Clinical trial NCT00088413
Conditions: Adenocarcinoma Colorectal Cancer Ovarian Cancer Breast Cancer
Keywords: CEA Vaccine Immunotherapy MUC-1 Cancer Adenocarcinoma Metastatic Adenocarcinoma
Sponsor: National Cancer Institute (NCI)
Start date: 2004-07-21; Completion date: 2018-05-31
Enrollment: 51 participants; Allocation: ; Intervention model: SEQUENTIAL

Brief summary:
Background:

* Many cancers produce two proteins, carcinoembryonic antigen (CEA) and mucin-1 (MUC-1).
* The PANVAC-V (PANVAC vaccinia) priming vaccine and PANVAC-F (PANVAC fowlpox) boosting vaccine contain human genes that cause production of CEA and MUC-1, which can be used as a target for the immune system to attack the cancer. The vaccines also contain genes that cause production of other proteins that enhance immune activity.
* Sargramostim is a protein that boosts the immune system.

Objectives:

* To evaluate the safety and effectiveness of PANVAC-V and PANVAC-F in patients with advanced cancer.
* To document the immune response to the vaccines and any anti-tumor responses that may occur.

Eligibility: Patients 18 years of age and older with advanced cancer whose tumors produce CEA or MUC-1 protein

Design:

* This trial has three cohorts: the first cohort includes 10 patients with advanced colorectal cancer and 10 to 15 patients with any advanced non-colorectal cancer that produces either EA or mitochondrial Ca2+ uniporter 1 (MCU-1); the second cohort includes 12 patients with advanced breast cancer and the third cohort includes 14 patients with advanced ovarian cancer.
* All patients receive PANVAC-V on study day 1, followed by PANVAC-F on days 15, 29 and 43 then every 28 days for up to 12 vaccines followed by every 3 months until disease progression or toxicity. The vaccines are given by injection under the skin. Sargramostim is injected at the vaccination site on the day of each vaccination and for the next 3 days following vaccination.
* Patients whose scans show that their disease has progressed, but who are otherwise clinically stable may revert back to monthly injections.
* Patients undergo apheresis to collect white blood cells (lymphocytes) on day 1 and day 71 of the study to measure the immune response to the treatment. Blood is collected through a needle placed in one arm and directed through a cell separator machine where the lymphocytes are extracted. The rest of the blood components are returned to the patient through the same needle.
* Patients are monitored with frequent blood tests and periodic imaging tests (scans) to monitor for safety and the response to treatment.

Detailed description:
Background:

* Carcinoembryonic antigen (CEA) and mucin-1 (MUC-1) are overexpressed in multiple adenocarcinomas.
* Pox viral vectors can induce a strong immune response to CEA and MUC-1.
* The use of agonist epitopes within the tumor associated antigen (TAA) can induce a better immune response than native peptides and have been associated with clinical responses
* Heterologous prime and boost regimens are superior in terms of generalizing immune responses; and this may translate into improved clinical responses
* The use of granulocyte-macrophage colony-stimulating factor (GM-CSF) does not add significant toxicity and in pre-clinical models is essential for induction for optimal immune responses.
* It is possible by using vectors directed against TAA that there may be additive or synergistic immune responses and this may be important in overcoming antigenic escape variance
* Evidence of clinical benefit has been noted in some patients treated with this vaccine

Objectives:

* For colorectal cancer and non-colorectal cancer Cohort: To evaluate the safety and tolerability of the vaccine.
* For the Ovarian Cancer and Breast Cancer Cohorts: To evaluate clinical response to the vaccine.

Eligibility:

* In the first cohort (colorectal and non-colorectal cancer), histologically confirmed adenocarcinoma that is CEA or MUC-1 positive described as metastatic disease (measurable or evaluable) or metastatic disease documented by biopsy but not evaluable by imaging (e.g. small volume peritoneal disease)
* For the ovarian and breast cancer cohorts, patients must have evaluable disease
* Normal organ function, Eastern Cooperative Oncology Group (ECOG) 0-1

Design:

* This is a non-randomized three cohort, pilot trial of pox viral vaccines that contain the transgenes for CEA and MUC-1 (both with modified human leukocyte antigen A2 (HLA-A2) agonist epitopes) as well as 3 human T-cell costimulatory molecules, B7-1, ICAM-1 (CD54), and LFA-3 (CD58) \[PANVAC(TM)-V (vaccinia) and PANVAC(TM)-F (fowlpox)\] in patients with metastatic carcinoma that express CEA or MUC-1 antigen.
* The first cohort will enroll 10 patients with metastatic colorectal adenocarcinoma and 10-15 patients with any metastatic non-colorectal carcinoma that expresses either CEA or MUC-1. .
* The second cohort will enroll 12 patients with metastatic breast carcinoma and 14 patients with metastatic ovarian carcinoma.
* All patients will receive the same vaccines on the same schedule. PANVAC(TM)-V (vaccinia) subcutaneously (s.c.) scheduled on day 1, followed by PANVAC(TM)-F (fowlpox) s.c. scheduled on days 15, 29, and 43 then every 28 days for up to 12 vaccines followed by every 3 months until disease progression or toxicity.
* Sargramostim (100 micro g) will be given at the site of the vaccination (PANVAC-V and PANVAC-F) on each vaccination day and for three consecutive days thereafter.
* Patients who have radiographic evidence of progressive disease, but who are otherwise clinically stable may revert back to monthly vaccinations.

Arms: arm 1: All cohorts receive the same intervention (Cohort 1: Colorectal arm, non-colorectal cancers; Cohort 2: breast cancer; Cohort 3: ovarian cancers)
Interventions: intervention 1: PANVAC-V intervention 2: PANVAC-F intervention 3: Sargramostim (GM-CSF, Leukine)
Intervention descriptions: intervention 1: Patients receive 2 x 10(8) pfu PANVAC-V (vaccinia) subcutaneously on Day 1. intervention 2: Patients receive 1 x 10(9) pfu PANVAC-F (fowlpox) or about days 15, 29, and 43 then every month for 12 doses then every 3 months until disease progression or toxicity. intervention 3: 100g sargramostim will be given subcutaneously at the site of the vaccination on each vaccination day and for three consecutive days thereafter.

Protocol documents:
Prot_SAP_ICF_000.pdf: 
Amendment
Protocol Number:
04C0246-U
Principal Investigator: James L Gulley,  MD PhD 
NCI 
GMB 
301.480.8870 
gulleyj@mail.nih.gov
(NIH Employee Name, Institute/Branch, Telephone and e-mail)
Reference Number:
370747
Protocol Title:
An Open Label Pilot Study to Evaluate the Safety and Tolerability of PANVAC(TM)-V (Vaccinia) and PANVAC (TM)-F (Fowlpox) in 
Combination with Sargramostim in Adults with Metastatic Carcinoma
SIGNATURES
Principal Investigator (*): 
James L Gulley,  MD PhD - applied signature on 06/20/2017 5:10 PM EDT
Accountable Investigator:
PI is the Accountable Investigator
Branch Chief/CC Department Head (**):
James L Gulley, MD PhD - applied signature on 06/20/2017 5:10 PM EDT
Medical Advisory Investigator (if applicable):
N/A
Lead Associate Investigator signature:
N/A
Referral Contact signatures:
N/A
Associate Investigators signatures:
N/A
For Institute/Center Scientific Review Committee:
N/A
Other IC Clinical Director signatures:
N/A
APPROVALS
IRB Chair:
Michael Hamilton - applied signature on 06/29/2017 12:39 PM EDT
Clinical Director:
N/A
CONCURRENCE
OPS Protocol Specialist:
Signature
Print Name
Date
* Signature signifies that investigators on this protocol have been informed that the collection and use of personally identifiable information at
the NIH are maintained in a system of record governed under provisions of the Privacy Act of 1974. The information provided is mandatory for
employees of the NIH to perform their assigned duties as related to the administration and reporting of intramural research protocols and
used solely for those purposes.  Questions may be addressed to the Protrak System Owner.
** I have reviewed this research project and considered the NIH Policy for Inclusion of Women and Minorities in Clinical Research. Taking into 
account the overall impact that the project could have on the research field involved, I feel the current plans adequately includes both sex/
gender, minorities, children, and special populations, as appropriate. The current enrollment is in line with the planned enrollment report for 
inclusion of individuals on the basis of their sex/gender, race, and ethnicity and is appropriate and of scientific and technical merit. 
IRB Meeting Date:
Expedited
DEC Clearance Date:
N/A
Protocol Version Date:05/04/2017
Kim Mitchell
07/10/17


 
 
         
 
 
 
 
 
Abbreviated Title: Vaccine for metastatic cancer 
NCI Protocol #: 04-C-0246                                                                        OSP #: 0403-636 
CTEP #: 6536                                                                                              IBC #: RD-04-VI-08  
NCT #: NCT00088413 
Version Date: 05/04/2017 
Amendment: U 
 
Title:  An open label pilot study to evaluate the safety and tolerability of PANVAC™-V 
(vaccinia) and PANVAC™-F (fowlpox) in combination with sargramostim in adults with 
metastatic carcinoma 
NCI Principal Investigator: 
 
 
 
 
 
James Gulley, M.D., Ph.D.A, B, C, D, E, F 
Genitourinary Malignancies Branch 
National Cancer Institute 
10 Center Drive 
Building 10, Room 13N240 
Bethesda, MD 20892 
Phone: (301) 480-7164 
Email: gulleyj@mail.nih.gov 
 
Statistician: 
 
 
 
 
 
*Seth Steinberg, Ph.D.E, F  
 
NIH Associate Investigators:  
 
 
 
 
 
 
 
William Dahut, M.D. GMB, CCR, NCIA, B, C, D, E, F 
Ravi Madan, M.D. GMB, CCR, NCIA, B, C, D, E, F 
Myrna Rauckhorst, R.N. OCD, CCR, NCIA, B, C, E, F  
Sheri McMahon, R.N. OCD, CCR, NCIA, B, C, E, F  
Responsible Research Nurses: 
 
 
Referral Contact/Study Coordinator: 
Myrna Rauckhorst, R.N. OCD, CCR, NCI A,B,C,E,F  
Sheri McMahon, R.N. OCD, CCR, NCI A,B,C,E,F  
 
Myrna Rauckhorst, R.N. OCD, CCR, NCI A,B,C,E,F  
10 Center Drive 
Building 10, Room 13N210 
Bethesda, MD 20892 
Phone: (240) 760-6069 
Email: mrauckhorst@mail.nih.gov 
 
Non-NIH Associate Investigator: 
     
 
 
Philip M. Arlen, M.D. GMB, CCR, NCIA, B, C, D, E, F 
* Indicates Associate Investigators who will not be making protocol related medical decisions. 
 
 


Abbreviated Title: Vaccine for metastatic cancer 
Version Date:  05/04/2017 
 
CTEP #: 6536 
 
2 
 
Investigator Roles: 
A. Obtain information by intervening or interacting with living individuals for research 
purposes 
B. Obtaining identifiable private information about living individuals 
C. Obtaining the voluntary informed consent of individuals to be subjects 
D. Makes decisions about subject eligibility 
E. Studying, interpreting, or analyzing identifiable private information or data/specimens for 
research purposes 
F. Studying, interpreting, or analyzing de-identified data or specimens for research purposes 
G. Some/all research activities performed outside NIH 
 
 
IND Information: 
 
 
 
 
 
 
 
 
Drug Name:  PANVAC-V[Recombinant-Vaccinia-CEA(D609)/MUC-1(L93)/TRICOM] 
 
 
NSC Number: 727026 
 
 
           
 
IND Number: 11660         
 
 
Sponsor: 
Cancer Therapy Evaluation Program (CTEP) 
 
 
National Cancer Institute (NCI) 
 
 
Drug Name:  PANVAC-F [Recombinant-Fowlpox-CEA (D609)/MUC-1(L93)/TRICOM]  
NSC Number: 727027 
 
 
           
 
IND Number: 11660  
        
 
 
Sponsor: 
Cancer Therapy Evaluation Program (CTEP) 
 
 
National Cancer Institute (NCI) 
 
Drug Name:  Leukine® (Sargramostim)  
NSC Number:  
 
 
           
 
IND Number:  
        
 
 
Sponsor: 
Manufactured by Berlex Laboratories, Inc., Richmond, CA 
 
 
 
 


Abbreviated Title: Vaccine for metastatic cancer 
Version Date:  05/04/2017 
 
CTEP #: 6536 
 
3 
 
PRÉCIS  
Background: 
CEA and MUC-1 are overexpressed in multiple adenocarcinomas
Pox viral vectors can induce a strong immune response to CEA and MUC-1 
The use of agonist epitopes within the TAA can induce a better immune response than native 
peptides and have been associated with clinical responses 
Heterologous prime and boost regimens are superior in terms of generalizing immune 
responses; and this may translate into improved clinical responses 
 The use of GM-CSF does not add significant toxicity and in pre-clinical models is essential 
for induction for optimal immune responses 
 It is possible by using vectors directed against TAA that there may be additive or synergistic 
immune responses and this may be important in overcoming antigenic escape variance 
 Evidence of clinical benefit has been noted in some patients treated with this vaccine 
Objectives: 
 For the first two arms (colorectal cancer and non-colorectal cancer): To evaluate the safety 
and tolerability of the vaccine 
 For the Ovarian Cancer and Breast Cancer arms: To evaluate clinical response to the vaccine  
 
Eligibility: 
 In the first two arms (colorectal and non-colorectal cancer), histologically confirmed 
adenocarcinoma that is CEA or MUC-1 positive described as metastatic disease (measurable 
or evaluable) or metastatic disease documented by biopsy but not evaluable by imaging (e.g. 
small volume peritoneal disease) 
 For the ovarian and breast cancer arms, patients must have evaluable disease 
 Normal organ function, ECOG 0-1 
Design: 
 This is a non-randomized four arm, pilot trial of pox viral vaccines that contain the 
transgenes for CEA and MUC-1 (both with modified HLA-A2 agonist epitopes) as well as 3 
human T-cell costimulatory molecules, B7-1, ICAM-1, and LFA-3 [PANVAC™-V 
(vaccinia) and PANVAC™-F (fowlpox)] in patients with metastatic carcinoma that express 
CEA or MUC-1 antigen 
 The first arm will enroll 10 patients with metastatic colorectal adenocarcinoma 
 The second arm will consist of 10-15 patients with any metastatic non-colorectal carcinoma 
that expresses either CEA or MUC-1 
 The third arm will consist of about 12 patients with metastatic breast carcinoma.  The fourth 
arm will consist of about 12 patients with metastatic ovarian carcinoma 
 All patients will receive PANVAC™-V (vaccinia) subcutaneously (s.c.) scheduled on day 1, 
followed by PANVAC™-F (fowlpox) s.c. scheduled on days 15, 29, and 43 (Core Phase)   


Abbreviated Title: Vaccine for metastatic cancer 
Version Date:  05/04/2017 
 
CTEP #: 6536 
 
4 
 
 Sargramostim (100 µg) will be given at the site of the vaccination on each vaccination day 
and for three consecutive days thereafter 
 Up to 12 additional monthly boosting vaccinations (Extension Phase) will be offered to 
patients who have completed the Core Phase of the study and who have not experienced 
disease progression 
 Following the 12 monthly vaccinations, patients without disease progression will be allowed 
to receive vaccine every 3 months 
 Patients who have radiographic evidence of progressive disease, but who are otherwise 
clinically stable may revert back to monthly vaccinations 


Abbreviated Title: Vaccine for metastatic cancer 
Version Date:  05/04/2017 
 
CTEP #: 6536 
 
5 
 
SCHEMA  
             Core Phase 
 
 
             Day 1 
 
PANVAC™-V (vaccinia) (2 x 108) pfu s.c. 
             On or about days 15, 29, 43 
      PANVAC™-F (fowlpox) (1 x 109) pfu s.c. 
 
              The day of and for 3 consecutive sargramostim 100 µg s.c. at vaccination site. 
              days following vaccine (on or about days 1- 4, 15-18, 29-32, and         43-46) 
 
 
 
 
  
 
Safety assessments will be scheduled on days 1, 15, 29, 43, and 71. 
 
PANVAC™-V (vaccinia) is a recombinant vaccinia virus that contains the transgenes for 
CEA and MUC-1 (both with modified HLA-A2 agonist epitopes) as well as 3 human T-
cell costimulatory molecules, B7-1, ICAM-1, and LFA-3 (designated TRICOM). 
PANVAC™-F (fowlpox) is a recombinant replication defective fowlpox virus that 
contains the identical transgenes as PANVAC™-V (vaccinia).   
 
 Optional Extension Phase                  (Up to 12 additional monthly boosting                                               
immunizations)     
                       
 
 
 About every 28 days             
PANVAC™-F (fowlpox) (1 x 109) pfu s.c.  
 
 Days 1- 4 with monthly 
 
sargramostim 100 µg s.c. at vaccination site. 
 PANVAC™-F (fowlpox) injection 
 
Safety assessments will continue about every 28 days during the Extension phase. 
 
Maintenance Phase 
 
Every 3 months 
 
 
boosting immunization 
subcutaneously 
 
 
PANVAC™-F (fowlpox) (1 x 109) pfu  
 
Days 1- 4 with each  
 
sargramostim 100 µg subcutaneously at 
 
PANVAC™-F (fowlpox) injection  vaccination site 
 
Restaging scans may be performed at PI discretion at an interval not to exceed one year  
Clinic visits for clinical assessment will take place prior to each vaccination at a 3-month 
interval  
 
*This identical schema (including identical dose and dose schedule) has been approved 
by the FDA under a Therion Biologics Corporation IND.   
 
 


Abbreviated Title: Vaccine for metastatic cancer 
Version Date:  05/04/2017 
 
CTEP #: 6536 
 
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TABLE OF CONTENTS 
Summary of Protocol Changes .................................................................................... Error! Bookmark not defined. 
PRÉCIS ......................................................................................................................................................................... 3 
SCHEMA ...................................................................................................................................................................... 5 
1 
INTRODUCTION ................................................................................................................................................. 8 
1.1 
Study Objectives .......................................................................................................................................... 8 
1.2 
Background and Rationale ........................................................................................................................... 8 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT ...................................................................................... 16 
2.1 
Eligibility Criteria ...................................................................................................................................... 16 
2.2 
Research Eligibility Evaluation .................................................................................................................. 19 
2.3 
Patient Registration and Treatment Randomization ................................................................................... 19 
3 
STUDY IMPLEMENTATION ........................................................................................................................... 20 
3.1 
Study Design .............................................................................................................................................. 20 
3.2 
Drug Administration .................................................................................................................................. 22 
3.3 
Treatment Modifications ............................................................................................................................ 22 
3.4 
On Study Evaluation: (See APPENDIX C) ............................................................................................... 24 
3.5 
Concurrent Therapies ................................................................................................................................. 27 
3.6 
Off Study Criteria ....................................................................................................................................... 27 
3.7 
Post Study Evaluation (see APPENDIX C) ............................................................................................... 28 
4 
SUPPORTIVE CARE ......................................................................................................................................... 28 
4.1 
Treatment of Vaccinia Vaccination Complications.................................................................................... 28 
5 
DATA COLLECTION AND EVALUATION .................................................................................................... 30 
5.1 
Data Collection .......................................................................................................................................... 30 
5.2 
Response Criteria ....................................................................................................................................... 31 
5.3 
Toxicity Criteria ......................................................................................................................................... 33 
5.4 
Statistical Considerations ........................................................................................................................... 34 
5.5 
Data Safety Monitoring Plan ...................................................................................................................... 36 
6 
HUMAN SUBJECTS PROTECTIONS .............................................................................................................. 37 
6.1 
Rationale for Subject Selection .................................................................................................................. 37 
6.2 
Participation of Children ............................................................................................................................ 38 
6.3 
Participation of NIH Subjects Unable to Give Consent ............................................................................. 38 
6.4 
Evaluation of Benefits and Risks/Discomforts ........................................................................................... 38 
6.5 
Risks/Benefits Analysis ............................................................................................................................. 39 
6.6 
Consent and Assent Process and Documentation ....................................................................................... 39 
7 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN............................ 40 
7.1 
Definitions .................................................................................................................................................. 40 
7.2 
NCI-IRB and Clinical Director Reporting ................................................................................................. 42 
8 
DATA REPORTING ........................................................................................................................................... 43 
8.1 
Provisions for Monitoring to Ensure Safety of Subjects ............................................................................ 43 
8.2 
Routine Adverse Event Reporting .............................................................................................................. 47 
8.3 
Secondary AML/MDS ............................................................................................................................... 47 


Abbreviated Title: Vaccine for metastatic cancer 
Version Date:  05/04/2017 
 
CTEP #: 6536 
 
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8.4 
Record Keeping .......................................................................................................................................... 47 
8.5 
Regulatory Issues ....................................................................................................................................... 47 
9 
PHARMACEUTICAL INFORMATION ............................................................................................................ 52 
9.1 
PANVAC-V (NSC 727026) ................................................................................................................... 52 
9.2 
PANVAC-F (NSC 727027) .................................................................................................................... 64 
9.3 
Sargramostim (GM-CSF, LEUKINE) .................................................................................................... 69 
10 REFERENCES .................................................................................................................................................... 71 
11 APPENDIX A: Performance Status Criteria ....................................................................................................... 76 
12  APPENDIX B: Instructions for Care of the Vaccine Site................................................................................... 77 
13 APPENDIX C: Treatment and Monitoring Schedule: Pre, During and Post Therapy ......................................... 80 
14 APPENDIX D: Response Evaluation Criteria in Solid Tumors (RECIST) Quick Reference ............................. 82 
15 APPENDIX E: ELISPOT ASSAY ...................................................................................................................... 88 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Abbreviated Title: Vaccine for metastatic cancer 
Version Date:  05/04/2017 
 
CTEP #: 6536 
 
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1 
INTRODUCTION 
 
1.1 
Study Objectives 
 
1.1.1 Primary 
 
For the first two arms (colorectal cancer and non-colorectal cancer): To 
evaluate the safety and tolerability of PANVAC™-V (vaccinia) and 
PANVAC™-F (fowlpox) in combination with sargramostim in patients with 
metastatic carcinoma that express CEA or MUC-1 antigen 
 
For the Ovarian Cancer and Breast Cancer arms: To evaluate clinical response 
to the vaccine 
 
1.1.2 Secondary 
 For the first two arms: To document any objective anti-tumor responses that 
may occur 
 For the Ovarian Cancer and Breast Cancer arms: To evaluate the safety and 
tolerability of PANVAC™-V (vaccinia) and PANVAC™-F (fowlpox) in 
combination with sargramostim 
 To evaluate immune response generated by this combination therapy as                                    
measured by ELISPOT assay 
 
1.2 
Background and Rationale 
 
1.2.1 Preclinical Support Data 
 
Colorectal cancer is the third most common malignancy and the second most common cause of 
cancer death in this country. According to the American Cancer Society, approximately 150,000 
new diagnoses of, and about 60,000 deaths from colorectal cancer will occur in the United States 
in 2003.  Current therapeutic strategies have had limited success in the metastatic colorectal 
setting. A promising approach for the treatment of human malignancies is the development of 
vaccines that target specific tumors.  This immunotherapeutic approach to the treatment of 
cancer is based on the observation that human tumor cells express a variety of tumor-associated 
antigens (TAAs) that are not expressed or are minimally expressed in normal tissues.  These 
antigens, which include viral tumor antigens, cellular oncogene proteins, and tissue-specific 
differentiation antigens, can serve as targets for the host immune system and elicit responses that 
result in tumor destruction.  Because tumors have developed a variety of mechanisms to evade 
immune detection and activation, the development of effective therapeutic vaccines for cancer 
will hinge on the ability to activate cellular immune responses.  Antigen-specific active 
immunotherapy is designed to generate immune responses, particularly cell-mediated responses, 
against specific TAAs using vaccines that express one or more of these antigens.  The 
identification and isolation of genes encoding TAAs has allowed the development of 
recombinant anti-tumor vaccines designed to elicit immune responses to one or more antigens 


Abbreviated Title: Vaccine for metastatic cancer 
Version Date:  05/04/2017 
 
CTEP #: 6536 
 
9 
 
known to be expressed by a particular tumor type.   
  
CEA 
Carcinoembryonic antigen (CEA) is an 180,000-dalton glycoprotein that is overexpressed on 
most adenocarcinomas of the colon, rectum, stomach, and pancreas, as well as on breast cancers 
and non-small-cell lung cancers.  In particular, CEA is overexpressed in > 90% of 
adenocarcinomas of the colon.  It has also been identified in fetal gut and in small amounts in 
normal adult colonic mucosa. The CEA gene family belongs to the immunoglobulin superfamily 
and resides on the long arm of chromosome 19.  CEA shares approximately 70% amino acid 
homology with non-specific cross-reacting antigen, which is found on normal granulocytes.(1)  
The clinical experience with CEA based vaccines is described below. 
 
MUC-1 
Mucin-1 (MUC-1) is a glycosylated transmembrane protein that is uniquely characterized by an 
extracellular domain that consists of a variable number of tandem repeats of 20 amino acids.(2) 
Differential expressions of MUC-1 and MUC-2 have been reported in colorectal adenomas (3-5) 
and colorectal cancers.(3;6;7) MUC-1 is overexpressed in > 90% of adenocarcinomas of the 
colon.  Several earlier studies in colorectal neoplasia have demonstrated that higher levels of 
expression of MUC-1 in colorectal cancer were correlated with increased incidence of regional 
lymph node metastasis and liver metastasis.(8-10) A few studies in colorectal neoplasia (10;11) 
as well as in other human malignancies (10;12), have suggested that increased expression of the 
core peptide of MUC-1 is associated with poor prognosis. The clinical experience with MUC-1 
based vaccines is described below. 
 
Thus, a vaccine directed against both CEA and MUC-1 targets may well be additive or even 
synergistic in terms of the breadth of immune responses generated, and perhaps will be important 
in overcoming antigenic escape variants from vaccine therapy. 
 
TRICOM 
Costimulatory molecules are critical in the generation of T-cell responses especially against 
weak antigens such as TAAs. The initiation of an immune response requires at least two signals 
for activation of naïve T cells by antigen-presenting cells. The first signal is antigen specific, 
delivered through the T-cell receptor via the peptide/MHC, and causes the T cell to enter the cell 
cycle. The second, “costimulatory,” signal is required for cytokine production and proliferation. 
At least three distinct molecules normally found on the surface of professional antigen-
presenting cells have been reported to be capable of providing the second signal critical for T-
cell activation: B7-1, ICAM-1, and LFA-3. Both antigen and costimulatory molecules must be 
expressed in the same cell to properly engage the TCR and costimulatory receptor. In order to 
achieve this, multigene constructs using poxviral vectors (avipox and vaccinia) have been 
generated. These vectors contain the costimulatory molecule transgenes B7-1, ICAM-1, and 
LFA-3, and have been given the designation TRICOM (TRIad of COstimulatory Molecules), 
i.e., rV-TRICOM and rF-TRICOM.(13) Each of these Costimulatory molecules binds to a 
different ligand, and the second messenger pathways of each ligand are unique, raising the 
potential for synergy of these molecules. 


Abbreviated Title: Vaccine for metastatic cancer 
Version Date:  05/04/2017 
 
CTEP #: 6536 
 
10 
 
 
1.2.2 Experimental Studies  
 
Pox virus vectors 
Vaccinia virus has been used for over 200 years as a vaccine for smallpox and has a well-
established safety profile with over 1 billion people inoculated.  This virus actively replicates in 
human cells, resulting in the presentation of high levels of antigen to the immune system over a 
period of one to two weeks, substantially increasing the potential for immune stimulation.  The 
immune response specific to vaccinia then eliminates the virus.  As a result of its safety profile 
and ability to elicit both humoral and cell-mediated immunity in humans, the vaccinia virus 
(genus Orthopoxvirus) was chosen as one of the vectors to deliver MUC-1, CEA, and 
TRICOM.(14;15) 
 
Fowlpox virus, like vaccinia, is a member of the Poxviridae family (genus Avipoxvirus) that can 
infect mammalian cells and express inserted transgenes to stimulate both humoral and cellular 
immunity.(16;17) Avipox vectors such as fowlpox cannot replicate in non-avian species, making 
the possibility of human systemic infections extremely remote thus making it potentially safer 
than a replicative virus.(18) Fowlpox virus can be given multiple times and unlike vaccinia, 
immune responses to the tumor-associated antigen continue to improve with each subsequent 
vaccination. Results from NCI-sponsored Phase 1 studies of other fowlpox-based vaccines 
support the safety of this vector (see section 1.2.3).   
  
 
 
Immunization with these live recombinant pox virus vectors that have been genetically 
engineered to express one or more antigens allows expression of TAAs and subsequent co-
presentation of antigenic peptides with host histocompatibility antigens, a strategy that favors the 
induction of cell-mediated immune responses.  Recombinant pox viruses can infect antigen-
presenting cells, including dendritic cells and macrophages, resulting in efficient expression of 
TAAs simultaneously with costimulatory molecules required for the elicitation of T cell 
responses.  TAAs expressed by recombinant pox viruses are presented to the immune system 
together with highly immunogenic virus proteins, which may act as adjuvants to enhance 
immune responses to the TAAs.  Thus, the use of recombinant pox virus vectors for the 
presentation of TAAs to the immune system results in the generation of cytotoxic T cells that can 
specifically destroy the selected tumor with little incremental toxicity. 
 
Murine models 
CEA transgenic mice have been developed in which the human CEA transgene, under the 
control of its endogenous promoter, is expressed in both fetal and adult tissues in a manner 
similar to that of humans (Eades-Perner Ca. Research 54: 4169-4179, 1994). Experimental 
studies have demonstrated that no anti-CEA immune responses can be generated in these mice 
when CEA protein in adjuvant is used as an immunogen.(19) However, when either recombinant 
vaccinia CEA (rV-CEA) vector or recombinant avipox CEA vector is used to vaccinate CEA 
transgenic mice, a vigorous CEA-specific T-cell response can be generated. (20)  
 
Experimental studies have also demonstrated that the use of rV-MUC-1 as a vaccine can lead to 


Abbreviated Title: Vaccine for metastatic cancer 
Version Date:  05/04/2017 
 
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the elimination of established experimental lung metastases in mice.(21) Preclinical studies in 
double transgenic mice that develop pancreatic tumors and contain MUC-1 as a self molecule 
that is expressed on these tumors, have demonstrated that adoptively transferred MUC-1–specific 
CTL can eliminate pancreatic tumors.(22)  
 
 
TRICOM 
Preclinical studies performed in the Genitourinary Malignancies Branch (GMB) and Laboratory 
of Tumor Immunology and Biology (LTIB) using these TRICOM constructs have shown them to 
be superior to those constructs that do not contain the costimulatory molecules.(23-25) In CEA 
transgenic mice, which contain CEA as a self-antigen, much greater anti-tumor activity against 
established CEA-expressing tumors was seen when CEA/TRICOM vectors were used as 
opposed to CEA vectors devoid of TRICOM. In- vitro studies using TRICOM vectors containing 
human costimulatory molecules have shown them to greatly enhance the activation of antigen-
specific human T cells including dendritic cells. (26) Recent studies have also shown that 
infection of antigen-presenting cells with TRICOM vectors leads to the generation of higher 
avidity T cells.(27) 
 
Experimental studies have also shown that vaccination with rV-CEA/TRICOM and rF-
CEA/TRICOM leads to the generation of even more vigorous T-cell responses to CEA and to 
improved anti-tumor immunity of established tumors when compared to the identical vaccine 
without the added costimulatory molecules.(28-30) Preclinical studies have also demonstrated 
that vaccination with CEA-TRICOM vectors can eliminate spontaneous tumor development.(31)  
 
Agonist epitopes 
Cancer immunity in humans may rest on the development of an effective immune response 
directed to “self” molecules that are common to tumor and normal cells. This of course has the 
inherent problem of breaking tolerance in order to generate and propagate tumor-associated 
specific T cells. In an attempt to circumvent this problem, novel peptides have been constructed 
to increase the immune response directed against “self” antigens. The advantage of using agonist 
epitopes has now been demonstrated in clinical trials in both melanoma and carcinoma 
patients.(32;33) Agonist epitopes have now been generated for both CEA and MUC-1. The 
PANVAC vectors contain the entire CEA and MUC-1 genes, respectively, with the 
modifications for the agonist epitopes.  
 
Protein antigens are presented to cytotoxic T lymphocytes as small peptides (approximately 9-10 
amino acids long) bound to class I molecules of the major histocompatibility (MHC) complex.  
One strategy to increase the immunogenicity of a self-antigen such as CEA is to modify selected 
epitopes within the protein sequence to enhance their binding to MHC class I alleles.  One such 
epitope, designated CAP-1, which is specific for the MHC class I A2 allele, was modified by the 
introduction of a single amino acid change (asn to asp) at position 6 in the epitope (designated 
6D).(34) The modified epitope, CAP-1(6D), was shown to be 100-1000 times more efficient than 
the native CAP-1 peptide in the induction of CAP-1-specific cytotoxic T lymphocytes (CTLs).  
In contrast to the native peptide, CAP-1(6D) was able to induce CD8+ CTLs from normal 
peripheral blood mononuclear cells that were able to recognize both the modified and native 


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peptides.  In addition, these CTLs recognized and lysed tumor cell lines expressing native CEA.  
These studies indicate that CEA glycoprotein containing the modified peptide may be more 
efficient in and capable of eliciting and sustaining antitumor responses than unmodified 
glycoprotein. 
 
As described above for CEA, a selected epitope within the MUC-1 protein sequence was 
modified to increase its binding to the MHC class I A2 allele in order to enhance the 
immunogenicity of the polypeptide.  This epitope, designated P92, was modified by the 
introduction of a single amino acid change (thr to leu) at position 2 in the epitope.  The modified 
epitope, designated P93L, was shown to be more efficient than the native P92 peptide in the 
stimulation of gamma-interferon production by MUC-1-specific T cell lines.(35)  P93L was also 
able to induce CD8+ CTLs from peripheral blood mononuclear cells collected from pancreatic 
patients that could recognize and lyse tumor cell lines expressing native MUC-1.  These studies 
indicate that MUC-1 glycoprotein containing the modified peptide may be more efficient in and 
capable of eliciting and sustaining antitumor responses than unmodified glycoprotein. 
 
GM-CSF  
GM-CSF has been shown to be an effective vaccine adjuvant because it enhances antigen 
processing and presentation by dendritic cells. Experimental and clinical studies suggest that 
recombinant GM-CSF can boost host immunity directed at a variety of immunogens.(36-38)  
 
 
 
Using murine tumor models, several researchers have now shown that modification of tumor 
cells to enhance GM-CSF expression, using retroviral vectors (16) or vaccinia virus vectors 
(39;40), results in enhanced tumor-specific immune responses capable of effecting tumor 
destruction.  Furthermore, this immune response is effective against not only the engineered, 
GM-CSF-expressing tumors, but also against unaltered tumor cells.  We have shown that with 
vaccine strategy, GM-CSF is a vital component with a significant decrease in anti-tumor efficacy 
in murine models when GM-CSF is deleted from the regimen. We will use GM-CSF locally, at 
the vaccination site, to enhance immune responses elicited by the recombinant vaccines. 
 
Diversified prime and boost regimens  
Several preclinical studies and now clinical studies have demonstrated the advantage of a prime 
vaccination with recombinant vaccinia and boosting with a recombinant avipox as compared to 
the continued use of either vector alone.(41;42) These and other studies showed one could boost 
with a recombinant avipox vaccine without the induction of host-neutralizing immunity.(43-45) 
 
In-vitro human studi es 
PANVAC™-V (vaccinia) and PANVAC™-F (fowlpox) have both been evaluated in-vitro. 
Infection of human dendritic cells with either vector was shown to result in faithful expression of 
CEA, MUC-1, B7-1, ICAM-1 and LFA-3, as measured by both Northern Blot analysis and 
FACS analysis. Human dendritic cells were also infected with PANVAC™-V (vaccinia) and 
PANVAC™-F (fowlpox) and tested for their ability to activate both CEA-specific and MUC-1–
specific human T-cell lines. Results demonstrated that the PANVAC vectors were as efficient as 
CEA/TRICOM or MUC/TRICOM vectors in activating CEA- and MUC-1–specific human T 


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cells, respectively.  
 
Preclinical studies performed in the Laboratory of Tumor Immunology and Biology, CCR, NCI 
were designed to look at the effect of the addition of trastuzumab to a breast cancer tumor cell 
line to determine its effects on the ability of specific T-cells to lyse this cell line.  MCF-7 is a 
breast cancer cell line that is HLA-A2 +, HER-2 neu +, and positive for MUC-1 expression. We 
have developed a cytotoxic T-cell line, T1191, that is HLA-A2 + and MUC-1 specific.  We 
performed a CTL (cytotoxic T-lymphocyte) killing assay using MCF-7 as target cells.  T-1101 
cells were used as CTL in this assay to determine the percent lysis of this breast cancer cell line 
with and without the addition of trastuzumab (at a concentration of 100μg/ml). A 16 hr 111In 
release assay was performed for the CTL assay. The T-cell specific killing was increased by 1.5 
fold (21% killing to 36.5 % killing) in those cells treated with the trastuzumab. This suggests that 
the use of trastuzumab may augment the ability of cytotoxic T-cells to kill tumor cells. 
 
Preclinical toxicology studies 
The above murine studies with CEA/TRICOM also demonstrated the absence of long-term 
toxicity, including autoimmunity, in mice that have eliminated established tumors.(46)  
 
A non-human primate toxicology study has been carried out by Therion involving priming with 
rV-CEA(6D)/TRICOM admixed with rV-MUC-1 and boosting with rF-CEA(6D)/TRICOM 
admixed with rF-MUC-1/TRICOM. All vaccinations also included human GM-CSF. Complete 
necropsies were performed on all animals and gross lesions, bone marrow smears and kidneys 
were examined microscopically. No test article-related lesions in the kidneys or bone marrow 
were observed in this study. Hematology, serum chemistry, urinalysis, food consumption, and 
body weights were also assessed. Test article related lesions were observed only at the vaccine 
administration sites. 
 
1.2.3 Clinical Studies 
 
CEA Vaccines 
The immunogenicity of CEA in humans has been demonstrated in several clinical trials.  Foon 
and coworkers reported the development of humoral and T cell immunity to CEA as a result of 
immunization with a CEA anti-idiotype vaccine.(47) In addition, a number of clinical trials using 
recombinant vaccinia and/or avipox viruses expressing CEA have been conducted.(48-53) These 
trials demonstrated for the first time that CEA, when expressed by a recombinant pox virus, can 
elicit or enhance human immune responses capable of recognizing and destroying tumor cells 
that express CEA. 
 
Pilot Study studies using rV-CEA (39) or avipox-CEA (40;54) vaccines demonstrated that both 
are capable of inducing T-cell responses specific for CEA in patients with metastatic carcinoma. 
These T cells were then shown to be capable of lysing human tumor cells expressing CEA. A 
subsequent clinical trial in collaboration with John Marshall at Georgetown University has 
indicated better immune responses and preliminary evidence of clinical benefit of priming with 
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sequence of vaccinations. (55) Patients were randomized to receive vaccinations priming with 
vaccinia-CEA (V) and boosting with 3 monthly avipox-CEA (A) vaccinations (designated 
VAAA regimen), or they received the 3 monthly avipox-CEA vaccinations followed by a fourth 
rV-CEA vaccine (designated AAAV regimen). In each group, patients were evaluated for 
immunologic responses using the ELISPOT assay.(56) Patients on the VAAA arm had 
statistically significantly increases in their numbers of CEA specific T cells.  Patients with stable 
disease or with clinical responses to their regimen continued to receive multiple boosts with 
avipox-CEA. This group of patients, with metastatic colorectal, pancreatic, lung, and breast 
carcinomas, who had failed multiple prior therapies, would be expected to have a median 
survival of approximately 6–12 months. Although there were only 9 patients in each randomized 
arm, patients were followed for survival with the intent of having a hypothesis generating 
analysis of survival in the 2 arms. After 2+ years of follow-up, 6 out of 9 patients randomized to 
the VAAA regimen exhibited stable disease with some patients receiving up to 24 monthly 
vaccinations. All 9 of the patients randomized to the AAAV arm had progressed at the 2-year 
follow-up. The results of the comparison in survival of these two groups were statistically 
significant (p=0.05). Furthermore, there was a statistically significant correlation between CEA-
specific immunologic responses and overall survival.(57) 
 
In another study, the agonist peptide epitope to CEA (designated CAP1-6D) has been shown to 
have activity in patients with CEA-expressing tumors. Patients received 2 monthly vaccinations 
with dendritic cells loaded with the CEA agonist peptide. Two of 12 patients experienced 
complete responses (CR), one patient had a mixed response, and 2 had stable disease. Clinical 
response correlated with CEA-specific T-cell responses.(58) 
 
A Phase I clinical study has recently been completed in collaboration with Georgetown 
University (John Marshall, PI) employing rV-CEA/TRICOM (V), avi-CEA/TRICOM (A), and 
both vaccines in a diversified prime and boost regimen. Fifty-nine patients with advanced CEA 
positive cancers have been accrued to 8 cohorts. Cohorts 1-3 received AAAA alone, 4–6 
received VAAA, 7–8 received VAAA+ sargramostim, 8 with divided doses of vaccine. Vaccines 
were administered every month for the 6 doses and then every 3 months. Most patients had GI 
cancers and were heavily pre-treated. No significant toxicity was observed. Mild fevers, skin 
reactions at the vaccination site and regional adenopathy were observed. One pathologic 
complete response (pCR), 5 decreasing serum CEA, 25 stable disease (SD) (>4 months) were 
observed; 7 of these patients have been stable for >12 months and 18 for >4 months. Significant 
CEA-specific immune responses were observed in all patients tested. This study thus 
demonstrated that the TRICOM vaccines are safe, generate a significant CEA-specific immune 
response in all A2+ patients, and may have significant clinical benefit in patients with advanced 
cancer.(59) Three other trials employing TRICOM vectors are ongoing at Fox Chase Cancer 
Center, Duke University Cancer Center, and Columbia Presbyterian. There have been no dose 
limiting toxicities (DLT) attributed to vaccine on any of these studies. 
 
MUC-1 vaccines 
In a Phase I study at the Dana-Farber Cancer Center, employing three vaccinations of rV-MUC-1 
in patients with advanced breast cancer, no serious adverse events were noted; drops in serum 


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markers were observed in some patients. In related studies, an rV-MUC-1 IL-2 vaccine was 
administered in a Phase I trial to patients with inoperable breast cancer. MUC-1–specific T-cell 
responses were detected in 2 of 9 patients.(60) In a multi-center Phase II study using this 
vaccine, 2 of 31 patients with metastatic breast cancer, who had visceral metastases and 
progressive disease after intensive chemotherapy, had objective tumor regression following 
vaccination.(61) Other vaccine trials are ongoing employing MUC-1–based vaccines with 
excellent safety profiles. Many have shown the ability of the vaccine to generate MUC-1–
specific T-cell responses. None of the above MUC-1–based vaccines, however, contain 
costimulatory molecule, an agonist MUC-1 epitope, or are being used in diversified prime and 
boost regimens. 
 
Vaccines containing MUC-1 and CEA  
As a precursor study for the PANVAC vaccines, an admixture study was carried out at Columbia 
Presbyterian (sponsored by Therion Biologics Corp.). In this safety and tolerability study, 
pancreatic cancer patients received a s.c. priming dose of rV-CEA(6D)-TRICOM admixed with 
rV-MUC-1 on day 0, followed by a s.c. boost dose of rF-CEA(6D)-TRICOM on days 14, 28, and 
42. sargramostim was given s.c. at the injection site on the day of each vaccine and for 3 
consecutive days thereafter. Twelve patients were vaccinated. No serious adverse events related 
to the treatment regimen have been identified, and no dose limiting toxicities have occurred. 
Three of 12 patients remained on trial with stable disease for more than 6 months. 
 
1.2.4 Summary 
 
In this pilot trial we will seek to translate the following observations from the laboratory and 
prior clinical trials into the clinic in patients with incurable tumors. 
 
CEA and MUC-1 are overexpressed in adenocarcinomas of the colon.  It is 
estimated that > 99% of patients with colorectal cancer have over-expression of 
one or both TAA.
Pox viral vectors can induce a strong immune response to TAA such as CEA and 
MUC-1. 
The use of agonist epitopes within the TAA can induce a better immune response 
than native peptides and have been associated with clinical responses 
Heterologous prime and boost regimens are superior in terms of generalizing 
immune responses; and this may translate into improved clinical responses 
 The use of GM-CSF does not add significant toxicity and in pre-clinical models is 
essential for induction for optimal immune responses. 
 A precursor study with viruses containing MUC-1, CEA and TRICOM showed no 
evidence of vaccine related toxicity and 3 of 12 advanced pancreatic cancer 
patients with stable disease for more than 6 months 
 It is possible by using vectors directed against TAA that there may be additive or 
synergistic immune responses and this may be important in overcoming antigenic 
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 Several hundred patients have been treated on clinical trials with pox viral vectors 
made in collaboration with Therion Biologics Corp., and there have been no dose 
limiting toxicities attributable to vaccines 
 This trial is identical in design to one approved by the FDA under a Therion 
Biologics Corp. IND that will be performed in pancreatic cancer patients.  This 
trial will allow us to provide initial evaluation of CEA and MUC-1 immune 
responses with this vaccine strategy. 
 
 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
 
2.1 
Eligibility Criteria 
 
2.1.1 Inclusion Criteria 
 
A. Histologically confirmed carcinoma that for patients in the first two arms 
(colorectal and non-colorectal cancer) is CEA or MUC-1 positive. Tumor that 
has been shown to express CEA or MUC-1 (≥ 20 % of cells) by 
immunohistochemical techniques or patients that have had an elevated serum 
CEA (> 5 μg/L) at any point during their disease course.  For patients in the 
ovarian and breast cancer arms, as >95% of these express MUC-1 or CEA, we 
will not require staining prior to coming onto trial. 
B. Patients must have completed at least one 5-FU containing chemotherapy 
regimen (e.g. 5-FU/LV with or without either irinotecan or oxaliplatin) for the 
colorectal cancer arm, or either failed or not be a candidate for therapy of 
proven efficacy for their disease in the non-colorectal, breast, and ovarian 
cancer arms. 
C. 18 years of age or greater. 
D. All patients on the colorectal adenocarcinoma cohort must be HLA-A2 
positive.   
E.  At least 10 patients on the non-colorectal carcinoma cohort must be HLA-A2 
positive. 
F. Patients on the breast and ovarian arms are not required to be HLA-A2 
positive. 
G. For the colorectal and non-colorectal cancer arms (the initial two arms), 
patients will be required to have: metastatic disease (measurable or evaluable), 
metastatic disease documented by biopsy but not evaluable by imaging (e.g. 
small volume peritoneal disease), and patients with surgically resected 
metastatic disease at high risk of relapse.  For the ovarian and breast cancer 
arms, patients will be required to have evaluable disease. 
H. Able to understand and give informed consent. 
I. Able to avoid close household contact (close household contacts are those 
who share housing or have close physical contact) for at least three weeks 
after recombinant vaccinia vaccination with persons with active or a history of 


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eczema or other eczematoid skin disorders; those with other acute, chronic or 
exfoliative skin conditions (e.g., atopic dermatitis, burns, impetigo, varicella 
zoster, severe acne, or other open rashes or wounds) until condition resolves; 
pregnant or nursing women; children  3 years of age and under; and 
immunodeficient or immunosuppressed persons (by disease or therapy), 
including HIV infection. 
J. ECOG performance status of 0 – 1. 
K. Serum creatinine not above the institution limits of normal, and AST  twice 
the upper limits of normal OR creatinine clearance on a 24 hour urine 
collection of  60 mL/min.  
L. Total bilirubin within the institution limits of normal OR patients with 
Gilbert’s syndrome, a total bilirubin  3.0 
M.  Recovered completely from any reversible toxicity associated with recent                                
therapy.  Typically this is 3-4 weeks for patients who most recently received 
cytotoxic therapy except for the nitrosoureas and mitomycin C for which 6 
weeks is needed for recovery. 
N.  Hematological eligibility parameters (within 16 days of starting therapy): 
 Granulocyte count 1,500/mm3 
 Platelet count 100,000/mm3 
 Hgb ≥ 10 Gm/dL 
O. Prior immune therapy (e.g. related vaccinia and fowlpox vaccines or antigen-
specific peptides) is allowed. 
P. Men and women must agree to use effective birth control or abstinence during 
and for a period of 4 months after the last vaccination therapy. 
Q. Patients with prostate cancer must continue to receive GnRH agonist therapy 
(unless orchiectomy has been done). 
R. Patients should appear clinically stable (in the opinion of the principal 
investigator) to complete the full 3 month course of vaccination with an 
anticipated survival of 6 months or longer 
 
2.1.1.1      Inclusion Criteria for Extension or Maintenance Phase 
 
A. Completion of Core phase of the protocol. 
B. Stable or responding disease (PR, CR). 
C. No dose limiting toxicity (see below) in Core phase possibly, probably or 
definitely related to the vaccine.  
 
Dose limiting toxicities include: 
 
Any Grade 2 generalized urticaria or Grade 3 or greater allergic reaction. 
 
Any Grade 2 or greater autoimmune response 
 
Any Grade 3 or greater hematologic or non-hematologic reaction, including 
injection-site reaction. 
 


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2.1.2 Exclusion Criteria 
 
A. Patients should have no evidence of being immunocompromised as listed 
below. 
 Human immunodeficiency virus positivity due to the potential for                           
decreased tolerance and risk for severe side effects 
 Active autoimmune diseases requiring treatment or a history of 
autoimmune disease that might be stimulated by vaccine treatment. 
This requirement is due to the potential risks of exacerbating 
autoimmunity. Patients with endocrine disease that is controlled by 
replacement therapy including thyroid disease and adrenal disease 
and vitiligo may be enrolled.  
B. Concurrent use of systemic steroids, except for physiologic doses for               
systemic steroid replacement or local (topical, nasal, or inhaled) steroid            
use. Limited doses systemic steroids to prevent IV contrast, allergic 
reaction, or anaphylaxis (in patients who have known contrast allergies) 
are allowed 
C. History of allergy or untoward reaction to prior vaccination with vaccinia 
virus 
D. Pregnant or breast-feeding women  
E. Altered immune function, including immunodeficiency or history of 
immunodeficiency; eczema; history of eczema, or other eczematoid skin 
disorders; or those with acute, chronic or exfoliative skin conditions (e.g. 
atopic dermatitis, burns, impetigo, varicella zoster, severe acne, or other 
open rashes or wounds)  
F. Serious intercurrent medical illness which would interfere with the ability 
of the patient to carry out the treatment program, including, but not limited 
to, inflammatory bowel disease, Crohn's disease, ulcerative colitis, or 
active diverticulitis   
G. Patients with a history of cardiomyopathy or symptomatic congestive 
heart failure (unless stable on treatment), symptomatic arrhythmia not 
controlled by medication.  Unstable atherosclerotic heart disease (e.g. 
unstable angina) who require active intervention and history of myocardial 
infarction or embolic stroke within the past 6 months. 
H. Clinically active brain metastasis, or a history of encephalitis, multiple 
sclerosis, or seizures within the last year (from seizure disorder or brain 
metastasis) 
I. Medical conditions, which, in the opinion of the investigators would 
jeopardize the patient or the integrity of the data obtained 
J. Concurrent chemotherapy; an exception to this is to allow for patients with 
breast cancer who are receiving trastuzumab, to continue therapy with 
trastuzumab while receiving the vaccine treatment 
K. Serious hypersensitivity reaction to egg products 
L. Clinically significant cardiomyopathy requiring treatment 


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M. Chronic hepatitis infection, including B and C, because of potential 
immune impairment 
N. Although 
topical 
steroids 
are 
allowed, 
steroid 
eye-drops 
are 
contraindicated 
O. Cardiac complications, including recent myocardial infarction or 
cerebrovascular accident within one year, and/or unstable or uncontrolled 
angina 
 
2.2 
Research Eligibility Evaluation  
 
A. Clinical Evaluation (within 16 days of before starting treatment). 
 History and physical examination  
 ECOG performance status (see Appendix A) 
B. Laboratory studies (within 16 days before starting treatment) 
 Complete blood count plus differential and platelet count 
 Serum chemistries (Na+, K+, Cl-, CO2, glucose, BUN, creatinine, 
albumin, calcium, magnesium, phosphorus, alkaline phosphatase, ALT, 
AST, total bilirubin, LDH) 
 with BUN and creatinine 
 Serum CEA,  
 ANA titer, CD4:CD8 ratio, CD3, 4, 8 subsets  
 Beta-HCG for women of child-bearing age (within 48 hours prior to day 
1).  In addition, patients, both male and female, should be willing to 
practice effective birth control during the study and four months following 
the last study treatment, unless they have had a prior hysterectomy or 
bilateral oopherectomy.   
C. Urinalysis  
D.  HIV test within the past 8 weeks 
E.  Electrocardiogram (EKG) within the past 28 days. 
F. Computerized Tomography (CT) of the chest/abdomen/pelvis, or Magnetic      
Resonance Imaging (MRI) within the past 28 days. 
G. HLA-A2 profile 
H.  Hepatitis B and C within the past 8 weeks 
I.  Document known prior vaccinia vaccination (small pox vaccine). 
 
2.3 
Patient Registration and Treatment Randomization 
 
Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) 
within 24 hours of signing the consent. A registration checklist from the Web site 
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encrypted email to: NCI Central Registration Office (HOIS) ncicentralregistration-
l@mail.nih.gov. After confirmation of eligibility, the Central Registration staff will call 
Pharmacy to advise them of the acceptance of the patient on the protocol prior to the release of 
any investigational agents.  Verification of Registration will be forwarded electronically via e-
mail to the research team. A recorder is available during non-working hours.  
 
3 
STUDY IMPLEMENTATION  
 
3.1 
Study Design 
 
This is a four arm, open label safety trial in which all enrolled patients receive  
2 x 108 pfu PANVAC™-V (vaccinia) subcutaneously on Day 1, followed by (1 x 109) pfu 
PANVAC™-F (fowlpox) or about days 15, 29, and 43 (Core phase).  100 µg sargramostim will 
be given subcutaneously at the site of the vaccination on each vaccination day and for three 
consecutive days thereafter.  The four arms will consist of 10 colorectal cancer patients, 10-15 
non-colorectal cancer patients, about 12 breast cancer patients, and about 12 ovarian cancer 
patients.  The enrollment on the latter two arms is based on preliminary evidence of clinical 
benefit from the first two arms.  Enrollment to these arms (ovarian cancer and breast cancer) will 
not begin until the first two arms have been enrolled.  The first 9 patients (total from the initial 
two arms) will be used to assess safety.  While the initial few non colorectal patients do not need 
to be HLA-A2 positive, all patients enrolled after the first 9 (from both arms combined) must be 
HLA-A2 positive in the colorectal and non-colorectal arm.  As we will be primarily assessing for 
clinical responses, patients in the breast and ovarian arms do not need to be HLA-A2 positive. 
 
An optional provision of up to 12 additional monthly boosting immunizations (Extension phase) 
with (1 x 109) pfu PANVAC™-F (fowlpox) subcutaneously in combination with sargramostim 
will be offered to patients who have completed the Core phase of the study and have not 
experienced disease progression, have not experienced unacceptable toxicity, and may benefit 
from continuing treatment.  If additional boosts are administered, patients must continue to 
follow study-prescribed criteria for remaining on trial (e.g., no concurrent chemotherapy until the 
last safety visit is completed, no concurrent steroid use, etc.).  Safety assessments will continue 
as during the Core phase.  
 
Patients who have completed the extension phase without evidence of progressive disease may 
continue vaccination every 3 months (Maintenance phase) with PANVAC™-F (fowlpox) (1 x 
109) pfu in combination with Sargramostim until vaccine is no longer available.  From the end of 
the extension phase, patients must continue to follow study-prescribed criteria for remaining on 
trial (e.g., no concurrent chemotherapy until the last safety visit is completed, no concurrent 
steroid use, etc.).  Safety and clinical assessments will continue at each regularly scheduled visit.  
Patients who are in the Maintenance phase (vaccines every 3 months) who show no radiographic 
evidence of metastatic cancer, may have their restaging exams performed at the discretion of the 
PI as clinically warranted on a per patient basis at an interval not to exceed one year.  These 
patients will have interval clinical evaluation every 3 months prior to each vaccination. 
  


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Patients who have radiographic evidence of progressive disease during the maintenance phase 
who are otherwise clinically stable may revert back to monthly vaccinations as in the extension 
phase (see above). 
 
Scans documenting progressive disease on the maintenance phase will be used as a baseline scan 
to assess for subsequent evaluation of disease response.  Patients having further progression will 
be taken off study per off-study procedure (Section 3.6.1). 
 
3.1.1 Trial Outline 
        
           Core Phase 
 
 
                       Day 1 
 
          PANVAC™-V (vaccinia) (2 x 108) pfu 
subcutaneously 
 
 
 
On or about days 15, 29, 43             PANVAC™-F (fowlpox) (1 x 109) pfu 
subcutaneously 
 
                
 
The day of and for 3 consecutive  
Sargramostim 100 µg s.c. at vaccination site. 
           
days following vaccine (on or about 
               
days 1- 4, 15-18, 29-32, and 43-46) 
  Optional Extension Phase 
 (Up to 12 additional monthly boosting 
immunizations)     
                       
 
 
About every 28 days 
PANVAC™-F (fowlpox) (1 x 109) pfu 
subcutaneously 
 
Days 1- 4 with monthly 
 
sargramostim 100 µg subcutaneously at  
PANVAC™-F (fowlpox) injection  vaccination site 
 
The monthly vaccinations of PANVAC-F and sargramostim will begin about 
28 days following completion of the last fowlpox vaccination of the core phase. 
The extension phase will be divided a 56 day cycle each containing vaccines (at 
day 1 and day 29). 
 
Maintenance Phase  
 
Every 3 months 
 
 
boosting immunization 
subcutaneously 
 
 
PANVAC™-F (fowlpox) (1 x 109) pfu  
 
Days 1- 4 with each  
 
sargramostim 100 µg subcutaneously at     
PANVAC™-F (fowlpox) injection  vaccination site 
 
 
 
Restaging scans may be performed at patient and PI discretion, at least every 12 months.  


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Clinic visits for clinical assessment will take place prior to each vaccination at a 3-month 
interval.  
 
3.2 
Drug Administration  
 
3.2.1 Study drugs 
 
Study drugs will be prepared and placed in syringes by the Warren Magnuson Clinical Center 
pharmacy personnel. Both vaccine and sargramostim are given subcutaneously at the same site 
(see Section 9). 
 
This pilot study will be conducted by delivering a priming dose of (2 x 108) pfu PANVAC™-V 
(vaccinia) subcutaneously, followed 2 weeks later by a boosting dose of (1 x 109) pfu 
PANVAC™-F (fowlpox) administered subcutaneously.  Boosting doses of (1 x 109) pfu 
PANVAC™-F (fowlpox) administered subcutaneously will be repeated at two week intervals, 
for a total of three vaccinations.  Sargramostim (100 µg) will be given subcutaneously at the site 
of the vaccine injection as an adjuvant, at the time of each immunization and for three 
consecutive days thereafter.  Up to 51 patients will be enrolled into this study.  Patients will be 
seen at each vaccination visit and four weeks following the final boosting vaccination for 
physical examination and collection of laboratory data and adverse event information.  A 
preliminary assessment of immune response will also be performed at the end of the study. 
Continued boosting immunizations of PANVAC™-F (fowlpox) will be available to patients who 
do not experience disease progression (see Trial Outline section 3.1.1).  Patients will continue to 
receive the vaccine as long as drug is available. 
 
 
 
 
3.2.2 Precautions 
 
 Prior to administration of the drugs, safe-handling precautions should be 
thoroughly reviewed (see precautions and special handling subsections of 
section 9, “Pharmaceutical Information”). 
 The proper procedure for disposing the live vaccine is a critical part of drug 
administration (see the disposal sections of section 9, “Pharmaceutical 
Information”). 
 
 
 
            
3.3 
 Treatment Modifications  
 
Patients must have recovered to < grade 2 toxicity for the parameters used to assess levels of 
organ function required for eligibility (see section 2) after each vaccination in order to receive a 
subsequent vaccination. If > grade 1 toxicity persists for > 42 days, the patient will not receive 
further vaccine inoculations and will be removed from protocol. Follow-up will be performed 
during each vaccination and blood draw interval for immunologic testing as described in section 


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3.4.5.  Vaccination will be held for > grade 2 proteinuria. 
 
If a scheduled dose of the vaccine is missed, the vaccine may be given within 7 days of the 
appointed time (which resets the appointed date for further vaccinations) or be considered a 
missed dose.  If the patient has a delay in vaccination not due to toxicity during the core phase, 
the vaccine may be delayed for up to 42 days without removal of the patient from study.  If the 
patient has a delay in vaccination not due to toxicity during the extension or maintenance phase, 
the vaccine may be delayed for up to 3 months without removal of the patient from study.   
 
Dosing Delay:  Patients should have resolution to < grade 2 or return to baseline of all toxicities 
prior to the start of the next injection of PANVAC™-F (fowlpox). 
 
Vaccine Dose Modification: None 
 
3.3.1 PANVAC™-V (vaccinia) and PANVAC™-F (fowlpox) (Vaccine)  
 
Patients must have recovered to < Grade 2 toxicity or to levels of organ function required for 
eligibility in Section 2 after each vaccination in order to receive a subsequent vaccination. No 
dose modifications will be made.  If > Grade 1 toxicity persists for > 42 days, the patient will not 
receive further vaccine inoculations and patients will be removed from protocol.  This study will 
utilize the CTCAE version 4.0 for grading systemic toxicity starting August 1, 2010 (all AE’s 
before August 1, 2010 will be graded using the CTCAE version 3). In addition, patients who 
develop ≥ grade 2 allergic disease to the vaccine or ≥ grade 2 autoimmune disease that may 
threaten vital organ function or any grade 3 or greater autoimmunity will be removed from the 
protocol. Any grade 3 or greater toxicity to sargramostim lasting more than 48 hours with the 
exception of fever, local reactions, rash, headache and adenopathy, and any grade 4 toxicity to 
sargramostim would require discontinuation of the sargramostim. Grade 3 toxicities not 
attributed to sargramostim lasting more than 48 hours or any grade 4 toxicity not attributed to 
sargramostim will require removal of the patient from protocol. 
 
Sargramostim (GM-CSF) 
 
If reversible grade ≥ 3 toxicity attributable to sargramostim administration is encountered, 
sargramostim will be reduced by 50% for the following cycle.  If similar reversible grade ≥ 3 
toxicity attributable to sargramostim recurs in more than two cycles, it will be discontinued and 
patient will be allowed to receive vaccinations without further sargramostim. 
 
In addition, patients who develop ≥ grade 2 allergic disease to the vaccine or ≥ grade 2 
autoimmune disease that may threaten vital organ function or any grade 3 or greater 
autoimmunity will be removed from the protocol.   Any grade 3 or greater toxicity to 
sargramostim lasting more than 48 hours with the exception of fever, local reactions, rash, 
headache and adenopathy, and any grade 4 toxicity to sargramostim would require 
discontinuation of the sargramostim.  Grade 3 toxicities not attributed to sargramostim lasting 
more than 48 hours or any grade 4 toxicity not attributed to sargramostim will require removal of 


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the patient from protocol. 
 
3.4 
On Study Evaluation: (See APPENDIX C)  
 
3.4.1 All patients who are deemed eligible and who sign the informed consent form will be 
enrolled onto this trial.  
 
 
3.4.2 Medical assessment, performance status will be completed within 3 days prior to 
vaccination. 
 
3.4.3 Consideration for work up of any history of symptoms of myopericarditis and coronary 
atherosclerotic heart disease following vaccinia vaccination.  This should include ECG, 
cardiac enzymes, echocardiogram as clinically appropriate.  All patients should be 
encouraged to minimize cardiovascular risk factors including encouraging evaluation and 
management of blood pressure, diabetes, hyperlipidemia, smoking cessation, and 
maintaining healthy diet and exercise. 
 
3.4.4 Laboratory studies: (within 16 days prior to on-study date) 
 
Baseline only: 
 
Hepatitis B, C and HIV panel (within 8 weeks prior to day 1) 
 
HLA-A2 profile 
 
Beta-HCG for women of child-bearing age (within 48 hours prior to day 
1).  In addition, patients, both male and female, should be willing to 
practice effective birth control during the study and four months 
following the last study treatment 
 
 
 
 
 
Baseline and during study: 
 
CBC/differential, with platelet count. 
 
Serum chemistries (Na+, K+, Cl-, CO2, glucose, BUN, creatinine, 
albumin, calcium, magnesium, phosphorus, alkaline phosphatase, ALT, 
AST, total bilirubin, LDH) 
 
PT and PTT 
 
Serum CEA  
 
ANA titer, CD4:CD8 ratio, CD3, 4, 8 subsets (baseline and around day 
71 prior to vaccination) 
 
Serum for NCA (CEA-CAM) titers will be drawn anytime that a patient 
exhibits new onset neutropenia. (ANC <1000) 
 
Urinalysis with dipstick protein prior to each vaccination, 4 weeks after 
the last vaccination, and monthly thereafter for 3 months where feasible 
 
These laboratory tests will be drawn prior to each vaccination (about days 1, 15, 29 and 43) and 
then again on around day 71, and thereafter in the follow-up phase for as long a period as 


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possible at the discretion of the Principal Investigator, for all patients. At a minimum we will 
obtain serum creatinine, electrolytes, and a dipstick protein prior to each vaccination and 4 weeks 
after the last vaccination. Laboratory studies will be repeated more frequently if clinically 
indicated, and any abnormalities potentially related to treatment will be followed until they have 
resolved, or have been determined to not be treatment-related. 
 
3.4.5 Collection of immunologic blood samples 
 
Baseline and around day 71 blood samples will be obtained via apheresis as described in section 
5.2.  In addition, prior to all other vaccinations on protocol, we will obtain 6 green top tubes. 
Prior to each vaccine, 2 “tiger” top tubes will be obtained.  
 
Immunologic testing will include: 
IFN-gamma ELISPOT assays for CEA-specific T lymphocytes and MUC-1-specific T 
lymphocytes. (Samples from baseline and about day 71.) 
 
Antibodies to CEA, vaccinia, fowlpox, MUC-1 and ANA titer.  (Samples from baseline and 
about around day 71.) 
 
CD3, CD4, and CD8 subsets, and CD4:CD8 ratio, will be done at baseline and about day 71 
prior to vaccination while the patient remains on trial. Serum for NCA (CEA-CAM) titers will be 
drawn anytime that a patient exhibits new onset neutropenia. (ANC <1000) Immunologic studies 
will be repeated more frequently if clinically indicated, and any abnormalities potentially related 
to treatment will be followed until they have resolved, or have been determined to not be 
treatment-related or until the participant’s primary medical care is transferred from the principal 
investigator. 
 
Blood samples may be used for other research studies which may include phenotypic and 
functional analysis of immune cell subsets, and analysis for cytokines, chemokines, antibodies, 
tumor-associated antigens and / or other markers. 
 
3.4.6 For all patients, appropriate imaging with computerized tomography (CT) of the 
chest/abdomen/pelvis or magnetic resonance imaging (MRI), to reassess tumor extent 
and to determine tumor measurements will be done every 2 months. 
 
3.4.7 Monitoring after the initial phase of vaccinations 
 
All patients who continue on treatment with PANVAC™-F (fowlpox) after the initial phase of 
four vaccinations will continue to have clinical / immunologic monitoring.  
 
 
3.4.8 The samples will be processed at 
 
Clinical Services Program (CSP) 


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NCI Frederick Cancer Research and Development Center 
PO Box B 
Frederick MD 21702 
301-846-1000 
 
On days samples are drawn, CSP should be notified (phone: [301] 846-5893; fax [301] 846-
6222).  She will arrange same day courier delivery of the specimens.  
 
Once a patient’s treatment schedule has been determined, it should be faxed to the Laboratory of 
Tumor Immunology and Biology/ NIH (Fax: [301] 496-2756; phone: [301] 496-9573) for 
planning purposes. 
 
3.4.9 Storage and Tracking of Collected Blood Samples 
 
All data associated with the patient samples is protected by using a secure database.  All samples 
drawn at the NIH Clinical Center will be transported to the NCI Frederick Central Repository by 
the Leidos couriers. 
 
Samples will be tracked and managed by Central Repository database.  All samples will be 
stored in either a -20 or -80˚C freezer.  These freezers are located at NCI Frederick Central 
Repository in Frederick, Maryland. 
 
Leidos Biomedical Research, Inc. manages the NCI-Frederick Central Repositories. NCI-
Frederick Central Repositories store, among other things, biological specimens in support of NIH 
clinical studies. All specimens are stored in secure, limited access facilities with sufficient 
security, back up and emergency support capability and monitoring to ensure long-term integrity 
of the specimens for research.  
 
Sample data is stored in the BioSpecimen Inventory System II (BSI). This inventory tracking 
system is used to manage the storage and retrieval of specimens as well as maintain specimen 
data. BSI is designed for controlled, concurrent access. It provides a real-time, multi-user 
environment for tracking millions of specimens. The system controls how and in what order 
database updates and searches are performed. This control prevents deadlocks and race 
conditions. For security, BSI has user password access, three types of user access levels, and 36 
user permissions (levels of access) that can be set to control access to the system functions. BSI 
provides audit tracking for processes that are done to specimens including shipping, returning to 
inventory, aliquoting, thawing, additives, and other processes. BSI tracks the ancestry of 
specimens as they are aliquoted, as well as discrepancies and discrepancy resolution for 
specimens received by the repository. If a specimen goes out of the inventory, the system 
maintains data associated with the withdraw request. Vials are labeled with a unique BSI ID 
which is printed in both eye readable and bar coded format. No patient specific information is 
encoded in this ID.  
 
Investigators are granted view, input and withdraw authority only for their specimens.  They may 


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not view specimen data or access specimens for which they have not been authorized. Access to 
specimen storage is confined to repository staff. Visitors to the repositories are escorted by 
repository staff at all times. 
 
3.4.10 Protocol Completion/Sample Destruction 
 
Once primary research objectives for the protocol are achieved, intramural researchers can 
request access to remaining samples providing they have an IRB approved protocol and patient 
consent. 
 
Samples, and associated data, will be stored permanently unless the patient withdraws consent.  
The PI will report destroyed samples to the IRB if samples become unsalvageable or destroyed 
by environmental conditions (ex. Broken freezer or lack of dry ice in shipping container) or if a 
patient chooses to withdraw his/her consent.  Samples will also be reported as lost if they are lost 
in transit or misplaced by a researcher. 
 
3.5 
Concurrent Therapies  
 
Concurrent anticancer treatment with chemotherapy, hormonal therapy, systemic glucocorticoids 
(topical and inhaled steroids allowed), major surgical procedures or radiation therapy or 
immunotherapy is not permitted. Patients with prostate cancer must continue to receive GnRH 
agonist therapy (unless orchiectomy has been done).  Patients with breast cancer may continue to 
receive trastuzumab. 
 
3.6 
Off Study Criteria 
 
 Progression of disease as described in section 5.2.  (Please note 
radiographic progression on maintenance phase may not be an off study 
criteria as outlined in Section 3.1)  If during the core phase of the study, 
patients are determined to have minimal progression of disease such as 1 
or 2 small lesions and do not require additional therapy, they may remain 
on study until evaluation for progression of disease after the core phase of 
the study. 
 Unacceptable treatment-related toxicity (dose limiting toxicity) as 
described in sections 2.1.1.1 and 5.3.  
 Intercurrent illness or medical circumstances: if at any time the constraints 
of this protocol are detrimental to the patient’s health, the patient may be 
removed from protocol therapy. In this event, the reasons for withdrawal 
will be documented. 
 Patient’s request to be taken off study. In this event, the reasons for 
withdrawal will be documented.  
 If patients are non-compliant with the protocol guidelines, they may be 
removed from the study at the discretion of the principal investigator. 
 Development of proteinuria >1g per 24 hours. 


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3.6.1 Off Protocol Therapy and Off Study Procedure 
Authorized staff must notify Central Registration Office (CRO) when a subject is taken off 
protocol therapy and when a subject is taken off-study. An Participant Status Updates Form from 
the web site (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be 
completed and sent via encrypted email to:  NCI Central Registration Office (HOIS) 
ncicentralregistration-l@mail.nih.gov. 
 
3.7 
Post Study Evaluation (see APPENDIX C) 
 
Patients will be referred to local physician for follow-up care off study. The follow-up data will 
be collected during the 3 month period after patient comes off study if available:   
 
A.  History and physical 
 
B.  Height, weight, BSA 
 
C.  Performance status 
 
D.  CBC and differential 
 
E.  Creatinine 
 
F. AST, ALT, T.bili 
 
G. Blood for immunologic tests 
 
H. Urinalysis  
I.  Serum ANA 
 
The Biologic Response Modifiers Advisory Committee has recommended that long-term follow-
up extend over a period of 15 years. This will be accomplished by signing patients onto protocol 
04-C-0274 “Follow-Up Study of Subjects Previously Enrolled in Poxviral Vector Gene Transfer 
Studies.” Patients will receive annual history and physical examinations for the first 5 years 
following the last vaccine. Additional data will be obtained annually for years six through fifteen 
via telephone contacts. These inquiries will focus on clinical information pertaining to 
development of de novo cancer, neurologic, autoimmune, and hematologic disorders. In addition, 
medical problems including information on unexpected hospitalizations and medications will be 
collected.  Information regarding the findings will be reported to the FDA. 
 
4 
SUPPORTIVE CARE 
 
4.1 
Treatment of Vaccinia Vaccination Complications 
 
4.1.1 Vaccinia Immune Globulin (VIG): First-line treatment of some of the complications of 
vaccinia caused by dissemination of vaccinia virus (severe cases of inadvertent 
inoculation involving extensive lesions or if comorbid conditions exist, severe cases of 
generalized vaccinia in patients that are systemically ill and whose condition might be 
toxic or who have serious underlying immunosuppressive illnesses, eczema vaccinatum, 
and progressive vaccinia) is with Vaccinia Immune Globulin (VIG). VIG is 
contraindicated, however, for the treatment of isolated vaccinial keratitis. VIG is a sterile 
solution of the immunoglobulin fraction of pooled plasma from individuals inoculated 


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with vaccinia vaccine. VIG is an investigational agent available through the CDC’s 
Strategic National Pharmaceutical Stockpile under an IND protocol by contacting the 
CDC’s Smallpox Vaccine Adverse Events Clinician Information Line at 1-877-554-4625. 
Upon receipt of a call from a patient or upon direct observation of a patient or contact 
who manifests signs and symptoms of any of the above conditions, the investigator 
should place a call to the CDC as soon as possible: 1) to initiate review of the clinical 
case, 2) to seek consultation on the appropriateness of VIG therapy, 3) to determine the 
appropriate VIG dose and dosing method for administration, if VIG therapy is required, 
and 4) to determine how to access and have the appropriate doses of VIG delivered. Early 
institution of VIG therapy is advised following recognition of clinical symptoms 
compatible with some vaccinia complications (eczema vaccinatum, severe generalized 
vaccinia, progressive vaccinia, and some cases of inadvertent inoculation). The 
effectiveness of VIG therapy appears to be time dependent. VIG has not proven to be of 
benefit in the treatment of post-vaccinial encephalitis, and is contraindicated for treatment 
of isolated vaccinial keratitis due to the increased risk of corneal scarring. A new 
intravenous formulation of VIG is available through the CDC, which has a lower level of 
aggregated protein, allowing it to be used by either the IM or IV route. This formulation 
will most likely be preferred for administration and investigators will be instructed by the 
CDC regarding appropriate dosing and method of administration based on formulation 
and availability. There is no guarantee that VIG will successfully treat complications. At 
present, there are no other anti-viral therapies of proven benefit for the treatment of 
vaccinia-related complications 
 
4.1.2 Cidofovir (Vistide®, Gilead Sciences): Cidofovir is an FDA-approved antiviral drug for 
the treatment of CMV retinitis among patients with AIDS. Cell-based in vitro studies and 
animal model studies have demonstrated antiviral activity of this agent against certain 
orthopoxviruses. Currently, efficacy in the treatment of vaccinia-related complications in 
humans is unknown. According to the CDC, “VIG is recommended as first line of 
therapy.  Cidofovir may be considered as a secondary treatment, and will only be released 
by the CDC after all inventories of VIG have been exhausted, after a patient fails to 
improve with VIG treatment, or as a last effort for a patient who is otherwise near death.” 
[Medical Management of Smallpox (Vaccinia) Vaccine Adverse Reactions: Vaccinia 
Immune Globulin and Cidofovir. Last updated February 21, 2003. Available at URL: 
https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5204a1.htm]. The CDC has informed 
the NCI/CTEP that cidofovir will not be supplied through Strategic National 
Pharmaceutical Stockpile to investigators involved in CTEP-sponsored protocols utilizing 
recombinant vaccinia-based vaccines. This agent will only be provided by the CDC in the 
occurrence of an emergency public health event.  Thus, investigators should obtain 
cidofovir for second-line therapy through commercial sources if necessary. NCI/CTEP 
investigators may use the CDC cidofovir IND protocol as a "guideline" when providing 
cidofovir for treatment under an off-label use. The CDC will provide their IND protocol 
for the use of cidofovir related to adverse reactions post vaccinia vaccination to 
NCI/CTEP for distribution to investigators of NCI-sponsored protocols. The CDC 
Clinician Information Line at 1-877-554-4625 should still be consulted regarding 


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appropriateness of therapy and guidance. 
 
For the vaccine administration, antiemetics and anti-diarrheal agents may be administered 
as required, but are not anticipated to be needed and should not be used prophylactically 
on the first cycle. The selection of the specific antiemetic regimen is at the discretion of 
the treating physician. Antiemetic regimens should not include dexamethasone or other 
steroids. 
 
Other supportive care with blood components, antibiotics, analgesics, general medical 
therapy, etc., will be delivered as required. Any patients taking antibiotics for any reason 
must complete that course of therapy and be free of evidence of further infection before 
receiving any dose of vaccine. 
 
 
Symptomatic anemia should be treated with appropriate red blood cell or erythropoietin 
support. 
Thrombocytopenia should be treated conservatively. In the absence of bleeding or a 
planned invasive procedure, platelet transfusions should be given for a platelet count 
below 10,000/mm3. If invasive procedures are planned or the patient develops bleeding, 
platelet transfusions should be administered in accordance with the standard of practice, 
usually maintaining a platelet count of >50,000/mm3. 
5 
DATA COLLECTION AND EVALUATION 
 
5.1 
Data Collection 
 
5.1.1 Eligible patients must be confirmed and checklist completed. Consent form must                                      
be signed prior to registration with Harris Technical Services. 
 
5.1.2 For adverse event reporting see sections 7 and 8. 
 
In addition, all serious adverse events should be reported to the Office of Science Policy (OSP), 
NIH per their requirements. Adverse events may be reported by using the Adverse Event 
Reporting template available on the NIH OSP website at:  http://osp.od.nih.gov/office-
biotechnology-activities/biomedical-technology-assessment/hgt/gemcrisor by using the FDA 
Form 3500a. 
 


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5.1.3 Data will be collected using protocol-specific case report forms, verified for accuracy and 
completeness, and submitted to Theradex electronically every 2 weeks.  Hard copies of 
data will be stored in locked secured areas and data will be entered onto a secured 
electronic data base. The following protocol-specific study forms will be complete and 
stored: eligibility checklist (developed by Harris Technical Services), Theradex forms, 
and blood sample flow sheets. A copy of all serious AE forms will be kept in the 
regulatory binder. 
All data obtained during the conduct of the protocol will be kept in secure network drives or in 
approved alternative sites that comply with NIH security standards. Primary and final analyzed 
data will have identifiers so that research data can be attributed to an individual human subject 
participant. 
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable.  
Loss or destruction of data: Should we become aware that a major breech in our plan to protect 
subject confidentiality and trial data has occurred, the IRB will be notified.  
 
5.1.4 Treatment is given according to protocol (dated notes about doses given, complications, 
and clinical outcomes). 
 
5.1.5 Toxicity is assessed according to protocol (laboratory report slips, etc.) 
 
5.1.6 Response is assessed according to protocol (X-ray, scan, lab reports, date noted on 
clinical assessment, as appropriate). 
 
5.1.7 Drug Accountability Records are kept for each patient. 
 
 
5.2 
Response Criteria 
 
All patients in this study must be assessed for response to treatment, even if there are major 
treatment deviations. Each patient will be assigned one of the following categories: 1) complete 
response; 2) partial response; 3) stable disease; 4) progressive disease; and 5) not evaluable 
(early death from malignant disease, early death from toxicity, early death due to other causes, or 
unknown-not assessable, insufficient data). This protocol will use CTEP’s Response Evaluation 
Criteria on Solid Tumors (RECIST) for assessing response. A quick reference to the RECIST 
guidelines can be downloaded at the following URL: 
https://ctep.cancer.gov/protocolDevelopment/default.htm.  A copy of this quick reference is 
found in APPENDIX D. 
 
The minimum restaging evaluation a patient who has measurable or non-measurable, evaluable 
disease to be considered for response assessment will be about 71 days. Patients who experience 


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rapid disease progression mandating discontinuation of therapy prior to completing two 
treatment cycles will be considered treatment failures. The same imaging studies used to define 
the extent of tumor at baseline upon study entry will be used for restaging. The time to disease 
progression will be defined as from the first date of therapy until the first notation of clinical 
progression. 
 
5.2.1 Criteria for Response Assessment 
 
Measurable disease will include any lesion with clearly defined borders that can be measured 
with rulers or calipers on physical exam or radiographically on X-rays or Computerized 
Tomography (CT) of the chest/abdomen/pelvis, or Magnetic Resonance Imaging (MRI) scans.  
Measurement of lesions by ultrasound is not generally recommended for obtaining reproducible 
tumor measurements but is acceptable.  Previously irradiated lesions (prior to study), malignant 
hepatomegaly and lesions visible on bone scan will not be considered measurable.  The measure 
should consist of the longest diameter only for all target lesions.  Photographs (which include a 
centimeter scale, the date and the patient's initials in the photographed field) should be obtained 
at the time of each tumor measurement for visible lesions. 
 
At the time of each assessment of tumor response, the measurement of the    longest diameter 
only for all target lesions should be obtained, and the sum of all of these computed. 
 
 
 
Complete Response: 
Disappearance of all clinical and laboratory signs and symptoms of disease for a minimum of 4 
weeks during which no new lesions may appear. Specifically, all tumor masses must disappear. 
There must be no cancer-associated deterioration in weight (>10%), performance status or 
symptoms. For bony metastases, CR means the re-calcification of all lytic lesions or the biopsy-
proven absence of tumor cells.  Normalization of the bone scan is not necessary for the patient to 
be considered to have a CR; however, any worsening of the bone scan needs to be evaluated. 
 
Partial Response: 
A minimum of 30% decrease in the sum of the longest diameter of target lesions, taking as 
reference the baseline sum longest diameter. If the bone scan was abnormal due to metastatic 
disease, it must show improvement; malignant hepatomegaly, if present, must decrease by 30%.  
There may be no new lesions and the response must last for at least 4 weeks during which time 
there should be no cancer-associated deterioration in weight, performance status or symptoms. 
 
 
 
Stable Disease: 
Neither sufficient shrinkage to qualify for partial response nor progressive disease, taking as 
reference the smallest sum longest diameter since the treatment started.  This condition should 
persist for at least 3 months.  Patients who at study entry are without radiographic or clinical 
evidence of disease will be considered having stable disease if there is no further evidence of 
disease by clinical assessment and surveillance radiographic studies. 
Progressive Disease: 


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A minimum of 20% increase in the sum of the longest diameter of target lesions, taking as 
reference the smallest sum longest diameter recorded since the treatment started or the 
appearance of one or more new measurable lesions.  
 
 
 
In the case of identification of progressive disease prior to end of the initial phase of 
vaccinations, patients may complete their initial 4 vaccinations, with subsequent re-staging and 
reassessment, if the investigator feels further treatment is safe and clinically appropriate. 
 
5.2.2 Assays for Immunologic Response 
 
Our studies in the GMB and LTIB have demonstrated the ELISPOT assay for IFN-γ production 
to be quantitative and reproducible as a measure of human T-cell responses to vaccination. (52-
54) The continued use of one reproducible assay has been instrumental in our ability to evaluate 
and compare patients’ immune responses using different vaccines and vaccine strategies in the 
same institution, and among different cancer centers. ELISPOT assays employing the CEA 
agonist peptide and the MUC-1 agonist peptide have already been developed. (See Appendix E 
for details). 
 
The primary immunologic endpoint for evaluating the immune response will be the frequency of 
interferon gamma-releasing T cells specific to CAP-1-6D, an HLA-A2 restricted epitope of 
CEA, or MUC-1 as measured by the ELISPOT assay.  It is planned that all patients will undergo 
exploratory analysis of the ability to detect CD4 positive responses using a whole protein CEA 
assay. 
 
In all patients undergoing apheresis, 5 x 108 to 2 x 109 mononuclear cells will be obtained by a 
single-access (single venipuncture) “four-pass” mononuclear cell procedure on the Haemonetics 
V-50 instrument, during which 2.0 liters of whole blood would be process at a flow rate of about 
70-80 ml/min.  The total duration of the procedure is 20 minutes per pass or about 80 minutes.  
Patients will be required to have a minimum HCT of 28% and a platelet count of at least 75,000 
to undergo a Haemonetics procedure.  
 
5.3 
Toxicity Criteria 
 
 
Common Terminology Criteria for Adverse Events, Version 4.0(CTCAE)  
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting beginning August 1, 
2010.  All AE’s before August 1, 2010 will be graded using the CTCAE version 3. All 
appropriate treatment areas should have access to a copy of the CTCAE version 4.0.  A copy of 
the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
 
Toxicity Grading for Vaccinia Toxicity (49) (see Section 8.1.2) 
Grade 1:  Cutaneous reaction extending no more than 10 cm from the vaccination site (i.e., 
limited to the upper arm) 
Grade 2:  Any autoinoculation syndrome that resolves without sequelae; Generalized vaccinia 


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34 
 
extending more than 10 cm from the vaccination site 
Grade 3:  Any toxicity that is between grade 2 and 4 
Grade 4:  Autoinoculation syndrome (e.g. blindness); post vaccinia encephalitis; vaccinia 
gangrenosum; eczema gangrenosum; Stevens-Johnson syndrome 
 
5.4 
Statistical Considerations 
 
The primary objectives of this pilot study are to determine whether PANVAC™-F (fowlpox) in 
combination with sargramostim is safe when administered to patients with colorectal 
adenocarcinoma or non-colorectal metastatic carcinoma, and to preliminarily assess immune 
response to the investigational vaccine by determining CEA-specific and MUC-1 specific cell-
mediated immune responses. 
 
Sample Size and Power 
 
A total of up to 51 patients may be enrolled onto this trial. All 10 patients with colorectal 
adenocarcinoma will he HLA-A2 positive, while at least 10 of 15 non-colorectal patients will 
also be HLA-A2 positive.  Patients in the breast and ovarian arm will not need to be HLA-A2 
positive.  
 
 
A safety evaluation will take place in the first 9 patients to be enrolled on the trial, regardless of 
disease type. This number of patients was chosen to provide an adequate initial demonstration of 
human safety and tolerability. Based upon the stopping rule for DLT attributable to the agents 
(see below; not taking into the account stopping due to a death or 2 Grade 4 toxicities), the 
following are the probabilities of stopping early: 
 
Probability (DLT in a given patient) Probability (early termination due to DLT) 
 
0.1                                                  0.13 
0.3                                                  0.65 
0.6                                                  0.96 
 
Thus, this study has a moderate probability of terminating early in the first 9 total patients if the 
probability of a DLT is 0.3 or greater. These probabilities will increase if allowance is made for 
the chance that a death or 2 grade 4 toxicities are noted. 
 
The primary endpoints based on laboratory assays will be assessed with exploratory intent.  All 
colorectal patients will be HLA-A2 positive, as well as at least 10 of the non-colorectal 
carcinoma patients, and these HLA-A2 positive patients will undergo analysis of immune 
response MUC-1 and CEA by ELISPOT assay.  If possible, up to three individual assay values 
will be determined from each patient for each type of assay (ELISPOT for CEA and MUC-1) at 
each time point to help determine the inherent variability in the marker value determinations. 
Differences of (average) assay values between baseline and post-vaccination will be estimated, 
and the standard deviation determined. This information will be used to help identify the number 


Abbreviated Title: Vaccine for metastatic cancer 
Version Date:  05/04/2017 
 
CTEP #: 6536 
 
35 
 
of patients which would be needed in a subsequent trial in order to detect a statistically  
significant difference in the change in the assay values from baseline to the two time points 
defined above. Although this is intended to be a pilot study, for any of the assays, 10 patients 
would provide 80% power to declare a single change of 1 standard deviation in magnitude as 
statistically significant at the two-sided 0.05 level. However, if such a difference were noted, we 
would declare it to be an exploratory finding since such differences were not expected to be 
identified in this intentionally small trial. Thus, both patients with colorectal adenocarcinoma and 
patients with non-colorectal carcinoma will be evaluated in this fashion, in separate cohorts of 10 
patients apiece. 
 
In the cohort of patients with non-colorectal, metastatic carcinoma, the initial few patients 
enrolled (up until a total of 9 have been enrolled, from both disease categories combined) do not 
need to be HLA-A2 positive, as they will be enrolled in order to obtain preliminary information 
about toxicity and evidence of clinical response in different disease states that are refractory to 
standard treatment. However, once the toxicity evaluation phase has concluded, all remaining 
patients with non-colorectal adenocarcinoma must be  HLA-A2 positive in order to undergo 
analysis of immune response MUC-1 and CEA by ELISPOT assay as an exploratory analysis of 
the magnitude of immune responses in non-colorectal cancer patients given this vaccine.  
 
 
 
 
Stopping Rules 
 
One occurrence of Grade 5 toxicity by the NCI-CTCAE (Version 4 starting August 1, 2010; All 
AE’s before August 1, 2010 will be graded using the CTCAE version 3) attributable to the 
treatment regimen will result in study termination.  In the first 10 patients, if there are two 
occurrences of Grade 4 toxicity that are attributed to the treatment regimen, the study will be 
terminated.  
 
If > 1 of the first 3 patients 
or 
≥ 2 of the first 6 patients 
or 
≥ 3 of the first 9 patients 
experience a dose limiting toxicity attributed to the treatment regimen, the 
maximum tolerable dose has been exceeded and the study must be terminated. 
 
 
Dose limiting toxicities include: 
 Any Grade 2 allergic reaction of asymptomatic bronchospasm or generalized 
urticaria or any other Grade 3 or greater allergic reaction. 
 Any Grade 2 or greater autoimmune response. 
 Any Grade 3 or greater hematologic or non-hematologic reaction, including 
injection-site reaction. 
 


Abbreviated Title: Vaccine for metastatic cancer 
Version Date:  05/04/2017 
 
CTEP #: 6536 
 
36 
 
These stopping rules apply only to the Core phase and will not apply to the Extension or 
Maintenance phase (optional additional monthly boosts). All serious adverse events (SAEs) 
attributed to the treatment regimen occurring in the Extension and/or Maintenance phase will be 
reported to the FDA and to the NIH. 
 
5.4.1 Statistical considerations for pilot portion of trial 
 
Amendment I will allow enrollment of patients with either breast cancer or ovarian cancer to 
determine, in a pilot fashion, if early indications of clinical benefit from the agents administered 
may suggest that further investigation is warranted.  
 
Among patients initially enrolled in the trial, the one patient with ovarian cancer experienced a 
large reduction of ascites and substantial improvement in clinical symptoms as well as CA125. A 
patient with breast cancer also showed a modest reduction of tumor volume, although less than 
required to be considered a partial response. 
 
In order to determine if the vaccine approach studied in this trial is worth pursuing in a phase II 
trial, this amendment will allow accrual of 12 additional, eligible patients with ovarian cancer 
and 12 additional, eligible patients with breast cancer.  In each category separately, with 12 
patients, there is 84% power to rule out a 5% PR rate in favor of a 25% PR rate, assuming that an 
exact binomial test with a one-sided 0.15 alpha level is used.  
 
By so doing, if 1/12 patients in either category has a clinical response, this has an associated one-
sided lower 85% confidence bound of 1.3%, while 2/12 with clinical response has an associated 
one-sided lower 85% confidence bound of 5.8%.  The information obtained in this pilot 
evaluation will be used to determine if a phase II trial is warranted and to help establish the 
parameters for such a trial. 
 
It is expected that approximately 1 year will be required to enroll the 12 patients in each 
category. Since there may be an occasional patient who is inevaluable, the ceiling of 26 
additional breast and ovarian cancer patients combined will be used. As a result, the accrual 
ceiling for the trial will be expanded from the original 25 to 51 after the amendment is in effect. 
 
 
5.5 
Data Safety Monitoring Plan 
 
5.5.1 The clinical research team will meet weekly at each clinic to review all adverse events for 
each subject in this trial.  Unexpected adverse events and/or serious adverse events will 
be reported to the NCI’s Institutional Review Board (IRB) and Cancer Therapy 
Evaluation Program (CTEP) (see section 7).  If trends are noted and/or risks warrant it, 
accrual will be interrupted and/or the protocol and/or consent will be modified 
accordingly. In addition, the drug monitor at CTEP will review the data regularly. The 
NCI/CCR DSMB will monitor the study at its meetings, which are held twice yearly.  
 


Abbreviated Title: Vaccine for metastatic cancer 
Version Date:  05/04/2017 
 
CTEP #: 6536 
 
37 
 
5.5.2 Submission of Data to NCI’s Clinical Trials Monitoring Service (CTMS) contractor:  
 
This protocol will be monitored by the NCI’s CTMS (contract held by Theradex, Princeton, N.J.) 
according to guidelines.  Data will be submitted to CTEP every two weeks. The NCI/DCT Case 
Report Form and the NCI database will be used to report to CTEP. 
 
Below are some of the services Theradex® provides under this contract:               
 Confirming fulfillment of all regulatory requirements 
 Verification of secure and appropriate pharmacy procedures 
 Adequacy of institutional review and consent procedures 
 Verification of laboratory competency 
 Verification of study data submitted to CTMS by investigators 
 Evaluation of eligibility of all patients 
 Evaluation of all course of treatment 
 Evaluation of investigator compliance 
 Quality assurance evaluation of incoming data from Theradex®'s proprietary 
 electronic data capture system, ACES® 
 Quality assurance evaluation of case report forms submission 
 
 
6 
HUMAN SUBJECTS PROTECTIONS 
 
6.1 
 Rationale for Subject Selection 
 
6.1.1 Selection Based on Gender, Ethnicity, and Race  
 
Subjects from all racial/ethnic groups and both genders are eligible for this study if they meet the 
eligibility criteria. To date, there is no information that suggests that differences in drug 
metabolism, immune response or disease response would be expected in one group compared 
with another. Efforts will be made to extend accrual to a representative population, but in this 
preliminary study, a balance must be struck between patient safety considerations and limitations 
on the number of individuals exposed to potentially toxic and/or ineffective treatments on one 
hand and the need to explore gender and ethnic aspects of clinical research on the other hand. If 
differences in outcome that correlate with ethnic identity are noted, accrual may be expanded or 
a follow-up study may be written to investigate those differences more fully.  
6.1.2 Strategies/Procedures for Recruitment 
Patient accrual for this protocol would be facilitated by the Clinical Center Support Center 
(CCSC), developed to increase the accrual to clinical studies via community outreach as well as 
recruitment letters to referring physicians. 
 
This protocol will be available through the physicians’ data query (PDQ) database. 
 


Abbreviated Title: Vaccine for metastatic cancer 
Version Date:  05/04/2017 
 
CTEP #: 6536 
 
38 
 
6.1.3 Justification for Exclusions 
 
Due to impaired cellular immunity, HIV patients are at an increased risk of serious side effects 
from vaccinations with infectious agents and are excluded. This is based on recommendations 
from the CDC and FDA. In addition, pregnant women are also excluded due to potentially 
increased risks of serious side effects from vaccinations with infectious agents.  
 
6.2 
Participation of Children 
 
Individuals under the age of 18 will not be eligible for participation in this study based on the 
fact that patients under 18 are unlikely to have this disease and there are unknown toxicities in 
pediatric patients. 
 
6.3 
Participation of NIH Subjects Unable to Give Consent 
Adults unable to give consent are excluded from enrolling in the protocol.  However re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (section 6.4), all subjects will be offered the opportunity to fill in their 
wishes for research and care, and assign a substitute decision maker on the “NIH Advance 
Directive for Health Care and Medical Research Participation” form so that another person can 
make decisions about their medical care in the event that they become incapacitated or 
cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH 
Ability to Consent Assessment Team for evaluation.  For those subjects that become 
incapacitated and do not have pre-determined substitute decision maker, the procedures 
described in MEC Policy 87-4 for appointing a surrogate decision maker for adult subjects who 
are (a) decisionally impaired, and (b) who do not have a legal guardian or durable power of 
attorney, will be followed. 
 
6.4 
Evaluation of Benefits and Risks/Discomforts 
 
There is no standard treatment for second line chemotherapy for this group of patients. 
Preliminary results of studies using a similar vaccine have shown promising early immunologic 
responses and indication of clinical benefit. 
 
6.4.1 Alternative Approaches or Treatments 
 
Patients will be consented verbally and in writing regarding the risks and benefits of this trial, the 
treatment requirements, and alternative approaches to entering on this trial. 
 
6.4.2 Procedure for Protecting Against or Minimizing any Potential Risks 
 
All care will be taken to minimize side effects, but they can be unpredictable in nature and 
severity. This study may involve risks to patients, which are currently unforeseeable.  All 


Abbreviated Title: Vaccine for metastatic cancer 
Version Date:  05/04/2017 
 
CTEP #: 6536 
 
39 
 
patients will have blood tests, examinations and CT scans of the chest/abdomen/pelvis as 
described in the monitoring schedule as described in appendix C. Patients will also be required to 
have a local physician to provide long-term care and to monitor for complications.  If patients 
suffer any physical injury as a result of the participation in this study, immediate medical 
treatment is available at the National Naval Medical Center, Bethesda, Maryland or the Warren 
Grant Magnuson Clinical Center, Bethesda, Maryland.  Although no compensation is available, 
any injury will be evaluated and treated in keeping with the benefits or care to which patients are 
entitled under applicable regulations. 
 
6.4.3 Provisions for Monitoring Data Collection to Ensure Safety of Subjects 
 
As information is gathered from this trial, clinical results will be shared with patients. Laboratory 
and clinical data will be frequently gathered and any new significant finding(s) found during the 
course of the research, which may affect a patient’s willingness to participate further, will be 
explained.  Confidentiality of information concerning participants will be maintained, including 
in all publications and presentations resulting from this study.  Names of participants or material 
identifying participants will not be released without permission, except as such release is 
required by law. Records at the National Naval Medical Center are maintained according to 
current legal requirements, and are made available for review by Cancer Therapy Evaluation 
Program, the Food and Drug Administration, or other authorized users, as stated under the 
guidelines established by the Federal Privacy Act.   
 
6.5 
Risks/Benefits Analysis 
 
The patients we will be enrolling will have metastatic colorectal cancer, for which no known 
cure exists. This study involves clinical research with an experimental vaccine designed to 
generate an immune response against antigens found in colon cancer. Patients will undergo 
multiple vaccinations and will be asked to undergo apheresis on at least two time points for 
investigational analysis immune responses. Alternative treatments include chemotherapy, other 
clinical trials, or supportive care.  The side effects of the vaccines and apheresis are outlined 
elsewhere (see section 8 and 5.2 respectively.)  Whether the vaccine will have any clinical effect 
is unknown, therefore, benefit cannot be promised nor can the chance of benefit be accurately 
predicted.  Patients’ participation in this study is voluntary and refusal will not result in penalty 
or loss of benefit to which patient is otherwise entitled.   
 
Participation may be discontinued at any time without penalty and the patient can ask questions. 
 
6.6 
Consent and Assent Process and Documentation 
 
The investigational nature and objectives of this trial, the procedures involved, and their 
attendant risks and discomforts, potential benefits, and potential alternative therapies will be 
explained to the patient and a signed informed consent document obtained. A screening consent 
form will also be provided to the referring physician to screen patients for eligibility to 
incorporate such tests as HLA testing for HLA-A2 positivity as well as CEA staining of the 


Abbreviated Title: Vaccine for metastatic cancer 
Version Date:  05/04/2017 
 
CTEP #: 6536 
 
40 
 
patient’s tumor. Moreover, any experimental invasive procedure will require a separate consent 
form. All listed associate investigators except those listed on the cover sheet as not being able to 
make clinical decisions are permitted to obtain informed consent.  
 
Outside Screening Sample Consent: Telephone consent may be employed in order to screen 
outside samples from prospective subjects for CEA expression and/or HLA-A2 expression. In 
such cases, the informed consent document will be sent to the subject.  An explanation of the 
study will be provided over the telephone after the subject has had the opportunity to read the 
consent form. The subjects will sign and date the informed consent form.A witness to the 
subject’s signature will sign and date the consent. 
The original informed consent document will be sent back to the consenting investigator who 
will sign and date the consent form with the date the consent was obtained via telephone.   
 
A fully executed copy will be returned via mail for the subject’s records. 
 
The informed consent process will be documented on a progress note by the consenting 
investigator and a copy of the informed consent document and note will be kept in the subject’s 
research record. 
 
Prospective subjects who consent to send such samples for outside testing will NOT be 
registered with the NCI Central Registration Office unless they are subsequently enrolled on 
protocol. Subjects and their referring medical team will be notified of the results and records will 
be maintained with the protocol research files. 
 
7 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING 
PLAN 
 
7.1 Definitions 
 
7.1.1 Adverse Event 
An adverse event is defined as any reaction, side effect, or untoward event that occurs during the 
course of the clinical trial associated with the use of a drug in humans, whether or not the event 
is considered related to the treatment or clinically significant. For this study, AEs will include 
events reported by the patient, as well as clinically significant abnormal findings on physical 
examination or laboratory evaluation. A new illness, symptom, sign or clinically significant 
laboratory abnormality or worsening of a pre-existing condition or abnormality is considered an 
AE.   
 
All AEs, including clinically significant abnormal findings on laboratory evaluations, regardless 
of severity, will be followed until return to baseline or stabilization of event. Serious adverse 
events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of at least possibly related to the agent/intervention 
should be recorded and reported as per sections 7.2 and 8.2.  
 


Abbreviated Title: Vaccine for metastatic cancer 
Version Date:  05/04/2017 
 
CTEP #: 6536 
 
41 
 
An abnormal laboratory value will be considered an AE if the laboratory abnormality is 
characterized by any of the following: 
 
Results in discontinuation from the study 
 
Is associated with clinical signs or symptoms  
 
Requires treatment or any other therapeutic intervention 
 
Is associated with death or another serious adverse event, including hospitalization.  
 
Is judged by the Investigator to be of significant clinical impact 
 
If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome. 
 
7.1.2 Suspected adverse reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable 
possibility’ means there is evidence to suggest a causal relationship between the drug and the 
adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug. 
 
7.1.3 Unexpected adverse reaction 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in 
the investigator brochure or is not listed at the specificity or severity that has been observed; or, 
if an investigator brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application. 
"Unexpected” also refers to adverse events or suspected adverse reactions that are mentioned in 
the investigator brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation. 
 
7.1.4 Serious  
An Unanticipated Problem or Protocol Deviation is serious if it meets the definition of a Serious 
Adverse Event or if it compromises the safety, welfare or rights of subjects or others. 
 
7.1.5 Serious Adverse Event 
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following: 
 
Death, 
 
A life-threatening adverse drug experience 
 
Inpatient hospitalization or prolongation of existing hospitalization 


Abbreviated Title: Vaccine for metastatic cancer 
Version Date:  05/04/2017 
 
CTEP #: 6536 
 
42 
 
 
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
 
A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
 
7.1.6 Disability 
A substantial disruption of a person’s ability to conduct normal life functions. 
 
7.1.7 Life-threatening adverse drug experience 
Any adverse event or suspected adverse reaction that places the patient or subject, in the view of 
the investigator or sponsor, at immediate risk of death from the reaction as it occurred, i.e., it 
does not include a reaction that had it occurred in a more severe form, might have caused death. 
 
7.1.8 Protocol Deviation (NIH Definition) 
Any change, divergence, or departure from the IRB-approved research protocol.   
 
7.1.9 Non-compliance (NIH Definition) 
The failure to comply with applicable NIH Human Research Protections Program (HRPP) 
policies, IRB requirements, or regulatory requirements for the protection of human research 
subjects. 
7.1.10 Unanticipated Problem 
Any incident, experience, or outcome that: 
  Is unexpected in terms of nature, severity, or frequency in relation to  
(a) the research risks that are described in the IRB-approved research protocol and 
informed consent document; Investigator’s Brochure or other study documents, and 
(b) the characteristics of the subject population being studied; AND 
 Is related or possibly related to participation in the research; AND 
 Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
 
7.2 NCI-IRB and Clinical Director Reporting 
 


Abbreviated Title: Vaccine for metastatic cancer 
Version Date:  05/04/2017 
 
CTEP #: 6536 
 
43 
 
7.2.1 NCI-IRB and NCI CD Expedited Reporting of Unanticipated Problems and Deaths 
 
The Protocol PI will report in the NIH Problem Form to the NCI-IRB and NCI Clinical Director: 
 All deaths, except deaths due to progressive disease  
 All Protocol Deviations 
 All Unanticipated Problems 
 All non-compliance 
 
Reports must be received within 7 days of PI awareness via iRIS. 
 
7.2.2 NCI-IRB Requirements for PI Reporting at Continuing Review 
The protocol PI will report to the NCI-IRB:  
1. A summary of all protocol deviations in a tabular format to include the date the deviation 
occurred, a brief description of the deviation and any corrective action. 
2. A summary of any instances of non-compliance 
3. A tabular summary of the following adverse events: 
 
All Grade 2 unexpected events that are possibly, probably or definitely related to the 
research;  
 
All Grade 3 and 4 events that are possibly, probably or definitely related to the 
research;  
 
All Grade 5 events regardless of attribution;  
 
All Serious Events regardless of attribution.  
NOTE: Grade 1 events are not required to be reported.  
 
7.2.3 NCI-IRB Reporting of IND Safety Reports 
Only IND Safety Reports that meet the definition of an unanticipated problem will need to be 
reported to the NCI IRB. 
 
8 
DATA REPORTING 
 
8.1 
Provisions for Monitoring to Ensure Safety of Subjects 
 
  


Abbreviated Title: Vaccine for metastatic cancer 
Version Date:  05/04/2017 
 
CTEP #: 6536 
 
44 
 
8.1.1 Data will be submitted to NCI's Clinical Trials Monitoring Service Contractor (CTMS--
contract held by Theradex, Princeton, N.J.). Data will be submitted to CTMS by express 
mail at least once every other Friday on standard Theradex reporting forms.   
 
8.1.2 Serious Adverse Event (SAE; formerly known as Adverse Drug                                                                  
Reaction). This protocol will follow CTEP, DCTD, NCI’s expedited reporting 
requirements for Investigational New Drugs sponsored by NCI.   Expedited AE reporting 
for this study must use CTEP-AERS (CTEP Adverse Event Reporting System), accessed 
via the CTEP Web site (https://eapps-ctep.nci.nih.gov/ctepaers).  The reporting 
procedures to be followed are presented in the “NCI Guidelines for Investigators: 
Adverse Event Reporting Requirements for DCTD (CTEP and CIP) and DCP INDs and 
IDEs” which can be downloaded from the CTEP Web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
).  These requirements are briefly outlined in the tables below (Section 8.1.3. 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 
24-hour notification phoned in must be entered electronically into CTEP-AERS by the 
original submitter at the site. 
 
 
A list of agent-specific expected adverse events can be found in the Pharmaceutical 
Section 9. 
 
All life-threatening events (Grades 4 and 5) and the first occurrence of any previously 
unknown reactions (regardless of grade) will be reported to Dr. Philip Arlen (Building 
10, Room 13N210; Tel: 301-496-4251), Dr. James Gulley (Building 10, Room 13N208; 
Tel: 301-480-7164), or Dr. Ravi Madan (Building 10, Room 12N226; Tel: 301-480-
7168) immediately by telephone or 301-496-1211 (after hours).  
 
8.1.3 CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.. 
 
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration 
of the Investigational Agent/Intervention 1, 2 


Abbreviated Title: Vaccine for metastatic cancer 
Version Date:  05/04/2017 
 
CTEP #: 6536 
 
45 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via electronic 
submission within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be submitted electronically within 24 hours of learning of 
the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted electronically within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, rounded 
UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above applies after 
this reporting period. 
 
 
 
 
Note:  All deaths on study must be reported using expedited reporting 
regardless of causality.  Attribution to treatment or other cause should be 
provided. 
 
 
Expedited AE reporting timelines defined: 


Abbreviated Title: Vaccine for metastatic cancer 
Version Date:  05/04/2017 
 
CTEP #: 6536 
 
46 
 
 
“24 hours; 5 calendar days” – The investigator must initially report the AE 
via CTEP-AERS within 24 hours of learning of the event followed by a 
complete CTEP-AERS report within 5 calendar days of the initial 24-hour 
report. 
 
“10 calendar days” - A complete CTEP-AERS report on the AE must be 
submitted within 10 calendar days of the investigator learning of the event.  
 
 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates 
hospitalization (or prolongation of existing hospitalization) must be reported 
regardless of attribution and designation as expected or unexpected with the 
exception of any events identified as protocol-specific expedited adverse event 
reporting exclusions. 
 
 
Any event that results in persistent or significant disabilities/incapacities, 
congenital anomalies, or birth defects must be reported via CTEP-AERS if the 
event occurs following treatment with an agent under a CTEP IND. 
 
 
Use the NCI protocol number and the protocol-specific patient ID provided 
during trial registration on all reports. 
 
 
An expedited AE report for all protocols utilizing agents under a CTEP IND 
must be submitted electronically to CTEP-AERS. 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_
events.htm  
 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is 
to be made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is 
restored, the 24-hour notification phoned in must be entered electronically into 
CTEP-AERS by the original submitter at the site. 
 
 
All expedited AE reports must also be sent to the local IRB according to local 
IRB policy and procedure. 
 
 
All AEs reported via CTEP-AERS must also be reported via the routine AEs 
reporting defined by the protocol. 
 
 
A list of agent-specific expected adverse events can be found in the 
Pharmaceutical section 9). 
 
In addition, all serious adverse events should be reported to OSP at NIH per their 
requirements. Adverse events may be reported by using the Adverse Event 
Reporting template available on the NIH OSP website at:  
http://osp.od.nih.gov/office-biotechnology-activities/biomedical-technology-
assessment/hgt/gemcrisor by using the FDA Form 3500a. 


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
All life-threatening events (Grades 4 and 5) and the first occurrence of any 
previously unknown reactions (regardless of grade) will be reported to Dr.  James 
Gulley (Building 10, Room 5B52) immediately by telephone (301) 480-7164 or 
301-496-1211 (after hours).  
 
8.2 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported through 
CTEP-AERS must also be reported in routine study data submissions. 
 
8.3 
Secondary AML/MDS 
 
AML/MDS events must be reported via CTEP-AERS (in addition to routine AE reporting 
mechanisms).  In CTCAE v 4.0, the event(s) may be reported as either: 1) Leukemia secondary to 
oncology chemotherapy, 2) Myelodysplastic syndrome, or 3) Treatment-related secondary 
malignancy. 
 
8.4 
Record Keeping  
 
Data will be CTMS monitored.  The NCI/DCT Case Report Form and the NCI database will be 
used to report to CTEP. 
 
All patients must have signed an Informed Consent and an on-study confirmation of eligibility 
form will be filled out before entering on the study. 
 
Data will be submitted to CTEP at least every 2 weeks. Data will be CTMS monitored.  The 
NCI/DCT Case Report Form and the NCI database will be used to report to CTEP. 
 
Summary of completed study will be submitted to IDB/CTEP within 2 months of study 
completion.  A status report will be submitted and presented at upcoming NCI meetings as 
requested. 
 
Complete records must be maintained on each patient, which will consist of the hospital chart 
with any supplementary information obtained from outside laboratories, radiology reports or 
physician's records. These records will serve as the primary source material that forms the basis 
for the research record. All relevant data will also be entered on a computer database from which 
formal analyses are done. The primary source documentation will assure the following: on-study 
information, including patient eligibility data and patient history; flow sheets, records of adverse 
events, specialty forms for pathology, radiation, or surgery; and off-study summary sheets, 
including a final assessment by the treating physician. 
 
8.5 
Regulatory Issues 
 


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The agent(s) (hereinafter referred to as Agent) to the NCI under a Clinical Trials Agreement 
(CTA) or a Cooperative Research and Development Agreement (CRADA) between BN Immuno 
Therapuetics (BNIT) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of 
Cancer Treatment and Diagnosis.  Therefore, the following obligations/guidelines apply to the 
use of the PANVAC™-V (vaccinia) and PANVAC™-F (fowlpox) in this study: 
PANVAC™-V (vaccinia) and PANVAC™-F (fowlpox) may not be used outside the scope of 
this protocol, nor can PANVAC™-V (vaccinia) and PANVAC™-F (fowlpox) be transferred or 
licensed to any party not participating in the clinical study. Collaborator(s) data from 
PANVAC™-V (vaccinia) and PANVAC™-F (fowlpox) are confidential and proprietary to 
Collaborator(s) and should be maintained as such by the investigators. 
For a clinical protocol in which an investigational Agent is used in combination with (an) other 
investigational Agent(s), each the subject of different CTAs or CRADAs, the access to and use 
of data by each Collaborator shall be as follows (data pertaining to such combination use shall 
hereinafter be referred to as “Multi-Party Data”): 
The NCI must provide all Collaborators with written notice regarding the existence and nature of 
any agreements governing their collaboration with NIH, the design of the proposed combination 
protocol, and the existence of any obligations that would tend to restrict the NCI’s participation 
in the proposed combination protocol. 
 
Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial by any 
other Collaborator to the extent necessary to allow said other Collaborator to develop, obtain 
regulatory approval or commercialize its own investigational Agent. 
Any Collaborator having the right to use the Multi-Party Data from these trials must agree in 
writing prior to the commencement of the trials that it will use the Multi-Party Data solely for 
development, regulatory approval, and commercialization of its own investigational Agent. 
 
The NCI encourages investigators to make data from clinical trials fully available to 
Collaborator(s) for review at the appropriate time. Clinical trial data developed under a CTA or 
CRADA will be made available exclusively to Collaborator(s), and not to other parties. 
 
 
When a Collaborator wishes to initiate a data request, the request should first be sent to the NCI, 
which will then notify the appropriate investigators (Group Chair for cooperative group studies, 
or Principal Investigator for other studies) of Collaborator’s wish to contact them. 
 
Any data provided to Collaborator(s) must be in accordance with the guidelines and policies of 
the responsible Data Monitoring Committee (DMC), if there is a DMC for this clinical trial. 
 
Any manuscripts reporting the results of this clinical trial must be provided to CTEP for 
immediate delivery to Collaborator(s) for advisory review and comment prior to submission for 
publication.  Collaborator(s) will have 30 days from the date of receipt for review.  An additional 
30 days may be requested in order to ensure that confidential and proprietary data, in addition to 


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Collaborator(s) intellectual property rights, are protected.  Copies of abstracts must be provided 
to Collaborator(s) for courtesy review as soon as possible and preferably at least 3 days prior to 
submission, but prior to presentation at the meeting or publication in the proceedings.  Press 
releases and other media presentations must also be forwarded to CTEP prior to release. Copies 
of any manuscript and/or abstract should be sent to: 
 
Email:  ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
 
8.5.1 The responsible investigator at each participating institution must be registered with 
CTEP, DCTD through an annual submission of FDA form 1572 and a CV. 
 
8.5.2 The investigator, or a responsible party designated by the investigator, must maintain a 
careful record of the inventory and disposition of all drugs received from DCTD using 
the NCI Drug Accountability Record (DAR) Form.  (See the NCI Investigator’s 
Handbook for Procedures for Drug Accountability and Storage.) 
 
8.5.3 Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
PANVAC-V [Recombinant Vaccinia-CEA(D609)/MUC1(L93)/TRICOM] (NSC 727026) 
PANVAC-F [Recombinant Fowlpox-CEA(D609)/MUC1(L93)/TRICOM] (NSC 727027) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted below). Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm for further clarification. Below 
is the CAEPR for PANVAC-VF/TRICOM. 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER. If this CAEPR is part of a combination protocol using 
multiple investigational agents and has an AE listed on different SPEERs, use the lower 
of the grades to determine if expedited reporting is required. 
 
Version 1.3, May 30, 20141 


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Adverse Events with Possible Relationship  
to PANVAC-VF/TRICOM 
(CTCAE 4.0 Term) 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
  
GASTROINTESTINAL DISORDERS 
  
Diarrhea 
  
Nausea 
  
Pancreatitis2 
  
Vomiting 
  
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Chills 
 Chills (Gr 2) 
Fatigue 
 Fatigue (Gr 2) 
Fever 
 Fever (Gr 2) 
Flu like symptoms 
 Flu like symptoms (Gr 2) 
Injection site reaction 
 Injection site reaction (Gr 2) 
Pain 
  
INVESTIGATIONS 
  
Alanine aminotransferase increased 
  
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
  
Hypoalbuminemia 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
Arthralgia 
  
Back pain 
  
Bone pain 
  
Generalized muscle weakness 
  
Myalgia 
 Myalgia (Gr 2) 
Pain in extremity 
  
NERVOUS SYSTEM DISORDERS 
  
Headache 
 Headache (Gr 2) 
Syncope 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
Cough 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
Hyperhidrosis 
  
Pruritus 
  
Skin induration 
  
1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed 
to all Principal Investigators at the time of revision. The current version can be obtained by 
contacting PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and 
the agent should be included in the e-mail. 
 
2Transient pancreatitis was observed in at least one patient who received endoscopic ultrasound 
(EUS)-guided intra-pancreatic tumor injection.  


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Non-serious adverse events also reported on PANVAC-VF/TRICOM trials but with the 
relationship to PANVAC-VF/TRICOM still undetermined due to low frequency (i.e., <3%): 
 
EYE DISORDERS - Eye pain 
GASTROINTESTINAL DISORDERS - Abdominal pain; Colitis; Gastrointestinal disorders - 
Other (fluid around pancreas); Mucositis oral; Stomach pain 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema face; 
Edema limbs; Non-cardiac chest pain 
IMMUNE SYSTEM DISORDERS - Allergic reaction 
INVESTIGATIONS - Alkaline phosphatase increased; Aspartate aminotransferase increased; 
Blood bilirubin increased; Lipase increased; Lymphocyte count decreased; Serum amylase increased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypomagnesemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Neck pain 
NERVOUS SYSTEM DISORDERS - Dysgeusia 
PSYCHIATRIC DISORDERS - Agitation; Insomnia 
RENAL AND URINARY DISORDERS - Proteinuria 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Allergic rhinitis 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Erythema multiforme; Rash maculo-
papular 
VASCULAR DISORDERS - Hot flashes; Hypotension 
Notes:   
1. PANVAC-V [Recombinant Vaccinia-CEA(D609)/MUC1(L93)/TRICOM] and 
PANVAC-F [Recombinant Fowlpox-CEA(D609)/MUC1(L93)/TRICOM] when used in 
combination with other agents, either commercial or investigational, could be associated 
with changes in the frequency or severity of known events or the emergence of new 
patterns of events.  
2. Other potential risks or complications associated with the use of the vaccinia vaccine 
strain from which the attenuated recombinant vector is derived, include those observed 
during the smallpox vaccination programs: 
 
 Inadvertent inoculation (autoinoculation and direct contact transmission) 
 Non-specific erythematous or urticarial rashes (generally self-limiting) and rarely, 
more serious bullous erythema multiforme (Stevens-Johnson syndrome) 
 Generalized vaccinia (disseminated maculopapular or vesicular rash of varying 
extent on any part of the body) 
 Eczema vaccinatum (vaccinial lesion development on areas of the skin that are, or 
had at one time been, eczematous) 
 Progressive vaccinia (local vaccination lesion fails to heal and develops 
progressive necrosis, with destruction of large areas of skin, subcutaneous tissue, 
and underlying structures. Progressive lesions may spread to other skin surfaces 
and to bone and viscera) 
 Post-vaccinial encephalitis/encephalomyelitis 


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 Fetal vaccinia 
 Myocarditis/pericarditis 
3. The inclusion of co-stimulatory molecules in these agents may theoretically stimulate 
autoimmunity or exacerbate existing disease in susceptible individuals. 
4. Thrombotic thrombocytopenic purpura (TTP) occurred with closely related agents, 
PROSTVAC-V/TRICOM [Recombinant Vaccinia-PSA(L155)/TRICOM] and 
PROSTVAC-F/TRICOM [Recombinant Fowlpox-PSA(L155)/TRICOM]. 
 
9 
PHARMACEUTICAL INFORMATION 
 
9.1 
PANVAC-V (NSC 727026) 
 
9.1.1 Other Names: Recombinant-Vaccinia-CEA(D609)/MUC-1(L93)/TRICOM 
 
9.1.2 Classification:  Recombinant vaccinia virus vector vaccine of the genus Orthopoxvirus. 
 
9.1.3 Product Description:  
PANVAC-V is a recombinant vaccinia virus vector vaccine containing genes for human CEA, 
MUC-1 and three co-stimulatory molecules: B7.1, ICAM-1 (intercellular adhesion molecule-1), 
and LFA-3 (leukocyte function-associated antigen-3).  The CEA gene has a single amino acid 
substitution (aspartic acid, instead of asparagine at protein amino acid position 609) in one 9-
mer, HLA-A2-restricted, immunodominant epitope to enhance immunogenicity. The MUC-1 
gene also contains a single amino substitution (leucine, instead of threonine at protein amino acid 
position 93) in one 10-mer, HLA-A2-restricted, immunodominant epitope to enhance 
immunogenicity. TBC-vTRICOM, which was used as the parental virus for this recombinant 
vaccine, was generated by insertion of the genes for the three co-stimulatory molecules into an 
attenuated, live, derivative of the Wyeth (New York City Board of Health) strain of vaccinia 
virus. A plasmid vector containing the modified CEA and MUC-1 genes was used for insertion 
into the TBC-vTRICOM viral geonome to generate the final recombinant vaccine.  Vaccinia 
virus can infect mammalian cells and express the inserted transgenes, and is a potent immune 
stimulator, eliciting both a strong humoral and cellular immune response. Vaccinia virus is 
replication competent in mammalian cells, making systemic infections possible. PANVAC-V 
is manufactured by plasmid transfection of primary chicken embryo dermal cells infected with 
the recombinant parental vaccinia virus (TBC-vTRICOM). 
 
9.1.4 How Supplied:  
Lot: 1-013003: PANVAC-V (vaccinia) is supplied in vials containing 0.3 mL of the vaccine at 
a final viral concentration titer of 1.29 x 109 pfu/mL formulated in phosphate-buffered saline 
containing 10% glycerol (total vial contents = 3.87 x 108 pfu’s). 
 
Lot: 2-050103: PANVAC-V (vaccinia) is supplied in vials containing 0.3 mL of the vaccine at a 
final viral concentration titer of 2.1 x 109 pfu/mL formulated in phosphate-buffered saline 


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containing 10% glycerol (total vial contents = 6.3 x 108 pfu’s). 
Note: The PANVAC-V (vaccinia) concentration varies between lots, requiring changes to dose 
preparation instructions. Use extreme caution when preparing each dose. 
 
9.1.5 Preparation:  
Thaw vials completely at room temperature. Ensure the thawed contents are at the bottom of the  
upright vial and vortex vigorously at high power for at least ten seconds prior to dose  
preparation. Perform all dilutions of the vaccine with 0.9% sodium chloride for injection, USP  
and vortex all dilutions vigorously again for at least ten seconds prior to withdrawing the final  
dose.  Note the concentration of the current supply of PANVAC-V (vaccinia) on your  
institutional preparation guidelines to avoid potentially serious dosing errors.  
 
PANVAC™-V (vaccinia) Lot: 1-013003 (1.29 x 109 pfu/mL, 0.3 mL vial):  
Allow the contents of one vial to thaw completely at room temperature. Ensure the thawed 
contents are at the bottom of the upright vial and vortex vigorously at high power for at least ten 
seconds. Withdraw 0.16 mL (2 x 108 pfu) from the thawed vial for subcutaneous administration.  
 
PANVAC™-V (vaccinia) Lot: 2-050103 (2.1 x 109 pfu/mL, 0.3 mL vial):  
Allow the contents of one vial to thaw completely at room temperature. Ensure the thawed 
contents are at the bottom of the upright vial and vortex vigorously at high power for at least ten 
seconds. Add 0.7 mL of 0.9% sodium chloride, USP to the thawed vial to yield 1 mL of 
PANVAC™-V (vaccinia) at a concentration of 6.3 x 108 pfu/mL. Vortex vigorously at high 
power for at least ten seconds. Withdraw 0.32 mL (2 x 108 pfu) for subcutaneous administration. 
 
9.1.6 Storage: Intact vials of PANVAC-V should be stored at –70oC or colder. 
 
9.1.7 Stability:  
Shelf-life studies of the intact vials are ongoing. Once the intact vials are thawed, the vaccines 
maintain their potency for up to 4 days when stored at 2-8oC. Thawed vials should not be re-
frozen. Vials of PANVAC-V are for single-use only and do not contain a preservative. It is 
recommended that prepared doses be administered as soon as possible following preparation 
(i.e., within one hour). If absolutely necessary, prepared doses may be stored at 2-8oC for up to 4 
hours following preparation. 
 
9.1.8 Route of Administration: PANVAC-V is administered by subcutaneous injection.  
  
9.1.9 Toxicities and Complications Associated with Vaccinia Vaccination  
Expected local reactions to vaccinia inoculation by scarification in patients who have not 
previously been vaccinated with vaccinia include the appearance of a red papule in 3-4 days, 
followed by vesiculation in 5-6 days, and then the formation of a pustule on days 8-9. A large 
area of erythema may surround the vesicle and pustule. A crusted scab usually forms by the 
second week and sloughs by the third week, leaving a well-formed scar. Maximal viral shedding 
occurs from days 4-14, but can continue until the scab is shed from the skin. Other normal local 
reactions can include development of local satellite lesions, regional lymphadenopathy that can 


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persist for weeks following healing of the skin lesion, considerable local edema, and intense 
inflammation from the vaccination (i.e., viral cellulites), which may be confused with bacterial 
cellulites. Systemic symptoms typically occur between 8-10 days post-vaccination and include 
fever, malaise, headache, chills, nausea, soreness at the vaccination site, myalgia, local 
lymphadenopathy, and intense erythema surrounding the vaccination site. 
 
Expected local reactions to vaccinia inoculation by scarification in patients who have previously 
been vaccinated with vaccinia include the appearance of a clear cut pustule 6-8 days following 
vaccination or the development of an area of definite induration around a central lesion that may 
be an ulcer or scab 6-8 days following vaccination. The response to re-vaccination depends on 
the degree of residual immunity following previous vaccination. Similar systemic symptoms may 
occur, but typically at a lower frequency. A milder local reaction is expected when recombinant 
vaccinia vaccines are administered by intradermal, intralesional, subcutaneous, or intramuscular 
routes of injection. 
 
There have been a number of complications from vaccinia vaccine reported in the literature. 
Complications from vaccinia vaccine when given by scarification include: a) auto-inoculation of 
other sites with vaccinia, b) generalized vaccinia, c) eczema vaccinatum, d) progressive vaccinia 
(vaccinia necrosum), or e) post-vaccinial encephalitis.  In a 1968 ten-state survey, cases of these 
complications per million vaccinations in adult recipients (> 20 years of age) of vaccinia primary 
vaccination and revaccination were: 
 
 
Primary Vaccination 
Revaccination 
auto-inoculation 
606.1 
25 
generalized vaccinia 
212.1 
9.1 
eczema vaccinatum 
30.3 
4.5 
progressive vaccinia 
none reported 
6.8 
postvaccinial encephalitis none reported 
4.5 
 
Based on a 1968 national survey, the number of deaths in primary vaccinees was approximately 
1 per million and the number of deaths in recipients of revaccination was approximately 0.25 per 
million. Deaths were most often the result of postvaccinial encephalitis or progressive vaccinia. 
 
Recent information has been reported by the US Department of Defense (DoD) during the post-
vaccination surveillance assessment of adverse events in military personnel following 
implementation of a smallpox vaccination program from the period of December 13, 2002 
through May 28, 2003. Although not directly comparable to historical numbers, due to 
differences in multiple population variables, estimated cases (number of cases per million 
vaccinations based on vaccination of 450,293 personnel, with a median age of 26 years and 
70.5% as primary vaccinees) of these same complications per million vaccinations were: 
 
auto-inoculation 
107 
generalized vaccinia 
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eczema vaccinatum 
none reported 
progressive vaccinia 
none reported 
postvaccinial encephalitis 
2.2 
  
Generally, self-limited adverse reactions that can be serious, but not life-threatening include 
autoinoculation, erythematous and urticarial rashes, and generalized vaccinia. More serious life-
threatening complications include progressive vaccinia, eczema vaccinatum, and post-vaccinial 
encephalitis/encephalomyelitis. The complications of vaccinia vaccination may involve a number 
of different reactions: 
1. Non-specific erythematous or urticarial rashes: These rashes can appear 
approximately 10 days after vaccination and may sometimes be confused with 
generalized vaccinia, but are generally self-limiting. Patients are usually afebrile and 
these benign rashes usually resolve spontaneously within 2-4 days. Erythema multiforme 
can present as different types of lesions, including macules, papules, urticaria, and bull’s 
eye lesions (dark papule or vesicle surrounded by a pale zone and an area of erythema). 
These lesions may be extremely pruritic, lasting up to four weeks. Rarely, more serious 
bullous erythema multiforme (Stevens-Johnson syndrome) may occur, requiring 
hospitalization. VIG therapy is not indicated to treat these rashes. Supportive care 
measures are warranted since these rashes are likely manifestations of an immune 
response or hypersensitivity reaction to the vaccine and are not likely to contain vaccinia 
virus. 
2. Bacterial Infection: Infection of the vaccination site, most likely due to staphylococcus 
and streptococcus normal skin flora, is rare. Onset is approximately 5 days post-
vaccination and is more common in children. Appropriate antibiotic therapy is required. 
3. Inadvertent Inoculation: This can occur in the vaccinee (autoinoculation) as well as in 
close contacts (contact transmission). Accidental infection is the most common 
complication of vaccinia vaccination, accounting for approximately 50% of all 
complications associated with vaccination and revaccination. This usually results from 
autoinoculation of vaccinia virus transferred from the site of the vaccination. Sites 
typically involved include the face, eyelids, nose, mouth, genitalia, or rectum, but can 
also involve the arms, legs, and trunk. Contact transmission of vaccinia, with 
accompanying toxicities, may occur when a recently vaccinated individual has contact 
with a susceptible individual.  In a 1968 ten-state survey, contact transmissions were 
reported to occur at a rate of 27 infections per million vaccinations.  The age group in 
which contact transmission occurred most commonly was in children  5 years. Eczema 
vaccinatum as a result of contact transmission may result in a more severe syndrome than 
that seen in vaccinees, perhaps because of multiple simultaneous inoculations. About 
30% of eczema vaccinatum cases reported in the 1968 ten-state survey were a result of 
contact transmission. It is possible that the number of cases of contact transmission would 
be greater in today’s population, due to a largely unvaccinated patient population against 
smallpox. Contact transmission rarely results in postvaccinial encephalitis or progressive 
vaccinia. Most cases of inadvertent inoculation usually resolve without specific therapy 
and resolution of lesions follow the same course as the vaccination site in 


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immunocompetent individuals. VIG can be used for severe cases involving extensive 
lesions or if comorbid conditions exist. VIG is contraindicated in the presence of isolated 
keratitis due to the risk of increased corneal scarring. VIG use can be considered in cases 
of ocular implantation, with keratitis, if vision-threatening or if other life-threatening 
vaccinia-related complications exist that require VIG therapy.   
4. Generalized vaccinia: Generalized vaccinia is characterized by a disseminated 
maculopapular or vesicular rash of varying extent on any part of the body and typically 
develops 6-9 days after vaccination. The lesions follow the same course as the 
vaccination site lesion. The lesions are hematogenously spread and may contain vaccinia 
virus. In immunocompetent individuals, the rash is generally self-limiting and requires 
supportive care therapy. Treatment with VIG can be utilized in severe cases of this 
condition in patients that are systemically ill and whose condition might be toxic or who 
have serious underlying immunosuppressive illnesses. 
5. Eczema vaccinatum: Eczema vaccinatum is a serious complication in persons with 
eczema and other types of chronic or exfoliative skin conditions. It can also occur among 
eczematous contacts of recently vaccinated persons. Vaccinial lesions (generalized 
papular, vesicular or pustular lesions) develop on areas of the skin that are, or had at one 
time been, eczematous. These areas become highly inflamed and lesions may spread to 
healthy skin. The rash is often accompanied by fever and individuals are systemically ill. 
The fatality rate for untreated cases (prior to availability of VIG) has been reported from 
30-40%. Following availability of VIG, mortality was reduced to approximately 7%. 
Early diagnosis and prompt treatment with VIG is necessary to reduce mortality.  
6. Progressive vaccinia: Progressive vaccinia is the most serious cutaneous complication 
that occurs when the local vaccination lesion fails to heal and develops progressive 
necrosis, with destruction of large areas of skin, subcutaneous tissue, and underlying 
structures. Progressive lesions may spread to other skin surfaces and to bone and viscera.   
Progressive vaccinia is associated with a high mortality rate. This complication has been 
seen in patients with a compromised immune system due to a congenital deficiency, 
lymphoproliferative disease, immunosuppressive treatment, or HIV infection. 
Management should include aggressive therapy with VIG. 
7. Post-Vaccinial Encephalitis/Encephalomyelitis: Vaccinial complications affecting the 
CNS are unpredictable. Post-vaccinial encephalitis typically affects children < 2 years of 
age and is characterized by an onset of symptoms 6-10 days following vaccination, which 
include seizures, hemiplegia, aphasia, and transient amnesia. Histopathological changes 
include generalized cerebral edema, mild lymphocytic meningeal infiltration, ganglion 
degenerative changes and perivascular hemorrhages. Older children and adults can 
develop encephalitis or encephalomyelitis characterized by an onset of symptoms 11-15 
days following vaccination, which include fever, vomiting, headache, malaise, and 
anorexia, progressing to loss of consciousness, amnesia, confusion, disorientation, 
restlessness, delirium, drowsiness, seizures and coma. Histopathological changes include 
demyelination with lymphocytic infiltration, but limited cerebral edema. Mortality rates 
have ranged from 15-25%, with 25% of patients who recover being left with varying 
degrees and types of neurological deficits. VIG has not been shown to be effective in 
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8. Fetal Vaccinia: Fetal vaccinia is a rare, but serious complication following vaccinia 
vaccination during pregnancy or shortly before conception (e.g., within four weeks).  To 
date, less than 50 cases have been reported and often result in fetal or neonatal death. 
Efficacy of VIG therapy in a viable infant or used prophylactically in women during 
pregnancy is unknown. The CDC has established a National Smallpox Vaccine in 
Pregnancy Registry. This registry will follow women during their pregnancies and their 
babies, after they are born, to follow the outcome of such pregnancies. The CDC can be 
contacted at (404) 639-8253. 
9. Myocarditis/Pericarditis:  The CDC has recommended a temporary medical deferral to 
the voluntary Smallpox Vaccination Program for persons with heart disease or 
cardiovascular risk factors (March 25, 2003) and issued “interim supplementary 
information” regarding evidence that smallpox vaccination may cause myocarditis and/or 
pericarditis (March 31, 2003) in people recently vaccinated with the smallpox vaccine. 
The cardiac events reported include myocardial infarction, angina, myocarditis, 
pericarditis, and myopericarditis. While the vaccinia strain used to prepare recombinant 
vaccinia virus vaccines is derived from the same NYC Board of Health strain as 
Dryvax® used in the current Smallpox Vaccination Program, the attenuation, preparation, 
quality control, and storage of the products are markedly different. The NCI/CTEP 
experience with recombinant vaccinia vectors reveals no reports of myocardial infarcts or 
angina associated with vaccinia vaccination, one patient with pericarditis associated with 
a malignant pleural effusion, and five patients with sudden death of unknown etiology. 
None were thought to be associated with recombinant vaccinia vaccination. Although the 
CDC believes that there is no evidence to conclude that Dryvax® causes angina or heart 
attacks, it acknowledges a possible causal relationship between the vaccination and heart 
inflammation.  The CDC continues to study the relationship, but in the meantime, 
recommends that individuals with underlying heart disease be excluded from 
participation in the current Smallpox Vaccination Program. While it is currently not 
possible to fully evaluate the risk of cardiac events or the risk of myocarditis, pericarditis, 
or myopericarditis associated with vaccinia vaccination, it is reasonable to inform 
patients participating in studies receiving recombinant vaccinia virus of these reports and 
provide relevant guidance for evaluating these events. Further investigation from the 
ongoing vaccine program may provide additional data regarding an association or lack of 
association with cardiovascular disease. Because patients are being immunized with 
recombinant vaccinia vaccines with therapeutic intent, currently it is not recommend 
excluding patients with known CAD, previous heart attack, history of angina, or other 
evidence of risk factors for coronary artery disease who are otherwise eligible for the 
study, but the patient’s cardiac disease should be controlled. At this time the evidence for 
an association with myocarditis, pericarditis, or myopericarditis seems plausible, but a 
rare event.  If not otherwise excluded, patients with known CHF or clinically significant 
cardiomyopathy requiring treatment should be excluded from protocol eligibility at this 
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9.1.10 Treatment of Vaccinia Vaccination Complications 
Vaccinia Immune Globulin (VIG): First-line treatment of some of the complications of 
vaccinia caused by dissemination of vaccinia virus (severe cases of inadvertent inoculation 
involving extensive lesions or if comorbid conditions exist, severe cases of generalized vaccinia 
in patients that are systemically ill and whose condition might be toxic or who have serious 
underlying immunosuppressive illnesses, eczema vaccinatum, and progressive vaccinia) is with 
Vaccinia Immune Globulin (VIG). VIG is contraindicated, however, for the treatment of isolated 
vaccinial keratitis. VIG is a sterile solution of the immunoglobulin fraction of pooled plasma 
from individuals inoculated with vaccinia vaccine. VIG is an investigational agent available 
through the CDC’s Strategic National Pharmaceutical Stockpile under an IND protocol by 
contacting the CDC’s Smallpox Vaccine Adverse Events Clinician Information Line at 1-877-
554-4625. Upon receipt of a call from a patient or upon direct observation of a patient or contact 
who manifests signs and symptoms of any of the above conditions, the investigator should place 
a call to the CDC as soon as possible: 1) to initiate review of the clinical case, 2) to seek 
consultation on the appropriateness of VIG therapy, 3) to determine the appropriate VIG dose 
and dosing method for administration, if VIG therapy is required, and 4) to determine how to 
access and have the appropriate doses of VIG delivered. Early institution of VIG therapy is 
advised following recognition of clinical symptoms compatible with some vaccinia 
complications (eczema vaccinatum, severe generalized vaccinia, progressive vaccinia, and some 
cases of inadvertent inoculation). The effectiveness of VIG therapy appears to be time 
dependent. VIG has not proven to be of benefit in the treatment of post-vaccinial encephalitis, 
and is contraindicated for treatment of isolated vaccinial keratitis due to the increased risk of 
corneal scarring. A new intravenous formulation of VIG is available through the CDC, which has 
a lower level of aggregated protein, allowing it to be used by either the IM or IV route. This 
formulation will most likely be preferred for administration and investigators will be instructed 
by the CDC regarding appropriate dosing and method of administration based on formulation 
and availability. There is no guarantee that VIG will successfully treat complications. At present, 
there are no other anti-viral therapies of proven benefit for the treatment of vaccinia-related 
complications. 
Cidofovir (Vistide®, Gilead Sciences): Cidofovir is an FDA-approved antiviral drug for the 
treatment of CMV retinitis among patients with AIDS. Cell-based in vitro studies and animal 
model studies have demonstrated antiviral activity of this agent against certain orthopoxviruses. 
Currently, efficacy in the treatment of vaccinia-related complications in humans is unknown. 
According to the CDC, “VIG is recommended as first line of therapy.  Cidofovir may be 
considered as a secondary treatment, and will only be released by the CDC after all inventories 
of VIG have been exhausted, after a patient fails to improve with VIG treatment, or as a last 
effort for a patient who is otherwise near death.” [Medical Management of Smallpox (Vaccinia) 
Vaccine Adverse Reactions: Vaccinia Immune Globulin and Cidofovir. Last updated February 
21, 2003. Available at URL: https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5204a1.htm. The 
CDC has informed the NCI/CTEP that cidofovir will not be supplied through Strategic National 
Pharmaceutical Stockpile to investigators involved in CTEP-sponsored protocols utilizing 
recombinant vaccinia-based vaccines. This agent will only be provided by the CDC in the 
occurrence of an emergency public health event.  Thus, investigators should obtain cidofovir for 


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second-line therapy through commercial sources if necessary. NCI/CTEP investigators may use 
the CDC cidofovir IND protocol as a "guideline" when providing cidofovir for treatment under 
an off-label use. The CDC will provide their IND protocol for the use of cidofovir related to 
adverse reactions post vaccinia vaccination to NCI/CTEP for distribution to investigators of 
NCI-sponsored protocols. The CDC Clinician Information Line at 1-877-554-4625 should still 
be consulted regarding appropriateness of therapy and guidance. 
  
9.1.11 Precautions (Healthcare workers)  
The risk of transmission of recombinant vaccinia viruses to exposed healthcare workers is 
unknown. To date, no reports of transmission to healthcare personnel from vaccine recipients 
have been published. If appropriate infection control precautions are observed (such as covering 
the vaccination site and washing hands after contact with the vaccination site or bandages), 
healthcare workers are probably at less risk of infection than laboratory workers because of the 
smaller volume and lower titers of virus in clinical specimens as compared with laboratory 
material. However, because of the potential for transmission of vaccinia or recombinant vaccinia 
viruses to such persons, it is suggested that healthcare personnel who are involved with the 
preparation or administration of doses, or have direct contact with contaminated dressings or 
other infectious material from participants in clinical studies, should adhere to appropriate 
infection control measures and be offered vaccination with vaccinia vaccine. Routine, non-
emergency vaccination with vaccinia vaccine should not be administered to healthcare workers if 
any of the following apply to either recipients, or for at least three weeks after vaccination, their 
close household contacts (close household contacts are those who share housing or have close 
physical contact):  
 individuals with active eczema or a history of eczema or atopic dermatitis, or 
individuals with Darier’s disease  
 individuals with other acute, chronic, or exfoliative skin conditions (e.g., burns, 
impetigo, varicella zoster, severe acne, or other open rashes or wounds) until the 
condition resolves  
 individuals who are pregnant or intend on becoming pregnant within 4 weeks of 
vaccination 
 individuals who are immunodeficient or immunocompromised (by disease or 
therapy), including individuals with HIV infection  
 
Additionally, routine, non-emergency vaccination with vaccinia vaccine should not be 
administered to healthcare workers if any of the following apply to the vaccinee only: 
   
 individuals with moderate or severe acute illnesses, until the illness resolves  
 individuals less than 18 years of age, unless specifically indicated 
 individuals who are breast-feeding  
 individuals undergoing topical steroid therapy for inflammatory eye diseases or 
undergoing therapy with systemic steroids due to the potential for immune 
suppression and increased risk for vaccinia-related complications. Localized topical 
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 As a precaution, the CDC has recommended that individuals with known cardiac 
disease (e.g., previous MI, angina, CHF, cardiomyopathy, stroke. or TIA) or who 
have > 3 known risk factors for cardiac disease (e.g., hypertension, 
hypercholesterolemia, diabetes, first degree relative with onset of cardiac 
complications prior to age 50, smoker) not receive routine, non-emergency, 
prophylactic vaccination with vaccinia vaccine while a possible causal relationship 
between vaccination and cardiac events is being evaluated. 
Healthcare workers with a prior history of allergy or serious reaction to prior vaccinia 
vaccination or any of its components should not receive vaccinia vaccine. Healthcare workers 
who are pregnant; who have a history or presence of active eczema or atopic dermatitis; that 
have acute, chronic or exfoliative skin conditions; or, who are immunocompromised should 
avoid exposure to the recombinant vaccinia vaccine, and any contaminated dressings, or other 
infectious materials from patients, or the patient’s inoculation site. 
For more information on vaccinia precautions for healthcare workers, see the following website: 
http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5010a1.htm#tab2. 
The CDC is the only source of vaccinia vaccine. The CDC will provide vaccinia vaccine to 
protect laboratory and other healthcare personnel, whose occupations place them at risk of 
exposure to vaccinia and other closely related orthopoxviruses, including vaccinia recombinants. 
The vaccine should be administered under the supervision of a physician selected by the study 
institution. Revaccination is recommended every 10 years. For instructions on obtaining vaccinia 
vaccine, contact Drug Services, National Center for Infectious Diseases, CDC at (404) 639-3670. 
 
9.1.12 Special Handling 
Vaccinia virus is classified as a Biosafety Level 2 organism (agents that are associated with 
human disease which is rarely serious and for which preventative or therapeutic interventions are 
often available). The recombinant product is a preparation of a live virus affecting humans and 
contains DNA sequences derived from the human genome. The product should be handled as an 
infectious hazardous biological substance and waste materials should be disposed of as infectious 
hazardous biological waste and incinerated according to local institutional policies and according 
to any local, state, or federal regulations. For more information regarding biohazard risk group 
classification and biohazard safety levels see NIH Guidelines for Research Involving 
Recombinant DNA Molecules (NIH Guidelines): April, 2016. Available at URL: 
http://osp.od.nih.gov/office-biotechnology-activities/biosafety/nih-guidelines and Biosafety in 
Microbiological and Biomedical Laboratories; 4th Edition. U. S. Department of Health and 
Human Services Centers for Disease Control and Prevention and National Institutes of Health. 
Available at URL: http://www.cdc.gov/od/ohs/biosfty/bmbl4/bmbl4toc.htm. 
 
 
Biosafety Level 2 General Requirements Related to Vaccinia Virus  
At a minimum, the following procedures should be adhered: 
1. All dose preparations and procedures (e.g., vortexing) with high potential for 
creation of aerosols are to be performed in an appropriately certified Class II 
biological safety cabinet. In general, procedures and guidelines (e.g., minimizing 


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creation of aerosols during dose preparation; no eating, drinking or applying 
cosmetics in the work area), and personal protective apparel utilized for 
preparation of antineoplastic agents [e.g., gowns, sterile latex gloves (double-
gloving is recommended), respirator masks, protective eyewear, hair cover] 
should be utilized during preparation of recombinant vaccinia products for patient 
administration. 
2. Access to preparation areas should be limited or restricted while dose preparation 
is in progress. 
3. Appropriate infection control measures (e.g., thorough hand washing) should be 
utilized after handling any materials. 
4. All procedures are performed carefully to minimize creation of aerosols. 
5. An autoclave for decontaminating waste is available. 
6. All contaminated liquid or solid wastes are to be decontaminated prior to disposal 
according to any local, state, or federal regulations. Contaminated materials that 
are to be decontaminated at a site away from the preparation area should be 
placed in a durable leak-proof container prior to being transported. 
7. Established policies and procedures are in place whereby only personnel who 
have been advised of the potential hazards and meet any specific requirements 
(e.g., immunization) should be allowed entry into areas where product is prepared 
or agents are stored. 
8. A biosafety manual is prepared whereby personnel are advised of special hazards 
and are required to read and follow instructions on practices and procedures. 
9. Warning hazard signs should be posted on the access door identifying the agents, 
the name and phone number of the Principal Investigator or other responsible 
person, and indicates any special requirements for entry. 
10. Only needle-lock syringes and needles should be utilized for preparation. Extreme 
caution should be used to prevent autoinoculation. Needles should not be bent, 
sheared, replaced in the needle guard, or removed from the syringe following use. 
Needles and syringe should be promptly placed in puncture-resistant containers 
and decontaminated prior to disposal. 
11. Spills and accidents resulting in overt exposure to recombinant DNA molecules 
are immediately reported to the Institutional Biosafety Committee and NIH/OBA 
(Office of Biotechnology Activities). Reports should be sent to the Office of 
Biotechnology Activities, National Institutes of Health, 6705 Rockledge Drive, 
Suite 750, MSC 7985, Bethesda, MD 20892-7985. Phone (301) 496-9838. 
Medical evaluation, surveillance, and treatment should be provided as appropriate 
and written records should be maintained. 
 
Preparat ion and Disposal  Procedur e Recommendations 
a. All necessary supplies should be on hand prior to beginning the preparation 
procedure. A detailed worksheet outlining all supplies, dose calculations and 
preparation procedures should be readily available prior to beginning the preparation 
procedure. 
b. Agent for dose preparation should be transported from the –70oC freezer to the work 


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area in leak proof bag.  
c. All dose preparations are to be performed in an appropriately certified Class II 
biological safety cabinet. In general, procedures and guidelines (e.g., minimizing 
creation of aerosols during dose preparation; no eating, drinking or applying 
cosmetics in the work area), and personal protective apparel utilized for preparation 
of antineoplastic agents [e.g., gowns, sterile latex gloves (double-gloving is 
recommended), respirator masks, protective eyewear, hair cover] should be utilized 
during preparation of recombinant vaccinia products for patient administration. 
d. Prior to dose preparation, all surfaces of the biological safety cabinet should be 
decontaminated by wiping down with sterile gauze soaked in 10% bleach solution 
(0.52% sodium hypochlorite solution), or other appropriate disinfectant suitable for 
decontamination, then wiped with sterile gauze soaked in 70% alcohol. 
Manufacturer’s recommendations, with respect to disinfectant concentration, contact 
time and method of application, should be consulted. 
e. An empty biohazard sharps container lined with a leak-proof biohazard bag should be 
placed in or near the biosafety cabinet to dispose of all waste generated in preparation 
of the final dose for patient administration. 
f. Dose preparation should be performed using aseptic technique in a sterile barrier field 
within the biological safety cabinet. Any items to be used for dose preparation should 
be sprayed or wiped with 70% alcohol prior to being placed in the biological safety 
cabinet. Disinfectants should remain in contact with the surfaces for at least five 
minutes prior to dose preparation. Caution should be exercised to avoid exposure of 
the virus to the disinfectants. 
g. The final prepared dose should be sprayed with 70% alcohol prior to removal from 
the biological safety cabinet and transported in a leak proof bag or container labeled 
with a biohazard symbol. 
h. All waste should be placed into the biohazard sharps container lined with the leak 
proof biohazard bag and the biological safety cabinet decontaminated again by 
wiping down all surfaces with sterile gauze soaked in 10% bleach solution, or other 
appropriate disinfectant, followed by sterile gauze soaked in 70% alcohol. Following 
decontamination, dispose of personal protective apparel in a biohazard safety bag. 
i. Ultimately, all waste contained within the biohazard bags should be placed in a large 
autoclave bag labeled with biohazard symbols. After a 30-minute steam autoclave 
sterilization cycle at 121oC, the autoclave bag should be placed in a biohazard sharps 
container for incineration according to institutional policy and according to any local, 
state, or federal regulations. If autoclaving is not possible, all waste and protective 
apparel should be placed in a leak proof biohazard bag, and the bag placed inside a 
biohazard sharps container for incineration according to institutional policy and 
according to any local, state, or federal regulations. 
j. Accidental spills should be handled similarly to antineoplastic spills according to 
institutional policy:  
1. Prevent others from entering the area and allow aerosols time to settle 
(approximately 10 minutes).  
2. Use protective clothing, eyewear, mask, and gloves. 


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3. Spill should be covered with absorbent towels.  
4. Area should be decontaminated with 10% bleach solution, or other 
appropriate disinfectant suitable for decontamination, allowing approximately 
a 20-minute contact time.  
5. All waste should be decontaminated prior to disposal and disposed of as 
biohazardous waste by incineration according to institutional policy and 
according to any local, state, or federal regulations.  
 
9.1.13 Patient Care Implications and Contraindications  
 
A sterile dry dressing (e.g., Telfa pad) should cover vaccination sites and patients should receive 
instruction regarding proper hand-hygiene, sterile dressing care, bathing, laundering of clothing, etc. 
Patient bandages or dressings removed from the vaccination site should be treated as infectious 
waste and disposed of in appropriate biohazard containers. The recombinant vaccinia vaccine 
should not be administered if any of the following apply to either recipients, or for at least three 
weeks after vaccination (i.e., until the scab has separated from the skin and the underlying skin has 
healed), their close household contacts (close household contacts are those who share housing or 
have close physical contact): 
 Individuals with active eczema or a history of eczema or atopic dermatitis. 
 Individuals with Darier’s disease. 
 Individuals with other acute, chronic, or exfoliative skin conditions (e.g., burns, 
impetigo, varicella zoster, severe acne, contact dermatitis, psoriasis, herpes or other open 
rashes or wounds) until the condition resolves. 
 Individuals who are pregnant or intend on becoming pregnant (due to the potential risk 
of fetal vaccinia).  Because there is no safety data available, patients (i.e., vaccinees) 
should avoid becoming pregnant, fathering a child, or breast-feeding for at least 4 
months following completion of therapy with the recombinant vaccine. 
 Individuals in close contact with children less than 3 years of age (due to the potential 
risk of contact transmission and inadvertent inoculation).  
 Individuals who are immunodeficient or immunocompromised (by disease or 
therapy), including individuals with HIV infection 
 
Additionally, the recombinant vaccinia vaccine should not be administered if any of the 
following apply to vaccinees only:  
 Individuals with moderate or severe acute illnesses, until the illness resolves. 
 Individuals who are breast-feeding (due to the potential risk of contact transmission 
and inadvertent inoculation). It is currently unknown if vaccinia virus or antibodies 
are excreted in breast milk. 
 Individuals undergoing topical steroid therapy for inflammatory eye diseases, or 
undergoing therapy with systemic steroids due to the potential for immune 
suppression and increased risk for vaccinia-related complications. Localized topical 
steroid use and inhaled steroid use may be permissible. 
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recommended that patients with known CHF or clinically significant cardiomyopathy 
should not be vaccinated with recombinant vaccinia-based vaccines, due to the 
potential for development of myocarditis and/or pericarditis.  
Although the CDC believes that there is no evidence to conclude that Dryvax® used 
in the Smallpox Vaccination Program causes angina or heart attacks, it acknowledges 
a possible causal relationship between the vaccination and heart inflammation.  The 
CDC continues to study the relationship, but in the meantime, recommends that 
individuals with underlying heart disease be excluded from participation in the 
current Smallpox Vaccination Program. Because patients are being immunized with 
recombinant vaccinia vaccines with therapeutic intent, it is currently not recommend 
to exclude patients with known CAD, previous heart attack, history of angina, or 
other evidence of risk factors for coronary artery disease who are otherwise eligible 
for the study, but patients should be informed of the potential risks and the patient’s 
cardiac disease should be controlled.   
 
Due to the method of manufacturing (virus grown in primary chicken embryo dermal 
cells), patients with a history of allergy to eggs or egg products should not receive the 
vaccine. Patients with a prior history of allergy or serious reaction to prior vaccinia 
vaccination (e.g., smallpox vaccination) should not receive the recombinant vaccinia 
product. 
 
 
9.2 
PANVAC-F (NSC 727027) 
 
9.2.1 Other Names: Recombinant – Fowlpox – CEA(D609)/MUC-1(L93)/TRICOMTM 
 
9.2.2 Classification: Recombinant fowlpox virus vector vaccine of the genus Avipoxvirus. 
 
 
9.2.3 Product Description:  
PANVACTM-F is a recombinant fowlpox virus vector vaccine containing genes for human CEA, 
MUC-1, and three co-stimulatory molecules (designated TRICOMTM): B7.1, ICAM-1 
(intercellular adhesion molecule-1), and LFA-3 (leukocyte function-associated antigen-3). The 
CEA gene coding sequence is modified to code for a single amino acid substitution (aspartic 
acid, instead of asparagines at amino acid position 609) in one 9-mer, HLA-A2-restricted, 
immunodominant epitope designed to enhance immunogenicity. The MUC-1 gene coding 
sequence is also modified to code for a single amino substitution (leucine instead of threonine at 
amino acid position 93) in one 10-mer, HLA-A2-restricted, immunodominant epitope designed 
to enhance immunogeniticity. An attenuated, live, plaque-purified isolate from the POXVAC-TC 
strain of fowlpox virus was used as the parental virus for this recombinant vaccine. A plasmid 
vector containing the modified CEA and MUC-1 genes and a plasmid vector containing the 
genes for the three co-stimulatory molecules were used to transfect primary chicken embryo 
dermal (CED) cells infected with the parental virus to generate the recombinant fowlpox virus.  
The final PANVACTM – F recombinant vaccine is manufactured by infection of primary CED 


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cells with the recombinant fowlpox virus. Fowlpox virus can infect mammalian cells and express 
the inserted transgenes to stimulate both humoral and cellular immunity, but cannot replicate in 
non-avian species, making systemic infections unlikely.  
 
9.2.4 How Supplied:  
 
Lot: 4-060503: PANVAC–F is supplied in vials containing 0.3 mL of the vaccine at a final viral 
concentration titer of 6.6 x 109 pfu/mL formulated in phosphate-buffered saline containing 10% 
glycerol (total vial contents = 1.98 x 109 pfu’s). 
 
Lot: 3-052203: PANVAC–F is supplied in vials containing 0.3 mL of the vaccine at a final viral 
concentration titer of 5.8 x 109 pfu/mL formulated in phosphate-buffered saline containing 10% 
glycerol (total vial contents = 1.74 x 109 pfu’s). 
 
Note: The PANVAC–F concentration varies between lots, requiring changes to dose 
preparation instructions. Use extreme caution when preparing each dose.  
 
9.2.5 Preparation:  
Thaw vials completely at room temperature. Ensure the thawed contents are at the bottom of the 
upright vial and vortex vigorously at high power for at least ten seconds prior to dose 
preparation. If necessary, perform all dilutions of the vaccine with 0.9% sodium chloride for 
injection, USP and vortex all dilutions vigorously again for at least ten seconds prior to 
withdrawing the final dose. Note the concentration of the current supply of PANVAC–F on 
your institutional preparation guidelines to avoid potentially serious dosing errors.  
 
Preparation Instructions for PANVAC–F, Lot 4-060503 (6.6 x 109 pfu/mL, 0.3mL vial) 
Thaw one vial completely at room temperature. Ensure the thawed contents are at the bottom of 
the upright vial and vortex vigorously at high power for at least 10 seconds. Withdraw 0.16mL (1 
x 109 pfu) from the thawed vial for subcutaneous injection.  
 
Preparation Instructions for PANVAC–F, Lot 3-052203 (5.8 x 109 pfu/mL, 0.3mL vial) 
Thaw one vial completely at room temperature. Ensure the thawed contents are at the bottom of 
the upright vial and vortex vigorously at high power for at least 10 seconds. Withdraw 0.18mL (1 
x 109 pfu) from the thawed vial for subcutaneous injection.  
 
9.2.6 Storage: Store intact vials of PANVAC TM – F at -70oC or colder.  
 
9.2.7 Stability:  
Shelf-life stability studies of the intact vials are ongoing. Once the intact vials are thawed, the 
vaccines maintain their potency for up to four days when stored at 2-8oC. Do not re-freeze 
thawed vials. Vials of PANVAC TM – F are for single-use only and do not contain a preservative. 
Administer prepared doses as soon as possible following preparation (i.e. within one hour). 
Prepared doses may be stored at 2-8oC for up to four hours following preparation.  
 


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9.2.8 Route of Administration: PANVAC TM – F is administered by subcutaneous injection.  
 
9.2.9 Special Handling 
Fowlpox virus is classified as a Biosafety Level 1 agent.  These agents are not known to cause 
disease in healthy human adults and are of minimal potential hazard to personnel and the 
environment under ordinary conditions of use.  Clinicians can use techniques generally 
acceptable for nonpathogenic material.  The recombinant vaccine is a preparation of a live virus 
(infectious for birds) containing DNA sequences derived from the human genome.  Handle the 
recombinant vaccine as a hazardous biological substance and dispose of waste materials as 
hazardous biological waste, with incineration according to local institutional policy and 
according to local, state, and federal regulations.  Healthcare workers handling the recombinant 
fowlpox vaccine should avoid direct contact with pet birds for at least 72 hours after working 
with the agent. 
 
Preparation, Handling, and Disposal Recommendations 
 
1. Strictly adhere to standard microbiological practices and techniques. 
 
2. Limit/restrict access to preparation areas while dose preparation is in progress. 
 
3. Use appropriate infection control measures (e.g., thorough hand washing) after 
handling any materials 
 
4. Institute and follow policies for safe handling of sharps. 
 
5. Perform all dose preparations in a certified Class II biological safety cabinet, 
generally using procedures, guidelines, and personal protective apparel used 
during preparation of antineoplastic agents [e.g. minimizing creation of aerosols; 
no eating, drinking, handling contact lenses or applying cosmetics in the work 
area; using appropriate personal protective apparel – gowns, sterile latex gloves 
(double-gloving is recommended), respirator masks, protective eyewear, hair 
cover]. 
 
6. Decontaminate the biological safety cabinet prior to dose preparation with sterile 
gauze soaked in 10% bleach solution (0.52% sodium hypochlorite solution), or 
other appropriate disinfectant suitable for decontamination, rinsing, then wiping 
down with sterile gauze soaked in 70% alcohol. Consult specific manufacturer’s 
recommendations with respect to disinfectant concentration, contact time and 
method of application.  
 
7. Have all necessary supplies on-hand before beginning the preparation procedure. 
Develop a detailed worksheet outlining all supplies, dose calculations, and 
preparation procedure, and keep it available.  
 


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8. Place an empty biohazard sharps container lined with a leak-proof biohazard bag 
in or near the biosafety cabinet to dispose of all waste generated.  
 
9. Transport the agent from –70oC freezer to the work area in a leak proof bag 
 
10. Wipe or spray items used for dose preparation with 70% alcohol before placing in 
the biological safety cabinet. Disinfectants should remain in contact with the 
surfaces for at least five minutes prior to dose preparation. Avoid exposing the 
virus to disinfectant.  
 
11. Wipe the syringe containing the prepared dose with 70% alcohol before removing 
it from the biological safety cabinet; transport it in a leak proof bag or contained 
labeled with a biohazard symbol.  
 
12. Place all waste into the sharps container lined with the leak proof biohazard bag 
and decontaminate the biological safety cabinet again by wiping down all surfaces 
with the sterile gauze soaked in 10% bleach solution, or other appropriate 
disinfectant, rinsing, then wiping down with sterile gauze soaked in 70% alcohol. 
Following decontamination, dispose of personal protective apparel in the 
biohazard safety bag.  
 
13. Incinerate waste according to institutional policy and according to local, state and 
federal regulations.  
 
14. Handle accidental spills similarly to antineoplastic spills and/or according to 
institutional policy.  
 Prevent others from entering the area and allow aerosols time to settle 
(approximately 10 minutes).  
 Use protective apparel, eyewear, mask and gloves.  
 Cover spills with disposable absorbent towels.  
 Decontaminate the area with 10% bleach, or appropriate disinfectant suitable 
for decontamination, allowing approximately a 20-minute contact time.  
 Dispose of all waste as biohazardous waste and incinerate according to 
institutional policy and according to local, state and federal regulations 
 
For more information about biohazardous risk group classification and biohazard safety 
levels see NIH Guidelines for Research Involving Recombinant DNA Molecules (NIH 
Guidelines): April, 2016 (http://osp.od.nih.gov/office-biotechnology-activities/biosafety/nih-
guidelines) and biosafety in Microbiological and Biomedical Laboratories; 4th Edition. U.S. 
Department of Health and Human Services Center for Disease Control and Prevention and 
National Institutes of Health (Http://www.cdc.gov/od/ohs/biosfty/bmbl4/bmbl4toc.htm). 
 
9.2.10 Patient Care Implications and Contraindictations  
 


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Cover vaccination sites with a sterile dry dressing (e.g., Telfa pad). Once the injection site is 
healed, no further barrier is necessary. As a precaution, protect injection sites that are exhibiting 
evidence of weeping, oozing, or ulceration with a sterile dry dressing. In these circumstances, 
instruct patients to avoid contact of the injection site with susceptible individuals (e.g., those who 
may be immunocompromised by disease or therapy). Because there is no safety data available, 
instruct patients to avoid becoming pregnant, fathering a child, or breast-feeding for at least 4 
months following therapy completion with the recombinant vaccine. Instruct patients receiving 
fowlpox vaccines to avoid direct contact with pet birds for at least 72 hours after vaccination or 
while there are any visible lesions at the injection site.  
 
Due to the method of manufacturing (virus grown in primary chicken embryo dermal  
cells), patients with a history of allergy to eggs or egg products should not receive the  
vaccine. 
 
9.2.11 Agent Procurement  
 
9.2.11.1 
Availability 
PANVAC-V (NSC 727026) and PANVAC-F (NSC 727027) are manufactured by Therion 
Biologics Corporation and supplied by the Pharmaceutical Management Branch, CTEP, DCTD, 
NCI. 
 
9.2.11.2 
Agent Ordering and Agent Accountability: 
NCI-supplied PANVAC-V (NSC 727026) and PANVAC-F (NSC 727027) may be 
requested by the Principal Investigator (or their authorized designee) at each participating 
institution.  Pharmaceutical Management Branch (PMB) policy requires that agent be shipped 
directly to the institution where the patient is to be treated.  PMB does not permit the transfer of 
agents between institutions (unless prior approval from PMB is obtained.) The CTEP assigned 
protocol number must be used for ordering all CTEP supplied investigational agents.  The 
responsible investigator at each participating institution must be registered with CTEP, DCTD 
through an annual submission of FDA form 1572 (Statement of Investigator), Curriculum Vitae, 
Supplemental Investigator Data Form, and Financial Disclosure Form. If there are several 
participating investigators at one institution, CTEP supplied investigational agents for the study 
should be ordered under the name of one lead investigator at that institution.  
Agent may be requested by completing a Clinical Drug Request (NIH-986) and mailing it to the 
Drug Management and Authorization Section, PMB, DCTD, NCI, 9000 Rockville Pike, EPN 
Room 7149, Bethesda, MD 20892-7422 or faxing it to (301) 480-4612.  For questions call (301) 
496-5725. 
 
Inventory Records - The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the inventory and disposition of all agents 
received from DCTD using the NCI Drug Accountability Record (DAR) Form.  (See the 
NCI Investigator’s Handbook for Procedures for Drug Accountability and Storage). 


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9.3 
Sargramostim (GM-CSF, LEUKINE) 
 
9.3.1 Product Description 
Refer to the FDA-approved package insert for complete product information. Sargramostim is a 
recombinant human granulocyte-macrophage colony stimulating factor (GM-CSF) produced by 
recombinant DNA technology in yeast (Saccharomyces cerevisiae). Sargramostim is a 127 
amino acid glycoprotein, altered from the native, natural human GM-CSF molecule; the position 
23 arginine has been replaced with a leucine to facilitate the expression of the protein in yeast.  
 
9.3.2 How supplied 
Sargramostim used in this protocol is a commercially available drug, manufactured by Berlex 
Laboratories and will be purchased from commercial sources. Sargramostim is available as a 
sterile, preserved injectable solution in a 500-µg multidose liquid vial. 
 
9.3.3 Formulation and Preparation:  
LEUKINE Liquid (Sargramostim, GM-CSF) is formulated as a sterile, preserved (containing 1.1% 
benzyl alcohol) solution containing 500 mcg/mL, 1mL per vial. Lyophilized LEUKINE is 
formulated as a sterile, white preservative-free powder containing 250 mcg per vial. Each mL of 
preserved solution (LEUKINE Liquid) and reconstituted Lyophilized LEUKINE contains 40 
mg/mL mannitol, USP, 10 mg/mL sucrose, NF, and 1.2 mg/mL tromethamine, USP. 
 
Reconstitute each 250 mcg vial of lyophilized LEUKINE with 1 mL of Sterile Water for Injection, 
USP or 1 mL of Bacteriostatic Sterile Water for Injection, USP containing 0.9% benzyl alcohol to 
yield a 250 mcg/mL solution. The diluent should be directed against the side of the vial to avoid 
excess foaming. Avoid vigorous agitation of the vial; do not shake. 
 
9.3.4 Stability and Storage:  
LEUKINE Liquid and Lyophilized LEUKINE should be stored refrigerated at 2-8oC. Each vial 
bears an expiration date. LEUKINE Liquid may be stored for up to 20 days at 2-8oC once the vial 
has been entered. Any remaining solution should be discarded after 20 days. Lyophilized LEUKINE 
reconstituted with Sterile Water for Injection, USP should be discarded within 6 hours of 
preparation. Lyophilized LEUKINE reconstituted with Bacteriostatic Sterile Water for Injection, 
USP (containing 0.9% benzyl alcohol) may be stored for up to 20 days at 2-8oC once the vial has 
been reconstituted. Any remaining solution should be discarded after 20 days. 
 
9.3.5 Administration procedures 
Route of administration: Sargramostim will be administered subcutaneously in a dose of 100 
g/day for 4 days starting on the day of the vaccination.  This will be done in one site which will 
be marked with a pen to identify. Subsequent sargramostim injections will be given 
subcutaneously in that site.  
 
9.3.6 Adverse Events, Contraindications and/or Toxicities 
Toxicities described in patients receiving sargramostim include: fever, chills,   diaphoresis, 
myalgia, fatigue, malaise, headache, dizziness, dyspnea, bronchospasm, pleural effusion, 


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anorexia, indigestion, nausea, vomiting, diarrhea, injection site tenderness, urticaria, pruritus, 
hypersensitivity reaction, bone pain, thromboembolic events, phlebitis, hypotension, peripheral 
edema, leukocytosis, thrombocytosis, or thrombocytopenia, hepatic enzyme abnormalities, and 
bilirubin elevation.  The first administration of sargramostim has provoked a syndrome of 
dyspnea and hypotension within two hours after sargramostim injection in a single patient 
received yeast sargramostim; this type of reaction has more been observed in patients receiving 
sargramostim produced in E. coli.  One report of vascular leak syndrome occurring after 
autologous bone marrow transplant in a patient receiving continuous IV infusion of 
sargramostim has been recorded.  All these toxicities were seen at much higher dose than what 
the patients will be receiving on this protocol, as explained above.  


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adoptively transferred. Journal of Immunology 2000; 165(6):3451-3460. 
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epitope of human carcinoembryonic antigen stimulates production of TC1-type cytokines and increases 
tyrosine phosphorylation more efficiently than cognate peptide. International Journal of Cancer 2000; 
85(6):829-838. 


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specific immune responses and antitumor effects. Cancer Res 2001; 61(11):4497-4505. 
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expression at the deepest invasive portion correlates with prognosis of colorectal cancer. Oncology 1998; 
55(4):307-319. 
 (29)  Zotter S, Hageman P, Lossnitzer A, Mooi W, Higers J. Tissue and tumor distribution of human 
polymorphic epithelial mucin. Cancer in Review 1988; 11:55-101. 
 (30)  Yonezawa S, Sato E. Expression of mucin antigens in human cancers and its relationship with malignancy 
potential. Pathology International 1997; 47(12):813-830. 
 (31)  Ramanathan R, Lee K, Mckolanis J, Hiltbold E, Dyky M, Alvelo-Rivera M et al. Phase 1 Study of a MUC-
1 Synthetic Vaccine Admixed with SB-AS2 Adjuvant in Resected and Locally Advanced Pancreatic 
Cancer. ASCO Abstract No 1791 2000. 
 (32)  Hodge JW, McLaughlin JP, Kantor JA, Schlom J. Diversified prime and boost protocols using recombinant 
vaccinia virus and recombinant non-replicating avian pox virus to enhance T-cell immunity and antitumor 
responses. Vaccine 1997; 15(6-7):759-768. 
 (33)  Hodge JW, Grosenbach DW, Rad AN, Giuliano M, Sabzevari H, Schlom J. Enhancing the potency of 
peptide-pulsed antigen presenting cells by vector-driven hyperexpression of a triad of costimulatory 
molecules. Vaccine 2001; 19(25-26):3552-3567. 
 (34)  Scheithauer W, Kornek GV, Schuell B, Ulrich-Pur H, Penz M, Raderer M et al. Second-line treatment with 
oxaliplatin + raltitrexed in patients with advanced colorectal cancer failing fluoropyrimidine/leucovorin-
based chemotherapy. Ann Oncol 2001; 12(5):709-714. 
 (35)  Tsang K, Palena C, Gulley J, Arlen P, Schlom J. Identification and characterization of a human cytotoxic 
T-lymphocyte epitope and agonist epitope from the non-variable number of tandem repeat sequence of 
MUC-1 tumor antigen. Clin Cancer Res. In press. 
 (36)  Hodge JW, Grosenbach DW, Rad AN, Giuliano M, Sabzevari H, Schlom J. Enhancing the potency of 
peptide-pulsed antigen presenting cells by vector-driven hyperexpression of a triad of costimulatory 
molecules. Vaccine 2001; 19(25-26):3552-3567. 
 (37)  Zhu MZ, Terasawa H, Gulley J, Panicali D, Arlen P, Schlom J et al. Enhanced activation of human T cells 
via avipox vector-mediated hyperexpression of a triad of costimulatory molecules in human dendritic cells. 
Cancer Research 2001; 61(9):3725-3734. 
 (38)  Oh S, Hodge JW, Ahlers JD, Burke DS, Schlom J, Berzofsky JA. Selective induction of high avidity CTL 
by altering the balance of signals from APC. Journal of Immunology 2003; 170(5):2523-2530. 
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GM-CSF administered via a poxvirus to enhance the concentration of antigen-presenting cells in regional 
lymph nodes. Cytokine 2000; 12(7):960-971. 


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 (40)  Moss B. Replicating and host-restricted non-replicating vaccinia virus vectors for vaccine development. 
Developments in Biological Standardization 1994; 82:55-63. 
 (41)  Aarts WM, Schlom J, Hodge JW. Vector-based vaccine/cytokine combination therapy to enhance induction 
of immune responses to a self-antigen and antitumor activity. Cancer Res 2002; 62(20):5770-5777. 
 (42)  Greiner JW, Zeytin H, Anver MR, Schlom J. Vaccine-based therapy directed against carcinoembryonic 
antigen demonstrates antitumor activity on spontaneous intestinal tumors in the absence of autoimmunity. 
Cancer Research 2002; 62(23):6944-6951. 
 (43)  Grosenbach DW, Barrientos JC, Schlom J, Hodge JW. Synergy of vaccine strategies to amplify antigen-
specific immune responses and antitumor effects. Cancer Res 2001; 61(11):4497-4505. 
 (44)  Aarts WM, Schlom J, Hodge JW. Vector-based vaccine/cytokine combination therapy to enhance induction 
of immune responses to a self-antigen and antitumor activity. Cancer Res 2002; 62(20):5770-5777. 
 (45)  Kass E, Panicali DL, Mazzara G, Schlom J, Greiner JW. Granulocyte/macrophage-colony stimulating 
factor produced by recombinant avian poxviruses enriches the regional lymph nodes with antigen-
presenting cells and acts as an immunoadjuvant. Cancer Res 2001; 61(1):206-214. 
 (46)  Hodge JW, Grosenbach DW, Aarts WM, Poole DJ, Schlom J. Vaccine Therapy of Established Tumors in 
the Absence of Autoimmunity. Clinical Cancer Research 2003; 9(5):1837-1849. 
 (47)  Scheithauer W, Kornek GV, Schuell B, Ulrich-Pur H, Penz M, Raderer M et al. Second-line treatment with 
oxaliplatin + raltitrexed in patients with advanced colorectal cancer failing fluoropyrimidine/leucovorin-
based chemotherapy. Ann Oncol 2001; 12(5):709-714. 
 (48)  Marshall JL, Hawkins MJ, Tsang KY, Richmond E, Pedicano JE, Zhu MZ et al. Phase I study in cancer 
patients of a replication-defective avipox recombinant vaccine that expresses human carcinoembryonic 
antigen. J Clin Oncol 1999; 17(1):332-337. 
 (49)  Marshall JL, Hoyer RJ, Toomey MA, Faraguna K, Chang P, Richmond E et al. Phase I study in advanced 
cancer patients of a diversified prime-and-boost vaccination protocol using recombinant vaccinia virus and 
recombinant nonreplicating avipox virus to elicit anti-carcinoembryonic antigen immune responses. J Clin 
Oncol 2000; 18(23):3964-3973. 
 (50)  Zhu MZ, Marshall J, Cole D, Schlom J, Tsang KY. Specific cytolytic T-cell responses to human CEA from 
patients immunized with recombinant avipox-CEA vaccine. Clin Cancer Res 2000; 6(1):24-33. 
 (51)  Arlen P, Tsang KY, Marshall JL, Chen A, Steinberg SM, Poole D et al. The use of a rapid ELISPOT assay 
to analyze peptide-specific immune responses in carcinoma patients to peptide vs. recombinant poxvirus 
vaccines. Cancer Immunol Immunother 2000; 49(10):517-529. 
 (52)  von Mehren M, Arlen P, Tsang KY, Rogatko A, Meropol N, Cooper HS et al. Pilot study of a dual gene 
recombinant avipox vaccine containing both carcinoembryonic antigen (CEA) and B7.1 transgenes in 
patients with recurrent CEA-expressing adenocarcinomas. Clin Cancer Res 2000; 6(6):2219-2228. 
 (53)  von Mehren M, Arlen P, Gulley J, Rogatko A, Cooper HS, Meropol NJ et al. The influence of granulocyte 
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 (54)  Moss B. Genetically engineered poxviruses for recombinant gene expression, vaccination, and safety. 


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Proceedings of the National Academy of Sciences of the United States of America 1996; 93(21):11341-
11348. 
 (55)  Taylor P, Weinberb R, Languet B. Fowlpox virus based recombinant vaccines. Advances in Vaccine 
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 (56)  Somogyi P, Frazier J, Skinner MA. Fowlpox Virus Host-Range Restriction - Gene-Expression, Dna- 
Replication, and Morphogenesis in Nonpermissive Mammalian-Cells. Virology 1993; 197(1):439-444. 
 (57)  Tsang KY, Zaremba S, Nieroda CA, Zhu MZ, Hamilton JM, Schlom J. Generation of human cytotoxic T 
cells specific for human carcinoembryonic antigen epitopes from patients immunized with recombinant 
vaccinia-CEA vaccine. J Natl Cancer Inst 1995; 87(13):982-990. 
 (58)  Hodge JW, McLaughlin JP, Kantor JA, Schlom J. Diversified prime and boost protocols using recombinant 
vaccinia virus and recombinant non-replicating avian pox virus to enhance T-cell immunity and antitumor 
responses. Vaccine 1997; 15(6-7):759-768. 
 (59)  Zhu MZ, Marshall J, Cole D, Schlom J, Tsang KY. Specific cytolytic T-cell responses to human CEA from 
patients immunized with recombinant avipox-CEA vaccine. Clin Cancer Res 2000; 6(1):24-33. 
 (60)  Nakamori S, Ota DM, Cleary KR, Shirotani K, Irimura T. Muc1 Mucin Expression As A Marker of 
Progression and Metastasis of Human Colorectal-Carcinoma. Gastroenterology 1994; 106(2):353-361. 
 (61)  Marshall JL, Hawkins MJ, Tsang KY, Richmond E, Pedicano JE, Zhu MZ et al. Phase I study in cancer 
patients of a replication-defective avipox recombinant vaccine that expresses human carcinoembryonic 
antigen. J Clin Oncol 1999; 17(1):332-337. 
 
 
 
 
 
 
 
 
 
 


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11 APPENDIX A: PERFORMANCE STATUS CRITERIA 
 
 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Descriptions 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 


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12  APPENDIX B: INSTRUCTIONS FOR CARE OF THE VACCINE SITE 
 
 
 
 
 
 
Instructions for Care of the Vaccine Site 
 
1. 
What vaccination site reactions can you expect? 
2. 
How should you care for the vaccination site?  
3. 
How should I dispose of the used needle and syringe? 
4. 
Are there any activities I should avoid? 
5. 
What about contact with other people? 
6. 
Whom do I contact when I have a question? 
 
 
1. What vaccination site reactions can you expect? 
 
In patients who have never received vaccinia intradermally (under the skin), or in some 
who received it a very long time ago, a red swelling may occur followed by a blister on 
day 5 to 6 and then formation of a pustule (or "boil") 1-2 inches in diameter on day 9 to 
11.  A large area of redness may surround this area.  A crusted scab usually forms by the 
second week and falls off by the third week leaving a scar roughly 1/2 inch in diameter.  
Fever and malaise (the "blahs") may occur during the blister and pustular phases.  
Swollen and tender lymph nodes may persist for months. 
 
Patients in this study will be receiving injections subcutaneously in their arm or leg.  Based on 
your previous exposure, most patients will have little skin reaction, except that the arm or leg 
that received the vaccine may be swollen.  Swollen or tender lymph nodes ("glands") in the 
armpit may also be felt. A fever to 100-101F may occur on the second or third day.  You may 
notice that you feel tired for 3 or 4 days. The vaccination site may itch for about two weeks 
while the scab is forming.  If you have any aches or fever, you can take acetaminophen 
("Tylenol"), but should avoid aspirin.  If fever continues for more than a day or two, or exceeds 
102F you should call to speak to the clinic nurse or the research nurse.  
 
2. 
How should you care for the vaccination site? 
 
Live vaccinia virus is in skin cells at the vaccination site during the 1-2 weeks until healing has 
occurred.  Maximal viral "shedding" from the vaccination site occurs from days 4-14, but can 
continue until the scab falls off from the skin.  After that there is no vaccinia virus in your body 
(until your next inoculation).  You can spread the virus to other parts of your body or to other 
people by touching the vaccination site and then touching your eyes, mouth, a cut or some 
other break in the skin.  You do not pass vaccinia virus by coughing or sneezing or by sharing 
food or cups and dishes. 
 
Center for Cancer Research 
 
Medical Oncology Branch 
(MOB) 
 
 
U.S. Department of Health 
and Human Services 
Public Health Service 
National Institutes of Health 
Clinical Center 
9000 Rockville Pike 
Bethesda, MD  20892 
(301) 496-0684 
 
 
 
 
 
 
 
 
 
 
Appendix B  


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In general, frequent careful hand washing by you and by any persons with physical contact 
with you is the best way to prevent transmission of the virus.  While you are receiving care 
in the Outpatient Cancer Center for your first cycle, you will be placed in a private room.  
You should also use two types of barriers over your vaccination site at all times until the 
scab has fallen off. These barriers are (1) the bandage and (2) long sleeves if the 
vaccination site is in your arm, or long pants (including nightclothes) if the site is in your 
leg.  For dressing care you will receive some no-stick dressings, disposable gloves, and 
zip-lock plastic bags.  If you should run out of supplies between visits, you can obtain 
some from your local store.  If your clothes become soiled, please remove them and wash 
in hot soapy water with bleach. 
 
The no-stick dressing should be worn until the site has healed.  If it remains clean and dry and 
is not coming off, you do not need to change it.  If the dressing gets wet either from drainage 
from the vaccination or from water when you are showering or if it starts coming off, you 
should remove it and put on a clean bandage.  Wear the gloves when handling the old 
dressings.  Put the old dressing and the gloves in the zip-lock bag, then wash your hands, put 
on the new bandage, and wash your hands again.  You do not need to wear gloves for the 
new bandage.  You do not need to wash the vaccination site, but while the dressing is off, you 
may wash it lightly with a disposable cloth, soap, and water.  If you do wash, blot the site dry 
with a disposable soft towel (don't rub), then dispose of the washcloth and the towel in a zip 
lock bag. Do not let the shower run on the unbandaged site because live virus could be 
washed onto other areas on your body.  Do not put any steroid cream, medicated 
creams, or other ointments on the vaccination site. 
 
Before you throw away the zip-lock bag with the old dressing and gloves in it, pour a little  
bleach (about a quarter cup) in the bag to help kill any virus. 
 
 
 
Wash your hands after each step! 
 
3. 
How should I dispose of the used needle and syringe? 
 
The needle and syringe that you use to inject GM-CSF into the 
vaccine site should be discarded in a closed container.  Use a sturdy 
empty container with a secure lid.  DO NOT RECAP THE NEEDLE.  
After you inject the GM-CSF, drop the syringe AS IS in the bottle.  Pour a small 
amount of bleach in the bottle (about 2 inches deep) and close securely.  You 
may return the bottle on your next visit to the clinic and we will dispose it for you. 
 
4. 
Are there any activities I should avoid or take special care? 
 
You should not go swimming or bathing (bath tub, hot tub, etc.) until the vaccination site has 
healed and you no longer need to wear a bandage on it. If you wear contact lenses, 


Abbreviated Title: Vaccine for metastatic cancer 
Version Date:  05/04/2017 
 
CTEP #: 6536 
 
79 
 
removable dentures, have a colostomy or any other "open" area on your body that needs daily 
care, always wash your hands very well before handling your contact lenses, dentures, 
dressings, etc.  Take care of all of these procedures before changing your vaccination 
dressing. 
 
5. 
What about contact with other people? 
 
Because you may “shed” live virus for several days after vaccination, you must be able to 
avoid close contact with certain individuals for at least two weeks after vaccination. These 
individuals include children <3 years of age; women who are pregnant or breast-feeding; 
individuals with eczema, a history of eczema or other skin conditions such as active cases of 
extensive psoriasis, exfoliative skin diseases, severe rashes, generalized itching, infections, 
burns, chicken pox, or skin trauma; and/or immune suppressed individuals such as individuals 
with leukemia or lymphoma, with AIDS or HIV positive blood test, or those receiving 
immunosuppressive treatment.  “Close contact” means that these people share your house, 
you have repeated bodily contact with them, and/or you take care of them and touch them 
with your hands.   
 
6. 
Whom do I contact when I have a question?  
 
If you have any questions at any time, please call.  A nurse or a physician is 
available 24 hours a day by telephone.   
 
PHONE NUMBERS FOR NIH PATIENTS 
 
3 South East Outpatient Cancer Center  
 (301) 451-1152 
 
On-Call physician                                               (301) 496-1211 
  


Abbreviated Title: Vaccine for metastatic cancer 
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CTEP #: 6536 
 
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13 APPENDIX C: TREATMENT AND MONITORING SCHEDULE: PRE, DURING 
AND POST THERAPY 
 
 
 
Baseline 1 
Day 
15 
Day 
29 
Day 
43 
Day 
71 
Every 28 days 
on Extension 
Phase 
Every 3 months 
on Maintenance 
Phase 
History and 
Physical1 
X 
 
 
 
 
 
 
NIH 
Advanced 
Directives 
Form12 
 
X 
 
 
 
 
 
 
Medical 
Assessments2 
X 
X 
X 
X 
X 
X 
X10 
Imaging 
studies3 
X 
 
 
 
X 
Every 2 months 
Every 3 months11 
Serum CEA 
& CA-125  
X 
 
X 
 
X 
X 
X10 
Urinalysis  
X 
X 
X 
X 
X 
X 
X10 
Serum HIV 
antibody4 
X 
 
 
 
 
 
 
Serum 
Hepatitis      
B & C5 
X 
 
 
 
 
 
 
CBC with 
differential 
X 
X 
X 
X 
X 
X 
X10 
Chemistry5 
X 
X 
X 
X 
X 
X 
X10 
PT, PTT  
X 
 
 
 
 
 
 
EKG  
X 
 
 
 
X 
 
 
Apheresis6 
X 
 
 
 
X 
 
 
Immunology 
(blood)7 
X 
X 
X 
X 
X 
X 
X10 
ANA titer, 
CD3, 4, 8 
subsets and 
CD4:CD8 
ratio7 
X 
 
 
 
X 
 
 
HLA typing 
X 
 
 
 
 
 
 
Serum Beta-
HCG8 
X 
 
 
 
 
 
 
1 Baseline: H & P and laboratory studies should be completed within 16 days of initiating treatment. Baseline 
radiographic and immunologic studies should be obtained within 28 days of initiating treatment.  
2 Medical assessments:  interim history (since last visit), vital signs, physical examination and ECOG performance 
status. 


Abbreviated Title: Vaccine for metastatic cancer 
Version Date:  05/04/2017 
 
CTEP #: 6536 
 
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3 Radiologic studies consisting of CT chest/abdomen/pelvis or MRI will be performed within 28 days prior to        
initiating treatment. 
4 Serum HIV antibody should be completed within 8 weeks of initiating treatment. 
5Serum Hepatitis B & C antibody should be completed within 8 weeks of initiating treatment 
6 Chemistry panel:  Na+, K+, Cl-, CO2, glucose, BUN, creatinine, albumin, calcium, magnesium, phosphorus, 
alkaline phosphatase, ALT, AST, total bilirubin, and LDH. 
7Apheresis will be requested for immunologic testing from patients at baseline and approximately day 71. 
8 Blood will be obtained for immunologic assays including ELISPOT assay. Research blood will be drawn prior to 
each vaccination (at baseline and about days 15, 29, 43, 71) then every 28 days on the extension phase. ANA titer, 
CD3, 4, 8 subsets and CD4:CD8 ratio will be drawn at baseline and about day 71.  
9In females of child-bearing age, Beta-HCG to be done at baseline within 48 hours prior to receiving vaccinia 
10 Medical assessment, clinical labs, and research labs will be performed monthly.  For patients on the Maintenance 
phase, these assessments will occur at least with every 3-month vaccination visit. 
11 Imaging studies will be performed for patients on the Maintenance phase who show no radiographic evidence of 
disease, at the clinical discretion of the PI with patient input, at least every 12 months, if the patient is clinically 
stable 
12As indicated in section 6.3, all subjects ≥ age 18 will be offered the opportunity to complete an NIH advanced 
directives form.  This should be done preferably at baseline but can be done at any time during the study as long as 
the capacity to do so is retained.  The completion of the form is strongly recommended, but is not required. 


Abbreviated Title: Vaccine for metastatic cancer 
Version Date:  05/04/2017 
 
CTEP #: 6536 
 
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14 APPENDIX D: RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) QUICK REFERENCE 
 
 
Eligibility 
 Only patients with measurable disease at baseline should be included in protocols where 
objective tumor response is the primary endpoint.  
 
Measurable disease - the presence of at least one measurable lesion. If the measurable 
disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by 
cytology/histology.  
Measurable lesions - lesions that can be accurately measured in at least one dimension 
with longest diameter 20 mm using conventional techniques or 10 mm with spiral CT 
scan. 
Non-measurable lesions - all other lesions, including small lesions (longest diameter <20 
mm with conventional techniques or <10 mm with spiral CT scan), i.e., bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast disease, 
lymphangitis cutis/pulmonis, cystic lesions, and also abdominal masses that are not 
confirmed and followed by imaging techniques. 
 All measurements should be taken and recorded in metric notation, using a ruler or calipers. 
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment.  
 The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  
 Clinical lesions will only be considered measurable when they are superficial (e.g., skin 
nodules and palpable lymph nodes). For the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Methods of Measurement 
 
 CT and MRI are the best currently available and reproducible methods to measure target 
lesions selected for response assessment. Conventional CT and MRI should be performed 
with cuts of 10 mm or less in slice thickness contiguously. Spiral CT should be performed 
using a 5 mm contiguous reconstruction algorithm.  This applies to tumors of the chest, 
abdomen and pelvis. Head and neck tumors and those of extremities usually require specific 
protocols. 
 
 Lesions on chest X-ray are acceptable as measurable lesions when they are clearly defined 
and surrounded by aerated lung. However, CT is preferable.  
 


Abbreviated Title: Vaccine for metastatic cancer 
Version Date:  05/04/2017 
 
CTEP #: 6536 
 
83 
 
 When the primary endpoint of the study is objective response evaluation, ultrasound (US) 
should not be used to measure tumor lesions. It is, however, a possible alternative to clinical 
measurements of superficial palpable lymph nodes, subcutaneous lesions and thyroid 
nodules. US might also be useful to confirm the complete disappearance of superficial 
lesions usually assessed by clinical examination. 
 
 The utilization of endoscopy and laparoscopy for objective tumor evaluation has not yet been 
fully and widely validated. Their uses in this specific context require sophisticated equipment 
and a high level of expertise that may only be available in some centers. Therefore, the 
utilization of such techniques for objective tumor response should be restricted to validation 
purposes in specialized centers. However, such techniques can be useful in confirming 
complete pathological response when biopsies are obtained. 
 
 Tumor markers alone cannot be used to assess response.  If markers are initially above the 
upper normal limit, they must normalize for a patient to be considered in complete clinical 
response when all lesions have disappeared. 
 
 Cytology and histology can be used to differentiate between PR and CR in rare cases (e.g., 
after treatment to differentiate between residual benign lesions and residual malignant lesions 
in tumor types such as germ cell tumors). 
 
Baseline documentation of “Target” and “Non-Target” lesions 
 All measurable lesions up to a maximum of five lesions per organ and 10 lesions in total, 
representative of all involved organs should be identified as target lesions and recorded and 
measured at baseline.  
 Target lesions should be selected on the basis of their size (lesions with the longest diameter) 
and their suitability for accurate repeated measurements (either by imaging techniques or 
clinically).  
 A sum of the longest diameter (LD) for all target lesions will be calculated and reported as 
the baseline sum LD. The baseline sum LD will be used as reference by which to 
characterize the objective tumor. 
 All other lesions (or sites of disease) should be identified as non-target lesions and should 
also be recorded at baseline. Measurements of these lesions are not required, but the 
presence or absence of each should be noted throughout follow-up.  
      
 
 
 
 
 


Abbreviated Title: Vaccine for metastatic cancer 
Version Date:  05/04/2017 
 
CTEP #: 6536 
 
84 
 
Response Criteria 
 
 
Evaluation of target lesions 
* Complete Response     
(CR): 
Disappearance of all target lesions 
* Partial Response 
(PR): 
At least a 30% decrease in the sum of the LD of target lesions, taking as 
reference the baseline sum LD 
* Progressive Disease 
(PD): 
At least a 20% increase in the sum of the LD of target lesions, taking as 
reference the smallest sum LD recorded since the treatment started or 
the appearance of one or more new lesions 
* Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum LD since the 
treatment started 
 
Evaluation of non-target lesions 
* Complete Response 
(CR): 
Disappearance of all non-target lesions and normalization of tumor 
marker level 
* Incomplete 
Response/          
Stable Disease (SD):  
Persistence of one or more non-target lesion(s) or/and maintenance of 
tumor marker level above the normal limits 
* Progressive Disease 
(PD): 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions (1)  
 
(1) Although a clear progression of “non target” lesions only is exceptional, in such 
      circumstances, the opinion of the treating physician should prevail and the      
      progression status should be confirmed later on by the review panel (or study chair). 


Abbreviated Title: Vaccine for metastatic cancer 
Version Date:  05/04/2017 
 
CTEP #: 6536 
 
85 
 
Evaluation of best overall response 
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements recorded 
since the treatment started). In general, the patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria  
 
 
Target lesions 
Non-Target lesions 
New Lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Incomplete 
response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
 Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
“symptomatic deterioration”. Every effort should be made to document the objective 
progression even after discontinuation of treatment.  
 In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete 
response status. 
 
Confirmation 
 The main goal of confirmation of objective response is to avoid overestimating the response 
rate observed.  In cases where confirmation of response is not feasible, it should be made 
clear when reporting the outcome of such studies that the responses are not confirmed. 
 To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by 
repeat assessments that should be performed no less than 4 weeks after the criteria for 
response are first met. Longer intervals as determined by the study protocol may also be 
appropriate.  


Abbreviated Title: Vaccine for metastatic cancer 
Version Date:  05/04/2017 
 
CTEP #: 6536 
 
86 
 
 In the case of SD, follow-up measurements must have met the SD criteria at least once after 
study entry at a minimum interval (in general, not less than 6-8 weeks) that is defined in the 
study protocol  
 
Duration of overall response 
 The duration of overall response is measured from the time measurement criteria are met for 
CR or PR (whichever status is recorded first) until the first date that recurrence or PD is 
objectively documented, taking as reference for PD the smallest measurements recorded 
since the treatment started. 
 
Duration of stable disease 
 SD is measured from the start of the treatment until the criteria for disease progression are 
met, taking as reference the smallest measurements recorded since the treatment started.  
 The clinical relevance of the duration of SD varies for different tumor types and grades. 
Therefore, it is highly recommended that the protocol specify the minimal time interval 
required between two measurements for determination of SD. This time interval should take 
into account the expected clinical benefit that such a status may bring to the population under 
study.  
 
Response review 
 For trials where the response rate is the primary endpoint it is strongly recommended that 
all responses be reviewed by an expert(s) independent of the study at the study’s 
completion.  Simultaneous review of the patients’ files and radiological images is the best 
approach.  
     
Reporting of results 
 
 All patients included in the study must be assessed for response to treatment, even if there 
are major protocol treatment deviations or if they are ineligible.  Each patient will be 
assigned one of the following categories: 1) complete response, 2) partial response, 3) 
stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early 
death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data). 
 
 All of the patients who met the eligibility criteria should be included in the main analysis 
of the response rate.  Patients in response categories 4-9 should be considered as failing 
to respond to treatment (disease progression).  Thus, an incorrect treatment schedule or 
drug administration does not result in exclusion from the analysis of the response rate.  
Precise definitions for categories 4-9 will be protocol specific. 
 
 All conclusions should be based on all eligible patients. 


Abbreviated Title: Vaccine for metastatic cancer 
Version Date:  05/04/2017 
 
CTEP #: 6536 
 
87 
 
 
 Subanalyses may then be performed on the basis of a subset of patients, excluding those 
for whom major protocol deviations have been identified (e.g., early death due to other 
reasons, early discontinuation of treatment, major protocol violations, etc.).  However, 
these subanalyses may not serve as the basis for drawing conclusions concerning 
treatment efficacy, and the reasons for excluding patients from the analysis should be 
clearly reported.   
 
 The 95% confidence intervals should be provided. 


Abbreviated Title: Vaccine for metastatic cancer 
Version Date:  05/04/2017 
 
CTEP #: 6536 
 
88 
 
15 APPENDIX E: ELISPOT ASSAY 
 
We plan to examine the immune response in selected patients (HLA-A2 positive) from each arm.  
Lymphocytes will be separated from heparinized blood using density gradient centrifugation.  
The lymphocytes will then be placed in human AB serum with 10% DMSO and stored in liquid 
nitrogen.  When samples are available from pre and post-treatment, the ELISOT assay will be 
performed.  The ELISPOT assay, measuring -IFN production, is used for determination of CTL 
precursor frequency to CAP-1 6D peptide (ALWGQDVTSV) and an HLA-A2 restricted MUC-1 
peptide (ALWGQDVTSV) in both pre and post-vaccination peripheral blood mononuclear cells 
(PBMC).(55) Briefly, 96-well milliliter HA plates (Millipore Corporation, Bedford, MA) are 
coated with 100l/well of capture MAb against human -IFN at a concentration of 10 g/ml for 
12h at RT.  Plates are blocked for 30 min with RPMI 1640 plus 10% human Ab serum.  2 x 105 
PBMC are added to each well. CAP-1 6D or MUC-1 peptide pulsed C1R-A2 cells are added into 
each well as antigen presenting cells (APC) at an effector:APC ratio of 1:1. Unpulsed C1R-A2 
cells are used as a negative control. HLA-A2 binding Flu matrix peptide 59-66 is used as a 
positive peptide control. (56)  We also perform each sample with six replicates to control for 
variability.  In addition, each sample is run with a flu peptide control (pre and post vaccine) as 
well as samples from a “normal” control HLA-A2+ individual with previously determined levels 
of flu-specific T cell precursors.  Cells are incubated for 24h and lysed with phosphate buffered 
saline (PBS)-Tween (.05%). Biotinylated anti -IFN antibody diluted to 2 g/ml in PBS-Tween 
containing 1% bovine serum albumin (BSA) is added and incubated overnight in 5% CO2 at 
37C.  Plates are washed 3 times and developed with avidin alkaline phosphatase (GIBCO/BRL, 
Grand Island, NY) for 45 min. After washing the plates 3 times, each well is examined for 
positive dots. This assay will be performed in the Laboratory of Tumor Immunology and 
Biology, NCI, NIH.  The number of dots in each well will be counted by two separate 
investigators in a blinded manner, and the frequency of responding cells is determined. It is 
planned that all patients will undergo exploratory analysis of the ability to detect CD4 positive 
responses using a whole protein CEA assay. 
 


CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
MEDICAL RECORD 
               •  Adult Patient or     •  Parent, for Minor Patient 
INSTITUTE: 
National Cancer Institute 
STUDY NUMBER: 
04-C-0246                         PRINCIPAL INVESTIGATOR:  James Gulley, M.D., PhD. 
STUDY TITLE: 
An Open Label Pilot Study to Evaluate the Safety and Tolerability of PANVAC™-V 
(Vaccinia) and PANVAC™-F (Fowlpox) in Combination with Sargramostim in Adults 
with Metastatic Carcinoma 
 
Continuing Review Approved by the IRB on 02/06/17 
Amendment Approved by the IRB on 06/29/17 (U) 
 
 
Date Posted to Web: 07/11/17 
Standard 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
RESEARCH STUDY 
•   Adult Patient or    •   Parent, for Minor Patient 
NIH-2514-1 (4-97)
P.A.: 09-25-0099 
File in Section 4:  Protocol Consent (1) 
Introduction 
 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
First, we want you to know that: 
 
Taking part in NIH research is entirely voluntary. 
 
You may choose not to take part, or you may withdraw from the study at any time.  In 
either case, you will not lose any benefits to which you are otherwise entitled.  
However, to receive care at the NIH, you must be taking part in a study or be under 
evaluation for study participation. 
You may receive no benefit from taking part.  The research may give us knowledge that 
may help people in the future. 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of 
medical or research treatments they would want to receive (such as blood transfusions).  If you 
have such beliefs, please discuss them with your NIH doctors or research team before you agree 
to the study. 
Now we will describe this research study.  Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with anyone at NIH, or with 
family, friends or your personal physician or other health professional. 
Why is this study being done?   
The purpose of this study is to see the effects of specific vaccines aimed at your cancer.  In this 
study, the safety and side effects of using specific vaccines will be evaluated.  This research is 
being done because studies in the laboratory using human tumor cells grown in culture dishes 
and studies on animals have shown that vaccines may be effective in killing cancer cells. 


CONTINUATION SHEET for either: 
MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
04-C-0246 
CONTINUATION:  page  2 of 18 pages 
 
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (10-84) 
NIH-2514-2 (10-84) 
P.A.: 09-25-0099 
One way in which your body can fight disease is with its own immune system. Your immune 
system can recognize certain proteins, e.g. bacterial or viruses as foreign and eliminate them from 
your body.  For unknown reasons however, the immune system fails to fully recognize proteins 
made by cancer cells.  This may be one reason why cancer may grow or spread.  Two proteins in 
particular are usually produced by many cancers and may be used as a target for your immune 
system to attack the cancer.  These proteins are carcinoembryonic antigen (commonly known by 
the initials CEA) and mucin-1 (known as MUC-1).  We have developed an experimental vaccine 
in which we place the genes for CEA and MUC-1 inside a virus vaccine in order for your body to 
recognize these proteins as “foreign” invaders.  If your immune system responds to this invasion, 
your tumor may become susceptible to your body’s immune system.  In this study, we are 
attempting to stimulate your body’s immune system to recognize and destroy the tumor cells that 
produce CEA or MUC-1.  This is a vaccination, in concept, like other vaccinations you have 
probably received, except that it is attempting to increase your body’s ability to specifically reject 
cancer cells.  In this study, you will be vaccinated against the CEA and MUC-1 proteins that your 
tumor contains.  These proteins are commonly present in your type of tumor.  Your tumor will be 
tested to confirm the presence of one or both of these proteins. All of this is an attempt to help 
your immune system fight the cancer. 
 
The vaccine consists of 3 parts.  Part 1 is a modified vaccinia virus, termed PANVAC-V.  
Vaccinia is the same virus that has been used for many years to vaccinate against smallpox.  We 
will refer to PANVAC-V as the “priming vaccination.”  This priming vaccine contains three 
kinds of human genetic material (DNA) that have been put inside of the vaccinia virus.  The first 
two types of DNA produce the CEA and MUC-1 proteins and are designed to focus the body’s 
immune response on CEA and MUC-1 found in your tumor.  The next type of DNA produces 
three other proteins (B7-1, ICAM-1, LFA-3), which help increase an immune cells ability to 
destroy its target.  Part 2 is a similar virus, called the fowlpox virus.  This virus also contains the 
same DNA genes as the vaccinia virus and is termed PANVAC-F.  We will refer to this as the 
“boosting vaccination.”  These 2 vaccines are experimental agents.  Part 3 is a protein that boosts 
the immune system, called granulocyte-macrophage colony stimulating factor (known as 
sargramostim).  Sargramostim will be used to try to increase the usefulness of the vaccine by 
increasing the number of immune cells at the vaccination site. 
 
This study is therefore undertaken to gain further knowledge regarding the interaction of vaccines 
in patients that have CEA or MUC-1 producing metastatic cancer.  The main focus of this study 
will be on the safety and tolerance of the vaccines. 
Why are you being asked to take part in this study? 
You have been asked to take part in this research study because you have metastatic cancer that 
has not been controlled by standard treatments.   


CONTINUATION SHEET for either: 
MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
04-C-0246 
CONTINUATION:  page  3 of 18 pages 
 
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (10-84) 
NIH-2514-2 (10-84) 
P.A.: 09-25-0099 
How many people will take part in this study?   
Up to 51 patients will be enrolled in this study. 
Description of research study
All patients in this study have CEA or MUC-1 producing metastatic cancers or have tumors 
(breast cancer or ovarian cancer) known to express MUC-1 or CEA in more than 90% of cases. 
The study is divided into 2 phases; the core phase and the extension phase.  The core phase is the 
first part of the study.  All patients in the study will start in the core phase where they will receive 
vaccine and sargramostim injections at a set schedule.  Sargramostim is also known as GM-CSF 
for “granulocyte-macrophage stimulating factor.  Patients will be monitored closely during this 
phase for any side effects from their treatment as well as for determining the status of their 
cancer.   At the completion of the core phase, patients who have not had major side effects from 
the vaccine and who have not had worsening of their cancer will have the option to continue on 
an extension phase of the trial.  The extension phase will be your choice if you are eligible. In the 
extension phase, patients will receive vaccine and sargramostim injections monthly for a year.  
Details of the study are provided below. 
 
What will happen if you take part in this research study?   
Before you begin the study 
Before starting this study you will be checked into the outpatient clinic to see if you qualify.  The 
overall evaluation time may take several days or several weeks, depending on your situation.  To 
find the extent of your cancer, scans will be done within 4 weeks of the start of the study.  The 
scans include computerized tomographic (CT) scans or magnetic resonance imaging (MRI) of the 
chest, abdomen and pelvis.  To qualify for this study and to receive the vaccine, you must not 
have a history of allergy to eggs or to egg products.  You must not have had your spleen removed 
for any reason.  Blood tests will be done to be sure that your immune system is normal.  The 
immune system is made up of certain blood cells, lymph nodes (glands), the spleen and other 
parts of the body and protects the body against foreign substances like bacteria and possibly 
certain tumor cells.  One of the tests of your immune system will be a blood test for the human 
immunodeficiency virus (HIV), the cause of acquired immunodeficiency syndrome (AIDS).  For 
the HIV blood test, you will need to sign a separate consent form, which explains how you will 
be notified if the HIV test is positive.  Another test that will be performed is to look for possible 
infection with Hepatitis B and C.  If either of these tests are positive you will not be eligible to 
participate in this study because of the potential harm the vaccine may cause in patients who test 
positive for HIV and Hepatitis B and C.  Additional blood tests will check to see if your liver, 
kidneys, and other organs are working well enough to be safe to start the treatment.  Women of 
childbearing potential will have a pregnancy test that must be negative before entering the study.  
In addition, your blood will also be tested for the CEA marker that is produced by most 
colorectal cancers.  Altogether these initial tests will require about 100 cc (6-7 tablespoonfuls) of 


CONTINUATION SHEET for either: 
MEDICAL RECORD 
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blood.  In order to qualify for the study your blood should be positive for the CEA marker or the 
tumor should show evidence of CEA or MUC-1. 
You will have blood drawn from a vein at almost every clinic visit.  The amount of blood drawn 
may vary, but will usually be approximately 4-7 tablespoons.  The blood tests will be drawn 
approximately every 2 weeks to monitor your liver, kidneys, and other organs (as previously 
mentioned above). 
During the study 
 
Core Phase:  On day 1 of the study you will receive the priming vaccination.  This vaccination 
will be given as an injection under your skin. You will return in 2 weeks to receive a different 
vaccine, the boosting vaccine.  This vaccine will also be given as an injection under the skin.  
You will return every 2 weeks 2 more times to receive the boosting vaccinations.  Overall, the 
boosting vaccinations will be given on or about days 15, 29 and 43 from the start of the study. 
 
With each vaccination (priming vaccination and boosting vaccination), you will also receive 
injections of sargramostim.  Sargramostim is designed to increase the effectiveness of the 
vaccine by increasing the number of immune cells at the vaccination site.  It will be given as an 
injection under your skin at the same site as the vaccine injection.  The sargramostim injections 
will be given on the day of vaccination and daily for the next 3 days after each vaccination.  
Therefore, sargramostim injections will be given on days 1-4, 15-18, 29-32 and 43-46 from the 
start of the study. 
 
While you are receiving the experimental treatments you will be monitored closely for any signs 
that might signal the earliest stage of toxicity so that appropriate intervention can be done.  This 
will include blood and urine testing as well as clinic visits every 2 weeks.  You will also be seen 
4 weeks after the final boosting vaccination for physical examination and collection of laboratory 
data and any information regarding any side effects from the treatment.  You may also undergo 
repeat imaging scans to assess the status of your cancer. 
 
Extension Phase: If your cancer has not gotten worse and there have been no serious side effects 
from the treatment, you will be offered to continue on the study with an optional extension phase.  
This phase of the trial offers continued monthly boosting vaccinations along with sargramostim 
injections.  Sargramostim will be given on the day of the boosting vaccination as well as the next 
3 days after the vaccination.  The extension phase will continue for 12 months. 
Maintenance Phase:  If you have completed the extension phase with no serious side effects and 
have not experienced progression of your disease, you may continue on the study beyond the 
extension phase.  In this part of the trial, you will receive vaccines every 3 months, while also 
getting sargramostim on the same day as the boosting vaccine and for the next 3 days following 
the vaccination.  If your tumor(s) starts to grow on the maintenance phase yet your doctor feels 
you are clinically stable, you may have the option to revert back to monthly vaccines. 


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Apheresis 
In order to measure your immune response, sufficient amount of immune cells called 
lymphocytes will be needed.  You will be asked to undergo a procedure called apheresis in order 
to obtain the quantity of lymphocytes needed to measure the immune response.  This testing will 
provide no benefit to you and is part of the experimental portion of this research therapy.  You 
will undergo this procedure 2 times, on day 1 and again on day 71 of the study.  Apheresis is a 
procedure in which blood will be taken from you by a machine that will take out lymphocytes 
and then return the rest of your blood to you.  Blood will be withdrawn via a needle placed in one 
arm and channeled into a cell separator machine.  The machine will separate the lymphocytes 
from the remaining blood elements.  The lymphocytes will be taken for processing and the rest of 
the components will be returned to you through the same needle.  The procedure will take from 2 
to 4 hours during which time you will have to remain in a bed or a reclining chair.  Individuals 
with bleeding disorders can be harmed by this procedure. You will be evaluated for such a 
condition before apheresis is done.  All attempts will be made to protect you from any 
complications.  Patients do not need to be hospitalized for the procedure.  The apheresis 
procedure will be done at the Department of Transfusion Medicine (Blood Bank) in the NIH 
Clinical Center and is supervised by Blood Bank physicians. 
PANVAC-V (Priming Vaccination) 
PANVAC-V is an investigational drug.  This vaccine will be given as injection (shot) under the 
skin, subcutaneously (usually in the thigh).  Your vaccination treatment will be given to you in 
the outpatient clinic.  The injections (shots), themselves, take less than a minute to give.  You 
will need to have blood tests prior to each vaccine.  After each vaccine, you will be observed in 
the clinic for 1 hour.  If you do experience bad side effects (see below), modifications, which 
may include withholding additional treatments, may be made to your vaccine therapy depending 
upon the side effects that may be experienced.  If side effects are severe enough to withhold the 
vaccine for a period of more than 6 weeks, you will be taken off the study. 
PANVAC-F (Boosting Vaccination) 
PANVAC-F is an investigational drug.  Previous CEA vaccine studies have shown increases in 
immune responses directed against CEA when patients were given the similar vaccine strategy 
(priming vaccination followed by boosting vaccinations).  This vaccine will be given as injection 
(shot) under the skin, subcutaneously (usually of the thigh). 
 
Your vaccination treatment will be given to you in the outpatient clinic.  The injections take less 
than a minute to give.  You will need to have blood tests prior to each vaccine.  After each 
vaccine, you will be observed in the clinic for 1 hour.  If you do experience bad side effects (see 
below), modifications, which may include withholding additional treatments, may be made to 


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your vaccine therapy depending upon the side effects that may be experienced. If side effects are 
severe enough to withhold the vaccine for a period of more than 6 weeks, you will be taken off 
the study. 
Sargramostim (GM-CSF) 
 
Sargramostim is an FDA approved drug that is usually used to increase a patient’s blood counts 
or to stimulate the immune system. However its use in this protocol is investigational.  
Sargramostim will be used to try to increase the usefulness of the vaccine by increasing the 
number of immune cells at the vaccination site.  This drug will be given as injection (shot) under 
the skin. It will be given at the site as the vaccine injection.  Sargramostim is given as a separate 
injection for 4 days beginning on the same day as either vaccine.  This administration is usually 
in the thigh. After the first vaccine cycle, you will be observed in the clinic for 1 hour after the 
first two doses (days) of sargramostim in order to detect and treat any side effects (described in 
detail below) should they occur.  The site of the injection will be marked with a marker since the 
other doses of sargramostim and vaccine will be administered at the same site.  Either someone 
in your family or you may be taught to give the sargramostim shot so that you do not need to 
come to the clinic for every injection. 
 
Risk or Discomforts of Participation 
 
If you choose to take part in this study, there is a risk that: 
• You may lose time at work or home and spend more time in the hospital or doctor’s 
office than usual 
• You may be asked sensitive or private questions which you normally do not discuss 
 
The PANVAC-VF used in this study may affect how different parts of your body work such as 
your liver, kidneys, heart, and blood. The study doctor will be testing your blood and will let you 
know if changes occur that may affect your health. 
There is also a risk that you could have side effects from the study drug(s)/study approach. 
Here are important points about side effects: 
• The study doctors do not know who will or will not have side effects. 
• Some side effects may go away soon, some may last a long time, or some may never go 
away. 
• Some side effects may interfere with your ability to have children. 
• Some side effects may be serious and may even result in death. 
Here are important points about how you and the study doctor can make side effects less of a 
problem: 


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• Tell the study doctor if you notice or feel anything different so they can see if you are 
having a side effect. 
• The study doctor may be able to treat some side effects. 
• The study doctor may adjust the study drugs to try to reduce side effects. 
 
The tables below show the most common and the most serious side effects that researchers know 
about. There might be other side effects that researchers do not yet know about. If important new 
side effects are found, the study doctor will discuss these with you. 
 
Possible Side Effects of PANVAC  
POSSIBLE, SOME MAY BE SERIOUS                                       
• Anemia which may require blood transfusion 
• Diarrhea, nausea, vomiting 
•
Pain
• Chills, tiredness, fever 
• Flu-like symptoms including body aches 
• Swelling and redness at the site of the medication injection 
• Loss of appetite 
• Muscle weakness 
• Headache, fainting 
• Cough 
• Increased sweating 
• Itching, skin changes 
REPORTED BUT UNDETERMINED 
• Rash
Vaccinia (Priming Vaccination) 
Many of the potential side effects from the vaccination are related to allergic responses to 
vaccinia or to an abnormal immune system.  If you previously have had a smallpox (vaccinia) 
vaccination, you must have never had an allergic or severe reaction to such a vaccination.  You 
must not have an allergy to eggs or egg products. You must have no skin diseases or open 
wounds. You must not have any other history of altered immune function, such as HIV.  You 
must not have eczema or a history of eczema or other eczematoid skin disorders.  You must not 
be pregnant or nursing. You must also not be immunosuppressed (by disease or therapy), 
including HIV infection, atopic dermatitis, or autoimmune disease (autoimmune neutropenia, 
thrombocytopenia, or hemolytic anemia; systemic lupus erythematous, Sjogren syndrome, or 
scleroderma; myasthenia gravis; Goodpasture syndrome; Addison’s disease, Hashimoto’s 


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thyroiditis, or active Graves’ disease).  There is a good chance that if you had any of these 
diagnoses in your medical history, you would know it and you would recognize these medical 
terms.  You must not have a history of seizures, encephalitis (brain infection) or multiple 
sclerosis (“MS”). 
 
Because you may “shed” live virus through your lesion for several days after vaccination, you 
must be able to avoid close contact with certain individuals for at least two weeks after each 
vaccination.  These individuals include children under 3 years of age; women who are pregnant 
or breast-feeding; individuals with active or a history of eczema or other eczematoid skin 
disorders such as active cases of extensive psoriasis, exfoliative skin diseases, severe rashes, 
generalized itching, infections, burns, chicken pox, or skin trauma; and/or immune suppressed 
individuals such as individuals with leukemia or lymphoma, with AIDS or HIV positive blood 
test, or those receiving immunosuppressive treatment.  “Close contact” means that these people 
share your house, you have repeated bodily contact with them, and/or you take care of them and 
touch them with your hands.  You must not start treatment if you have any healing scars or skin 
rashes (for example, a burn or poison ivy), until the skin condition has healed.  If you have any 
questions about this list of precautions or any of these medical terms and diagnoses, you should 
ask about them before starting treatment.  It is very important that you tell us if you have any 
concerns about these precautions for your own safety and the safety of those you may come in 
contact with.  Furthermore, due to the unknown risk to the fetus, you are advised to avoid 
pregnancy and avoid fathering a child by practicing effective birth control during and four 
months following the last injection. 
Vaccinia vaccinations have been given to over a billion people to immunize against smallpox.  
These vaccinations rarely have resulted in serious or fatal (deadly) complications (widespread 
infection of the virus in the skin, or infections of the eyes, or the brain). 
On average, vaccinia stays active in your body for approximately 13-14 days.  Therefore, prior to 
receiving your next vaccine, you will be evaluated for evidence of pyoderma, vesicles (lesions 
seen on your skin at or around your vaccine site), or evidence of persistent vaccinia infection.  
Physical evidence of persistent viral replication (which would be evidenced by the skin lesions, 
swelling of lymph nodes, and or fever) would require an evaluation prior to next vaccine 
administration that might include a skin or lymph node biopsy and may delay the next vaccine. 
When vaccinia is given to protect against smallpox, it is usually scratched into the outer layers of 
the skin (scarification) with a two-pronged needle.  You will be receiving your vaccine under the 
skin.  A normal reaction after the “scarification” administration in a person who has been 
previously vaccinated with vaccinia includes appearance of a small bump (papule) in 3 days, a 
small blister or cluster of blisters in 5-7 days, and healing with little scarring within 2 to 3 weeks.  
Swollen lymph nodes (“swollen glands”) and/or fever are infrequent.  In individuals who have 
not previously received vaccinia, a red bump appearing on the third to fifth day is followed by a 
blister on day 5 to 6 and then by a pustule or “boil” 1-2 inches in diameter on day 9 to 11.  A 


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large area of redness may surround the blister and boil.  A crusted scab usually forms by the 
second week and falls off by the third week leaving a vaccination scar roughly one inch in 
diameter.  Fever and feeling like the flu (malaise) may occur during the blister and boil phases.  
Enlarged lymph nodes may develop and persist for months.  Because you will receive your 
vaccine by a shot under the skin rather than by scratching it onto the skin the way a smallpox 
vaccination is given, you may have less of a skin reaction than is described above. 
Side effects from the vaccinia vaccine are most common in young children, patients with 
disorders of the immune system, and individuals with skin disorders.  That is why precautions are 
taken to exclude such individuals from exposure.  It is important that you not touch the 
vaccination site and then touch other parts of your body.  This is because the vaccinia virus may 
be transferred to other sites including the eye, the mucus membrane of the nose or mouth, or 
other area by rubbing the vaccination site and subsequently rubbing the eye or an open skin area.  
Spreading the virus in this way is known as autoinoculation.  Healing usually occurs in 5-7 days.  
Blindness can result if vaccinia gets into the eye.  A dressing will be placed over the vaccination 
site to reduce this risk.  Generalized vaccinia may be characterized by several small blisters 
around the vaccination site or by widely distributed lesions developing 7-12 days after 
immunization.  This is also known as a disseminated vaccinia infection.  These lesions tend to 
follow a course of healing similar to that of the inoculation site.  An allergic reaction to the 
vaccine with a rash or hives may occur within 7-10 days of vaccination and usually goes away 
within 2-4 days.  Rarely, a serious allergic reaction requiring hospitalization may occur.  The 
most serious reactions include post-vaccinia encephalomyelitis (“brain infection”), which can 
lead to coma and death and vaccinia gangrenosum which leads to a large non-healing sore and 
may lead to death.  They occur almost exclusively in very young children who are exposed to 
vaccinia for the first time or in patients with impaired immunity; such individuals are not eligible 
for this study and those that must be avoided after vaccinia vaccination.  The death rate for 
people receiving revaccination with vaccinia for smallpox is about 0.1 per million.  Vaccinia 
Immune Globulin (VIG) has been successful as a therapy for some but not all of these 
complications.  VIG is an injectable antibody preparation made from the plasma of people 
vaccinated with the vaccinia vaccine.  VIG not a commercially available drug and is considered 
an experimental agent.  If symptoms develop suggestive of one of the previously described 
vaccinia complications, or a close contact occurs between a recently vaccinia-vaccinated patient 
and a susceptible person with one of the pre-existing medical conditions described above, the 
patient should report the findings immediately to the protocol investigator or other established 
contact, for consideration for VIG therapy, since VIG may work better if given early.  There is 
currently no other known effective treatment for these complications.  
 
During the reintroduction of smallpox vaccination, several individuals thought to be at risk for 
heart disease experience heart attacks or angina.  It is not known if the vaccinations had any 
connection to these events. A few individuals who had not been previously vaccinated developed 
inflammation in or around the heart.  This was seen in <0.5% and generally peaked 2 weeks after 
getting vaccinia. If you notice symptoms such as chest pain, shortness of breath, cough, irregular 


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heart beat, or leg swelling after the first vaccine (vaccinia) you should seek prompt medical 
advice. 
Fowlpox (Boosting Vaccination) 
The virus does not grow (replicate) in human cells, thus it does not have some of the safety 
concerns listed above with vaccinia.  However, with any experimental compound, there is the 
risk of unexpected and serious or deadly complications even if they have not been seen 
previously.  The most common side effect from the boosting vaccination is cutaneous (skin) 
reactions.  You may also experience fatigue, fever, anemia (low red blood cell count), and 
leukopenia (low white blood cell count). Other side effects possibly related to vaccine include 
itchy skin, anorexia, vomiting, constipation, dry mouth, and muscle pain. An additional side 
effect could be caused by an immune response to the CEA or MUC-1 protein that may be 
induced by either the priming or boosting vaccinations.  If the vaccine causes an immune reaction 
against normal cells, you could develop inflammation of these tissues.  This may cause no 
symptoms or it could cause pain.  If these symptoms are caused by an immune (or “allergic”) 
reaction to your own normal tissues, the effect could be prolonged and difficult to reverse.  It is 
also possible that if you develop a very active antibody (immune) reaction to CEA or MUC-1 
after the vaccination, you could develop an immune-complex disease (or serum sickness) which 
can cause fevers, rashes, joint pains, and, less commonly, kidney failure and severe allergic 
reaction inside blood vessels (vasculitis) of any part of your body.  Care will be taken to 
minimize the side effects but other unknown or unanticipated side effects that could be severe or 
fatal are possible.  While on this study you will be monitored for side effects and will be treated 
with appropriate medical care if they occur. Patients receiving fowlpox vaccines should avoid 
direct contact with pet birds for at least 72 hours after vaccination or while there are any visible 
lesions at the injection site. 
Sargramostim (GM-CSF) 
 
Some of the side effects with sargramostim depend on the dose.  The dose of sargramostim that 
will be used in this trial is relatively low.  You will be receiving 100 micrograms per day for 4 
days as a shot under the skin.  In contrast, when sargramostim is given to help the blood counts in 
patients who are receiving chemotherapy, the doses are usually 350-500 micrograms per day 
intravenously (into a vein) for 10-14 days.  Giving sargramostim by injection under the skin (as is 
planned in this trial) is better tolerated than when given by vein.  Common side effects of 
sargramostim include fever, chills, muscle aching, fatigue, nausea and facial flushing.  Some 
patients have complained of headaches.  These side effects have usually responded to medication 
such as acetaminophen (Tylenol®).  Bone pain has occurred with sargramostim, especially at 
doses higher than will be used in this study. The bone pain has generally responded to pain 
medication and quickly goes away upon stopping the sargramostim.  Temporary weight gain 
from fluid retention may occur.  Small numbers of patients have had arthritis (painful joints), 
pleuritis (inflammation of the lining of the lung) and pericarditis (inflammation around the heart), 


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fluid around the lung in the chest cavity, and fluid around the heart.  Irregular heart beats have 
occurred in a few patients.  In general, these symptoms have gotten better when the dose of 
sargramostim is lowered or stopped, and when other medicines are given (anti-inflammatory and 
pain medication).  Blood clots have occurred in some patients.  At very high doses of 
sargramostim, a small number of patients have developed temporary difficulty in breathing, 
related to fluid collection in the lungs.  This has improved with oxygen therapy and medicines.  
When the dose of sargramostim is lowered or stopped, the breathing problems have gotten better 
and have not come back.  Sudden lowering of the blood pressure has occurred, but this is an 
uncommon side effect.  In rare cases, patients have experienced chest pain (angina) following 
administration of sargramostim.  Elderly patients, particularly those with a history of heart 
disease, may be at increased risk for these side effects.  Since sargramostim is a protein, there is a 
risk that you might develop a serious allergic reaction to it.  “Anaphylactic shock,” a very severe 
allergic reaction (as seen, for example, when an individual highly allergic to bee stings is stung 
by a bee), has been observed rarely in patients treated with sargramostim.  Mild skin reactions 
near the site of drug injection have occurred.  Appropriate precautions will be used during 
therapy as mentioned above. 
Although we feel it would be unlikely for kidney damage to be seen in humans, you will have 
blood and urine tests to look for any signs of kidney damage.  If you develop any signs of kidney 
damage now or in the future, your doctor should contact the Principal Investigator of this study 
for further information. 
 
Apheresis 
 
There will be minimal discomfort due to the needle stick.  Insertion of the intravenous lines may 
cause temporary discomfort, pain, or bruising at the site of insertion and there is the remote 
possibility of fainting and/or bleeding.  Numbness or tingling may be experienced during 
apheresis but would be expected to go away after the procedure.  Blood infections from 
contamination of the apheresis machine are a remote possibility, but this has not occurred at the 
NIH.  There is a very small chance of introducing infection at the site of the needle.  The 
procedure is generally very safe for individuals without anemia, bleeding problems, or heart 
problems.  A small amount of anti-coagulant ("blood thinning" medication) is in the blood that is 
returned to you, but your body rapidly eliminates this.  This medication may cause chills, nausea, 
heartburn, nasal stuffiness, or a tingling feeling when the blood is returned to your body.  These 
symptoms are brief and may often be stopped by slowing the procedure. TUMS will be 
administered for symptoms of hypocalcemia. 
Duration of Treatment 
Your participation in this research project may continue as long as your cancer has not 
progressed (gotten worse) or there have been no serious side effects from the treatment, and as 
long as the vaccine is available.  In general, the core phase is expected to take approximately 71 
days to complete.  An additional 12 months on the study can take place if you qualify and wish to 


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continue onto the extension phase of the study.  Furthermore, you can continue on the study into 
the maintenance phase and receive vaccine/sargramostim every 3 months.  Your participation in 
this project may be ended by the investigator, the National Cancer Institute, or by the Food and 
Drug Administration (FDA) for reasons that would be explained to you.  For example, the 
investigator may stop your protocol therapy for medical or safety reasons.  New information 
developed during the course of this study that may affect your willingness to continue in this 
research project will be given to you as it becomes available. 
The FDA requires patients that receive gene therapy be monitored even after the completion of 
the study.  Once you have completed this study, you will be monitored on long-term basis (for up 
to 15 years) to see how well you’re doing.  At a minimum, you will be contacted yearly and 
asked questions about your health.  This will include questions such as whether you have 
developed any new cancers or have developed problems with your blood or immune system.  
You will also be asked about unexpected hospitalizations as well as the medications you are 
taking. 
Additional data will be obtained annually for years six through fifteen years following your last 
vaccination via telephone contacts. Information from these findings will be reported to the FDA. 
It is important for you to provide a current address and telephone number. 
Potential Benefit for Participation 
For patients with metastatic cancer, second line chemotherapy is available and may be of clinical 
benefit.  However, for patients who have progressed on second line treatment and for those who 
have no remaining standard treatment options, the proposed protocol therapy represents a 
reasonable alternative.  Theoretically, this vaccine could stimulate your own immune system to 
fight the cancer, although there is no guarantee that the therapy will stimulate the body to fight 
the cancer.  The information we obtain form both the laboratory studies and the vaccination will 
also allow us to design more effective treatments in the future.  This is an investigational study; 
therefore, no benefit is known or guaranteed.  You will be monitored closely while you are 
receiving this experimental treatment for any signs that might signal the earliest stage of toxicity 
so that appropriate intervention can be done. 
Alternative Approaches or Treatments 
What other choices do I have if I do not take part in this study? 
You may or may not benefit from participation in this study.  Participation in this study is purely 
voluntary.  Choosing not to participate (or withdrawing at any point) from this study will in no 
way penalize your medical care or your relationship with you physicians.  If you choose not to 
participate in this study or have disease progression on the maintenance phase of study (vaccine 
every 3 months) but are told you may be eligible to revert to monthly vaccines, there are several 
alternative treatments/therapy for your cancer. They include: 


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• Treatment with standard chemotherapy or hormonal therapy 
• Other Clinical Trials 
• Surgery 
• Radiation therapy 
• Supportive care 
• No further therapy at all 
Treatments with standard chemotherapy for colorectal cancer include 5-fluorouracil and 
leucovorin either alone, with oxaliplatin or with irinotecan.  These newer combination therapies 
may offer a survival benefit depending on which chemotherapy you have previously received. 
Each of these alternative therapies has a unique set of benefits and risks.  Your physician will 
discuss these options with you.  Furthermore, other centers are performing clinical trials with 
investigational agents as well as standard chemotherapy that you may consider as an alternative 
to this proposed trial. 
Research Subject’s Rights 
Your participation in this study is entirely voluntary, and you may refuse to participate, or 
withdraw from this protocol at any time and receive care from a physician of your choice.  Your 
participation in this study may be ended by the Principal Investigator or an Associate Investigator 
without your consent if they feel termination is medically indicated. 
What are the costs of taking part in this study?  
If you choose to take part in the study, the following will apply, in keeping with the NIH policy: 
• 
You will receive study treatment at no charge to you. This may include 
surgery, medicines, laboratory testing, x-rays or scans done at the Clinical 
Center, National Institutes of Health (NIH), or arranged for you by the 
research team to be done outside the Clinical Center, NIH if the study 
related treatment is not available at the NIH.  
• 
There are limited funds available to cover the cost of some tests and 
procedures performed outside the Clinical Center, NIH.  You may have 
to pay for these costs if they are not covered by your insurance company. 
• 
Medicines that are not part of the study treatment will not be provided or 
paid for by the Clinical Center, NIH. 
• 
Once you have completed taking part in the study, medical care will no 
longer be provided by the Clinical Center, NIH. 


CONTINUATION SHEET for either: 
MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
04-C-0246 
CONTINUATION:  page  14 of 18 pages 
 
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (10-84) 
NIH-2514-2 (10-84) 
P.A.: 09-25-0099 
Will your medical information be kept private?  
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Organizations that may look at and/or 
copy your medical records for research, quality assurance, and data analysis include: 
• The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), which are involved in keeping research safe for people. 
• National Cancer Institute Institutional Review Board 
• The study Sponsor, NCI CTEP or their agent(s)  
• Qualified representatives from BN Immuno Therapeutics (BNIT), the pharmaceutical 
company with a commercial interest in PANVAC-V and PANVAC-F. 
A description of this clinical trial will be available on ://www.Clinicaltrials.gov, as required by 
U.S. Law.  This Web site will not include information that can identify you.  At most the Web 
site will include a summary of the results.  You can search this Web site at any time. 
Completion of Study 
Upon completing this study, you may be given the choice of taking part in other research 
protocols that may be appropriate for you.  If you are not eligible for this study, we will use these 
tests (CEA, MUC-1 / HLA) to assess eligibility for other research studies.  Otherwise, you will 
be returned to the care of your referring physician.  It is important to stress that your participation 
in this study does not constitute a promise of long term care at the NIH Clinical Center.  If there 
is no research study that can help you, you will be returned to the care of your private doctor.  It 
is important to remember that if you do take part in this study, it is possible that you may be 
ineligible for certain future clinical trials because you would have received a form of gene or 
viral therapy.  You may decide now not to receive treatment in this protocol, or you may choose 
at any time to stop the drug and withdraw from the protocol. In either case, you would be 
returned to the care of your referring physician. 
Your signature on this form indicates that you agree to participate in this medical research 
study under the direction of the principal investigator as listed above. 
Stopping Therapy  
Your doctor may decide to stop your therapy for the following reasons: 
• if he/she believes that it is in your best interest 
• if your disease comes back during treatment 
• if you have side effects from the treatment that your doctor thinks are too severe 


CONTINUATION SHEET for either: 
MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
04-C-0246 
CONTINUATION:  page  15 of 18 pages 
 
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (10-84) 
NIH-2514-2 (10-84) 
P.A.: 09-25-0099 
• if new information shows that another treatment would be better for you 
In this case, you will be informed of the reason therapy is being stopped. 
You can stop taking part in the study at any time. However, if you decide to stop taking part in 
the study, we would like you to talk to the study doctor and your regular doctor first. 
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to NCI CTEP and BN 
Immuno Therapeutics or designated representatives. If you withdraw your consent and leave 
the trial, any samples of yours that have been obtained for the study and stored at the NCI can 
be destroyed upon request. However, any samples and data generated from the samples that 
have already been distributed to other researchers or placed in the research databases cannot be 
recalled and destroyed. 
 
Conflict of Interest 
 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a Protocol Review Guide.  You may ask your research 
team for a copy of the Protocol Review Guide or for more information.  Members of the research 
team who do not work for NIH are expected to follow these guidelines but they do not need to 
report their personal finances to the NIH. 
 
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest.  
 
The National Institutes of Health and the research team for this study are using a vaccine 
provided by BN Immuno Therapeutics (BNIT) through a joint study with your researchers and 
the company.   The company also provides financial support for this study. 
 
The National Institute of Health and members of the research team have developed a drug 
which is being used in this research.  This means that it is possible that the results of this study 
could lead to payments to NIH scientists and to the National Institute of Health.  By law, 
government scientists are required to receive such payment for their inventions.  You will not 
receive any money from development of the drug/device/product.
 
Use of Specimens and Data for Future Research
To advance science, it is helpful for researchers to share information they get from studying 
human samples.  They do this by putting it into one or more scientific databases, where it is 
stored along with information from other studies. A researcher who wants to study the 


CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
MEDICAL RECORD 
•  Adult Patient or    •  Parent, for Minor Patient 
STUDY NUMBER: 
04-C-0246 
CONTINUATION:   
16  of  18 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
RESEARCH STUDY (Continuation Sheet) 
•  Adult Patient or   •  Parent, for Minor Patient 
NIH-2514-1 (5-98) 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
information must apply to the database and be approved.  Researchers use specimens and data 
stored in scientific databases to advance science and learn about health and disease.   
We plan to keep some of your specimens and data that we collect and use them for future 
research and share them with other researchers. We will not contact you to ask about each of 
these future uses.  These specimens and data will be stripped of identifiers such as name, address 
or account number, so that they may be used for future research on any topic and shared broadly 
for research purposes. Your specimens and data will be used for research purposes only and will 
not benefit you.  It is also possible that the stored specimens and data may never be used.  Results 
of research done on your specimens and data will not be available to you or your doctor.  It might 
help people who have cancer and other diseases in the future.   
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data.  Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers. 


CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
MEDICAL RECORD 
•  Adult Patient or    •  Parent, for Minor Patient 
STUDY NUMBER: 
04-C-0246 
CONTINUATION:   
17  of  18 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
RESEARCH STUDY (Continuation Sheet) 
•  Adult Patient or   •  Parent, for Minor Patient 
NIH-2514-1 (5-98) 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
OTHER PERTINENT INFORMATION 
 
1. Confidentiality.  When results of an NIH research study are reported in medical journals or 
at scientific meetings, the people who take part are not named and identified.  In most cases, 
the NIH will not release any information about your research involvement without your written 
permission.  However, if you sign a release of information form, for example, for an insurance 
company, the NIH will give the insurance company information from your medical record.  
This information might affect (either favorably or unfavorably) the willingness of the insurance 
company to sell you insurance. 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, 
you should know that the Act allows release of some information from your medical record 
without your permission, for example, if it is required by the Food and Drug Administration 
(FDA), members of Congress, law enforcement officials, or other authorized hospital 
accreditation organizations. 
2.  Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-
term medical care for any injury resulting from your participation in research here.  In general, 
no long-term medical care or financial compensation for research-related injuries will be 
provided by the National Institutes of Health, the Clinical Center, or the Federal Government.  
However, you have the right to pursue legal remedy if you believe that your injury justifies 
such action. 
3.  Payments.  The amount of payment to research volunteers is guided by the National Institutes 
of Health policies.  In general, patients are not paid for taking part in research studies at the 
National Institutes of Health. Reimbursement of travel and subsistence will be offered consistent 
with NIH guidelines. 
 
4. Problems or Questions.  If you have any problems or questions about this study, or about 
your rights as a research participant, or about any research-related injury, contact the Principal 
Investigator, James Gulley, M.D., Ph.D.; Building 10, Room 13N208, Telephone:  301-480-
7164.  You may also call the Clinical Center Patient Representative at 301-496-2626. If you 
have any questions about the use of your specimens or data for future research studies, you may 
also contact the Office of the Clinical Director, Telephone:  240-760-6070. 
5. Consent Document.  Please keep a copy of this document in case you want to read it again. 


CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
MEDICAL RECORD 
•  Adult Patient or    •  Parent, for Minor Patient 
STUDY NUMBER: 
04-C-0246 
CONTINUATION:   
18  of  18 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
RESEARCH STUDY (Continuation Sheet) 
•  Adult Patient or   •  Parent, for Minor Patient 
NIH-2514-1 (5-98) 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
COMPLETE APPROPRIATE ITEM(S) BELOW:
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby consent to 
take part in this study. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby give 
permission for my child to take part in this 
study.   
(Attach NIH 2514-2, Minor’s Assent, if 
applicable.)
 
  
  
 
 
 
Signature of Adult Patient/ 
Legal Representative 
Date 
Signature of Parent(s)/ Guardian Date 
 
 
Print Name 
 
 
Print Name 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to 
participate in the study. 
 
  
  
 
Signature of Parent(s)/Guardian 
Date 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM FEBRUARY 6, 2017 THROUGH FEBRUARY 5, 2018. 
 
 
 
 
 
 
Signature of Investigator 
Date 
Signature of Witness 
Date 
 
Print Name 
 
 
Print Name