. 
 
 
 
10.  Fever (temperature > 38.1o C orally). 
 
 
 
11.  Receiving chronic systemic corticosteroids (> 3 
weeks) 
or 
any 
chronic 
immunosuppressive 
medications within 14 days prior to first injection of 
Ad/PNP. Subjects receiving short courses of 
corticosteroids are considered eligible for the study. 
 
 
 
12.  Receiving anticoagulants other than those to 
maintain patency of venous lines, 
 
 
 
13.  Women who are pregnant or breast feeding, 
 
 
 
14.  History of HIV infection. No requirement for testing. 
 
 
 
* 
All subject files must include supporting documentation to confirm subject eligibility. The method of 
confirmation can include, but is not limited to, laboratory test results, radiology test results, subject self-report, 
and medical record review. 
 


CONFIDENTIAL 
GeoVax, Inc. 
 
Ad/PNP-F-araAMP 
Protocol No. PNP-002 
V4.0 06 May 2022 
 
 
 
Page 71 
V. 
Statement of Eligibility 
By signing this form of this trial I verify that this subject is [ 
eligible / 
ineligible] for 
participation in the study. This study is approved by the Stanford Cancer Institute Scientific 
Review Committee, the Stanford IRB, and has finalized financial and contractual agreements as 
required by Stanford School of Medicine’s Research Management Group. 
 
 
Treating Physician Signature: 
Date: 
Printed Name: 
 
 
 
Secondary Reviewer Signature: 
Date: 
Printed Name: 
 
 
 
Study Coordinator Signature: 
Date: 
Printed Name: 
 

SAP_001.pdf: 
 
 
CONFIDENTIAL 
           Page 1 of 35 
 
 
 
Statistical Analysis Plan 
 
PHASE 1/2, OPEN-LABEL STUDY EVALUATING THE SAFETY 
OF REPEAT ADMINISTRATION OF  
AD/PNP-F-ARAAMP (AD/PNP ADMINISTERED 
INTRATUMORALLY WITH CO-ADMINISTRATION OF  
FLUDARABINE PHOSPHATE INTRAVENOUSLY) IN 
SUBJECTS WITH RECURRENT,  
LOCAL HEAD AND NECK CANCER 
 
Protocol Number: PNP-002 
 
SAP Version and Date:   
Final Version 1.0, 
 19-Oct-2023 
 
STUDY DRUG:  
Ad/PNP-F-araAMP 
 
PREPARED FOR: 
GeoVax, Inc. 
1900 Lake Park Drive Suite 380 
Smyrna, GA 30080 
 
PREPARED BY: 
Allucent 
2000 Centergreen Way, Suite 300 
Cary, NC 27513 


Sponsor: GeoVax
Statistical Analysis Plan
Protocol Number: PNP-002
Final Version 1.0, 19-Oct-2023
CONFIDENTIAL
Page 2 of 35
Approval Signature Page 
Allucent
Author: Kenneth J. Peschell, PhD
Project Director, Biostatistics
Date
Document Reviewer: Vanessa Beddo, PhD
Vice President, Global Head of Biostatistical Consulting
Date
GeoVax, Inc.
Document Reviewer: Kelly McKee, MD, MPH
Chief Medical Officer
Date
Document Reviewer: Erica Raiden
Director, Clinical Operations
Date


Sponsor: GeoVax 
 
Statistical Analysis Plan 
Protocol Number: PNP-002  
 
Final Version 1.0, 19-Oct-2023 
CONFIDENTIAL 
           Page 3 of 35 
 
Revision History 
 
SAP Revision Chronology: 
 
 
N/A 
19-Oct-2023 
Final Version 1.0  
 
 
 


Sponsor: GeoVax 
 
Statistical Analysis Plan 
Protocol Number: PNP-002  
 
Final Version 1.0, 19-Oct-2023 
CONFIDENTIAL 
           Page 4 of 35 
 
 
Contents 
1 
Introduction ............................................................................................................................. 8 
1.1 
Changes to the Planned Analysis ..................................................................................... 8 
2 
Study Objectives and Endpoints ............................................................................................. 9 
3 
Study Design ......................................................................................................................... 10 
3.1 
General Description........................................................................................................ 10 
3.2 
Randomization and Blinding .......................................................................................... 12 
3.3 
Sample Size .................................................................................................................... 12 
3.4 
Study Committees .......................................................................................................... 13 
3.4.1 
Safety Monitoring Committee ................................................................................ 13 
3.5 
Timing of Analyses ........................................................................................................ 13 
4 
Analysis Populations ............................................................................................................. 13 
5 
General Considerations ......................................................................................................... 13 
5.1 
General Data Handling ................................................................................................... 13 
5.2 
General Definitions ........................................................................................................ 14 
5.3 
Data Imputation Rules .................................................................................................... 16 
5.4 
Visit Windows ................................................................................................................ 16 
5.5 
Pooling of Sites/Centers ................................................................................................. 16 
6 
Analysis Methods.................................................................................................................. 16 
6.1 
Study Participant Data .................................................................................................... 16 
6.1.1 
Participant Enrollment and Disposition .................................................................. 16 
6.1.2 
Protocol Deviations ................................................................................................. 17 
6.1.3 
Demographic and Baseline Characteristics ............................................................ 17 
6.1.4 
Medical History ...................................................................................................... 18 
6.1.5 
Prior and Concomitant Medication ......................................................................... 18 
6.1.6 
Prior and Concomitant Procedures ......................................................................... 18 
6.1.7 
Study Drug Exposure and Compliance ................................................................... 19 
6.2 
Efficacy .......................................................................................................................... 20 
6.2.1 
Primary Efficacy Endpoint(s) and Analyses ........................................................... 20 
6.2.2 
Secondary Efficacy Endpoints and Analyses ......................................................... 20 
6.2.3 
Exploratory Efficacy Endpoints and Analyses ....................................................... 24 
6.2.4 
Multiplicity ............................................................................................................. 24 
6.3 
Interim Analysis ............................................................................................................. 24 


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6.4 
Subgroup Analyses ......................................................................................................... 24 
6.5 
Correlative/Special Studies ............................................................................................ 25 
6.6 
Safety .............................................................................................................................. 25 
6.6.1 
Adverse Events ....................................................................................................... 25 
6.6.2 
Clinical Laboratory Evaluations ............................................................................. 27 
6.6.3 
Vital Signs ............................................................................................................... 27 
6.6.4 
ECOG Performance Status ..................................................................................... 28 
6.6.5 
Electrocardiogram (ECG) ....................................................................................... 28 
6.6.6 
Physical Examinations ............................................................................................ 28 
7 
References ............................................................................................................................. 29 
8 
APPENDICES ...................................................................................................................... 31 
8.1 
APPENDIX 1: Partial Date Conventions ....................................................................... 31 
Algorithm for Treatment Emergence of Adverse Events: ........................................................ 31 
Algorithm for Prior / Concomitant Medications:...................................................................... 32 
8.2 
APPENDIX 2: Protocol Study Procedures Table .......................................................... 34 
 
 
 
 


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ABBREVIATIONS 
AE  
Adverse event  
ALT  
Alanine aminotransferase  
aPTT  
Activated partial thromboplastin  
AST  
Aspartate aminotransferase  
ATC 
Anatomic Therapeutic Class 
BOR  
Best overall response  
BUN  
Blood urea nitrogen  
CBER  
Center for Biologics Evaluation and Research (of the FDA)  
CDER  
Center for Drug Evaluation and Research (of the FDA)  
CI  
Confidence Interval 
CR  
Complete response  
CRF  
Case report form  
CT  
Computed tomography  
CTCAE  
Common Terminology Criteria for Adverse Events  
DLT  
Dose-limiting toxicity  
DOR  
Duration of response  
ECG  
Electrocardiogram  
ECOG  
Eastern Cooperative Oncology Group  
F-araA  
Fludarabine  
F-araAMP  
Fludarabine phosphate  
FDA  
Food and Drug Administration  
INR  
International normalized ratio  
IV  
Intravenous(ly)  
kg  
Kilogram  
LD  
Longest diameter  
mg  
Milligram  
mL  
Milliliter  
MRI  
Magnetic resonance imaging  
NCI  
National Cancer Institute  
ORR  
Objective response rate  
OS  
Overall survival  
PD  
Progressive disease  
PFS  
Progression free survival  
PI  
Principal Investigator  
PJP  
Pneumocystis jiroveci  
PNP  
Purine Nucleoside Phosphorylase  
PR  
Partial response  
PT  
Prothrombin time  
RECIST  
Response Evaluation Criteria in Solid Tumors  
SAE  
Serious adverse event  
SAP 
Statistical Analysis Plan 
SD  
Stable disease  
SE 
Standard Error 
SMC  
Safety Monitoring Committee  
SOC 
System Organ Class 


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Statistical Analysis Plan 
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STD 
Standard Deviation 
TEAE  
Treatment-emergent adverse event  
TTR  
Time to response  
VP  
Viral particle  
 
 
 
 


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           Page 8 of 35 
 
1 INTRODUCTION 
The statistical analysis plan (SAP) details the planned statistical analysis methods required to 
address the study objectives as described in GeoVax’s protocol PNP-002:  A Phase 1/2, Open-label 
Study Evaluating the Safety of Repeat Administration of Ad/PNP-F-araAMP (Ad/PNP 
Administered Intratumorally with Co-administration of Fludarabine Phosphate Intravenously) in 
Subjects with Recurrent, Local Head and Neck Cancer.   
This SAP should be read in conjunction with the study protocol, case report form (CRF), and any 
other applicable study documents. This version of the SAP is based on the protocol PNP-002, 
Version 4.0 06MAY2022, Protocol Clarification Letter v.04 08MAR2023, and CRF 02NOV2022.  
Changes to these documents may result in subsequent changes to the SAP. The final, 
sponsor-approved version of the SAP must occur prior to database lock.  
A table of contents for tables, figures, and listings, as well as mock shells, will be maintained in a 
separate document.  
1.1 Changes to the Planned Analysis 
Additional details may have been provided for analyses and data presentations described in the 
protocol, but no changes were made to analyses specified in the protocol.  Any deviations from 
the approved statistical analysis plan will be described and justified in the final clinical study 
report. 
 
 


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2 STUDY OBJECTIVES AND ENDPOINTS 
 
Objectives 
Endpoints 
Primary:  
● To evaluate the safety of repeat administration of a 
dose level of Ad/PNP-F-araAMP that 
demonstrated anti-tumor activity in participants 
with advanced head and neck cancer in the 
completed Phase 1 study. 
● The primary endpoint is safety with repeat cycles 
of treatment. Safety measures include adverse 
events (AE) and laboratory parameters. 
Secondary: 
● To evaluate the anti-tumor activity of repeat 
administration of Ad/PNP-F-araAMP, defined as 
participants who receive three intratumoral 
administrations of Ad/PNP and any infusion of F-
araAMP. 
 
● Objective response rate (ORR), defined as the 
percentage of participants with a best overall 
response (BOR) of a complete response (CR) or a 
partial response (PR). BOR is the best response 
achieved during the up to 5 cycles of treatment, 
separately for injected tumors and overall as 
determined by RECIST v.1.1.  
● Durable response rate defined as a BOR of CR or 
PR, separately for injected tumors and overall as 
determined by RECIST v.1.1 persisting for at least 
4 weeks.  
● Time to response (TTR) defined as time from first 
intratumoral injection to date of first response 
value of CR or PR, separately for injected tumors 
and overall as determined by RECIST v.1.1.  
● Overall survival (OS) defined as time from first 
intratumoral injection to date of death for any 
cause.  
● Progression free survival (PFS) defined as time 
from first intratumoral injection to date of 
progression or death for any cause, whichever 
occurs first, separately for injected tumors and 
overall as determined by RECIST v.1.1.  
● Duration of response (DOR) defined as time from 
first documentation of CR or PR until disease 
progression or death for any cause, whichever 
occurs first, separately for injected tumors and 
overall as determined by RECIST v.1.1 . 
 
 
 


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3 STUDY DESIGN 
3.1 General Description 
This multi-center, open-label, phase 1/2, single-arm trial will evaluate the safety and anti-tumor 
activity of Ad/PNP-F-araAMP in participants with recurrent cancer of the head and neck region 
who have relapsed following curative treatment and without additional potentially curative 
treatment options. The study is designed to evaluate repeat administration (up to 5 cycles) of a 
single dose level of Ad/PNP administered intratumorally followed by intravenous (IV) F-
araAMP. This study is to be conducted at Stanford University, Emory University, and Thomas 
Jefferson University. 
 
Ad/PNP will be injected intratumorally twice on Day 1 and once on Day 2 followed by 25 
mg/m2 per infusion F-araAMP daily on Days 3, 4, and 5 infused over approximately 30 minutes. 
The 25 mg/m2 F-araAMP dose level is the same as that evaluated in the two highest cohorts in 
the Phase 1 study. Each enrolled study participant shall receive 0.5 ml/dose of Ad/PNP, to which 
an amount of diluent will be added based on the volume of tumors selected for treatment. The 
dilution of study agent is described in protocol section 4.2 and shall not exceed 5 ml regardless 
of the number of tumors accessible for injection.   
 
Tumor measurements taken on Day 1 of each cycle should be used to calculate dosing for Day 1 
and Day 2 of that cycle. 
 
Participants will receive repeat administration of Ad/PNP-F-araAMP every 4 weeks (i.e., each 
cycle) for 5 cycles or until injected tumor progresses, unacceptable toxicity occurs, no tumor is 
present for injection, or participant death.  
 
Tumor selection and classification of target vs non-target should be performed according to 
RECIST 1.1. Target tumors should be selected for treatment at the participant’s initial treatment 
visit. Following the participant’s initial treatment, no additional tumors should be identified as 
target or selected for treatment.  
 
The same tumors should be treated at each administration of study agent. It is possible for target 
tumors to be identified but not treated. Non-target tumors should not be treated with study agent.  
 
Tumor response in the injected tumor(s) will be assessed by physical examination (tumor 
measurement using ruler or calipers, if tumor can be assessed by palpation) as well as by 
radiographic imaging (magnetic resonance imaging [MRI] or computed tomography [CT] scan). 
The same methods to assess the injected tumor(s) will be used at baseline and subsequent time 
points.  
 
Participants will be assessed for safety frequently, including Day 14 of each cycle. Participants 
will be assessed 4 weeks after completion of the last or fifth cycle. During the study, participants 
will be monitored for AEs including signs of infection, and changes in hematological or 
chemistry parameters (see Appendix 2, Protocol Study Procedures Table).  
 


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Participants who withdraw early from treatment will be asked to complete Day 56 (of the last 
treatment cycle) study visit evaluations. The study schema is presented in Figure 1. 
Figure 1: Study Design 
 
DLT = Dose-limiting toxicity; IV = intravenously; PD = progressive disease, VP = viral particle; 


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Protocol Number: PNP-002  
 
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3.2 Randomization and Blinding 
PNP-002 is an unblinded, open label study. 
3.3 Sample Size  
Regarding efficacy, no formal hypotheses or sample size estimates will be generated for this study. It 
is anticipated that approximately 10 to 20 participants will be enrolled into the to achieve 10 
participants evaluable for efficacy. This number of participants is sufficient to assess preliminary safety 
and activity to guide design of subsequent clinical studies. 
 
A total of 10 to 20 participants in the safety population provides sufficient precision to rule out a 
treatment-related serious adverse event (SAE) rate of 38.5% or more using a one-sided 80% upper 
confidence limit as per the following table: 
 
 
Safety Population N 
 
N of Events 
Observed Proportion 
of Events 
One-sided 80% Upper 
Confidence Limit 
10 
2 
0.2000 
0.38094 
11 
2 
0.1818 
0.35005 
12 
2 
0.1667 
0.32382 
13 
3 
0.2308 
0.38397 
14 
3 
0.2143 
0.35917 
15 
3 
0.2000 
0.33735 
16 
4 
0.2500 
0.38452 
17 
4 
0.2353 
0.36388 
18 
4 
0.2222 
0.34528 
19 
5 
0.2632 
0.38418 
20 
5 
0.2500 
0.36646 
 
 
With 10 participants evaluable for efficacy, there is 83% power to reject a null hypothesis ORR of 10% 
or less when the alternative hypothesis ORR is at least 40% using a one-sided exact binomial test with 
a target alpha level of 10% (actual alpha is 7%). The null hypothesis is rejected if 3 or more responses 
are observed (i.e., observed ORR is at least 30%) and is considered sufficient evidence of efficacy to 
warrant further study of the treatment. 
 
An alternative hypothesis ORR of at least 40% in this study with five cycles of therapy is considered 
reasonable based on the published phase I results, where 66.7% of participants in the higher dosing 
cohorts achieved a BOR of CR or PR with a single cycle of treatment.   
  
 
 


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3.4 Study Committees 
3.4.1 Safety Monitoring Committee 
The Safety Monitoring Committee (SMC) will review accumulating safety data (i.e., AE reporting, 
reactions to study treatment, deaths, etc.) and protocol deviations at time intervals specified in the 
SMC Charter and at any other time when it is determined by the SMC or GeoVax that such a review 
is warranted.  Additional details on the timing, format, and content of data provided to the SMC will 
be described in the SMC Charter. 
3.5 Timing of Analyses 
The final analysis will occur once all participants complete their end of study visit or their last 
scheduled assessment per the Protocol Study Procedures Table (Appendix 2), or the sponsor 
terminates the study for any reason. 
No interim analysis is planned. 
4 ANALYSIS POPULATIONS 
Enrolled Population: Defined as all participants who sign an informed consent. The Enrolled 
Population will be used for summaries of enrollment and participant disposition. 
Safety Population (SAF): Defined as all participants who receive any intratumoral administrations 
of Ad/PNP or any infusion of F-araAMP. The SAF will be the primary population for all safety 
reporting.  
Efficacy Evaluable Population:  Defined as all participants who receive at least three intratumoral 
administrations of Ad/PNP and any infusion of F-araAMP. The efficacy evaluable population will 
be used as the primary analysis population for all efficacy reporting. 
5 GENERAL CONSIDERATIONS 
5.1 General Data Handling 
All analyses will be conducted based on SAS 9.4 or higher. 
Study data will be recorded in eCRFs for all screened and enrolled participants. The electronic 
data capture (EDC) vendor for this study is Allucent. 
The protocol deviation data will be provided in spreadsheet format from the clinical trial 
management system (CTMS). 
Analysis tables will be presented in aggregate (overall) for a specified population. 
Data will be presented in by-participant data listings. Unless otherwise stated, all listings will be 
sorted by site ID, participant number, and assessment date (and time, if available). 
Continuous data will be summarized by treatment group based on n, mean, median, standard 
deviation (STD), first quartile (Q1), third quartile (Q3), minimum value, and maximum value.  


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Categorical data will be summarized by treatment arm using frequency counts and percentages. 
Where applicable, 95% confidence intervals (CIs) will be provided. Unless otherwise stated, the 
denominator of percentages will be the number of participants in the population or the number 
with non-missing data.   
• The number of missing values will be presented as a separate category with no percentage, 
but only if one or more participants are missing data. 
• Counts of zero will be presented without percentages. 
Relative to the number of digits after the decimal in the raw data, summary statistics will have the 
following number of digits after the decimal:  
• Minimum and Maximum: same number of significant digits as the raw data 
• Mean, Median, Q1, and Q3: one additional significant digit 
• Standard Deviation (STD) or Standard Error (SE): two additional significant digits 
• Percentages <100% will be reported to one decimal place and percentages of 100% will be 
reported with no decimal place. 
• P-values will be reported to four decimal places. If the value is below 0.0001 it will be 
noted as < 0.0001; if the value is above 0.9999 it will be noted as > 0.9999. 
• Summary statistics will not exceed four digits after the decimal. Some laboratory 
parameters or other data may require judicious deviation from this rule. 
Unless otherwise noted, statistical inference will be based on a 2-sided 5% significance level. 
All data up to the time of study completion/withdrawal from the study will be included in the 
analysis, regardless of duration of treatment. 
Numbering for data displays will be based on ICH E3. 
5.2 General Definitions 
   
Variable 
Definition 
Study Day 
• Study Day = date of interest - reference date + 1, when the date 
of interest >= reference date; 
• otherwise, Study Day = date of interest - reference date. 
Note: if either day is missing, reference date calculations will not be 
performed. Should imputation be performed, then Study day may be 
computed, where appropriate. 
Baseline 
Defined as the last non-missing value collected prior to receiving the 
first intratumoral injection (based on date and time of administration 
as applicable). 
Post-baseline 
Defined as values collected after receipt of first intratumoral 
injection (based on date and time of administration as applicable) 
Change from 
Baseline 
Defined as: Post-baseline value - Baseline value  


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Percent Change from 
Baseline 
Defined as: (Post-baseline value - Baseline value)/Baseline value x 
100. 
Note: To calculate percent change from baseline, the baseline value 
cannot be equal to zero. 
Most Extreme 
Change 
The maximum most extreme change will be based on be the 
maximum post-baseline value; the minimum most extreme change 
will be based on the smallest post-baseline value. For laboratory 
data assessed with CTCAE grading, data from scheduled or 
unscheduled visits will be utilized. 
Maximum Reduction 
from Baseline 
The maximum reduction from baseline will be based on the 
minimum post-baseline value collected and calculated per the 
change from baseline formula above. For tumor measurements, 
post-baseline values will be considered until an overall response of 
PD; measurements collected after start of new cancer therapies will 
not be included. 
Maximum Percent 
Reduction 
Defined as the percent change that is associated with the minimum 
most extreme change (i.e., the largest decrease from baseline).  For 
tumor measurements, the maximum percent reduction will be the 
percent change from baseline for the maximum reduction from 
baseline.   
Maximum Percent 
Increase 
Defined as the percent change that is associated with the maximum 
most extreme change. 
Duration on Study (in 
days) 
End of study date - informed consent date +1.  
Duration of Time 
from Initial Diagnosis 
to Informed Consent 
(in months) 
(Date of Informed Consent - Date of Initial Diagnosis +1) / 30.4375.  
Duration of Adverse 
Event (in days) 
• Stop date of event - start date of event + 1, if time is not 
collected. 
• (Stop date/time of event - start date/time of event)/24, if time is 
collected. 
Time to Event (in 
months) 
(Date of event - first intratumoral injection +1) / 30.4375. If the 
event does not occur, participant will be censored as described for 
the appropriate endpoint in section 6.2. 
Reporting in Months 
Divide number of days by 30.4375  
Reporting in Years 
Divide number of days by 365.25  
Reporting in Weeks 
Divide number of days by 7 
Height (in cm) 
= height (in inches) * 2.54 
Weight (in kg) 
= weight (in lbs) * 0.4536 
BMI (kg/m2) 
= weight(kg)/[height(m)2] 
Age (yr) 
Age is collected in the EDC system (or through the IXRS system)  


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5.3 Data Imputation Rules  
Generally, missing data will not be imputed, and will be presented as collected in the study 
database. 
In cases where adverse event or medication dates are missing, the imputation methods described 
in Appendix 1 will be used to determine flags for treatment-emergent events and concomitant 
medications. 
Conventions for censoring for time-to-event efficacy endpoints are described within the definitions 
of the endpoints in section 6.2.2. 
5.4 Visit Windows 
Both efficacy and safety endpoints will be analyzed according to the recorded scheduled visits.  
Unscheduled visits will not be summarized in tables but will be presented in data listings.  
5.5 Pooling of Sites/Centers 
Not Applicable. 
6 ANALYSIS METHODS 
6.1 Study Participant Data 
6.1.1 Participant Enrollment and Disposition 
Participant enrollment and disposition data will be summarized for the enrolled 
population and listed.  Enrollment and disposition summaries will include: 
• Number of participants in each analysis population 
• Number of participants who have discontinued the study 
• Primary reason for early withdrawal/discontinuation from study 
o 
Progressive disease 
o 
Adverse Event 
o 
Withdrawal by Subject 
o 
Lost to follow-up 
o 
Protocol Specified Withdrawal Criterion Met  
o 
Protocol Violation  
o 
Physician Decision  
o 
Pregnancy  
o 
Non-Compliance with Study Drug 
o 
Non-Compliance with Study Schedule 
o 
Study Terminated by Sponsor 
o 
Site Terminated by Sponsor 
o 
Sponsor Request 
o 
Death 
o 
Other 


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• Is early withdrawal/discontinuation from study related to COVID-19? 
• Time (months) on study 
• Primary reason for early withdrawal/discontinuation from treatment 
o 
Progressive disease 
o 
Adverse Event 
o 
Withdrawal by Subject 
o 
Lost to follow-up 
o 
Protocol Specified Withdrawal Criterion Met  
o 
Protocol Violation  
o 
Physician Decision  
o 
Pregnancy  
o 
Non-Compliance with Study Drug 
o 
Non-Compliance with Study Schedule 
o 
Study Terminated by Sponsor 
o 
Site Terminated by Sponsor 
o 
Sponsor Request 
o 
Death 
o 
Other 
• Is early withdrawal/discontinuation from treatment related to COVID-19? 
   
Completion of treatment is defined as participants who have received at least three 
administrations of Ad/PNP and at least 1 infusion of F-araAMP prior to their withdrawal from 
the study.  
Completion of the study is defined as any participant who completes one or more cycles (visits 
1-7).  
 
Participants who are discontinued from the study via the discretion of the investigator, or no 
longer receiving IP by other criteria specified in the protocol, will be considered to have 
completed the study if at least 1 cycle (visits 1-7) is completed. 
 
Participants who withdraw from the study will be considered to have completed the study if at 
least 1 cycle (visits 1-7) is completed. 
Participants contributing to each analysis population and final disposition status will be listed. 
6.1.2 Protocol Deviations 
A listing of protocol deviations will be provided. 
6.1.3 Demographic and Baseline Characteristics 
Participant demographics will be summarized and listed.  These will include age, sex (Male / 
Female), child-bearing potential (Yes / No), ethnicity (Hispanic / Non-hispanic / Not Reported / 
Unknown), race (American Indian or Alaska Native / Asian / Black or African American / Native 
Hawaiian or Pacific Islander / White / Not Reported), baseline height (cm), baseline weight (kg), 
and baseline BMI (kg/m2). 


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Disease history and baseline disease characteristics will be summarized.  These will include: 
Duration of time from initial diagnosis to screening (in months), primary site of cancer, histology 
type, stage at diagnosis, TNM at study entry, Progression/Recurrence/Metastasis observed after 
diagnosis, Progression/Recurrence/Metastasis specification and location, extent of disease, 
baseline tumor measurements, prior chemotherapy (Yes/No), prior immunotherapy (Yes/No), 
prior radiation (Yes/No), prior surgery (Yes/No), baseline ECOG, Chest Radiograph results, 
baseline CT scan/MRI results will be summarized, as well as baseline prognostic laboratory values 
for the following selected laboratory tests:  
• Hemoglobin, hematocrit, white blood cell count, lymphocytes (absolute), lymphocytes 
(percentage), neutrophils (absolute), neutrophils (percentage), platelet count. 
• Prothrombin time (PT), activated partial thromboplastin time (aPTT), international 
normalized ratio (INR). 
Listings of demographics, disease history, baseline disease characteristics, and Smoking/Alcohol 
History will be provided.   
6.1.4 Medical History 
Medical History will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 26.0 and will be listed by System Organ Class and Preferred Term. 
A listing of medical history will be provided. 
6.1.5 Prior and Concomitant Medication  
The incidence of medication use will be summarized by WHO Drug Dictionary (WHODD) B3 
Global March 2023 anatomic therapeutic chemical (ATC) Level 2 classification (i.e. therapeutic 
main group) and preferred name. A participant will be counted only once at each level of reporting.  
Prior medications are those which have been identified to have been discontinued prior to the 
treatment start date (e.g., taken exclusively during the pre-therapy period).  Concomitant 
medications are those which have been identified to have been taken at any point during the 
on-therapy or post-therapy periods.  Prior and concomitant medication use will be summarized 
separately. 
All prior and concomitant medication data will be listed including the verbatim and preferred drug 
name and ATC Level 2.  If anticancer medications have been recorded as taken during study, these 
will be identified via medical review and flagged in data listings. 
6.1.5.1 PJP Prophylaxis Antibiotic Treatment 
The incidence of PJP Prophylaxis Antibiotic Treatment use will be summarized. A participant 
will be counted only once for any use.   
All PJP Prophylaxis Antibiotic Treatment data will be listed. 
6.1.6 Prior and Concomitant Procedures 
Number and percentages of prior and concomitant procedures will be summarized by indication, 
procedure, location, and laterality.  Prior procedures are those which have been identified to have 


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been discontinued prior to the procedures start date (e.g., taken exclusively during the pre-therapy 
period).  Concomitant procedures are those which have been identified to have been taken at any 
point during the on-therapy or post-therapy periods.  Prior and concomitant procedures will be 
presented in data listings. 
6.1.7 Study Drug Exposure and Compliance 
For both Ad/PNP and F-araAMP (separately), completion of a given cycle is defined as follows: 
• Completed cycle is defined as all 3 administrations performed. 
• Partial cycle is defined as < 3 administrations performed. 
Note that, based on the data collection in the eCRF, an administration is either performed or not 
performed; there is no consideration of partially vs. fully performing an administration. In contrast, 
a partial Ad/PNP injection or a partial F-araAMP infusion are considered below. 
For Ad/PNP, an administration is defined farther below. For F-araAMP, an administration is 
defined as a full infusion or a partial infusion.  
Exposure to Ad/PNP will be summarized using the following measures:   
• Total Number of Cycles Completed. 
• Total Number of Cycles Received.  Defined as the total number of completed or partial 
cycles.  
• Number of administrations performed 
• Number of administrations not performed 
• Number of administrations delayed 
• Number of injections administered (fully or partially) 
• Number of injections fully administered 
• Number of injections partially administered 
• Number of injections not administered 
• Treatment Duration (days): Last dose date - First dose date + 1 
For the Ad/PNP exposure endpoints listed above, a single Ad/PNP administration is defined 
without regard to the number of injections or the number of tumors treated, while the number of 
injections is defined considering the number of tumors treated.  For example, a participant might 
have: 
• 3 administrations during any given cycle, comprised of 
• 1 tumor treated at each administration, yielding a total of 3 injections.  
or, 
• 3 administrations during any given cycle, comprised of 
• 2 tumors treated at each administration, yielding a total of 6 injections.  
F-araAMP exposure will also be summarized using mg/m2. 
• Total Number of Cycles Completed. 
• Total Number of Cycles Received.  Defined as the total number of completed or partial 
cycles.  


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• Total Cumulative Dose Received. Defined as total mg/m2 received from first dose date 
up to and including last dose date. 
• Number of infusions administered (fully or partially) 
• Number of infusions which were temporarily interrupted or had flow rate modified. 
• Number of infusions fully administered 
• Number of infusions partially administered 
• Number of infusions not administered 
• Number of infusions delayed 
• Dose Intensity (mg/m2/Cycle). Defined as [total cumulative dose (mg/m2)] / [number 
of Cycles Received]. 
• Treatment Duration (days): Last dose date - First dose date + 1 
No assessment of study drug compliance will be performed for this study. 
6.2 Efficacy  
Efficacy analyses will be conducted on the Efficacy Evaluable Population (refer to section 4). 
In addition to the tabular summaries detailed below, efficacy data will be provided in 
by-participant data listings. 
6.2.1 Primary Efficacy Endpoint(s) and Analyses 
There is no primary efficacy endpoint, and therefore no primary efficacy analysis, as the primary 
endpoint for this study is safety.  However, an efficacy endpoint of primary focus is defined in 
section 6.2.2. 
6.2.2 Secondary Efficacy Endpoints and Analyses 
 
Secondary efficacy endpoints involving response, including progression, will be assessed 2 distinct 
ways: 
• For injected tumors (per the criteria specified in protocol section 9.3.4), and 
• Overall as determined per RECIST v1.1 (http://www.ctep.info.nih.gov). 
 
Efficacy responses assessments for injected tumors should be performed using the (RECIST-like) 
assessment according the to the criteria established in section 9.3.4 (Tumor Response) of the 
protocol (CR, PR, PD, SD).  Per the protocol, this response for injected tumors is the primary focus 
for response, with the efficacy endpoint of primary focus being ORR for injected tumors. 
 
Overall efficacy response assessments should be performed per RECIST 1.1 for target and 
non-target tumors without consideration for which tumors were treated with the study agent.  Per 
the protocol, this overall response per RECIST 1.1 is not the primary focus for response. Total 
tumor burden is also being evaluated because there is a possibility of immune-mediated anti-tumor 
benefit. 
 
RECIST and protocol established response evaluation criteria should be performed/evaluated in 
combination with CT scan/MRI at the timepoints specified in the protocol (Visit 7 of the first, 


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second (if PD after first cycle), third, and last cycle. Participants with CR, PR, or SD in the injected 
tumor at Day 14 of the fifth or last cycle will have imaging on Day 56). 
 
To emphasize: 
• Injected tumors will not be assessed per RECIST v1.1 but solely per the criteria (from protocol 
section 9.3.4) which are specified below. 
• Many of the endpoints differ for injected tumors vs. overall as determined per RECIST v.1.1 
due to differences in their underlying component definitions of CR, PR, and PD. 
• All efficacy endpoints are secondary. 
 
Injected Tumor Response Criteria Details  
 
The following criteria will be used to define response in injected tumors: 
 
• Complete Response (CR): Disappearance of the injected tumor(s). 
• Partial Response (PR): At least a 30% decrease in the longest diameter (LD) of the injected 
tumor(s), taking as reference the smallest LD. 
• Progression (PD): At least a 20% increase in the LD of the injected lesion(s), taking as 
reference the smallest LD recorded on study (this includes the baseline LD if that is the smallest 
on study). Note: appearance of one or more new lesions will be considered progression in 
assessing overall tumor response. 
• Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
quality for PD taking as reference the smallest LD while on study. 
 
Regarding injected tumors, only tumors identified as target per RECIST 1.1 at the initial study 
visit should be treated with the study agent (AdPNP). It is possible, based on the size(s) and 
location(s) of the target tumor(s), that not all target tumors will be treated with the study agent. At 
each administration, investigators should treat only the same tumor(s) based on those target tumors 
treated at the initial treatment visit. No other target tumors should be treated with the study agent 
at any subsequent visit.  Non-target tumors should not be treated with the study agent. Response 
for injected lesions is assessed by the investigator and recorded in the eCRF.    
 
Regarding non-injected tumors, the protocol does not define response assessment criteria for these 
tumors.  Therefore, efficacy response for non-injected tumors will be taken into consideration only 
as an input to the RECIST 1.1 response assessment. No formal criteria-based response assessment 
will be performed or analyzed for non-target tumors alone.  Any observable effect on non-injected 
tumors may be recorded by investigators in the study database.   
 
Response Per RECIST v1.1 Criteria Details 
 
Response status per RECIST v1.1 will also be assessed by the investigator using all lesions (target, 
non-target, and new [if present]) as part of each evaluation. Post-baseline evaluation CT or MRI 
imaging (per RECIST) is to be done in all participants at Screening and at Visit 7 of the first, 
second (if PD after first cycle), third, and last cycle. Participants with CR, PR, or SD in the injected 
tumor at Day 14 of the fifth or last cycle will have imaging on Day 56.  There will be no PFS 
follow up beyond the treatment period. RECIST v1.1 results will be assessed by the investigator 


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and entered into applicable eCRF pages, including separate assessment of response for overall, 
target lesions, and non-target lesions.    
 
Secondary Efficacy Analyses 
 
All efficacy analyses are secondary, because all efficacy endpoints are secondary. 
Efficacy analyses will be conducted on the Efficacy Evaluable Population (refer to section 4). 
Regarding analyses, efficacy response results for injected tumors and overall (per RECIST v1.1) 
will be reported separately.  Generally, though, unless otherwise specified, both ways of 
assessment will be analyzed in the same manner. 
6.2.2.1 Best Overall Response, Objective Response Rate and Durable Response Rate 
Best Overall Response 
 
Separately for injected tumors and overall (per RECIST v1.1), a participant’s best overall response 
(BOR) is determined by the highest qualitative value assessed during the study for the following 
hierarchy of objective response results: CR > PR > SD > PD > NE.  In order for a valid value of 
SD to be assigned, there must be evidence of stable disease for at least 6 weeks.  If the minimum 
time for SD has not been met on the first assessment, the assignment of BOR will depend on 
subsequent response assessments.  Participants which do not have follow up data after a first 
assessment of SD prior to the minimum time requirement will be considered as not evaluable (NE).  
BOR will be based on assessments collected after the first intratumoral injection until disease 
progression; assessments collected after the start of new anticancer treatment will not be 
considered.  Confirmation of response will not be required for BOR. Participants who do not have 
any post-baseline results for response will be considered as not evaluable (NE).  
 
Separately for injected tumors and overall (per RECIST v1.1), BOR will be summarized using the 
efficacy evaluable population. 
 
Waterfall plots of BOR results for each criterion will be presented graphically using maximum 
percent reduction. Swimmer plots identifying participant response patterns over time will also be 
separately provided. 
 
Objective Response Rate 
 
Separately for injected tumors and overall (per RECIST v1.1), the objective response rate (ORR) 
is defined as the number of participants who exhibit a BOR response of CR or PR during the up to 
5 cycles of treatment divided by the number of participants in the efficacy evaluable population.   
 
Separately for injected tumors and overall (per RECIST v1.1), the ORR will be presented; 
corresponding two-sided 95% Clopper-Pearson exact confidence intervals (CIs) and the 
underlying number of participants will also be provided. The efficacy analysis of primary focus 
will be the analysis of ORR for injected tumors. 
 


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Durable Response Rate 
 
Separately for injected tumors and overall (per RECIST v1.1), the durable response rate will be 
determined via persistence of CR or PR for at least 28 days, with the corresponding response 
duration calculation, in days, as (the earliest date of PD or death for any cause - the date of first 
documentation of CR or PR + 1).  Participants who do not have at least 28 days of data following 
BOR of CR or PR will be considered to not have had durable response. Participants who 
discontinue prior to being evaluated for post-baseline tumor assessments will be considered as 
non-responders.   
 
Separately for injected tumors and overall (per RECIST v1.1), the durable response rate will be 
presented; corresponding two-sided 95% Clopper-Pearson exact CIs will also be provided. 
 
6.2.2.2 Progression Free Survival 
Separately for injected tumors and overall (per RECIST v1.1), PFS is defined as time from first 
intratumoral injection to date of progression or death for any cause, whichever occurs first, and is 
calculated, in months, as: 
 
(Date of first PD or death or censoring - date of first intratumoral injection + 1) / 30.4375.  
 
PFS derivation will not include tumor assessments collected after the end of study treatment as 
these are not planned for collection beyond the final cycle. Tumor assessments taken after switch 
to another anti-cancer therapy will be excluded from consideration. 
 
The first date of PD would be the earliest date of any post-baseline response finding of progressive 
disease or death unless a participant is censored at an earlier date.  If an assessment occurs over 
several days, the date of assessment as collected on the Response Assessments eCRF page will be 
used.  If there are no adequate assessments for a participant, they will be censored on their first 
intratumoral injection date unless they died prior to having their first assessment (in which case 
the death would be treated as an event).  If a participant receives subsequent anticancer therapy 
prior to documentation of progressive disease, PFS will be censored at the latest adequate 
assessment prior to additional therapy initiation.  Otherwise, if a participant does not have 
documented progression within this PFS observation period (i.e., until any PFS event or 
censoring), the participant will be censored at the latest adequate assessment. 
 
Separately for injected tumors and overall (per RECIST v1.1), PFS will be analyzed based on 
Kaplan-Meier methods; Kaplan-Meier curves will be plotted over time. The number and 
percentage of participants identified to have had a PFS event and those who were censored will be 
displayed. The median time to PFS and its corresponding 95% CI will also be produced.   
 
6.2.2.3 Time to Response 
Separately for injected tumors and overall (per RECIST v1.1), TTR is defined as time from first 
intratumoral injection to date of first response value of CR or PR during the PFS observation period 
(i.e., until any PFS event or censoring), and is calculated, in months, as: 
 


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(Date of first response or censoring - date of first intratumoral injection + 1) / 30.4375. 
 
TTR will be analyzed in the same manner as PFS, including the same censoring conventions with 
exception that date of death is used for censoring, not as an event). 
 
6.2.2.4 Overall Survival 
Separately for injected tumors and overall (per RECIST v1.1), overall survival (OS) is defined as 
time from first intratumoral injection to date of death for any cause, and is calculated, in months, 
as:  
(Date of death or censoring - date of first intratumoral injection + 1) / 30.4375.  
Participants still alive as of the data cut-off date will be censored on the last known alive date 
from mortality status follow up. For participants that are lost to follow up, the last visit in the 
database or last contact date where the participant is documented to be alive will be used to 
estimate last known date alive. 
OS will be analyzed based on the Kaplan-Meier methods described for PFS. 
6.2.2.5 Duration of Response 
Separately for injected tumors and overall (per RECIST v1.1), for participants who have been 
identified as a responder (achieved an overall response of CR or PR during the PFS observation 
period, i.e., until any PFS event or censoring), duration of response (DOR) is defined as time 
from first documentation of CR or PR until disease progression or death for any cause, 
whichever occurs first, and is calculated, in months, as:  
(Date of PD or death - date of first response + 1) / 30.4375.   
Censoring algorithms analogous to those for PFS will be used for DOR.  If sample size permits, 
DOR will be analyzed based on the Kaplan-Meier methods described for PFS. 
6.2.3 Exploratory Efficacy Endpoints and Analyses 
Not Applicable. 
6.2.4 Multiplicity 
No multiplicity adjustments will be performed for multiple analyses or multiple endpoints.  
6.3 Interim Analysis 
No interim analysis will be performed. 
6.4 Subgroup Analyses 
No subgroup analyses are planned.  


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6.5 Correlative/Special Studies   
Correlative/special studies, as described in protocol section 8., are outside of the scope of this SAP. 
6.6 Safety  
The primary endpoint of the study is safety which will be assessed on clinical examination and 
measurement of laboratory parameters.  
All participants who receive a dose of Ad/PNP-F-araAMP will be included in the safety analysis 
population. Each participant will be followed for safety for ~ 60 days following their final study 
dose. All safety assessments including adverse events, clinical laboratory evaluations, and vital 
signs will be summarized with descriptive statistics, where appropriate, and listed in the data 
listings using Medical Dictionary for Regulatory Activities (MedDRA) terms.  
Protocol section 12.2 states consideration of the repeat administration of Ad/PNP-F-araAMP as 
safe if the one-sided 80% upper confidence limit of the percentage of participants in the safety 
population experience treatment-related Serious Adverse Events as defined in Protocol section 
7.2. For example, if 2 of 10 participants experience a treatment related SAE, then the one-sided 
80% upper confidence limit is 38.1% and the repeat administration of Ad/PNP-F-araAMP would 
be considered safe. However, evaluations of the investigational product’s (potential) safety 
profile will not be considered strictly using only assessment of that criterion, but rather will 
involve broader considerations in addition to assessment of that criterion. 
All safety analysis reporting will be based on the Safety Population. 
6.6.1 Adverse Events 
An adverse event (AE) is any unfavorable and unintended diagnosis, symptom, sign (including an 
abnormal laboratory finding), syndrome or disease which either occurs during the study, having 
been absent at baseline, or, if present at baseline, appears to worsen. For this study, only abnormal 
laboratory findings with clinical significance as determined by the PI are considered AEs.  AEs will 
be recorded from the date of informed consent through the study follow-up period (~ 60 days after 
last dose of study drug). AEs will be assessed for severity, using the NCI-CTCAE version 5.0, 
relationship to study treatment, relationship to non-study treatment, and seriousness. Relationship 
assessments of possibly related or greater are defined to be related. Any missing relationship 
assessments will be assumed to be related, and any missing severity assessments will be assumed 
to be Severe/Grade 3. Disease progression is not an AE (non-serious or serious), although signs 
and symptoms thereof may be reportable as AEs. 
A treatment-emergent adverse event (TEAE) is defined as an AE with onset occurring at any time 
point after the first intratumoral administration of Ad/PNP. A TEAE also may be a continuing AE 
reported prior to the date of the first dose of study drug, which worsens in severity after the first 
administration of Ad/PNP.  
A serious adverse event (SAE) is defined as any adverse experience that suggests a significant 
hazard, contraindication, side effect, or untoward medical occurrence that: 
• 
Results in death, 


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• 
Is life-threatening (Note: the term “life-threatening” refers to an event in which the 
participant was at risk of death at the time of the event rather than to an event which 
hypothetically might have caused death if it were more severe.), 
• 
Requires (or prolongs) hospitalization, 
• 
Causes persistent or significant disability/incapacity, 
• 
Results in congenital anomalies or birth defects, or 
• 
Important Medical Event Requiring Medical or Surgical Intervention to Prevent Serious 
Outcome. 
An overview of TEAEs will be produced, including counts and percentages of participants with 
any incidences of:  TEAEs, TEAEs related to study treatment, TEAEs related to non-study 
treatment, TEAEs related to study treatment or non-study treatment, TEAEs of grade 3 or greater, 
related TEAEs of grade 3 or greater, TEAEs that are dose limiting toxicities (DLTs), serious 
adverse events (SAEs), TEAEs leading to study treatment discontinuation, and fatal SAEs. 
Adverse events will be coded based on the Medical Dictionary for Regulatory Affairs (MedDRA) 
version 21.0 for reporting by system organ class (SOC) and preferred term in descending order of 
overall incidence.   
Summaries of adverse events by SOC and preferred term will include the following types:  
• TEAEs; 
• TEAEs related to study treatment; 
• TEAEs related to non-study treatment;  
• TEAEs related to study treatment or non-study treatment; 
• TEAEs by maximum CTCAE Grade; 
• TEAEs with CTCAE Grade 3 or greater; 
• TEAEs with CTCAE Grade 3 or greater related to study treatment; 
• DLTs; 
• SAEs; and 
• TEAEs leading to study treatment discontinuation. 
When calculating the incidence of AEs, each AE will be counted only once for a given participant 
within a MedDRA category (e.g., overall, system organ class, or preferred term).  When AEs are 
summarized within levels of another AE assessment (e.g., relatedness or severity), AEs will be 
counted once per participant at the worst level of the assessment (e.g., strongest relationship to 
study treatment or greatest severity).   
A comprehensive listing of all AEs will be provided in a by-participant data listing. In addition, 
the following by-participant data listings will be provided:  
• SAEs;  
• TEAEs related to study treatment or non-study treatment; 
• TEAEs leading to study treatment discontinuation; and 
• Fatal AEs. 
 


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6.6.2 Clinical Laboratory Evaluations 
Clinical laboratory tests (including hematology, serum chemistry, coagulation, CD4/CD8 T-Cell 
Subsets, and urinalysis) will be performed at local laboratory facilities at each site, at visits per the 
Protocol Study Procedures Table (Appendix 2). Hematology and serum chemistry test values will 
be converted as required to values based on the International System of Units (SI).  All summaries 
and listings will use SI units.  
The following laboratory tests will be reported in data summaries: 
Hematology: hematocrit, hemoglobin, platelet count, RBC, and WBC, MCH, MCHC, MCV, 
neutrophils (absolute), eosinophils (absolute), basophils (absolute), lymphocytes (absolute), and 
monocytes (absolute). Percentage differentials of neutrophils, eosinophils, basophils, 
lymphocytes, and monocytes. 
Serum chemistry: sodium, potassium, carbon dioxide, chloride, glucose, magnesium, calcium, 
blood urea nitrogen (BUN), creatinine (Cr), phosphorus, albumin, alkaline phosphatase, ALT, 
AST, total bilirubin, total protein. 
Coagulation: PT, INR, aPTT. 
CD4/CD8 T-Cell Subsets: CD4/CD8 T-cell. 
Urinalysis: pH, specific gravity, Leukocyte esterase (Leukocytes), Nitrite, Urolbilinogen, Protein, 
Phosphorus, Occult blood (Hemoglobin & erythrocytes), Ketones, Bilirubin, Glucose. 
Pregnancy: serum/urine pregnancy test. 
Results of laboratory tests from hematology and chemistry evaluations that are outside of the 
reference range will be flagged and displayed in the summary tables. Descriptive statistics (e.g., 
number of participants, mean, STD, median, Q1, Q3, minimum, and maximum) for hematology 
and serum chemistry measurements will be calculated for each time point. The same descriptive 
statistics will be generated for these changes from baseline for each measurement. For the selected 
laboratory tests identified in section 6.1.3, a spaghetti plot will visually track measurements over 
time for each participant. Baseline is defined as the last measurable value prior to dosing on Day 
1. All clinical laboratory data will be provided in data listings, with values outside of the reference 
range flagged. No grading of laboratory tests results will be performed. 
6.6.3 Vital Signs 
Vital signs include: pulse rate (bpm), respiratory rate (bpm), temperature (oC), systolic and 
diastolic blood pressure (mmHg). Observed values and changes from baseline for these vital signs 
will be summarized at each visit and time point.   
Vital signs will be provided in a by-participant data listing. 


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6.6.4 ECOG Performance Status  
ECOG data will be summarized by score categories 0-4 at scheduled visits with frequency count 
and percent. Percentages will be based on the number of non-missing observations. In addition, a 
shift table of baseline to the last visit will be provided. ECOG data will be provided in a by-
participant data listing.  
6.6.5 Electrocardiogram (ECG) 
Electrocardiogram (ECG) parameters include: HR, PR, QT, QTcF.  Observed values and changes 
from baseline for ECG parameters will be summarized at each visit and time point.    
ECG data will be provided in a by-participant data listing. 
6.6.6 Physical Examinations 
Physical examination results will be presented in a by-participant data listing. 
  
 
 
 


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7 REFERENCES 
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use.  ICH E3 Guideline: Structure and content of clinical study reports 
questions & answers (R1). 2012.            
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E3/E3_QAs_
R1_Step4.pdf.  Accessed 13 Jan 2016. 
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use.  ICH Harmonised Tripartite Guideline: Structure and content of 
clinical 
study 
reports 
E3. 
Step 
4. 
1995. 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E3/E3_Guide
line.pdf. Accessed 13 Jan 2016. 
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use.  ICH E9: Statistical principles for clinical trials. 1998. 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E9/Step4/E9
_Guideline.pdf . Accessed 15 June 2016. 
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use.  E14 Clinical Evaluation of QT/QTc Interval Prolongation and 
Proarrhythmic 
Potential 
for 
Non-Antiarrhythmic 
Drugs. 
2005.  
https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E14/E14_G
uideline.pdf. Accessed 17 February 2017. 
Hamilton S, Bernstein AB, Blakey G, Fagan V, Farrow T, Jordan D, Seiler W, Shannon A, Gertel 
A, Budapest Working Group: Developing the Clarity and Openness in Reporting: E3-based 
(CORE) Reference user manual for creation of clinical study reports in the era of clinical trials 
transparency. Research Integrity and Peer Review. (2016) 1:4. 
PhUSE CSS Development of Standard Scripts for Analysis and Programming Working Group.  
Analyses and Displays Associated with Demographics, Disposition, and Medications in Phase 2-
4 
Clinical 
Trials 
and 
Integrated 
Summary 
Documents. 
 
2014. 
http://www.phusewiki.org/wiki/images/c/c9/CSS_WhitePaper_DemoDispMed_v1.0.pdf 
. 
Accessed 03 Jan 2017. 
PhUSE CSS Development of Standard Scripts for Analysis and Programming Working Group.  
Analyses and Displays Associated to NonCompartmental Pharmacokinetics – With a Focus on 
Clinical 
Trials. 
2014. 
http://www.phusewiki.org/wiki/images/e/ed/PhUSE_CSS_WhitePaper_PK_final_25March2014.
pdf . Accessed 31 Dec 2016. 
PhUSE CSS Development of Standard Scripts for Analysis and Programming Working Group.  
Analyses 
and 
Displays 
Associated 
with 
Thorough 
QT/QTc 
Studies. 
2016. 
http://www.phusewiki.org/docs/CSS%20White%20Papers%202016/230316%20CS_WhitePaper
_TQTStudies_v1.0.pdf .  Accessed 03 Jan 2017. 


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National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human 
Services. [Accessed January 2, 2017];Common Terminology Criteria for Adverse Events 
(CTCAE) Version 4.0. Published May 28, 2009; Revised Version 4.03 June 14, 2010 (Vol. 
Available 
from: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf. 
Eisenhauer E.A., Therasse P, Schwartz LH, et. al. New Response Criteria in Solid Tumors: 
Revised RECIST Guidelines (Version 1.1).  European Journal of Cancer.  (2009) 45: 228-247. 
CDER/CBER. 2007. Guidance for industry: Clinical Trial Endpoints for the Approval of Cancer 
Drugs 
and 
Biologics. 
Silver 
Spring, 
MD: 
Food 
and 
Drug 
Administration.  
https://www.fda.gov/downloads/drugsGuidanceComplianceRegulatoyInformation/Guidance/UC
M071590.pdf. Accessed 07 December 2018. 
 
 


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8 APPENDICES 
8.1 APPENDIX 1: Partial Date Conventions  
ALGORITHM FOR TREATMENT EMERGENCE OF ADVERSE EVENTS: 
START DATE 
STOP DATE 
ACTION 
Known 
Known/Partial/
Missing 
If start date < study treatment start date, then not TEAE 
If start date >= study treatment start date and < (end of 
treatment + 60 days), then TEAE 
If start date > (end of treatment + 60 days), then not TEAE 
*if time is collected, consider time in determining if event is a 
TEAE 
 
 
 
Partial, but known components 
show that it cannot be on or 
after study treatment start date 
Known/Partial/
Missing 
Not TEAE 
 
 
 
Partial, could be on or after 
study treatment start date 
Known 
If stop date < study treatment start date, then not TEAE 
If stop date >= study treatment start date, then TEAE 
*if time is collected, consider time in determining if event is a 
TEAE 
 
Partial 
Impute stop date as latest possible date (i.e., last day of month 
if day unknown or 31st December if day and month are 
unknown), then: 
If stop date < study treatment start date, then not TEAE 
If stop date >= study treatment start date, then TEAE 
 
Missing or 
ongoing is 
checked 
Assumed TEAE 
 
 
 
Missing 
Known 
If stop date < study treatment start date, then not TEAE 
If stop date >= study treatment start date, then TEAE 
*if time is collected, consider time in determining if event is a 
TEAE 
 
Partial 
Impute stop date as latest possible date (i.e., last day of month 
if day unknown or 31st December if day and month are 
unknown), then: 
If stop date < study treatment start date, then not TEAE 
If stop date >= study treatment start date, then TEAE 
 
Missing or 
ongoing is 
checked 
Assumed TEAE 
 


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ALGORITHM FOR PRIOR / CONCOMITANT MEDICATIONS: 
START DATE 
STOP DATE 
ACTION 
Known 
Known 
If stop date < study treatment start date, assign as prior 
If stop date >= study treatment start date and start date <= end of treatment + 60 
days, assign as concomitant 
If stop date >= study treatment start date and start date > 60 days after the end 
of treatment, assign as subsequent 
 
Partial 
Impute stop date as latest possible date (i.e., last day of month if day unknown 
or 31st December if day and month are unknown), then: 
If stop date < study treatment start date, assign as prior 
If stop date >= study treatment start date and start date <= end of treatment + 60 
days, assign as concomitant 
If stop date >= study treatment start date and start date > 60 days after the end 
of treatment, assign as subsequent 
 
Missing 
If “Ongoing” is flagged, assign as concomitant  
If “Ongoing” is not flagged and stop date is missing, assign as concomitant 
If start date <= end of treatment + 60 days, assign as concomitant 
If start date > 60 days after the end of treatment, assign as subsequent 
 
 
 
Partial 
Known 
Impute start date as earliest possible date (i.e., first day of month if day unknown 
or 1st January if day and month are unknown), then: 
If stop date < study treatment start date, assign as prior 
If stop date >= study treatment start date and start date <= end of treatment + 60 
days, assign as concomitant 
If stop date >= study treatment start date and start date > 60 days after the end 
of treatment, assign as subsequent 
 
Partial 
Impute start date as earliest possible date (i.e., first day of month if day unknown 
or 1st January if day and month are unknown) and impute stop date as latest 
possible date (i.e., last day of month if day unknown or 31st December if day 
and month are unknown), then: 
If stop date < study treatment start date, assign as prior 
If stop date >= study treatment start date and start date <= end of treatment + 60 
days, assign as concomitant 
If stop date >= study treatment start date and start date > 60 days after the end 
of treatment, assign as subsequent 
 
Missing 
If “Ongoing” is flagged, assign as concomitant  
Impute start date as earliest possible date (i.e., first day of month if day unknown 
or 1st January if day and month are unknown), then: 
If stop date is missing, assign as concomitant 
If start date <= end of treatment + 60 days, assign as concomitant 
If start date > 60 days after the end of treatment, assign as subsequent 
 
 
 
Missing 
Known 
If stop date < study treatment start date, assign as prior 
If stop date >= study treatment start date, assign as concomitant 
Cannot be assigned as subsequent 


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START DATE 
STOP DATE 
ACTION 
 
Partial 
 
 
Impute stop date as latest possible date (i.e., last day of month if day unknown 
or 31st December if day and month are unknown), then: 
If stop date < study treatment start date, assign as prior 
If stop date >= study treatment start date, assign as concomitant 
Cannot be assigned as subsequent 
 
Missing 
If “Ongoing” is flagged, assign as concomitant 
If “Ongoing” is not flagged, assign as concomitant 
 
Partial dates for additional anticancer therapies, as recorded in the concomitant medication eCRF 
forms, will not typically be imputed, but may be needed to support efficacy outcome derivation 
(i.e., PFS and similar).  This is applicable to anticancer therapy and radiotherapy but may also 
apply to surgical procedures.  In this case, should it be needed after every attempt to gather 
information from the investigative site(s), the following will be applied for imputation of new 
anticancer therapies taken after treatment start date: 
• If the new anticancer therapy start date is completely missing, no imputation will be 
conducted. 
• For other missing data scenarios for new anticancer therapy, concomitant medication data 
will be reviewed, and conventions will be developed only if needed. 
 
 
 


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8.2 APPENDIX 2: Protocol Study Procedures Table 
 


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