A Pilot Safety Study of Vaccination With Autologous, Lethally Irradiated Colorectal Cancer Cells Engineered by Adenoviral Mediated Gene Transfer to Secrete Human Granulocyte-Macrophage Stimulating Factor
Phase: PHASE1
Conditions: Colorectal Cancer
Sponsor: Massachusetts General Hospital

October 4, 2017 
Status Page 
PROTOCOL #: 12-436 
The following site(s) are open to 
enrollment:  
MGH 
Study closed to enrollment at DFCI 
ClinicalTrials.gov Identifier: NCT01952730

Log Sheet 
Page 1 of 1 
 
Protocol Number: 12-436 
 
Approval Date:  
11/27/2012 
(IRB meeting date when protocol/consent  
 approved or conditionally approved) 
 
Activation Date:  
09/12/2013 
(Date when protocol open to patient entry) 
 
Approval signatures are on file in the Office for Human Research Studies, tel. 617-632-3029. 
  
 
 
 
 
 
 
            
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CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
Protocol Version Date:   May 31, 2017 
NCI Protocol #: N/A 
Local Protocol #: 12-436 
Title:  A Pilot Safety Study of Vaccination with Autologous, Lethally Irradiated Colorectal 
Cancer cells Engineered by Adenoviral Mediated Gene Transfer to Secrete Human Granulocyte-
Macrophage Stimulating Factor in patients with Stage IV colorectal cancer 
Principal Investigator:  Cristina R. Ferrone, M.D. /Massachusetts General Hospital 
IND Sponsor: Robert Soiffer, MD/Dana-Farber Cancer Institute 
Coordinating Center: MGH 
Co-Investigators: Jeffrey Clark, MD,  David Ryan, MD , Andrew Zhu, MD PhD, Lawrence 
Blaszkowsky, MD, -, Patricia Tammaro, NP, Theresa McDonnell, NP, Kenneth Tanabe, MD, -, 
Caroline Kuhlman, MS, NP, AOCNP, Emily Olson, NP, Mellisa Woolwine, NP, Aralee Galway, 
NP, Janet Murphy, MD, Fernandez del Castillo, MD, , MD; Christine Canning, PA-C, Robert 
Soiffer, MD 
Statistician: Zheng Hui, PhD 
Study Coordinator: Eamala Sundaram 
Responsible Research Nurse:  Susan Sheehan, RN, Patricia Lynch, RN 
Responsible Data Manager: Eamala Sundaram  
Agent(s):   
Lethally irradiated, autologous colorectal cancer cells engineered by 
adenoviral mediated gene transfer to secrete GM-CSF 
ClinicalTrials.gov Identifier: NCT01952730

 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Resectable Hepatic Metastases from 
Colorectal Cancer  
for which surgery will render the patient 
NED 
Signed informed consent, 
Eligibility screening 
Blood for research 
 
To OR  
For Liver Resection 
 
Determined Unresectable by surgeon 
 
Off study  
No vaccine 
1)   Resectable 
2) Vaccine Made 
 
 
 
 
 Schema  
Chemotherapy (FOLFOX, 
FOLFIRI, FOLFOXIRI) or no 
additional chemotherapy per 
treating MD 
Vaccine Administration  
Day 1, 8, 15, 29, 43, 57 
(must be > 4 weeks s/p chemo, or 
surgery)  

GVAX for CRC Mets 
 
 
May 31, 2017 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
TABLE OF CONTENTS 
1. 
OBJECTIVES...................................................................................................................................................................... 4 
1.1 
Study Design................................................................................................................................................................ 4 
1.2 
Primary Objectives..................................................................................................................................................... 4 
1.3 
Secondary Objectives................................................................................................................................................. 4 
2. 
BACKGROUND ................................................................................................................................................................. 4 
2.1 
Study Agent(s) ............................................................................................................................................................. 4 
2.2 
Study Disease .............................................................................................................................................................. 5 
2.3 
Rationale ..................................................................................................................................................................... 6 
2.4 
Correlative Studies Background .............................................................................................................................. 7 
3. 
PARTICIPANT SELECTION ........................................................................................................................................ 7 
3.1 
Eligibility Criteria ...................................................................................................................................................... 7 
3.2 
Exclusion Criteria ................................................................................................................................................... 8 
4. 
REGISTRATION PROCEDURES................................................................................................................................ 9 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions ............................................................................... 9 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions .......................................................................... 9 
5. 
TREATMENT PLAN ......................................................................................................................................................10 
    5.1          Tumor Procurement..................................................................................................................................10 
    5.1.2        Vaccine Administration.............................................................................................................................10 
    5.2           Pre-Treatment Criteria.............................................................................................................................11 
    5.2.1        Primary Tumor Procurement...................................................................................................................11 
    5.2.2        Cell Preparation ......................................................................................................................................12    
    5.3          Subsequent Vaccines...........................................................................................................12 
5.4 
Agent Administration .............................................................................................................................................13 
5.5 
Duration of Therapy .................................................................................................................................................14 
5.6 
Duration of Follow Up ............................................................................................................................................14 
6. 
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS ........................................14 
     6.1 Anticipated Toxicites ................................................................................................................14 
6.2 
Toxicity Management...............................................................................................................................................16 
6.3 
Dose Modifications/Delays.....................................................................................................................................16 
 
7.     DRUG FORMULATION and ADMINISTRATION ...........................................................16 
    
  7.1         Description ..............................................................................................................................................16 
 7.2           Form .......................................................................................................................................................17 
7.3           Storage  &  Stability ...............................................................................................................................17 
7.4           Handling ................................................................................................................................................17 
7.5          Availability ..............................................................................................................................................17 
7.6           Preparation ............................................................................................................................................17 

GVAX for CRC Mets 
May 31, 2017 
 
 
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This document is confidential. Do not disclose or use except as authorized. 
7.7          Administration.........................................................................................................................................18 
7.8           Ordering .................................................................................................................................................18 
7.9          Accountability...........................................................................................................................................18 
7.10        Destruction  & Return ..............................................................................................................................18                     
  
8. 
CORRELATIVE/SPECIAL STUDIES .................................................................................................................19 
9. 
STUDY CALENDAR .................................................................................................................................................19 
10.       MEASUREMENT OF EFFECT...................................................................................................20 
        10.1 Antitumor Effect-Solid Tumors.....................................................................................................................21 
       10.1.1 Disease Parameters....................................................................................................................................21 
       10.1.2 Methods for Evaluation of Measurable Disease.........................................................................................22 
       10.1.3 Response Criteria .......................................................................................................................................23 
       10.1.4 Duration of Response .................................................................................................................................26 
       10.1.5 Progression-Free Survival ........................................................................................................................26             
11. 
ADVERSE EVENT REPORTING REQUIREMENTS.........................................................................................26 
11.1 
 Definitions ................................................................................................................................................................26 
11.2 
 Procedures for AE and SAE Recording and Reporting ....................................................................................28 
11.3 
 Reporting Requirements .........................................................................................................................................29 
    11.4 Reporting to the Principal Investigator...........................................................................................................29 
11.5Reporting to the INDSponsor .........................................................................................................................................30 
11.6 
 Reporting to the Institutional Review Board (IRB) ...........................................................................................30 
11.7 
Reporting to the Food and Drug Administration (FDA) ...................................................................................30 
11.8 
 Reporting to the NIH Office of Biotechnology Activities (OBA) .....................................................................31 
11.9 
 Reporting to the Institutional Biosafety Committee (IBC) ...............................................................................31 
11.10 
 Reporting to Hospital Risk Management ............................................................................................................31 
11.11 
Monitoring of Adverse Events and Period of Observation ...............................................................................32 
12. 
DATA AND SAFETY MONITORING .................................................................................................................33 
12.1 
Data Reporting..........................................................................................................................................................33 
12. 2 
 Safety Meetings ........................................................................................................................................................33 
12.3 
 Monitoring ................................................................................................................................................................34 
13. 
REGULATORY CONSIDERATIONS .................................................................................................................34 
13.1 
 Protocol Review and Amendments .......................................................................................................................34 
13.2 
 Informed Consent ....................................................................................................................................................34 
13.3 
 Ethics and Good Clinical Practice (GCP)..........................................................................................................35 
13.4 
 Study Documentation..............................................................................................................................................35 
13.5 
 Records Retention ...................................................................................................................................................36 
13.6 
 Multi-center Guidelines..........................................................................................................................................36 
13.7 
Cooperative Research and Development Agreement (CRADA)/Clinical Trials Agreement (CTA)...........36 

GVAX for CRC Mets 
May 31, 2017 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
14. 
STATISTICAL CONSIDERATIONS ...................................................................................................................36 
14.1 
Study Design/Endpoints ..........................................................................................................................................36 
 
14.2 
Sample Size/Accrual Rate .......................................................................................................................................37 
14.3 
Reporting and Exclusions .......................................................................................................................................37 
15 
PUBLICATION PLAN ...................................................................................................................................................38 
16 
REFERENCES ..................................................................................................................................................................38 
17 
APPENDICES....................................................................................................................................................................41 
 

GVAX for CRC Mets 
May 31, 2017 
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4 
1. OBJECTIVES 
 
1.1 Study Design 
 
The purpose of this study is to evaluate the feasibility, safety, and toxicity of an adenoviral 
mediated GMCSF vaccination strategy in stage IV colorectal cancer patients. The Phase I trial 
employing adenoviral mediated gene transfer in patients with metastatic melanoma demonstrated 
that a simplified method of vaccine production was feasible, safe and immunogenic.  We now 
propose a Phase I study utilizing the same constructs and vaccine strategy aimed at treating 
patients who have undergone hepatic resection for their colorectal cancer metastases.  Only 
patients with resectable liver metastases are eligible to participate since the resected liver 
metastasis will be used to construct the vaccine. 
 
Subjects may be enrolled if they will be undergoing a hepatic resection for colorectal metastases 
at the MGH.  We will analyze both toxicity and immunity in this patient cohort.  If this trial 
reveals significant biologic activity without substantive toxicity, then these results would provide 
a foundation for undertaking a subsequent Phase III study testing the therapeutic efficacy of 
vaccination in the adjuvant setting.   
 
Further, we will evaluate the biologic activity of this vaccination scheme in stage IV colorectal 
cancer patients with resected hepatic metastases.  Blood, skin punch biopsies and tumor samples 
obtained during the course of immunization will function as critical reagents for detailed analysis 
of the vaccine-induced immune responses.   
 
 
1.2 Primary Objectives 
 
1.2.1 To determine the safety of 6 vaccinations with lethally irradiated, autologous 
colorectal cancer cells engineered by adenoviral mediated gene transfer to secrete 
GM-CSF in stage IV colorectal cancer patients who are completely resected. 
 
1.3 Secondary Objectives 
1.3.1 To determine the progression free survival and two-year survival of stage IV 
colorectal cancer patients vaccinated with lethally irradiated, autologous colorectal 
cancer cells engineered by adenoviral mediated gene transfer to secrete GM-CSF. 
1.3.2 To evaluate the immune response elicited by the vaccine. 
2. BACKGROUND 
 
2.1 Study Agent(s) 
 
A vaccine composed of cells from lethally irradiated, autologous colorectal cancer 
hepatic metastasis engineered by adenoviral mediated gene transfer to secrete GM-CSF 
(GVAX). 
 

GVAX for CRC Mets 
May 31, 2017 
 
 
 
5
 
2.2 Study Disease 
 
2.2.1 Background of Chemotherapy for Colorectal Cancer  
 
 
 
In the United States, colorectal cancer is the fourth most common malignancy and the 
second most frequent cause of cancer-related death.1  In 2011, an estimated 141,210 
cases of colorectal cancer will be diagnosed and 49,380 people will die from this 
disease.  Metastases to the liver are identified in up to 25% of patients at the time of 
diagnosis1.  For the remaining patients anywhere from 50-70% of patients will develop 
hepatic metastases during follow-up1.  Surgical resection continues to be the only 
modality which can provide patients with a long term cure.  Multi drug chemotherapy 
and targeted therapies have improved patients’ survival and have converted patients 
from unresectable to resectable, but usually cannot offer a cure.  Additionally, 
chemotherapy often causes steatosis and steatohepatitis which increases the morbidity 
and mortality of hepatic resections.  In addition to the hepatic damage caused by 
chemotherapy, different agents result in a multitude of side effects which can limit their 
utility. 
 
Adjuvant therapy has evolved in the past two decades for stage IV colon cancer from 
just 5-FU to the addition of Oxaliplatin, Irinoetecan and numerous targeted agents.  
Current multi-drug regimens for metastatic colorectal cancer have improved the overall 
survival (OS) from 6 to 20 months or more3.  One of the first positive phase III multi 
drug regimens added Irinotecan to 5FU (IFL), resulting in an improved overall survival 
from 14mo to 17mo4.  Oxaliplatin was added to 5FU (FOLFOX) resulting in an 
improved progression free survival of nearly 3mo5.  FOLFOX was found to be superior 
to IFL with an OS of 19.5months vs. 15months in the N9741 trial6.  Subsequently 
FOLFOX and FOLFIRI were compared which demonstrated similar times to 
progression and overall survivals7. 
 
In the randomized trial by Nordlinger et al perioperative chemotherapy surrounding 
hepatic resection did offer a 9.2% longer progression free survival than an operation 
alone2.  This data along with the now known hepatic toxicity of Oxaliplatin and 
Irinotecan, has prompted most clinicians to offer 6 cycles of chemotherapy followed by 
hepatic resection and an additional 6 cycles of chemotherapy post operatively.  The 
majority of patients receive 5-FU with either Oxaliplatin and/or Irinotecan (FOLFOX, 
FOLFIRI, or FOLFOXIRI). Immunotherapy utilizing autologous hepatic colorectal 
cancer metastases has not been extensively explored.  This clinical trial offers a novel 
immunotherapeutic strategy as an adjunct to conventional chemotherapy. 
 
 
 
                                                 
 

GVAX for CRC Mets 
May 31, 2017 
 
 
 
6
 
2.2.2 Anti-Colorectal Cancer Immune Responses 
 
The role of immune cells in human neoplasia is unclear8.  Tumor infiltrating 
lymphocytes in melanoma9, colorectal cancers10-12 and ovarian cancer13 have been 
shown to inhibit tumor growth and are associated with improved prognoses.  Recent 
data from Pages et al14,15 demonstrated a significant difference in DFS and OS between 
patients who had primary tumors with vascular emboli, lymphatic invasion and 
perineural invasion (VELIPI) after adjustment for TNM and Duke’s stage (VELIPI + 
and -: DFS3.3 mo vs. 26.9mo and 5yr OS 12% vs. 32.4%, p<0.001).  Interestingly, 
VELIPI- tumors were associated with a strong immune infiltrate.  Specifically, VELIPI- 
tumors had increased T cell differentiation (CD45R0, CD45RA, CD27, CD28, CCR7, 
and CD127), increased evidence of T cell migration (CD62L-, CCR7, CD103, CD49d, 
CXCR3), increased evidence of T cell activation (HLA-DR, CD98, CD80, CD86, 
CD134), and increased effector memory T cells (CD45RO+CCR7-CD28-CD27-) 
(p<0.05).  Additionally, a high density of memory T cells (CD45RO+) was associated 
with tumors without lymph node involvement and metastases (p<0.001).  Lymphocytic 
and memory T cell infiltrates are prognostic biomarkers associated with longer survival 
of patients independent of other clinicopathologic factors such as MSI status, Kras, 
BRAF, PIK3CA mutations, etc16,17.  
  
2.3 
Rationale 
 
This recent data supports the idea that after antigen stimulation a small population of 
antigen-specific memory T cells remains in the tissue and may “control” the primary 
cancer from recurring.  Notwithstanding these provocative data, most patients fail to 
develop anti-colorectal cancer responses that are sufficiently potent to prevent lethal 
tumor progression.  The understanding that tumor cells generally stimulate poor antigen 
presentation has motivated the design of several new strategies to increase anti-tumor 
immunity18  19.  Among the approaches using gene transfer, Dr. Dranoff’s group at 
DFCI has demonstrated that vaccination with irradiated tumor cells engineered to 
secrete granulocyte-macrophage colony stimulating factor (GM-CSF) generates potent, 
specific, and long-lasting anti-tumor immunity in multiple murine models, including 
the B16 melanoma20.  Vaccination involves enhanced tumor antigen presentation by 
recruited dendritic cells and macrophages; the coordinated functions of CD4+ and CD8+ 
T cells, CD1d-restricted NKT cells, and antibodies mediate protective immunity20 21 18 
22 . 
 
Further, Phase I trials conducted by Drs. Dranoff and Hodi at DFCI employing      
adenoviral mediated gene transfer in patients with  metastatic 
melanoma 
demonstrated 
that a simplified method of vaccine production was  feasible, safe and immunogenic.  
We now propose a Phase I study utilizing the same  constructs and vaccine strategy 
aimed at treating patients who have undergone hepatic  resection for their colorectal 
metastases. 
 

GVAX for CRC Mets 
May 31, 2017 
 
 
 
7
First, we will evaluate the feasibility, safety, and toxicity of this vaccination strategy in 
stage IV colorectal cancer patients.  Subjects may be enrolled if they will be undergoing 
a hepatic resection for colorectal metastases at MGH.  We will analyze both toxicity 
and  immunity in this patient cohort.  If this trial reveals significant biologic activity 
without  substantive toxicity, then these results would provide a foundation for 
undertaking a  subsequent Phase III study testing the therapeutic efficacy of vaccination 
in the adjuvant  setting.   
 
2.4 
Correlative Studies Background 
 
We will evaluate the biologic activity of this vaccination scheme in stage IV colorectal 
cancer patients with resected hepatic metastases.  Prior to liver resection, blood samples 
will be collected and fresh frozen tissue from the hepatic metastases will be stored. 
Blood and skin punch biopsies obtained during the course of immunization, and pre-
immunization tumor samples will function as critical reagents for detailed analysis of 
the vaccine-induced immune responses. Biopsies will be obtained two days after the 
first and fifth vaccinations. Specifically, we will evaluate the immune cell composition 
(CD4+ and CD8+ T cells, T regulatory cells, macrophage, etc) in the resected 
specimens and in the circulating blood.  ELISPOTs will be performed to evaluate the 
specificity of the CD8+ T cell response to known colorectal cancer antigens. In patients 
with recurrent disease, biopsy of recurrence may also be evaluated when clinically 
appropriate.  
 
3. PARTICIPANT SELECTION 
 
3.1 
Eligibility Criteria 
 
Participants must meet the following criteria on screening examination prior to their 
planned liver resection to be eligible to participate in the study: 
 
3.1.1 Stage IV patients must have: 
A) Histologically documented hepatic colorectal cancer metastasis 
B) Resectable hepatic lesion(s) as judged by PI or surgeon with the intent of an R0 
resection. 
C) Primary tumor previously resected or planned resection at time of hepatic 
surgery 
 
3.1.2 ECOG Performance Status 0 or 1 
 
 
3.1.3 Age > 18 years 
 
3.1.4 Patients may receive chemotherapy (FOLFOX, FOLFIRI, FOLFOXIRI) after their 
hepatic resection, but must be >4 weeks from the last dose of chemotherapy in 
order to be eligible to receive vaccine. 

GVAX for CRC Mets 
May 31, 2017 
 
 
 
8
 
3.1.5 Patients must be fully recovered from their hepatic resection per their surgeon or 
the study PI. 
 
3.1.6 Participants must be > 4 weeks from chemotherapy, radiotherapy, immunotherapy, 
systemic glucocorticoid therapy or the operation to receive the first vaccine dose.  
 
 
 
3.1.7 Must be able to understand and willing to sign a written informed consent 
document. 
 
3.1.8 The primary colorectal cancer must be resected before hepatic resection or at the 
time of hepatic resection.   
 
3.1.9 Laboratory values must demonstrate:  
A. 
Total bilirubin <2.0mg/dl 
B. 
AST (SGOT) < 9 x ULN 
C. 
ALT (SGPT) < 9 x ULN 
D. 
Alkaline Phosphatase < 3 x ULN 
E. 
Creatinine <2.0 mg/dl 
 
 
3.1.10 Negative Serum pregnancy test in women of childbearing potential. 
 
3.2 
Exclusion Criteria 
 
Participants who exhibit any of the following conditions at screening will not be 
eligible for admission into the study. 
 
3.2.1 Uncontrolled active infection 
 
3.2.2 Infection with HIV, Hepatitis B or C 
 
3.2.3 Other current malignancies except any in situ cancer or basal or squamous cell 
carcinoma  
 
3.2.4 Active autoimmune disease including but not limited to: ALS, MS, SLE 
 
3.2.5 Active corticosteroid therapy 
 
3.2.6 Hepatic metastases involving both branches of the portal vein (right and left) or all 
three hepatic veins (left, middle and right)  
 

GVAX for CRC Mets 
May 31, 2017 
 
 
 
9
3.2.7 Peritoneal metastases identified at the time of attempted resection 
 
3.2.8 Residual/recurrent disease  
 
 
3.2.9 Pregnant and or nursing women are excluded from this study because GM-CSF 
based vaccines have not been performed in animal or human reproduction studies. 
It may have potential for teratogenic or abortifacient effects. Because there is an 
unknown but potential risk of adverse events in nursing infants secondary to 
treatment of the mother with GM-CSF, breastfeeding should be discontinued if the 
mother is treated with GM-CSF. These potential risks may also apply to other 
agents used in this study. 
 
3.2.10 Greater than 1 month since resection of liver metastasis for vaccine production. 
 
4. REGISTRATION PROCEDURES 
 
  
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions 
 
Institutions will register eligible participants with the DF/HCC Quality Assurance 
Office for Clinical Trials (QACT) central registration system. Registration must 
occur prior to the initiation of therapy. Any participant not registered to the protocol 
before treatment begins will be considered ineligible and registration will be denied.  
 
A member of the study team will confirm eligibility criteria and complete the 
protocol-specific eligibility checklist. 
  
Following registration, participants may begin protocol treatment. Issues that 
would cause treatment delays should be discussed with the Principal Investigator. If 
a participant does not receive protocol therapy following registration, the participant’s 
protocol status must be changed. Notify the QACT Registrar of participant status 
changes as soon as possible. 
 
4.2 Registration Process for DF/HCC and DF/PCC Institutions 
 
The QACT registration staff is accessible on Monday through Friday, from 8:00 AM to 
5:00 PM Eastern Standard Time. In emergency situations when a participant must begin 
treatment during off-hours or holidays, call the QACT registration line at 617-632-3761 
and follow the instructions for registering participants after hours. 
   
The registration procedures are as follows: 
 
1. 
Obtain written informed consent from the participant prior to the performance 
of any study related procedures or assessments. 
 
2. 
Complete 
the 
protocol-specific 
eligibility 
checklist 
using 
the 
eligibility 
assessment documented in the participant’s medical/research record. To be 

GVAX for CRC Mets 
May 31, 2017 
 
 
 
10
eligible for registration to the study, the participant must meet each 
inclusion and exclusion criteria listed on the eligibility checklist. 
  
Reminder: Confirm eligibility for ancillary studies at the same time as 
eligibility for the treatment study. Registration to both treatment and ancillary 
studies will not be completed if eligibility requirements are not met for all 
studies. 
  
3. 
Fax the eligibility checklist(s) and all pages of the consent form(s) to the 
QACT at 617-632-2295. 
  
4. 
The QACT Registrar will (a) validate eligibility, (b) register the participant on 
the study, and (c) randomize the participant when applicable. 
  
5. 
The QACT Registrar will send an email confirmation of the registration 
and/or randomization to the person initiating the registration immediately 
following the registration and/or randomization. 
 
5. TREATMENT PLAN  
 
5.1 Tumor procurement 
 
At the time of the liver resection at MGH the specimen will be handled according to 
CVC SOP B1.01 (Appendix) and transferred to DFCI CMCF by an authorized study 
team member, for example Bethyl Rose (617-643-6189 or 617-771-2975) or Matteo 
Ligorio, MD (617-583-3640). 
 
5.1.2Vaccine administration 
 
Treatment will be administered on an outpatient basis.  It is expected that patients will 
have fully recovered from surgery and chemotherapy prior to administration of vaccine, 
per treating surgeon. In addition, patients may receive postoperative chemotherapy at 
the discretion of the treatment team.  Treatment with GVAX may not start prior to 4 
weeks after the last dose of chemotherapy or the operation.  GVAX treatment must 
begin within 6 months of the date of operation. If enough vaccine is made patients may 
elect to have an additional 6 vaccines if they still meet the eligibility criteria. 
 
Following notification by the treating provider that vaccine may be administered, the 
CMCF staff will be notified to thaw the vaccine.  Vaccines will be retrieved from the 
CMCF by an authorized study team member as noted, according to CMCF policy and 
brought to the MGH on ice via the Partners shuttle or in a taxi between 1-4 hours prior 
to vaccine administration.  The vaccine will be stored on ice until it is ready to be 
administered. 
 
Expected toxicities and potential risks as well as dose modifications for GVAX are 
described in Section 6 (Expected Toxicities and Dosing Delays/Dose Modification). No 

GVAX for CRC Mets 
May 31, 2017 
 
 
 
11
investigational or commercial agents or therapies other than those described below may 
be administered with the intent to treat the participant’s malignancy. 
 
 
 
Vaccination Plan 
Agent 
Pre-medications; 
Precautions 
Range 
 
Route 
Schedule 
Cycle Length 
GVAX 
No 
premedications 
1x105 to 1x107 
cells/vaccine 
 
Subcutaneous 
and 
Intradermal 
Days 
1,8,15, 
29,43, 
57 
57 days 
 
 
5.1.2.1Vaccinations will be administered on days 1, 8, 15, and every two weeks thereafter 
until 6 vaccines have been administered or the patient is removed from study.  As indicated 
in 5.2.2.4, individual vaccine cell dose will vary depending on the final cell yield from 
vaccine production.  The total cell yield will be divided in 6 equal aliquots, and the minimal 
dose will be 1x105 cells/vaccine and maximal dose will be 1x107 cells/vaccine. This 
variation in cell dosage is designed to maximize each patient’s opportunity of receiving 
vaccinations and is not based on any expectation of significant differences in toxicity as a 
function of cell number.  
5.1.2.2 All patients receiving at least one vaccination will be evaluable for toxicity.  
Patients will be considered evaluable for biologic activity if at least six vaccinations have 
been administered at a given dose level.   There is no requirement for a particular number 
of patients at each cell dose level. 
5.1.2.3 Vaccinations may be administered within 24 hours of the scheduled vaccine 
administration date (e.g. day 8, 15, 29) beginning with the day 8 vaccine. 
5.1.2.4 Patients must be greater than 28 days from any chemotherapy, radiotherapy, 
immunotherapy, systemic glucocorticoid therapy, or resection of hepatic colorectal 
metastasis. 
 
5.2       Pre-treatment Criteria 
 
5.2.1Primary Tumor Procurement 
 
5.2.1.1Patients will undergo a surgical procedure (hepatic resection) to obtain 
tissue for vaccine preparation.  
 
5.2.1.2The responsible surgeon will send a portion of the tumor for standard of 
care pathology review. Then, the surgeon will place the research tumor specimen 
in sterile media in a sterile container.  After gross evaluation by the pathologist of 

GVAX for CRC Mets 
May 31, 2017 
 
 
 
12
the entire specimen in the operating room, the tissue will be transferred to the 
authorized study team member for vaccine processing at the DFCI CMCF.  
 
 
5.2.1.3 Patients will receive routine post-operative care.  
  
5.2.1.4At the discretion of the treating physician patients may receive post 
operative chemotherapy prior to vaccine administration.  Participants will 
undergo a separate standard of care chemotherapy consent session with their 
treating physician as the chemotherapy is not a part of the investigational agent in 
this study. 
 
5.2.1.5If recurrent disease is identified on the restaging scans prior to vaccine, 
vaccine will not be administered.  
 
5.2.2 Cell Preparation  
 
5.2.2.1Tumors will be transferred to the CMCF at the Dana-Farber Cancer 
Institute by approved personnel and processed to single cell suspension by 
mechanical and enzymatic digestion as required; short-term tumor cultures 
may be established if necessary to obtain sufficient cells. 
 
5.2.2.2Tumor cells will be transduced with a replication defective adenoviral 
vector encoding human GM-CSF.   
 
 
5.2.2.3After transduction, the tumor cells will be washed extensively and 
irradiated with 10,000 cGy. 
 
5.2.2.4A small aliquot of the transduced cells will be placed into culture and 
GM-CSF secretion will be determined by ELISA.  The target level for GM-
CSF production will be at least 40 ng/106 cells/24 hours, although achieving 
this secretion will not be required for vaccine administration.  Routine 
sterility cultures and testing for endotoxin and mycoplasma contamination 
will be performed 
 
5.2.2.5Individual vaccine cell dose will vary depending on the final cell yield 
from vaccine production.  The total cell yield will be divided in 6 equal 
aliquots, and the minimal dose will be 1x105 cells/vaccine and maximal dose 
will be 1x107 cells /vaccine.  This variation in cell dosage is designed to 
maximize each patient’s opportunity of receiving vaccinations and is not 
based on any expectation of significant differences in toxicity as a function of 
cell number.  
 
5.3   
 
Subsequent Vaccines 

GVAX for CRC Mets 
May 31, 2017 
 
 
 
13
5.3.1 If in the judgment of the treating physician, the clinical status of the patient   
following completion of the first six vaccinations permits, the option for expansion 
of tumor cells previously cryopreserved, vaccine production, and vaccination will 
be offered to the patient.  The patient will need to satisfy the same eligibility criteria 
as for entry on the first round of treatment, except for the requirement that greater 
than four weeks have elapsed since prior GVAX immunotherapy.  The decision to 
enter this second phase can be made at any time following completion of the six 
initial vaccinations required for toxicity evaluation. 
It is recognized that initiation of a second round of treatment may obscure the 
ability to evaluate potential delayed toxicities associated with the first round of 
vaccination.  The likelihood of such toxicities given the experience with earlier 
melanoma trials seems remote, however, and additional data regarding the safety of 
repeat courses of vaccine procurement and vaccination is a higher priority.  
Additional rounds of vaccination may be considered as long as the patient continues 
to meet eligibility criteria. 
 
5.3.2 For patients proceeding to one additional round of vaccine, the procedures outlined 
in sections 5.1-5.4 will be followed.  It is anticipated that the cell dosage for 
additional rounds of vaccination may be different from that used in the first round. 
5.1.3 Patients may opt to discontinue treatment after the first round of vaccines to 
undergo another type of treatment or participate in another clinical trialPatients also 
have the option of a second round of vaccination if enough vaccine is available. The 
subject will need to satisfy the same eligibility criteria for entry as done with the 
first round of vaccines. 
 
5.4            Agent Administration  
 
5.4.1 Vaccinations will be administered on days 1, 8, 15, and every two weeks thereafter 
until 6 vaccines have been administered or the patient is removed from study.  As 
indicated in 5.2.9, individual vaccine cell dose will vary depending on the final cell 
yield from vaccine production.  The total cell yield will be divided in 6 equal 
aliquots, and the minimal dose will be 1x105 cells/vaccine and maximal dose will be 
1x107 cells/vaccine. This variation in cell dosage is designed to maximize each 
patient’s opportunity of receiving vaccinations and is not based on any expectation 
of significant differences in toxicity as a function of cell number.  
 
5.4.2 Vaccinations may be administered within 24 hours of the scheduled vaccine 
administration date (e.g. day 8, 15, 29) beginning with the day 8 vaccine. 
 
5.4.3 Vaccination Procedure 

GVAX for CRC Mets 
May 31, 2017 
 
 
 
14
5.4.3.1 Cells will be thawed in a dedicated laminar flow biosafety cabinet in the 
CMCF and washed.  Cells will be resuspended in a volume of 1 ml. for 
administration.  2 injections (1/2 dose subcutaneously and 1/2 dose intradermally at 
the same site with repositioning of the needle) will be given and will constitute a 
single vaccination.  The volume of each injection will be 0.5 ml.  
5.4.3.2 Injections will be administered according to standard procedures in the 
patient’s arms, thighs, or trunk on a rotation basis.  
 
5.4.3.3 A treating physician, NP, PA, or RN designated by the PI will administer 
the injections in the outpatient facilities of the Massachusetts General Hospital. 
 
 
    
5.5 
   Duration of Therapy 
 
Duration of therapy will depend on individual response, evidence of disease 
progression and tolerance. In the absence of treatment delays due to adverse events, 
treatment may continue for a total of 6 vaccines or until one of the following 
criteria applies: 
• Disease progression, intercurrent illness that prevents further administration 
of treatment, 
• Unacceptable adverse event(s), 
• Participant demonstrates an inability or unwillingness to comply with  the 
protocol requirements. 
• Participant decides to withdraw from the study, or 
• General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the opinion of the treating investigator. 
If enough vaccine is available and patients meet eligibility criteria he/she may be a 
candidate for an additional 6 vaccines. 
 
5.6 
  Duration of Follow Up  
 
Participants will be followed for 3 months after the last vaccine then every 6 
months for 3 years, then yearly for up to 5 years.  Since they are receiving a gene 
modified product, each patient will remain in long term follow up and followed 
annually for survival for a period of fifteen years for surveillance and toxicity 
evaluation.  
  
6. EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS  
 
6.1      Anticipated Toxicities 
  

GVAX for CRC Mets 
May 31, 2017 
 
 
 
15
6.1.1 GM-CSF is widely used for accelerating hematopoietic recovery and its spectrum 
of toxicity well established.  It is likely that the highest dose level used in this 
study will generate far lower amounts of GM-CSF than the usual starting dose for 
systemic application (350 μg/day).  While we cannot predict the exact toxicities 
attributable to local secretion of GM-CSF delivered by adenoviral mediated gene 
transfer, toxicities observed from the previous trial were restricted to errythema, 
pruritus, and swelling.  Local toxicities of GM-CSF protein injection have 
included pustular eruption, necrotizing vasculitis, errythema, pruritus, recall 
errythema at previous injection sites, general papular rash, and phlebitis.  
Systemic toxicities have included fever, bone pain, malaise and diarrhea, transient 
liver function test (LFT) abnormalities, leukopenia, leukocytosis, arthralgia, 
dyspnea, fluid retention, serous effusions, and recrudescence of various auto-
immune diseases.   
 
 
 
 
6.1.2  A theoretical potential exists for the induction of auto-immune disease by the  
 
 
 
 
 
vaccination, although no evidence of vitiligo or visual disturbances was noted in 
 
 
 
 
 
the previous melanoma studies.  Mechanisms which allow the immune system to 
 
 
 
 
 
recognize tumor antigens in principle could also lead to the breakdown of   
 
 
 
 
 
 
tolerance to normal self antigens.  Because of this concern, patients entered on  
 
 
 
 
 
study will be closely monitored for any clinical or laboratory evidence of auto- 
 
 
 
 
 
immune phenomena.  
 
6.1.3 A final source of toxicity in this study relates to the use of adenoviral vectors.  
Wild type adenovirus serotype 5 (from which the vector used in this study is 
derived) is associated with an upper respiratory infection and conjunctivitis.  
There is controversy regarding a role in infantile intussusceptions.  Other 
adenovirus serotypes are associated with cystitis,  gastroenteritis, and pneumonia 
in military recruits during basic training. The adenoviral vector used in this study 
will be certified to contain less than one replication competent serotype 5 viral 
particle per vaccine inoculum.  In the event that recombination between a latent 
wild type  adenovirus and the introduced adenoviral vector occurs in the tumor 
cell, this will not lead to production of a replication competent GM-CSF 
expressing virus, as the GM-CSF cDNA is inserted in the E1 deleted region of the 
vector.  Transduced cells will be injected into the skin; thus in the absence of an 
open wound, there is no significant risk of transmitting the virus to close contacts.  
If skin breakdown does occur, the skin should be covered with an adherent 
bandage until healing has occurred. 
 
6.1.4 Lethal irradiation represents an important safeguard against some toxicities 
associated with vaccinating cells.  Irradiation will prevent the outgrowth of tumor 
cells potentially rendered more virulent by virtue of in vitro manipulation or 
insertional mutagenesis, as well as the autonomous  proliferation 
of any non-
neoplastic elements in the vaccinating inoculum  induced 
by 
the 
autocrine 
secretion of GM-CSF. Toxicities observed from the previous adenovirus-based 
melanoma trial were restricted to erythema, pruritus, and swelling (all easily 
treated with either ice packs or topical lotions such as Aloe cream).  It is possible, 

GVAX for CRC Mets 
May 31, 2017 
 
 
 
16
although 
unlikely, 
that 
additional 
toxicities 
including 
blister 
formation 
or 
ulceration may occur. 
 
6.2      Toxicity Management 
 
      6.2.1 Treatment of toxicities will be supportive. If possible, symptoms should be 
managed symptomatically. In the case of toxicity, appropriate medical treatment 
should be used.  This may include for example, cold compresses and or 
moisturizing lotions applied to localized vaccine site reactions. 
 
All adverse events experienced by participants will be collected from the time of 
the first vaccine administration, through the study and until the final study visit. 
Participants continuing to experience toxicity at the off study visit will be 
followed until the toxicity has resolved, stabilized, determined to be irreversible 
or the participant is lost to follow-up. 
 
             6.2.2    General Concomitant Medication and Supportive Care Guidelines 
Patients are prohibited from taking steroids, NSAIDS, antihistamines (by mouth 
or IV) but may use local measures such as ice packs or topical moisturizers 
between the time of the first vaccination and two weeks after the sixth 
vaccination.  Use of topical anesthetics such as EMLA © and topical 
antihistamines are prohibited at injection sites. 
 
 
6.3       Dose Modifications/Delays 
  
6.3.1    There will be no dose adjustments for Grade 1 and 2 toxicities seen on this    
            study.  
 
 
6.3.2   If a patient develops grade 3 toxicity attributable to the vaccine, additional         
              treatment will be withheld until all toxicity has resolved, then he or she may be 
retreated at monthly intervals. If the toxicity recurs with resumption of vaccine 
then the patient will be removed from study.  If a patient develops a grade 4 
toxicity attributable to the vaccine, he or she will be removed from study.  If 
three grade 4 or greater toxicities attributable to the vaccine are observed at any 
time, the trial will be suspended to investigate the causes of these unexpected 
toxicities. 
 
7.      DRUG FORMULATION AND ADMINISTRATION  
 
7.1  Description 
 
    GVAX is a vaccine composed of cells from lethally irradiated, autologous   
 
 
               
    colorectal or hepatic metastasis engineered by adenoviral mediated gene transfer to      
  secrete GM-CSF 
 

GVAX for CRC Mets 
May 31, 2017 
 
 
 
17
 
7.2 Form 
 
  
 
Cells will be thawed in a dedicated laminar flow biosafety cabinet in the CMCF  
  
 
and washed. Cells will be resuspended in a volume of 1 ml. of sterile saline for  
  
 
administration.  
 
7.3 Storage and Stability 
 
Tumor cells for vaccination and immunologic evaluation will be cryopreserved 
and stored in liquid nitrogen. A minimum of six individual vaccine aliquots will 
be prepared for each patient. Cell dose per aliquot will be fixed for an individual 
patient and will range from a minimum of 1x105 cells per aliquot to 1x107 cells 
per aliquot. The  dosage will be determined by dividing the total cell yield 
following transduction into six aliquots (after QC removal). Thus, a minimum of 
6.5x105 cells total will be required to prepare six aliquots of 1x105 cells. For total 
cell yields greater than  6x107cells total, individual aliquots will remain at 1x107 
cells per dose. 
7.4 Handling 
 
Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and 
safe disposal of the chemotherapeutic agent in a self-contained and protective 
environment. 
 
7.5 Availability 
 
GVAX is an investigational agent and will be supplied free-of-charge from 
CMCF. 
 
7.6 Preparation 
 
  
 
Tissue obtained from a patient by hepatic resection will transferred to the Cell  
  
 
Manipulation Core Facility (CMCF) at the Dana Farber Cancer Institute in a   
  
 
sterile container containing sterile media. The tissue will be processed to single  
  
 
cell suspension by mechanical and enzymatic digestion as required; short-term  
  
 
tumor cultures may be established if necessary. Tumor cells will be transduced  
  
 
with a replication defective adenoviral vector encoding human GM-CSF.   
  
 
 
After transduction, the tumor cells will be washed extensively and irradiated with 
10,000 cGy.  
 
  
 
A small aliquot of the transduced cells will be placed into culture and GM-CSF  
  
 
secretion will be determined by ELISA.  The target level for GM-CSF production 
  
 
will be at least 40 ng/106 cells/24 hours, although achieving this secretion will not 

GVAX for CRC Mets 
May 31, 2017 
 
 
 
18
  
 
be required for vaccine administration.  Routine sterility cultures and testing for  
  
 
endotoxin and mycoplasma contamination will be performed.  
 
Individual vaccine cell dose will vary depending on the final cell yield from 
vaccine production.  The total cell yield will be divided in 6 aliquots, and the 
minimal dose will be 1x105 cells/vaccine and maximal dose will be 1x107 
cells/vaccine. This variation in cell dosage is designed to maximize each patient’s 
opportunity of receiving  vaccinations and is not based on any expectation of 
significant differences in toxicity as a function of cell number.  
 
7.7 Administration 
 
  
Vaccinations will be administered on days 1, 8, 15, and every two weeks   
 
 
  
thereafter until 6 vaccines have been administered or the patient is removed from 
  
study.   
 
Individual vaccine cell dose will vary depending on the final cell yield from vaccine 
production.  The total cell yield will be divided in 6 aliquots, and the minimal dose 
will be 1x105 cells/vaccine and maximal dose will be 1x107 cells/vaccine. Cells 
will be thawed in a dedicated laminar flow biosafety cabinet at CMCF and washed.  
Cells will be resuspended in a volume of 1 ml. for administration.  2 injections (1/2 
dose subcutaneously and 1/2 dose intradermally) will be given and will constitute a 
single vaccination.  The volume of each injection will be 0.5 ml.    
 
A study team physician, PA, NP or RN will administer the injections. Injections 
will be administered in the outpatient setting according to standard procedure in 
the patient’s arms and thighs on a rotating basis.   
 
7.8 Ordering 
 
The vaccine will be manufactured at the Cell Manipulation Core Facility, 
(CMCF). Once an Order for Processing has been received by CMCF, cells will be 
thawed for administration.  
 
7.9 Accountability 
 
Study reagent accountability is maintained by the Cell Manipulation Core 
Facility (CMCF).  
 
7.10 Destruction and Return 
 
CMCF will receive reagents.  If they are not used the reagents will be held for 
future use until they are out of date at which point they will be destroyed 
according to institutional policies. Destruction will be documented in the Drug 
Accountability Record Form. 
 

GVAX for CRC Mets 
May 31, 2017 
 
 
 
19
8. CORRELATIVE/SPECIAL STUDIES  
 
 
 
Immunologic studies will be performed on peripheral blood at designated time points as 
well as the resected hepatic metastasis and skin punch biopsies.  Punch skin biopsies will 
be obtained 2 days after the first and fifth vaccinations.   A piece of the resected hepatic 
metastasis will be fresh frozen and stored at -80 degrees at MGH.  The remainder of the 
specimen will be stored in paraffin at MGH.  If the patient had a colorectal resection at 
MGH in the past we may analyze the immune infiltrate of the primary cancer which is 
banked in paraffin (see 8.1.3); however, resection of the primary tumor at a hospital other 
than MGH is not an exclusion criterion. 
 
If the patient develops recurrent disease, and undergoes clinically indicated resection, 
biopsies may also be obtained for immune analysis as well. 
 
8.1.1 Vaccine site reactions:  Punch skin biopsies will be obtained 2 days after the first 
and fifth vaccinations. Histological analysis for macrophages, dendritic cells, 
eosinophils, and lymphocytes will be performed as a research test. Specimen’s will 
be transported in 10% formalin to the CMCF where they will be logged in for 
research. 
 
8.1.2 
Tumor infiltrates:  The primary and hepatic lesions will be scored, as a research test, 
for cellular infiltrates (CD8+ T cells, CD4+ T cells, Treg, macrophages, etc), 
inflammation, edema, fibrosis, and percentage tumor cell death.   Ten high power 
fields will be evaluated and the numbers summed.  The character and type of 
infiltrating cells will be evaluated by routine histological and appropriate 
immunohistochemical analysis. Attempts will be made to obtain discarded tissue 
from biopsies performed to document disease recurrence as part of the patients’ 
standard of care.  The discarded tissue from the recurrent disease biopsies will also 
be assessed for immune infiltrates as part of the correlative science in this protocol.   
 
8.1.3    Blood analyses:  Serum and circulating mononuclear cells will be frozen prior to 
beginning vaccination and at regular intervals thereafter as described in Section 9.0.  
These samples will be used in research studies aimed at identifying the target 
antigens of vaccination.  We may also use these samples, in research tests to 
measure immune responses against adenoviral proteins expressed in the vector used 
for vaccine preparation. 
 
 
9.0 
STUDY CALENDAR 
 
 

GVAX for CRC Mets 
May 31, 2017 
 
 
 
20
Data Collection 
 
 
Test 
 
Day -21* 
Day 1 
Days 8, 15    Days 29, 43, 57  Restage1  
Additional Vaccines 
 
 
History/PE 
    X 
    X 
    X  
    X               X 
Weight/VS 
    X 
    X9 
    X  
    X               X 
            X 
CBC with Diff 
    X 
    X 
    X  
    X               X 
            X 
PT, PTT     
    X 
 
 
 
 
  
     X7 
Lytes/BUN/Cr 
    X 
    X 
 
 
    X               X 
            X 
LFT 
 
    X 
    X 
 
 
    X               X 
            X 
Glucose     
    X 
 
 
 
 
  
     X 
β-HCG 9      
    X 
 
 
 
 
  
     X 
HIV/ID profile6 
    X 
 
 
 
       
  
     X8 
Staging Scans2 
    X 
 
 
 
                       X 
           X 
Immune3      
    X 
    X 
                        X                X 
           X3 
Biopsy  
     
    X4                         
      X5 
  
      X4 
CEA 
 
 
   X 
 
                     X 
           X 
       *  or later 
  
1. Participants will be monitored before the first vaccine and every 3 months with a CEA 
level (1 tsp) for the first 3 years and then every 6-12 months for a total of 5 years.  
Restaging CT scans (chest, abdominal, pelvic CT) will be performed at 3 months (or 
sooner if clinically indicated) following completion of vaccine and then every 6 months for 
the first three years and then yearly to year 5.  After 5 years imaging will be at the 
discretion of the treating physician.   
2. Staging scans should be a chest, abdominal, and pelvic CT and must be obtained within 
three weeks (21 days) of tumor harvest.  
3. Approximately 50 cc of blood on a monthly basis during vaccination and every 3 months 
after completing all vaccinations for two years.   
4.  Biopsies of vaccination reaction (vaccine #1) will be taken 2 days after administration.  
5. Biopsies of vaccination reaction (vaccine #5) will be taken 2 days after administration. 
6. Testing for Infectious Disease Markers (IDM testing) should be performed within seven 
days of liver resection. IDM testing requires: Syphillis, CMV, HepBSAg, Hep B Core, HCV, 
HIV ½, HTLV ½, WNV. 
      7.  Repeat if Tumor Harvest is required for second round of vaccine. 
      8.  Serum pregnancy tests only required of women of childbearing potential 
      9.  Vital signs are to be recorded 20-30 minutes after vaccine administration. 
 
10. MEASUREMENT of EFFECT 
Although response is not the primary endpoint of this trial, participants with measurable 
and/or non-measurable disease will be assessed by RECIST criteria. Restaging CT scans 
(chest, abdominal, pelvic CT) will be performed 3 months (or sooner if clinically 
indicated) following completion of vaccine and then every 6 months for the first three 
years and then yearly to year 5.  After 5 years imaging will be at the discretion of the 
treating physician.  In addition to a baseline scan, confirmatory scans should also be 
obtained twelve weeks following initial documentation of an objective response 
 

GVAX for CRC Mets 
May 31, 2017 
 
 
 
21
10.1 Antitumor Effect– Solid Tumors 
Restaging CT scans (chest, abdominal, pelvic CT) will be performed 3 months (or 
sooner if clinically indicated) following completion of vaccine and then every 6 
months for the first three years and then yearly to year 5.  After 5 years imaging will 
be at the discretion of the treating physician. In addition to a baseline scan, 
confirmatory scans should also be obtained every 12 weeks following initial 
documentation of objective response. 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) 
guideline.  Changes in the diameter (unidimensional measurement) of the tumor 
lesions are used in the RECIST criteria  
Definitions 
Evaluable for toxicity. All participants who receive at least one dose of study 
treatment will be evaluable for toxicity from the time of their first treatment. 
Evaluable for objective response. Only those participants who have 
measurable disease present at baseline, have received at least one cycle of 
therapy, and have had their disease re-evaluated will be considered evaluable 
for response. These participants will have their response classified according 
to the definitions stated below. (Note: Participants who exhibit objective 
disease progression or die prior to the end of the first 6 vaccines will also be 
considered evaluable.} 
10.1.1        Disease Parameters 
Measurable disease.  
Measurable disease is the presence of at least one (1) lesion that can be 
accurately measured in at least one dimension with longest diameter >20 
millimeters (mm) using conventional techniques (CT, MRI, x-ray) or >10 mm 
with spiral CT scan. Measurable lesions must be at least 2 times the slice 
thickness in mm. All tumor measurements must be recorded in millimeters (or 
decimal fractions of centimeters). 
Malignant lymph nodes. To be considered pathologically enlarged and         
measurable, a lymph node must be > 15 mm in short axis when assessed by 
CT scan (CT scan slice thickness recommended to be no greater than 5 
mm). At baseline and in follow-up, only the short axis will be measured and 
followed 
 
Non-measurable disease.  
 

GVAX for CRC Mets 
May 31, 2017 
 
 
 
22
All other lesions (or sites of disease), including small lesions (longest diameter 
<20 mm with conventional techniques or <10 mm using spiral CT scan), are 
considered non-measurable disease. Bone lesions, leptomeningeal disease, 
ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory 
breast disease, abdominal masses identified by physical exam that are not 
measurable by reproducible imaging techniques, and cystic lesions are all 
considered non-measurable. 
10.1.2        Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation, using a ruler, 
calipers, or digital measurement tool. 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. 
Imaging-based evaluation is preferred to evaluation by clinical examination 
when both methods have been used to assess the anti-tumor effect of a 
treatment. 
Clinical lesions. 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. 
Chest x-ray. Lesions on chest x-ray are acceptable as measurable lesions when 
they are clearly defined and surrounded by aerated lung; however, CT is 
preferable. 
Conventional CT and MRI. These techniques 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. 
Ultrasound (US). When the primary endpoint of the study is objective 
response evaluation, 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. 
FDG PET and PET/CT. The acquisition of FDG PET and FDG PET/CT scans 
should follow the NCI Guidelines for using FDG PET as an indicator of 

GVAX for CRC Mets 
May 31, 2017 
 
 
 
23
therapeutic response {Shankar, 2006 #3452}, Patients should avoid strenuous 
exercise and be on a low carbohydrate diet for 24 hours prior to the scan. Patients 
should fast for 4 hours or longer prior to the FDG injection and should have a 
serum glucose of less than 200 mg/dL at the time of FDG injection. A 10-20 mCi 
dose of FDG should be injected for typical adult patients. For longitudinal studies 
with multiple scans, particular attention should be paid to ensure consistent 
patient preparation and acquisition parameters between the follow-up scan and the 
baseline scan. When designing a study where PET scans are going to be utilized 
as one of the modalities to evaluate efficacy, it is important to consult with 
physicians in nuclear medicine in designing the appropriate criteria to be utilized. 
Tumor markers. Tumor markers alone cannot be used to assess response. If 
markers are initially above the upper normal limit, they must normalize for 
a subject to be considered in complete clinical response. Specific additional 
criteria for standardized usage of prostate-specific antigen (PSA) and CA-125 
response in support of clinical trials are being developed. 
Cytology, Histology. These techniques can be used to differentiate between 
partial responses (PR) and complete responses (CR) in rare cases (e.g., residual 
lesions in tumor types, such as germ cell tumors, where known residual 
benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that 
appears or worsens during treatment when the measurable tumor has met 
criteria for response or stable disease is mandatory to differentiate between 
response or stable disease (an effusion may be a side effect of the treatment) 
and progressive disease. 
           10.1.3   Response Criteria 
 
10.1.3.1    Evaluation of Target Lesions 
 
Complete Response (CR):  
Disappearance of all target lesions. Any pathological lymph node must 
have reduction in short axis to < 10 mm. 
Partial Response (PR):  
At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  
 
At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study with at least a 5 

GVAX for CRC Mets 
May 31, 2017 
 
 
 
24
mm absolute increase in the sum of all lesions. The 
appearance of one or more new lesions* denotes disease 
progression.  
 
 
Stable Disease (SD):  
 
Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum diameters 
while on study. 
Unknown (UN): Assessment of target lesions cannot be made due to 
insufficient or unevaluable data. In this case, a concise explanation must 
be given. 
Note: If tumor response data is missing for target lesions, the overall 
assessment must be UN unless there is new disease that would result in 
an overall assessment of PD. However, if there is missing or 
unevaluable data for non-target lesions, but data is available for all 
target lesions, the overall response for that time point will be assigned 
based on the sum LD of all target lesions. Additionally, the assessment 
of CR cannot be made if there is missing or unevaluable data for non-
target lesions. In this case, the overall assessment would be PR. 
         
  *Definition of New Lesion: The finding of a new lesion should be 
unequivocal (i.e. not due to difference in scanning technique, imaging 
modality, or findings thought to represent something other than tumor 
(ex: new bone lesions may be healing or flare of pre-existing lesions). 
However, a lesion identified on a follow-up scan in an anatomical 
location that was not scanned at baseline is considered new and will 
indicate PD. If a new lesion is equivocal (because of small size, etc.), 
follow-up evaluation will clarify if it truly represents new disease and if 
PD is confirmed, progression should be declared using the date of the 
initial scan on which the lesion was discovered.  
10.1.3.2       
 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 progressive disease the smallest measurements recorded since the 
treatment started). The participant's best response assignment will 
depend on the achievement of both measurement and confirmation 
criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 

GVAX for CRC Mets 
May 31, 2017 
 
 
 
25
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response for 
when Confirmation is 
Required: 
CR 
CR 
No 
CR 
>4 wks confirmation 
CR 
Non-CR/Non-PD 
No 
PR 
>4 wks confirmation 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/Not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/Not 
evaluated 
No 
SD 
Documented at least once 
>4 wks from baseline 
PD 
Any 
Yes or No 
PD 
No prior SD, PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Note:   Participants with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as "symptomatic deterioration". Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New 
Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
NonCR/non-PD 
Not all evaluated 
No 
Not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
Non-CR/non-PD is preferred over stable disease for non-target disease since SD is 
increasingly used an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised.  
 
10.1.4   Duration of Response 

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26
Duration of overall response: The duration of overall response is measured from 
the time of operation until the first date that recurrence is objectively documented or 
death.  
Duration of overall complete response: The duration of overall CR is measured 
from the time measurement criteria are first met for CR until the first date that 
recurrent disease is objectively documented. 
Duration of stable disease: Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started. 
10.1.5     Progression-Free Survival  
Progression-Free Survival (PFS) is defined as the length of time during and after the 
treatment of a cancer, that a patient lives with the disease but it does not get worse, 
as per the NCI. For this clinical trial it is measured as the duration of time between 
the hepatic resection to the time of objective disease progression (recurrence) or 
death. 
10.1.6     Response Review 
 
 
Central review of staging scan will not be performed. 
11  ADVERSE EVENT REPORTING REQUIREMENTS 
 
11.1 
Definitions 
Adverse Event (AE) 
 
Dana-Farber Cancer Institute/Harvard Cancer Care guidelines for reporting SAEs 
should 
be 
followed, 
including 
the 
guidelines 
for 
gene 
transfer 
studies. 
(http://www.dana-farber.org/res/OPRS/advevent/default.asp). 
 
These 
guidelines 
require the following events to be reported to the DFCI IRB: (1) Grade 2 
(moderate) and Grade 3 (serious) events that are unexpected and possibly, 
probably, or definitely related/associated with the intervention; (2) all Grade 4 
(life threatening) events, and (3) all Grade 5 (fatal) events, occurring while the 
subject is enrolled and actively participating in the trial, or when the event 
occurred within 30 days of the last study intervention. In accordance to these 
guidelines, the following steps will be taken to report a SAE: 
Serious adverse event (SAE) 
 
A serious adverse event (SAE) is any adverse event, occurring at any dose and 
regardless of causality that:  

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27
• Results in death 
• Is life-threatening. Life-threatening means that the person was at 
immediate risk of death from the reaction as it occurred, i.e., it does not 
include a reaction which hypothetically might have caused death had it 
occurred in a more sever form. 
• Requires or prolongs inpatient hospitalization (i.e., the event required at 
least a 24-hour hospitalization or prolonged a hospitalization beyond the 
expected length of stay). Hospitalization admissions and/or surgical 
operations scheduled to occur during the study period, but planned prior to 
study entry are not considered SAEs if the illness or disease existed before 
the person was enrolled in the trial, provided that it did not deteriorate in 
an unexpected manner during the trial (e.g., surgery performed earlier than 
planned). 
• Results in persistent or significant disability/incapacity. Disability is 
defined as a substantial disruption of a person’s ability to conduct normal 
life functions. 
• In a congenital anomaly or birth defect; or 
• Is an important medical event when, based upon appropriate medical 
judgment, it may jeopardize the participant and require medical or surgical 
intervention to prevent one of the outcomes listed above. Examples of 
such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home; blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
 
Events not considered to be serious adverse events are hospitalizations for: 
• routine treatment or monitoring of the studied indication, not associated 
with any deterioration in condition, or for elective procedures 
• elective or pre-planned treatment for a pre-existing condition that did not 
worsen 
• emergency outpatient treatment for an event not fulfilling the serious 
criteria outlined above and not resulting in inpatient admission 
• respite care 
 
Expectedness 
 
Adverse events can be 'Expected' or 'Unexpected.'  
Expected adverse event 
 
Expected adverse events are those that have been previously identified as 
resulting from administration of the agent. For the purposes of this study, 
an adverse event is considered expected when it appears in the current 
adverse event list, the Investigator’s Brochure, the package insert or is 
included in the informed consent document as a potential risk.   

GVAX for CRC Mets 
May 31, 2017 
 
 
 
28
 
Refer to Section 6.1 for a listing of expected adverse events associated 
with the study agent(s). 
Unexpected adverse event 
 
 
For the purposes of this study, an adverse event is considered unexpected 
when it varies in nature, intensity or frequency from information 
provided in the current adverse event list, the Investigator’s Brochure, 
the package insert or when it is not included in the informed consent 
document as a potential risk.   
Attribution 
 
Attribution is the relationship between an adverse event or serious adverse 
event and the study treatment. Attribution will be assigned as follows: 
 
• Definite – The AE is clearly related to the study treatment. 
• Probable – The AE is likely related to the study treatment. 
• Possible – The AE may be related to the study treatment.  
• Unlikely - The AE is doubtfully related to the study treatment. 
• Unrelated - The AE is clearly NOT related to the study treatment. 
11.2  
Procedures for AE and SAE Recording and Reporting 
 
Participating investigators will assess the occurrence of AEs and SAEs at all participant 
evaluation time points during the study.  
 
All AEs and SAEs whether reported by the participant, discovered during questioning, 
directly observed, or detected by physical examination, laboratory test or other means, 
will be recorded in the participant’s medical record and on the appropriate study-
specific case report forms.  
 
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 website at: 
 
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
11.3  Reporting Requirements 
All life-threatening events which may be due to vaccine administration 
All fatal events while on study 

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29
 All such events will be reported to the DFCI Office for the Protection of Research 
Subjects by the protocol chairperson within 48 hours. 
 
11.4  
Reporting to the Principal Investigator  
11.4.1 
Serious Adverse Event Reporting 
 
All serious adverse events that occur after the initial dose of study treatment, 
during treatment, or within 30 days of the last dose of treatment must be reported 
to the DF/HCC Overall Principal Investigator on the local institutional SAE form. 
This includes events meeting the criteria outlined in Section 9.1, as well as the 
following: 
 
• Grade 2 (moderate) and Grade 3 (severe) Events – Only events that are 
unexpected and possibly, probably or definitely related/associated with the 
intervention. 
 
• All Grade 4 (life-threatening or disabling) Events – Unless expected AND 
specifically listed in the protocol as not requiring reporting. 
 
• All Grade 5 (fatal) Events – When the participant is enrolled and actively 
participating in the trial OR when the event occurs within 30 days of the 
last study intervention.  
 
Note: If the participant is in long term follow up, report the death at the time 
of continuing review.  
 
Participating investigators must report each serious adverse event to the DF/HCC 
Overall Principal Investigator within 24 hours of learning of the occurrence. In 
the event that the participating investigator does not become aware of the serious 
adverse event immediately (e.g., participant sought treatment elsewhere), the 
participating investigator is to report the event within 24 hours after learning of it 
and document the time of his or her first awareness of the adverse event. Report 
serious adverse events by telephone, email or facsimile to: 
 
 
 
Cristina Ferrone, M.D. 
 
 
Tel : 617-643-6189 
 
 
cferrone@partners.org 
 
 
Fax: 617-643-6116 
 
Within the following 24-48 hours, the participating investigator must provide 
follow-up information on the serious adverse event. Follow-up information should 
describe whether the event has resolved or continues, if and how the event was 
treated, and whether the participant will continue or discontinue study 
participation. 

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30
11.4.2 
Non-Serious Adverse Event Reporting  
 
Non-serious adverse events will be reported to the DF/HCC Overall Principal 
Investigator on the toxicity Case Report Forms.   
 
11.5    Reporting to the IND Sponsor  
 Adverse events meeting the following criteria, regardless of relatedness or expectedness, must be 
reported to the IND Sponsor (or designee) for those subjects who received at least 1 vaccine:  
o Grade ≥3 Non-Hematologic 
o  Grade ≥3 Hematologic 
o All Grade 5 events 
 
Reporting to the Sponsor begins at time of first vaccine and goes until 15 years after the 
subject’s last vaccine. 
 
All events meeting the criteria above must be forwarded to the IND Sponsor (or designee) 
within 2 business days of knowledge of the event using an FDA Form 3500A.  
11.6 Reporting to the Institutional Review Board (IRB) 
 
Investigative sites within DF/HCC will report all serious adverse events directly to 
the DFCI Office for Human Research Studies (OHRS). 
 
 
 
11.7   Reporting to the Food and Drug Administration (FDA) 
 
Robert Soiffer, MD as holder of the IND (IND Sponsor), will be responsible for all 
communication with the FDA. The IND Sponsor will report to the FDA, regardless of 
the site of occurrence, any adverse event that is serious, unexpected and reasonably 
related (i.e., possible, probable, definite) to the study treatment. 
 
Unexpected fatal or life-threatening experiences associated with the use of the study 
treatment will be reported to FDA as soon as possible but in no event later than 7 
calendar days after initial receipt of the information. 
 
All other serious unexpected experiences associated with the use of the study treatment 
will be reported to FDA as soon as possible but in no event later than 15 calendar days 
after initial receipt of the information. 
 
  
Events will be reported to the FDA by telephone (1-800-FDA-1088) or by fax (1-800-
FDA-0178) using Form FDA 3500A (Mandatory Reporting Form for investigational 
agents) or FDA Form 3500 (Voluntary Reporting Form for commercial agents). Forms 
are available at http://www.fda.gov/medwatch/getforms.htm.  

GVAX for CRC Mets 
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31
11.8  Reporting to the NIH Office of Biotechnology Activities (OBA) 
 
  
The IND Sponsor will be responsible for all communication with OBA. The IND 
Sponsor will report to OBA, regardless of the site of occurrence, any adverse event that 
is serious, unexpected and reasonably related (i.e., possible, probable, definite) to the 
gene transfer product. 
 
Unexpected fatal or life-threatening experiences associated with the use of the gene 
transfer product will be reported to OBA as soon as possible but in no event later than 7 
calendar days after initial receipt of the information (i.e., at the same time the event is 
reported to FDA).  
 
All other serious unexpected experiences associated with the use of the gene transfer 
product will be reported to OBA as soon as possible but in no event later than 15 
calendar days after initial receipt of the information (i.e., at the same time the event is 
reported to FDA). 
 
The serious adverse event report must include:  (1) the date of the event; (2) designation 
of the report as an initial report or a follow-up report, identification of all safety reports 
previously filed for the clinical protocol concerning a similar adverse event, and an 
analysis of the significance of the adverse event in light of previous similar reports; (3) 
clinical site; (4) the Principal Investigator; (5) NIH Protocol number; (6) FDA’s 
Investigational New Drug (IND) Application number; (7) vector type , e.g., adenovirus; 
(8) vector subtype, e.g., type 5, relevant deletions; (9) gene delivery method, e.g., in 
vivo, ex vivo transduction; (10) route of administration, e.g., intratumoral, intravenous; 
(11) dosing schedule; (12) a complete description of the event; (13) relevant clinical 
observations; (14) relevant clinical history; (15) relevant tests that were or are planned 
to be conducted; (16) date of any treatment of the event; and (17) the suspected cause 
of the event.  These items may be reported on the Form FDA 3500A, or other means 
provided that all of the above elements are specifically included.  
11.9  
Reporting to the Institutional Biosafety Committee (IBC) 
 
The Overall Principal Investigator will report to the IBC any adverse event that is 
serious, unexpected and reasonably related (i.e., possible, probable, definite) to the gene 
transfer product, provided that the event occurred at their investigative site.  
 
Unexpected fatal or life-threatening experiences associated with the use of the gene 
transfer product will be reported to the IBC as soon as possible but in no event later 
than 7 calendar days after initial receipt of the information.  
 
All other serious unexpected experiences associated with the use of the gene transfer 
product will be reported the IBC as soon as possible but in no event later than 15 
calendar days after initial receipt of the information. 
 

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32
Copies of all IBC submissions should be emailed to the IND Sponsor (or designee) 
within 2 business days of submission.  
 
Participating investigators should obtain from the IND Sponsor a copy of the adverse 
event report submitted to the FDA and OBA, and forward this information to their 
respective IBC as soon as possible. 
11.10 Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any subject 
safety reports or sentinel events that require reporting according to institutional policy. 
 
11.11 Monitoring of Adverse Events and Period of Observation 
 
All adverse events, both serious and non-serious, and deaths that are encountered from 
initiation of study intervention, throughout the study, and within 30 days of the last 
study intervention should be followed to their resolution, or until the participating 
investigator assesses them as stable, or the participating investigator determines the 
event to be irreversible, or the participant is lost to follow-up. The presence and 
resolution of AEs and SAEs (with dates) should be documented on the appropriate case 
report form and recorded in the participant’s medical record to facilitate source data 
verification.  
 
For some SAEs, the study sponsor or designee may follow-up by telephone, fax, and/or 
monitoring visit to obtain additional case details deemed necessary to appropriately 
evaluate the SAE report (e.g., hospital discharge summary, consultant report, or 
autopsy report).  
 
Participants should be instructed to report any serious post-study event(s) that might 
reasonably be related to participation in this study. Participating investigators should 
notify the DF/HCC Overall Principal Investigator and their respective IRB of any 
unanticipated death or adverse event occurring after a participant has discontinued or 
terminated study participation that may reasonably be related to the study.   
 
 
 
12. DATA AND SAFETY MONITORING 
12.1 Data Reporting 
12.1.1   Method  
The QACT will collect, manage, and monitor data for this study.  

GVAX for CRC Mets 
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33
12.1.2 Data Submission  
The schedule for completion and submission of case report forms (paper or 
electronic) to the QACT is as follows: 
 
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration with QACT 
On Study Form 
Within 14 days of registration 
Baseline Assessment Form 
Within 14 days of registration 
Treatment Form 
Within 10 days of the last day of the cycle 
Adverse Event Report Form 
Within 10 days of the last day of the cycle 
Response Assessment Form 
Within 10 days of the completion of the cycle 
required for response evaluation 
Off Treatment/Off Study Form 
Within 14 days of completing treatment or 
being taken off study for any reason 
Follow up/Survival Form 
Within 14 days of the protocol defined follow 
up visit date or call 
 
12. 2  
Safety Meetings 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor 
toxicity and accrual data from this trial. The committee is composed of clinical 
specialists with experience in oncology and who have no direct relationship with the 
study. Information that raises any questions about participant safety will be addressed 
with the Principal Investigator and study team. 
 
The DSMC will meet quarterly and/or more often if required to review toxicity and 
accrual data.  Information to be provided to the committee may include:  up-to-date 
participant accrual; current dose level information; DLT information; all grade 2 or 
higher unexpected adverse events that have been reported; summary of all deaths 
occurring within 30 days for Phase I or II protocols; for gene transfer protocols, 
summary of all deaths while being treated and during active follow-up; any response 
information; audit results, and a summary provided by the study team. Other 
information (e.g. scans, laboratory values) will be provided upon request.  
12.3  
Monitoring  

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34
 
Involvement in this study as a participating investigator implies acceptance of 
potential audits or inspections, including source data verification, by representatives 
designated by the DF/HCC Overall Principal Investigator (or Protocol Chair) or 
DF/HCC. The purpose of these audits or inspections is to examine study-related 
activities and documents to determine whether these activities were conducted and 
data were recorded, analyzed, and accurately reported in accordance with the protocol, 
institutional policy, Good Clinical Practice (GCP), and any applicable regulatory 
requirements.  
 
All data will be monitored for timeliness of submission, completeness, and adherence 
to protocol requirements. Monitoring will begin at the time of participant registration 
and will continue during protocol performance and completion.  
 
13 REGULATORY CONSIDERATIONS 
 
13.1  
Protocol Review and Amendments 
This protocol, the proposed informed consent and all forms of participant 
information related to the study (e.g., advertisements used to recruit participants) and 
any other necessary documents must be submitted, reviewed and approved by a 
properly constituted IRB governing each study location.  
Any changes made to the protocol must be submitted as amendments and must be 
approved by the IRB prior to implementation. Any changes in study conduct must be 
reported to the IRB. The DF/HCC Overall Principal Investigator (or Protocol Chair) 
will disseminate protocol amendment information to all participating investigators.  
All decisions of the IRB concerning the conduct of the study must be made in 
writing. 
13.2  
Informed Consent 
 
All participants must be provided a consent form describing this study and 
providing sufficient information for participants to make an informed decision 
about their participation in this study. The formal consent of a participant, using 
the IRB approved consent form, must be obtained before the participant is 
involved in any study-related procedure. The consent form must be signed and 
dated by the participant or the participant’s legally authorized representative, and 
by the person obtaining the consent. The participant must be given a copy of the 
signed and dated consent document. The original signed copy of the consent 
document must be retained in the medical record or research file.  
 
13.3  
Ethics and Good Clinical Practice (GCP) 

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35
This study is to be conducted according to the following considerations, which 
represent good and sound research practice: 
• 
E6 Good Clinical Practice: Consolidated Guidance 
www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM129515.pdf  
• 
US Code of Federal Regulations (CFR) governing clinical study conduct and 
ethical principles that have their origin in the Declaration of Helsinki 
o Title 21 Part 11 – Electronic Records; Electronic Signatures 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr11_02.html 
o Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html  
o Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html  
o Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr56_02.html  
o Title 21 Part 312 – Investigational New Drug Application 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr312_02.html  
• 
State laws 
• 
DF/HCC research policies and procedures        
http://www.dfhcc.harvard.edu/clinical-research-support/clinical-research-unit-
cru/policies-and-procedures/  
It is understood that deviations from the protocol should be avoided, except when 
necessary to eliminate an immediate hazard to a research participant. In such case, 
the deviation must be reported to the IRB according to the local reporting policy.  
13.4  
Study Documentation 
 
The investigator must prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each 
research participant. This information enables the study to be fully documented and the 
study data to be subsequently verified. 
 
Original source documents supporting entries in the case report forms include but are 
not limited to hospital records, clinical charts, laboratory and pharmacy records, 
recorded data from automated instruments, microfiches, photographic negatives, 
microfilm or magnetic media, and/or x-rays.  
13.5  
Records Retention 

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36
 
All study-related documents must be retained for the maximum period required by 
applicable federal regulations and guidelines or institutional policies.  
 
13.6  
Multi-center Guidelines     
N/A 
13.7 
Cooperative Research and Development Agreement (CRADA)/Clinical Trials 
Agreement (CTA)  
N/A 
 
14 STATISTICAL CONSIDERATIONS  
 
The study consists of a single stage of accrual of patients with hepatic metastases from colorectal 
cancer.   
 
Patient safety will be assured by monitoring the number of patients who fail to receive the first 
six scheduled vaccinations because of toxicity.  If three or more patients experience grade 4 or 
worse toxicity due to the vaccine before completing six immunizations, the study will be 
terminated.  If the unknown true rate of grade 4 or worse toxicity is 0.05, then the probability of 
early termination is 0.04.  Similarly, if the unknown true rate is 0.25, then the probability of early 
termination is 0.76. 
 
Feasibility will be assessed by the ability to make vaccine from resected hepatic metastases in 
quantities sufficient for six vaccinations.  Fifteen patients will be entered.  If fewer than 9 
patients receive six vaccinations, the study will cease.  A success rate under 65% (true rate) may 
imply that the method needs further development or that the amount of tissue available in this 
population limits the feasibility of this strategy.  This study will have 75% power against the null 
of 45% success rate, testing at the one-sided 0.18 significance level and using exact methods.  
 
The percentage of patients who successfully receive 6 vaccinations and the number of 
vaccinations received by patients will be described.  Any late occurrences of grade 3 or worse 
toxicity and the vaccination number at which they occur will be reported. 
 
For the correlative science it is unclear which changes will occur in the circulating immune cells 
since a study like this has never been done in patients with resected hepatic metastases from 
colorectal cancer.  Currently we do not have estimates to present a statistical model or plan.  No 
changes in the correlative science should influence administration of the vaccine in the patients. 
 
Table 1.  90% confidence intervals for the true proportion of patients who receive all six 
injections 
 
Observed number of 
Observed rate of patients 
90% confidence interval for 

GVAX for CRC Mets 
May 31, 2017 
 
 
 
37
patients who receive all six 
injections 
who receive all six 
injections 
the true rate of patients who 
receive all six injections 
8 
53% 
(30%, 76%) 
10 
67% 
(42%, 86%) 
11 
73% 
(49%, 90%) 
12 
80% 
(56%, 94%) 
 
14.1 Study Design/Endpoints 
 
 
 
 
 
Primary 
 
14.1.1To 
determine 
the 
feasibility 
of 
manufacturing 
lethally 
irradiated, autologous 
colorectal cancer cells engineered by adenoviral mediated gene transfer to secrete GM-
CSF from hepatic metastases. 
 
 
14.1.2 To determine the safety and biologic activity of vaccination with lethally  
 
 
 irradiated, autologous colorectal cancer cells engineered by adenoviral   
 
 mediated gene transfer to secrete GM-CSF in stage IV colorectal cancer   
 
 patients. 
 
Secondary 
14.1.3 To determine the progression free survival and two-year survival of stage IV 
colorectal cancer patients vaccinated with lethally irradiated, autologous colorectal 
cancer cells engineered by adenoviral mediated gene transfer to secrete GM-CSF 
 
14.2   Sample Size/Accrual Rate 
 
The plan is to enroll 15 patients with in two (2) years. 
14.3   Reporting and Exclusions 
14.3.1 
Feasibility- Feasibility will be defined by the capacity for patients in this 
specific population to initiate the vaccination process, i.e., to receive at least 
one vaccination   This will be governed by the ability to successfully harvest a 
minimum number of viable tumor cells at the time of surgery.   
At the treating physician’s discretion, patients with progressive disease or 
treatment-related complications between surgery and initiation of vaccination 
who are deemed incapable of or inappropriate for treatment will not initiate 
vaccination and will be included in the feasibility analysis. 
We will consider this treatment plan feasible in this patient population if at 

GVAX for CRC Mets 
May 31, 2017 
 
 
 
38
least 60% of initially enrolled patients go on to begin vaccination.   
If an enrolled patient withdraws from the study for a reason that is not 
associated with surgical morbidity or disease progression, that patient will not 
be counted in the feasibility analysis. 
14.3.2 
Safety and Biologic Activity:  All participants who receive at least one vaccine    
will be considered evaluable for toxicity.  All participants who receive all 6 
vaccines will be evaluable for biologic response. 
14.3.3 
Evaluation of response.  All participants 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 participant should 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). By arbitrary convention, category 9 usually designates the 
"unknown" status of any type of data in a clinical database. 
              
15 PUBLICATION PLAN 
 
 
 
 
The Primary Investigator, Cristina Ferrone, M.D., will submit the results for the  
 
 
 
Publication with in twenty-four months of closing the trial. 
 
 
 
 
 
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May 31, 2017 
 
 
 
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Dranoff G, Jaffee E, Lazenby A, et al: Vaccination with irradiated tumor 
cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates 
potent, specific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci U S A 90:3539-43, 
1993 
 
21. 
Huang AY, Golumbek P, Ahmadzadeh M, et al: Role of bone marrow-derived cells in 
presenting MHC class I-restricted tumor antigens. Science 264:961-5, 1994 
 
22. 
Reilly RT, Machiels JP, Emens LA, et al: The collaboration of both humoral and 
cellular HER-2/neu-targeted immune responses is required for the complete eradication of HER-
2/neu-expressing tumors. Cancer Res 61:880-3, 2001 
 
23. 
Soiffer R, Lynch T, Mihm M, et al: Vaccination with irradiated autologous melanoma 
cells engineered to secrete human granulocyte-macrophage colony-stimulating factor generates 

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potent antitumor immunity in patients with metastatic melanoma. Proc Natl Acad Sci U S A 
95:13141-6, 1998 
 
24. 
Mulligan RC: The basic science of gene therapy. Science 260:926-32, 1993 
 
 

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17 APPENDICES  
 
17.1 
Certification of Vector and Transduced Tumor Cells 
 
17.1.1 Vector Manufacturing Process 
 
Description 
 
A portion of the resected hepatic metastasis measuring between 1-2 cm2 will be placed in sterile 
saline and transported on ice to the DFCI by one of the study staff members.  
 
The CG6444 vector is a replication-defective, E1/E3-deleted type 5 adenoviral vector containing 
a full-length, human genomic GM-CSF expression cassette inserted in the E1 region. 
 
Derivation of the CG6444 Vector 
 
The human genomic GM-CSF (hgGM-CSF) gene was amplified by polymerase chain reaction 
(PCR) from a plasmid artificial chromosome (PAC) (PAC282; Genome Systems, St. Louis, MO) 
using forward and reverse primers complementary to genomic nucleotide sequences immediately 
flanking the hgGM-CSF gene.  To aid in recombinant DNA cloning of the PCR-amplified 
product, EcoRI restriction endonuclease recognition sequences were included at the 5-prime ends 
of both primers.  Following EcoRI digestion, the amplified product was non-directionally cloned 
into the EcoRI site of an Ad E1-targeting shuttle vector, plox III-4 CMV.  Resulting clones were 
screened by restriction endonuclease digestion for proper orientation of the insert, relative to the 
promoter.  One properly oriented clone (plox III-4 CMV/hgGM-CSF # 5) was identified and the 
insert sequenced.  Exon coding regions for the cloned hgGM-CSF insert were identical to 
sequences published in GenBank. 
 
An infectious adenovirus clone was generated by homologous recombination in yeast.  For 
recombination, transfer vector plox III-4 CMV/hgGM-CSF #5 and PAC A/U  E1E3, E4+ 
(containing the remainder of the adenovirus genome) were chemically transformed into yeast 
strain, YPH857.  Yeast clones were screened by restriction digestion and Southern blot analysis 
using probes for both total adenovirus genomic- and hgGM-CSF-DNA.  One clone  E1E3 
hgGM-CSF #8, with proper DNA fragment size and identity profile was isolated.  DNA 
fragment migration and hybridization patterns confirmed insertion of hgGM-CSF in the E1 
region, and maintenance of the E3 deletion from the adenovirus backbone.  Presence of 
adenoviral E4 genomic sequences was confirmed by PCR analysis.  Infectious virus was rescued 
from cloned  E1E3 hgGM-CSF #8 DNA by transfection into 293 cells.  Viral clones were triple 
plaque-purified on 293 cells and screened by DNA restriction analysis.  A plaque-purified 
CG6444 clone was isolated and the E1 region was sequenced.  Inserted hgGM-CSF coding 
sequences were identical to sequences published in GenBank.  The CG6444 virus construct, 
derived from the Master Virus bank, has been sequenced in its entirety. (This sequence is 
presented as Attachment 3 in the Master File CMC BB-IND 8793).  
 
 

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Certificates of Analysis for Master and Working Cell Banks and Virus Banks 
 

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Appendix (letter): Performance Status Criteria 

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ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Description 
Percent 
Description 
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.