A Phase I/II Study of Active Immunotherapy With Ad5 [E1-,E2b-]-CEA(6D) Vaccine in Patients With Advanced or Metastatic Malignancies Expressing CEA
Phase: PHASE1
Conditions: Colorectal Cancer, Lung Cancer, Breast Cancer, Prostate Cancer
Sponsor: NantCell, Inc.

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A PHASE I/II STUDY OF ACTIVE IMMUNOTHERAPY WITH Ad5 [E1-, E2b-]-
CEA(6D)  
VACCINE 
(ETBX-011) 
IN 
PATIENTS 
WITH 
ADVANCED 
OR 
METASTATIC MALIGNANCIES EXPRESSING CEA  
 
Principal Investigator: 
 
Michael Morse, M.D. 
 
 
 
 
 
Duke University Medical Center 
 
 
Agents Used in This Study:  
Ad5 [E1-, E2b-]-CEA(6D)  (ETBX-011) 

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Names and addresses of key study personnel: 
Study Chairman and Principal Investigator 
Name:  Michael Morse, MD 
Address: Duke University Medical Center 
Box 3233, Durham, NC 27710 
Telephone:  (919) 681-3480 
Fax:  (919) 681-7970 
Email: michael.morse@duke.edu 
Bioassay Oversight/Laboratory Oversight 
Name:  Joseph P. Balint, PhD 
Address: Etubics Corporation                      
410 West Harrison Street,       
Seattle, Wa 98119 
Telephone:  (206) 838-5110 
Fax:  (206) 838-2978 
Email: joe@etubics.com 
Biostatistician  
Name:  Donna Niedzwiecki, PhD 
Address: Duke University Medical Center 
Box 3958, Durham, NC 27710 
Telephone: (919) 681-5030 
Fax:  (919) 691-8028 
E-mail: donna.niedzwiecki@duke.edu 
Other Applicable Staff 
Title:  Acting Medical Director  
Name: H. Kim Lyerly, MD 
Address: 2424 Erwin Road, Suite 601 
                Durham, NC  27710 
Telephone:  (919) 684-5613 
Fax:  (919) 684-5653 
Email: lyerl001@mc.duke.edu 
Pharmacist or Person Responsible for Drug 
Accountability       
Name: Cheryl Morgan 
Address: Morris Pharmacy, Duke University 
Medical Center, Trent Drive, 
Durham, NC 27710 
Telephone:  (919) 668-0657 
Fax: (919) 668-3895 
Email: cheryl.morgan@duke.edu 
Other Applicable Staff: 
Title:  CEO and CSO, Etubics Corporation 
Name:  Frank R. Jones, Ph.D. 
Address: Etubics Corporation 
   410 West Harrison Street 
   Seattle, WA 981119 
Telephone: 206-838-5110 Ext 101 
Fax:  206-838-2978 
Email: frank@etubics.com 
Other Consultants: 
Andrea Amalfitano, DO, PhD, Michigan State 
University 
Elizabeth Gabitzsch, Etubics Corporation 
Raj Dua, Ph.D., Etubics Corporation 
Timothy Clay, PhD, Duke University 
 

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TABLE OF CONTENT 
 
 
 
 
 
 
 
 
 
 
 
Page Number 
 
 
1. Protocol Summary …………………………………………………..  4 
 
2. Study Objectives …………………………………………………….  6 
 
3. Background and Significance ……………………………………….  6 
 
4. Patient Selection …………………………………………………….. 15 
 
5. Pre-Treatment Evaluation …………………………………………… 19 
 
6. Treatment Plan ………………………………………………………. 20 
 
7. Treatment Evaluation ………………………………………………... 25 
 
8. Statistical Considerations ……………………………………………. 28 
 
9. Patient Withdrawal …………………………………………………... 29 
 
10. Study Conduct and Ethical and Regulatory Considerations …………. 29 
 
11.  References …………………………………………………………… 37 
 
12.  Appendix …………………………………………………………….. 43 
 

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1. PROTOCOL SUMMARY 
Title 
A PHASE I/II STUDY OF ACTIVE IMMUNOTHERAPY WITH 
Ad5 [E1-, E2b-]-CEA(6D)  VACCINE (ETBX-011) IN PATIENTS 
WITH 
ADVANCED 
OR 
METASTATIC 
MALIGNANCIES 
EXPRESSING CEA 
Objectives 
a) The primary objective of this protocol is to determine the safety of 
immunization with Ad5 [E1-, E2B-]-CEA(6D), in patients with 
advanced or metastatic CEA-expressing malignancies.  
b) The secondary objectives are to evaluate CEA-specific immune 
responses to the immunizations and to obtain preliminary data on 
clinical response rate. 
Major Inclusion/ 
Exclusion Criteria 
Patients with a histologically confirmed diagnosis of metastatic 
malignancy who were previously treated with standard therapy known to 
have a possible survival benefit or refused such therapy.  The tumor must 
express CEA as defined by any of the following: immunohistochemical 
staining, a CEA level in the peripheral blood greater than 5 ng/dL, or a 
tumor known to be universally CEA positive (i.e. colon and rectal 
cancer).  Patients will not be treated until 4 or more weeks after any prior 
chemotherapy or radiation therapy, but may be receiving non-cytotoxic 
targeted therapy (bevacizumab, cetuximab, trastuzumab, erlotinib, or 
gefitinib) or hormonal therapy.  They must not have a history of 
autoimmune disease, serious intercurrent chronic or acute illness, active 
hepatitis, serologic evidence for HIV, or be receiving steroid or 
immunosuppressive therapy.  All patients must be >18 years old and 
have an ECOG Performance Status of 0 or 1. Pregnant women and 
nursing mothers are excluded.  
Study Design 
Phase I/II study with three dosage levels of Ad5 [E1-, E2B-]-CEA(6D)  
vaccine (phase I component), and the maximally tolerated dose of Ad5 
[E1-, E2B-]-CEA(6D)  vaccine (phase II component).  The study drug is 
Ad5 [E1-, E2B-]-CEA(6D) given by subcutaneous (SQ) injection every 
3 weeks for 3 immunizations.  The following procedures will occur: 
1) Peripheral blood draw of 90 mL for immune analysis 
2) Cohort 1: Three patients will receive Ad5 [E1-, E2B-]-CEA(6D)  at a 
dose of 1 x 109 particles SQ in 0.5 mL every 3 weeks for 
3 immunizations.  Assessment of dose-limiting toxicities (DLT) for 
dose escalation will be made after all patients in this cohort have had 
a study visit at least 3 weeks after receiving their first dose of 
vaccine.  If there are no DLT, defined as any Grade 2, 3 or 4 
immediate hypersensitivity reactions or neurological toxicity, other 
Grade 3 or 4 allergic or major organ toxicity, or Grade 4 fever, that 
may possibly be associated with the immunization), then patients may 

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begin enrolling into cohort 2.  If there is 1 DLT, then an additional 3 
patients will be enrolled at this dosage level. Assessment of DLT for 
dose escalation will be made after the 3 additional patients have had a 
study visit at least 3 weeks after receiving their first dose of vaccine.  
If none of these latter 3 patients have DLT (i.e., 1 DLT in the 6 total 
patients), then patients may begin enrolling into cohort 2. 
3) Cohort 2: Three patients will receive Ad5 [E1-, E2B-]-CEA(6D)  at a 
dose of 1 x 1010 particles SQ in 0.5 mL every 3 weeks for 
3 immunizations.  Assessment of DLT for dose escalation will be 
made after all patients in this cohort have had a study visit at least 
3 weeks after receiving their first dose of vaccine.  If there are no 
DLT, then patients may begin enrolling into cohort 3.  If there is 1 
DLT then an additional 3 patients will be enrolled at this dosage 
level. Assessment of DLT for dose escalation will be made after the 3 
additional patients have had a study visit at least 3 weeks after 
receiving their first dose of vaccine.  If none of these latter 3 patients 
have DLT, then patients may begin enrolling into cohort 3. 
4) Cohort 3: Six patients will receive Ad5 [E1-, E2B-]-CEA(6D)  at a 
dose of 1 x 1011 particles SQ in 0.7 mL every 3 weeks for 
3 immunizations.  Assessment of DLT for proceeding to phase II 
enrollment will be made after all patients in this cohort have had a 
study visit at least 3 weeks after receiving their first dose of vaccine.  
If there is 0 or 1 DLT, then patients may begin enrolling into the 
phase II portion of the study.  
5) Phase II cohort: An additional 12 patients will receive Ad5 [E1-, 
E2B-]-CEA(6D) at the maximally tolerated dose every 3 weeks for 
3 immunizations.  
6) Patients will have 90 mL peripheral blood drawn prior to each 
immunization and at Week 9 to determine whether there is an effect 
on the immune response at specific time points during the study 
and/or after a specific number of immunizations. 
7) Time to progression will be measured using CT scans performed as 
per standard of care (approximately 3 month intervals). 
Risks/toxicities 
Potential risks associated with the vaccine include anaphylaxis, fever, 
skin reaction, autoimmunity (colitis), and hepatic insufficiency.   
Number of Patients 
Planned: 24 evaluable patients (plus up to 12 replacements); may require 
30-42 patients if DLT occur. 
Duration of Study 
6 months after the last patient is enrolled; approximately 2 years total 
Criteria for 
Evaluation 
Toxicity will be assessed using CTC toxicity criteria.  CEA-specific 
immune response will be measured by ELISpot.  Time to recurrence will 
be determined by RECIST criteria. 
Statistical Analysis 
Safety: We will evaluate safety in each cohort at least 3 weeks after the 
last patient in the previous cohort has received their first injection.  A 
dosing scheme will be considered safe if <33% of patients treated at a 

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dosage level experience DLT (e.g., 0 of 3, ≤1 of 6, ≤3 of 12 or ≤5 of 18 
patients).  A patient will be considered evaluable for safety if treated with 
at least one immunization. 
Rate of immune response:  We will determine the percentage of patients 
with a positive immune response.  We define a positive immune response 
by ELISpot as described at the 2002 Society of Biologic Therapy 
Workshop on “Immunologic Monitoring of Cancer Vaccine Therapy”, 
i.e. a T cell response is considered positive if the mean number of spots 
in six wells with antigen exceeds the number of spots in six control wells 
by 10 and the difference between single values of the six wells 
containing antigen and the six control wells is statistically significant at a 
level of p ≤ 0.05 using the Student’s t test.  Immunogenicity assays will 
occur prior to each immunization and at week 12.  Immune response will 
be assessed at the MTD.  An observed immune response in 9 of 18 
patients will be considered sufficient evidence of immune response to 
justify further investigation.  Meeting this criterion establishes that the 
immune response rate is at least 33% with approximately 90% 
confidence.  The magnitude of response will also be described.  A patient 
will be considered evaluable for immune response if they receive at least 
1 immunization. 
  
2. STUDY OBJECTIVES 
a) The primary objective of this protocol is to determine the safety of immunization with 
Ad5 [E1-, E2B-]-CEA(6D)  in patients with advanced or metastatic CEA-expressing 
malignancies.  
b) The secondary objectives are to evaluate CEA-specific immune response to the 
immunizations and obtain preliminary data on response rate. 
3. BACKGROUND AND SIGNIFICANCE 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 

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4. PATIENT SELECTION 
4.1. Criteria for Patient Eligibility 
4.1.1. 
Histologically confirmed diagnosis of metastatic malignancy due to a tumor 
expressing CEA.  Because this is a safety and immunogenicity study, patients are 
NOT required to have measurable or evaluable disease by Response Evaluation 
Criteria in Solid Tumors (RECIST).  
4.1.2. 
The tumor must express CEA as defined by any of the following:  
immunohistochemical staining (at least 50% of the tumor with at least moderate 
intensity of staining), a CEA level in the peripheral blood greater than 5.0 ng/mL 
at any time prior to enrollment, or a tumor known to be universally CEA positive 
(i.e. colon and rectal cancer.)   
4.1.3. 
Patients must have received treatment with standard therapy known to have a 
possible overall survival benefit or refused such therapy.  
For the following common cancers, the following eligibility criteria apply: 
 Colorectal cancer: Must have received and progressed through at least one 
line of palliative chemotherapy consisting of one of the following regimens: 

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Palliative chemotherapy for metastatic colorectal cancer with 
5-fluorouracil (or capecitabine) and oxaliplatin. 
- 
Palliative chemotherapy for metastatic colorectal cancer with 
5-fluorouracil (or capecitabine) and irinotecan. 
- 
Palliative chemotherapy regimen for metastatic colorectal cancer that 
includes bevacizumab. 
- 
Colorectal cancer patients currently receiving palliative single-agent 
bevacizumab or cetuximab will be eligible for this trial and may 
continue these therapies concomitant with study treatment (if they 
have been on these therapies for at least 3 months). 
 Breast cancer: Must have received and progressed through at least one line of 
chemotherapy for metastatic breast cancer consisting of one of the following 
regimens: 
- 
Palliative anthracycline- or taxane-based chemotherapy 
- 
Patients with tumors that over express HER2 (IHC 3+ or FISH+) must 
have received and progressed through at least one line of palliative 
therapy that combines trastuzumab with chemotherapy.  
- 
Breast cancer patients currently receiving palliative endocrine therapy 
or single-agent trastuzumab will be eligible for this trial and may 
continue these therapies concomitant with study treatment (if they 
have been on these therapies for at least 3 months). 
 Lung cancer: Must have received and progressed through chemotherapy for 
metastatic disease consisting of one of the following regimens: 
- 
Palliative platinum-based (cisplatin or carboplatin) chemotherapy if 
the patient has not received chemotherapy previously. 
- 
Palliative taxane-based (docetaxel or paclitaxel) or vinorelbine 
chemotherapy if the patient has received chemotherapy previously. 
- 
Lung cancer patients currently receiving palliative single-agent 
erlotinib or gefitinib will be eligible for this trial and may continue 
these therapies concomitant with study treatment (if they have been on 
these therapies for at least 3 months). 
 Pancreatic cancer: Must have received and progressed through chemotherapy 
including gemcitabine. 
- 
Pancreatic cancer patients currently receiving palliative single-agent 
erlotinib will be eligible for this trial and may continue this therapy 
concomitant with study treatment (if they have been on this therapies 
for at least 3 months). 
 
For other malignancies, if a first line therapy with survival or palliative benefit 
exists, it should have been administered and there should have been 
progressive disease. 

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Patients who have received and progressed through first-line palliative 
chemotherapy must be advised regarding second-line therapy before being 
enrolled on this investigational study.  
4.1.4. 
ECOG 0 or 1 performance status 
4.1.5. 
Estimated life expectancy > 3 months.. 
4.1.6. 
Age ≥ 18 years, but <75. 
4.1.7. 
Adequate hematologic function, with WBC ≥ 3000/microliter, hemoglobin 
≥ 9 g/dL (may transfuse or use erythropoietin to achieve this level), platelets 
≥ 75,000/microliter; PT-INR <1.5, PTT <1.5X ULN 
4.1.8. 
Adequate renal and hepatic function, with serum creatinine < 1.5 mg/dL, bilirubin 
< 1.5 mg/dL (except for Gilbert’s syndrome which will allow bilirubin 
≤ 2.0 mg/dL), ALT and AST ≤ 2.5 x upper limit of normal. 
4.1.9. 
Patients who have received prior CEA-targeted immunotherapy are eligible for 
this trial, if this treatment was discontinued at least 3 months prior to enrollment. 
4.1.10. Patients who are taking medications that do not have a known history of 
immunosuppression are eligible for this trial. 
4.1.11. Ability to understand and provide signed informed consent that fulfills 
Institutional Review Board’s guidelines. 
4.1.12.    Ability to return to Duke University Medical Center for adequate follow-up, as         
required by this protocol. 
4.2. Criteria for Patient Exclusion 
4.2.1  
Patients with concurrent cytotoxic chemotherapy or radiation therapy should be 
excluded. There are no exclusions based on the number of prior chemotherapy, 
biologic, hormonal, or experimental regimens. Except for the permitted 
concomitant therapies (bevacizumab, cetuximab, trastuzumab, erlotinib, gefitinib, 
or hormonal therapy which patients must have been on for at least 3 months at the 
time of enrollment if they intend to continue them with the vaccine), there must 
be at least 3 months between any prior CEA-targeted immunotherapy and study 
treatment and at least 4 weeks between any other prior therapy (including 
radiotherapy) and study treatment.  Patients must have recovered from all acute 
toxicities from prior treatment. 
4.2.2. 
Patients with a history of brain metastases will not be permitted 
4.2.3.  
Patients with a history of autoimmune disease, such as but not restricted to, 
inflammatory bowel disease, systemic lupus erythematosus, ankylosing 
spondylitis, scleroderma, or multiple sclerosis.  Autoimmune related thyroid 
disease and vitiligo are permitted. 
4.2.4. 
Patients with serious intercurrent chronic or acute illness, such as cardiac disease 
(NYHA class III or IV), hepatic disease, or other illness considered by the 
Principal Investigator as unwarranted high risk for investigational drug treatment. 
4.2.5. 
Patients with a medical or psychological impediment to probable compliance with 
the protocol should be excluded. 

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4.2.6. 
Concurrent (or within the last 5 years) second malignancy other than 
non-melanoma skin cancer, cervical carcinoma in situ, controlled superficial 
bladder cancer, or other carcinoma in situ that has been treated. 
4.2.7. 
Presence of an active acute or chronic infection including: a urinary tract 
infection, HIV (as determined by ELISA and confirmed by Western Blot) or viral 
hepatitis (as determined by HBsAg and Hepatitis C serology).  Patients with HIV 
are excluded based on immuno-suppression, which may render them unable to 
respond to the vaccine; patients with chronic hepatitis are excluded because of 
concern that hepatitis could be exacerbated by the injections.  Patients with active 
CMV disease will be excluded, but CMV seropositive patients will be eligible. 
4.2.8. 
Patients on steroid therapy (or other immuno-suppressives, such as azathioprine 
or cyclosporin A) are excluded on the basis of potential immune suppression.  
Patients must have had 6 weeks of discontinuation of any steroid therapy (except 
that used as pre-medication for chemotherapy or contrast-enhanced studies) prior 
to enrollment. 
4.2.9. 
Patients with allergies to any component of the vaccine will be excluded from the 
protocol. 
4.2.10. Pregnant and nursing women should be excluded from the protocol since this 
research may have unknown and harmful effects on an unborn child or on young 
children.  If the patient is sexually active, the patient must agree to use a 
medically acceptable form of birth control while receiving treatment and for a 
period of 4 months following the last vaccination therapy. It is not known whether 
the treatment used in this study could affect the sperm and could potentially harm 
a child that may be fathered while on this study. 
4.2.11. Patients with acute or chronic skin disorders that will interfere with injection into 
the skin of the extremities or subsequent assessment of potential skin reactions 
will be excluded. 
4.2.12. Patients will be allowed warfarin 1mg po qd for port prophylaxis but not full dose 
warfarin or low molecular weight heparin. 
4.3. Accrual 
We expect to accrue a minimum of 24 evaluable patients (plus up to 12 replacements 
for patients removed from the study prior to completion of the assigned vaccine 
schedule for any reason other than toxicity).  The study may require 30-42 patients if 
DLT occur that necessitate re-dosing at a lower dosage levels (see section 6 for a 
description of the dose escalation criteria). 
 
4.4 Assignment of study number: Patients will be assigned study numbers in order of their 
screening using the following: ETBX-011-xxx. 
 Assignment of study day: Day 0 is the day of the first immunization. The second 
immunization is at Day 21. 
 

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5. PRE-TREATMENT EVALUATION 
(See also Schema in Appendix 1.) The following pre-treatment evaluations will be completed 
within 1 month (+/- 2 weeks) before starting study treatment: 
 History and physical exam, to include ECOG Performance Score and review of inclusion 
and exclusion criteria 
 ß-HCG for women with childbearing potential 
 Hematological, biochemical and immunological tests: 
CBC with differential 
PT INR and PTT 
Na, K, Cl, CO2, BUN, creatinine, Ca, total protein, albumin, total bilirubin, alkaline 
phosphatase, AST, ALT and glucose 
Urinalysis 
 Infectious Disease 
HIV antibody, Hepatitis BsAg, Hepatitis C serology, CMV serology 
 ECG 
 Biological Markers: 
Serum will be obtained to measure antibodies to CEA and the neutralizing antibodies to 
Ad vector, and other available serum markers (e.g., CEA  or CA15-3) will be reviewed. 
 Archive Samples: 
An additional 20 mL of blood may be drawn during the first clinic visit, when the patient 
history and physical exam are conducted, at the discretion of the immune monitoring 
laboratory, and serum stored for later analysis of immune responses. 
 Imaging studies: 
CT or MRI scans of the chest, abdomen, brain, and/or pelvis will be requested within 1 
month (±2 weeks) before starting study treatment to document the presence and size of 
any measurable metastatic disease that might present.  CT and MRI are the best currently 
available and reproducible methods to measure target lesions selected for response 
assessment.  Conventional CT and MRI should be performed with cuts of 10 mm or less 
in slice thickness contiguously.  Spiral CT should be performed using a 5 mm contiguous 
reconstruction algorithm.  This applies to tumors in the chest, abdomen, and pelvis. 
 
6. TREATMENT PLAN 
In the phase I component, patients will be enrolled into successive dosage level cohorts 
of 3 or 6 patients and monitored for dose-limiting toxicity (DLT).  

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 DLT (based on CTCAE4.0 criteria) is defined as any Grade 2, 3 or 4 immediate 
hypersensitivity reactions, other Grade 3 or 4 allergic or major organ toxicity, or Grade 4 fever 
that may possibly be associated with the immunization.  
During dose escalation through the first three patients of cohort 3, there will be a 
minimum of 1 week between enrolling successive patients.  If no DLT have been observed at 
this point, then further enrollment can occur in cohort 3 and phase II component without the 
1-week waiting period.  Between dosage levels, assessment of DLT for dose escalation will be 
made after all patients in a cohort have had a study visit at least 3 weeks after receiving their first 
dose of vaccine and all the available safety data and laboratory results have been reviewed by the 
Principle Investigator. If DLT occurs in <33% of patients in a given dosage level cohort, 
progression to the next dosage level will proceed.  If DLT occurs in ≥33% of patients in a given 
cohort, the next lower dosage level will be defined as the maximum tolerated dose (MTD).  If 
DLT occurs in <33% of patients in the highest dosage level tested, that dosage level will be 
defined as the MTD.  In phase II, 12 additional patients will be enrolled at the MTD.  In phase II, 
if at any time the rate of DLT in patients enrolled at the MTD (for the phase I and phase II 
cohorts combined) is ≥33%, the MTD will be re-defined as the next lower dosage level, and 
phase II will proceed with enrollment of additional patients at this lower dosage level.  
Additional details of this dose escalation and de-escalation plan are provided below and in 
Figures 3A, 3B and Table 3.  
1) Phase I: Cohort 1: Three patients will receive Ad5 [E1-, E2B-]-CEA(6D)  at a dose of 1 x 
109 particles in 0.5 mL subcutaneously (SQ) in the same thigh every 3 weeks for 
3 immunizations. Immunizations should be separated by 5 cm.  Assessment of DLT for 
dose escalation will be made after all patients in this cohort have had a study visit at least 
3 weeks after receiving their first dose of vaccine.  If there are no DLT (as defined 
above), then patients may begin enrolling into cohort 2.  If there is 1 DLT then an 
additional 3 patients will be enrolled at this dosage level. Assessment of DLT for dose 
escalation will be made after the 3 additional patients have had a study visit at least 3 
weeks after receiving their first dose of vaccine.  If none of these latter 3 patients have 
DLT, then patients may begin enrolling into cohort 2.  If 2 patients have DLT at this 
lowest dosage level, dosing will be suspended and the study re-evaluated. 
2) Cohort 2: Three patients will receive Ad5 [E1-, E2B-]-CEA(6D) at a dose of 1 x 1010 
particles in 0.5 mL SQ in the same thigh every 3 weeks for 3 immunizations.  Assessment 
of DLT for dose escalation will be made after all patients in this cohort have had a study 
visit at least 3 weeks after receiving their first dose of vaccine.  If there are no DLT, then 
patients may begin enrolling into cohort 3.  If there is 1 DLT then an additional 3 patients 
will be enrolled at this dosage level. Assessment of DLT for dose escalation will be made 
after the 3 additional patients have had a study visit at least 3 weeks after receiving their 
first dose of vaccine.  If none of these latter 3 patients have DLT, then patients may begin 
enrolling into cohort 3.  If 2 patients have DLT at this dosage level, the dosage level in 
cohort 1 will be considered the MTD.  If only 3 patients were enrolled in cohort 1, an 
additional 3 patients will be enrolled at that dosage before proceeding to phase II. 
3) Cohort 3: Six patients will receive Ad5 [E1-, E2B-]-CEA(6D)  at a dose of 1 x 1011 
particles in 0.7  mL SQ in the same thigh every 3  weeks for 3 immunizations.  

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Assessment of DLT for proceeding to phase II enrollment will be made after all patients 
in this cohort have had a study visit at least 3 weeks after receiving their first dose of 
vaccine.  If there is 0 or 1 DLT, then this dosage level will be considered the MTD and 
patients may begin enrolling into the phase II portion of the study.  If 2 patients have 
DLT at this dosage level, the dosage level in cohort 2 will be considered the MTD.  If 
only 3 patients were enrolled in cohort 2, an additional 3 patients will be enrolled at that 
dosage before proceeding to phase II. 
4) Phase II cohort: After the MTD is established, an additional 12 patients will receive Ad5 
[E1-, E2B-]-CEA(6D) at the MTD every 3 weeks for 3 immunizations. 
 
Note: if during accrual of patients in the phase II cohort, DLT occurs at a sufficient rate 
such that the rate of DLT amongst the total number of patients (those treated at MTD in 
phase I and those in phase II) is ≥33%, then phase II will be restarted at the dosage level 
which is one level below the prior MTD.  
5) Patients will have 90 mL peripheral blood drawn prior to each immunization and 
approximately 3 weeks after the third immunization (Week 9) to determine whether there 
is an effect on the immune response at specific time points during the study and/or after a 
specific number of immunizations. 
6) Time to progression will be measured using CT scans performed at approximately 
3 month intervals (based on clinical standard of care). 
7) For all patients, if scheduling conflicts arise, the scheduled 3-week interval between 
immunizations may be modified so that the interval between immunizations is between 
20 and 28 days (3 weeks -1 day to 3 weeks +7 days).  If the second and/or third 
immunization is delayed, the subsequent immunizations should occur no earlier than 
20 days after the previous immunization. 
9) The following safety events will trigger a temporary suspension of study vaccinations: 
a) If ≥66% of patients in cohort 1 experience DLT 
b) If ≥33% of patients in the phase II cohort experience DLT at dosage level 1 (i.e.,1 x 
109 particles) 
c) If one or more patients develop a Grade 4 allergic reaction without a clear 
attributable cause, other than study vaccine 
d) If, at any time, more than 50% of patients experience a Grade 3 or 4 major organ 
toxicity 
e) Death not attributed to disease. 
 
Assessment of these halting rules is a review of cumulative events for all study 
participants, and should not be confused with reasons for delaying or terminating the 
immunization schedule of any individual patient. 
The Scientific Monitoring Subcommittee of the Cancer Protocol Committee (CPC) will 
fully review all available safety data, consult with the principal investigator, medical 

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Figure 3B. 
 
 
Table 3. Calculation of rates of DLT during patient accrual in phase I and phase II 
# evaluable 
for toxicity 
1,2,3 
4,5,6 
7,8,9 
10,11,12 
13,14,15 
16,17,18 
# with DLT 
to be ≥33% 
1 
2 
3 
4 
5 
6 
 
Phase II cohort 
N=12  
(monitor DLT rate for phase I  
and phase II cohorts at this 
dose level combined) 
DLT > 33% at any point  
(see table) 
DLT 
<33% 
Complete accrual 
If phase II is 
at dosage  
level 3 
Restart phase II  
at dosage  
level 2 
If phase II is 
at dosage  
level 2 
Restart phase II  
at dosage  
level 1 
If phase II is 
at dosage  
level 1 
Stop and 
Re-evaluate 
study 

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6.1. Pharmaceutical Information 
6.1.1 Dosage and Administration 
 
Patients will receive Ad5 [E1-, E2B-]-CEA(6D) at a dose of 1 x 109, or 1 x 1010,    
particles subcutaneously (SQ) in 0.5 mL of a buffered saline solution every 3 
weeks for 3 immunizations and patients who receive 1x1011 VP will receive 
Ad5[E1-, E2b-]-CEA(6D) in 0.7 mL of ARM formulation buffer SQ every 3 
weeks for 3 immunizations. 
 
6.1.2 How Supplied 
ETBX-011 will be provided in a frozen state in a 2ml vial with a fill volume of 
0.5 ml of extractable vaccine which contains 1X1011 total virus particles. The 
volume of injection for 1x1011 virus particles is 0.5 mL. The lower doses will be 
produced by dilution in 0.9% saline using the following directions. The product 
should be stored at </= –20°C until used. 
 
Instructions for dose preparation: 
1.  To administer 1x10e9 virus particles by subcutaneous injection: 
From a 5.0mL vial of 0.9% sterile saline remove 0.05mL of fluid which leaves 
4.95mL. Then remove 0.05mL from the vial labeled ETBX-011 and deliver this 
volume into the 5mL sterile saline vial. Mix the contents by inverting the 5mL 
diluted drug. Then with draw 0.5mL of diluted drug and deliver to the patient by 
subcutaneous injection (detailed description of dose preparation is described in 
the packaging insert). 
 
2. To administer 1x10e10 virus particles by subcutaneous injection: 
From a 5.0mL vial of 0.9% sterile saline remove 0.5mL of fluid which leaves 
4.5mL. Then remove 0.5mL from the vial labeled ETBX-011 and deliver this 
volume into the 5mL sterile saline vial. Mix the contents by inverting the 5mL 
diluted drug. Then with draw 0.5mL of diluted drug and deliver to the patient by 
subcutaneous injection (detailed description of dose preparation is described in 
the packaging insert). 
 
3. To administer 1x10e11 virus particles by subcutaneous injection: 
Withdraw 0.5mL of contents from vial and administer each subject without any 
further manipulation. 
 
 
 
 
 
 

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6.1.3 Disposal of Unused Vaccine 
Unless other arrangements are agreed in writing, all unused vaccine should be 
delivered to Dr. Joseph P. Balint, Etubics Corporation, 410 West Harrison Street, Suite 100, 
Seattle, Wa 98119 for disposal at or before the completion of the clinical study. 
7. TREATMENT EVALUATION 
7.1. Short-Term Evaluation During and After Active Immunotherapy  
On vaccine administration days, blood will be drawn before administration.  Evaluations 
will also be conducted for patients who discontinue from the study if they have received any 
treatment.  The investigator will determine the degree of evaluation based on the patient's 
condition and/or reason for discontinuation from the study. 
7.1.1 General Evaluations (each visit for immunization) 
General evaluations include medical history, Karnofsky performance status, and 
complete physical examination with weight.  Any other treatments, medications, 
biologics, or blood products that the patient is receiving or has received since the 
last visit will be recorded.  Patients will remain in the clinic for approximately 
30 minutes following receipt of vaccine to monitor for any adverse reactions.  Local 
and systemic reactogenicity after each dose of vaccine will be assessed daily for 3 
days (on the day of immunization and 2 days thereafter) using diary cards to report 
symptoms and a ruler to measure local reactogenicity. 
7.1.2 Hematological and Biochemical Assessment 
Blood chemistry and hematology, including CBC with differential, Na, K, Cl, CO2, 
BUN, creatinine, Ca, total protein, albumin, total bilirubin, alkaline phosphatase, 
AST, ALT and glucose will be drawn at Week 0,3,6,9, at discontinuation of 
treatment (if treatment is discontinued early), and as clinically indicated. 
7.1.3 Biological Markers 
Serum (5ml) to measure antibodies to CEA and the Ad5 vector will be obtained at 
Week 0, approximately 3 weeks after the last immunization (approximately 
Week 12), and every 3 months thereafter. 
7.1.4 Immunological Assessment 
Peripheral blood (90 mL = 9 yellow tops = 62ml; 1 purple top = 7 ml; 3 red tops = 
21ml) will be drawn prior to each immunization and approximately 3 weeks after 
the last immunization to determine whether there is an effect on the immune 
response at specific time points during the study and/or after a specific number of 
immunizations.  Peripheral blood mononuclear cells (PBMC) will be assayed for T 
cell responses to CEA using ELISPOT at all time points, plus proliferation assays, 
multi-parameter flow cytometric analysis, and cytoxicity assays, if possible and at 
the discretion of the investigator.  Plasma will be archived from the initial and 
Week 9 blood draws for evaluating antibody levels. 

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7.1.5 Imaging Studies 
CT or MRI scans of the chest, abdomen, and/or pelvis, will be requested (but not 
required) within 1-4 weeks after the third dose of vaccine.  At a minimum, the same 
imaging modality of the same portion of the body should be performed at each time 
point. 
7.1.6: Ad 5 neutralizing Ab assessment 
Serum will be sent to Etubics for Ad5 neutralizing level determination 
7.1.7: Monitoring for replication competent virus 
 
If patients become febrile to >101.0 F or AST or ALT> 3 x ULN, then we will draw 
serum for replication competent virus analysis. 
 
7.2. Long-Term Follow-Up 
Patients will be requested to continue long-term follow-up at Duke University 
Medical Center every 3 months for 1 year, while on the study (i.e., have not 
progressed or been removed from the study for other reasons). At each visit, a 
medical history and physical exam and labs (Blood chemistry and hematology, 
including CBC with differential, Na, K, Cl, CO2, BUN, creatinine, Ca, total protein, 
albumin, total bilirubin, alkaline phosphatase, AST, ALT and glucose) will be 
drawn. 
At each visit, 40-90 mL of peripheral blood for immune analysis may be drawn, if 
there was previous evidence of an immune response or at the discretion of the 
investigator. 
7.3. Management of Intercurrent Events 
7.3.1 Concomitant Medications 
Patients will be removed from the protocol treatment if they initiate concomitant 
chemotherapeutic agents, corticosteroids, or other immunosuppressive agents, or 
other forms of immunotherapy.  After meeting the inclusion criteria, all other 
medications deemed appropriate for the patient, by the investigator, may be 
administered to the patient.  All medications and changes in medication during 
treatment will be recorded.  Hormonal therapy and bisphosphonates may be 
continued in breast cancer patients if they have been stable on the agents for at least 
1 month prior to enrollment. 
7.3.2 Adverse Events 
7.3.2.1 Toxicity will be graded according to the NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 (which can be downloaded from 
the CTEP web site (http://ctep.cancer.gov).)  Dose-limiting toxicity (DLT) is 
defined in section 6. 
7.3.2.2 Possible side effects from immunization may include local effects (pain, 
tenderness, rednesss or swelling), systemic effects (malaise, fatigue, myalgia, 

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arthralgia, headache, nausea, vomiting, chills or fever), and allergic reactions 
such as hives, rash or anaphylactic reactions.  Induction of auto-immunity, 
manifest as arthritis, serositis, nephritis, thyroiditis, colitis, neutropenia, etc., 
is theoretically possible, but has not been observed in our prior CEA vaccine 
studies.  Also, liver function test abnormalities and liver failure are 
theoretically possible. 
7.3.3 Treatment of Toxicity 
For acute allergic reactions, use of diphenhydramine 25-50 mg IV, corticosteroids 
(Solumedrol 100 mg), and epinephrine (1:1000, 0.3-1 mL sq) should be considered.  
These medications are available in the clinical setting where the vaccine will be 
administered.  For auto-immunity, corticosteroids (prednisone 0.5-1 mg/kg/d) 
should be considered.  Clinical assessment of other targets, such as thyroid, 
arthritis, urticaria, or proteinuria, for auto-immunity and serum sickness like 
antigen-antibody complex disease, will also be performed as indicated. 
7.3.4 Active Immunotherapy will be Discontinued for: 
7.3.4.1 Life-threatening anaphylactic reactions related to active immunotherapy 
7.3.4.2 Dose-limiting toxicity related to active immunotherapy 
7.3.4.3 Disease progression (by RECIST criteria).  Patients will be offered 
referral to a medical oncologist at Duke University Medical Center for 
discussion of other treatment options, and for continued medical care.   
7.3.4.3.1 
Disease progression prior to completing the 3 study 
immunizations: In the event that a patient undergoes reimaging studies 
prior to the completion of their 3 study immunizations and is found to 
have disease progression, they will be permitted to continue on the study 
as long as the progression has been 50% or less by RECIST criteria. 
7.3.4.4 If non-dose-limiting toxicity occurs in a patient having at least a partial 
response to the vaccine (as defined below and including mixed 
responses), if the toxicity is not threatening to vital organs, and it 
appears to be reversible; then individual patients will be allowed to 
continue on the study, once the risks and benefits of continuing on the 
study have been discussed and documented. 
If a patient is removed from the study prior to completion of the assigned vaccine 
schedule for any reason other than toxicity, that patient will be replaced, in order to 
obtain data to help determine the toxicity of the immunizations. We will allow up to 3 
replacements per cohort (Phase I, Dose levels 1 and 2; Phase II, MTD). 
8. STATISTICAL CONSIDERATIONS 
8.1. Safety:  
We will evaluate safety continuously in a cohort.  We will make our overall assessment 
of whether to escalate to the next dose level at least 3 weeks after the last patient in the previous 
cohort has received their first injection.  A dosage level will be considered safe if <33% patients 

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treated at a dose level experience dose-limiting toxicity (i.e., 0 of 3, 1 of 6, 3 of 12, or 5 of 18 
patients).  Dose-limiting toxicity is defined in section 6.  Safety will be evaluated in 3 or 6 
patients at each dosage level in phase I.  Safety will continue to be monitored among additional 
patients treated at the MTD in phase II.  A patient will be considered evaluable for safety if 
treated with at least one immunization.  DLTs will be observed through 9 weeks to accommodate 
safety evaluation of all 3 product doses. 
8.2. Rate of Immune Response:  
We will determine the percentage of patients with a positive immune response.  We 
define a positive immune response by ELISpot as described at the 2002 Society of Biologic 
Therapy Workshop on “Immunologic Monitoring of Cancer Vaccine Therapy”, i.e. a T cell 
response is considered positive if the mean number of spots adjusted for background in six wells 
with antigen exceeds the number of spots in six control wells by 10 and the difference between 
single values of the six wells containing antigen and the six control wells is statistically 
significant at a level of p ≤ 0.05 using the Student’s t test.  Immunogenicity assays will occur 
prior to each immunization and at week 12.  Immune response will be assessed among the 18 
patients treated at the MTD (12 in phase I and 12 in Phase II).  The therapy will be considered of 
further interest if 9 of 18 patients treated at the MTD dose exhibit an immune response as 
defined above.  Meeting this criterion establishes that the immune response rate is at least 33% 
with approximately 90% confidence.  At significance level 0.1 there is 82% power to test the null 
hypothesis that the immune response rate is ≤ 0.33 versus the alternative that the immune 
response rate is ≥ 0.58.  The magnitude of response will also be described.  A patient will be 
considered evaluable for immune response if they receive at least 3 immunizations. 
8.3. Determination of Clinical Response 
Among patients with measurable/evaluable disease, response determination will be made 
according to the RECIST criteria: 
Complete Response (CR): 
Disappearance of target lesion, confirmed at 4    
weeks 
Partial Response (PR): 
30% decrease in longest dimension of target lesion, 
confirmed at 4 weeks 
Stable Disease (SD): 
 
Neither PR nor PD 
Progressive Disease (PD): 
20% increase in longest dimension of target lesion; 
no CR, PR, or SD documented before increased 
disease. 
The exact binomial confidence interval for the proportion of subjects with a clinical 
response of CR or PR will be calculated. 
9. PATIENT WITHDRAWAL 
Patients may be removed from the study for the following reasons: 
 Dose-limiting toxicity, as defined in section 6.   
 Patient voluntarily decides to withdraw. 

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 Patient non-compliance with the study protocol. 
 Intercurrent disease which in the opinion of the patient’s treating physician would 
affect the ability of the patient to continue on the clinical study.  
In the event that a patient withdraws, the patient will be asked to have “off treatment” 
evaluations performed, which may include 40-90 mL of blood drawn for immunologic testing. 
10. STUDY CONDUCT AND ETHICAL AND REGULATORY CONSIDERATIONS 
10.1. Departure from the Protocol 
There should be no departure from the protocol if at all possible.  If an emergency occurs 
that requires departure from this protocol, the investigator or other physician in attendance in 
such an emergency will, if circumstances and time permit, contact the principal investigator 
(Dr. Michael Morse) or in his absence, Dr. H. Kim Lyerly, immediately by telephone 
(Page operator 919 684-8111).  Such contacts with the principal investigator will be made to 
permit a decision as to whether or not the patient will be continued on the study.  Such 
departures need to be clearly documented and reported to the IRB and the sponsor (Etubics) by 
the principal investigator. 
10.2. Informed Consent 
In accordance with guidelines in the Federal Register, Vol. 48, No. 17, 1982, pp. 8951-2, 
all patients are required to sign a statement of informed consent.  This phase I/II study involves 
research that presents risk, but holds the prospect of direct benefit to the individual patient 
(46.405-45 Code of the Federal Regulations part 46).  The investigator will report to the IRB and 
the sponsor (Etubics) will report to FDA changes in the research protocol and all unanticipated 
problems involving risks to human patients and others, and no changes will be made in the 
research activity without IRB approval. 
10.3. Institutional Review 
This study must be approved by the Institutional Review Board (IRB).  IRB approval of 
the protocol and the informed consent form for this study must be given in writing.  The IRB 
must also approve any significant changes to the protocol as well as a change of principal 
investigator.  Records of all study review and approval documents must be kept on file by the 
investigator and are subject to FDA inspection during or after completion of the study.  Adverse 
events must be reported to the IRB.  The IRB will receive notification of the completion of the 
study and final report within three months of study completion or termination.  The investigator 
must maintain an accurate and complete record of all submissions made to the IRB, including a 
list of all reports and documents submitted. 
 
10.4. Documentation and Monitoring 
Data will be collected for all patients.  Accurate completion of the computer data forms 
for all patients is the responsibility of the investigator.   
 

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10.4.1 Case Report Forms 
Case Report Forms (CRFs) are used to record study data and are an integral part of the 
study and subsequent reports.  Therefore, all reports must be legible and complete.  All forms 
should be filled out using a black ballpoint pen.  Errors should be lined out but not obliterated 
and the correction inserted, initialed, and dated by the principal investigator, co-investigators, 
study coordinator, or data manager.  A Case Report Form must be completed and signed by the 
principal investigator for each patient enrolled, including those removed from the study for any 
reason.  The reason for removal must be noted on the Final Report Form by the investigator for 
each patient.  Case Report Forms must be kept current to reflect patient status at each phase 
during the course of the study.  Patients are not to be identified on case report forms by name; 
appropriate coded identification and patient initials must be used.  The investigator must keep a 
separate log of patient names and addresses.  This log is subject to FDA inspection.  Because of 
the potential for errors, inaccuracies, and illegibility in transcribing data onto case report forms, 
originals of laboratory and other test results must be kept on file with patient's case report form 
or clinical chart.  Case report forms and copies of test results must be available at all times for 
inspection by the FDA.   
 
10.4.2 Maintenance of Study Documentation 
The following will be maintained: 
a. Case Report Forms - which must be kept legible, accurate, and up-to-date. 
b. Patient Files/Signed Informed Consent - which substantiates the data entered 
on the case report forms for all required test and evaluation procedures and 
verifies that the patient has signed an informed consent to enter the study. 
c. Patient Exclusion Record - which should reflect the reason any patient was 
screened and found ineligible for the study. 
d. Monitoring Log - listing dates of monitor visits. 
e. Regulatory Documents - including protocol, investigator brochure, FDA Form 
1572, CVs, IRB correspondence, IRB approval/renewals and IRB approved 
consent form. 
f. Adverse Experience Report Form - which should explain any serious or 
unexpected adverse experiences. 
All study documentation pertaining to the conduct of the study must be kept on file by the 
investigator for a period of 2 years following the date a marketing application is approved for the 
drug for the indication for which it is being investigated; or, if no application is to be filed or if 
the application is not approved for such indication, until 2 years after the investigation is 
discontinued and FDA is notified.  The sponsor will notify the investigator if a marketing 
application is approved or if the investigation is discontinued and the FDA notified. 
10.5. Monitoring of the Protocol 
Protocol data and safety will be monitored by the Scientific Monitoring Subcommittee of 
the Cancer Protocol Committee (CPC) with the following plan: 

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1.  Purpose:  This is a phase I/II clinical study with more than minimal risk and as such 
will be monitored for the occurrence of a greater frequency of AEs. 
2.  Monitoring: Up to 24 patients will be enrolled.  The principal investigator will 
continuously monitor the study.  The principal investigator will review the data and 
safety of the study after the enrollment of three patients in cohort 1, after enrollment 
of three patients in cohort 2, and after enrollment of six patients in cohort 3.  Formal, 
independent monitoring by CPC will occur after enrollment of the three patients in 
cohort 1 and again after enrollment of three patients in cohort 2; then a scientific 
progress review will occur yearly, assuming a result of “satisfactory” on the initial 
review.  The exceptions are as follows:  If more than one patient experiences a Grade 
4 or greater allergic reaction, the principal investigator will request a monitoring 
review by CPC.  If at any time, more than 50% of patients experience a Grade 3 or 4 
major organ toxicity, we will request a monitoring review by CPC. 
3.  Description of Monitoring:  Adverse event reports will be reviewed with tabulation of 
all Grade 2, 3 or 4 toxicity.  
4. Toxicity:  see section 7.3.2 of the protocol.  
5. Reporting Adverse Events: An adverse experience is any adverse change from the 
study patient's baseline (pre-treatment) condition, including any clinical or laboratory 
test abnormality that occurs during the course of the proposed clinical study after 
treatment has started.  All adverse experiences that are classified as serious as 
described in section 10.7 of the protocol should be reported to the sponsor (Etubics) 
by telephone or fax within 24 hours, and reported in writing to the sponsor (etubics) 
within 72 hours.  All study-related deaths should be reported to the IRB within 24 
hours; all other serious adverse experiences should be reported to the IRB within 5 
business days. All deaths, whether considered study-related or not, must also be 
reported immediately to the principal investigator, with a copy of the autopsy report 
and the death certificate.  All adverse experiences will be recorded on the Adverse 
Experience Case Report Form.  This report form should include severity, duration, 
outcome, and the investigator's judgment as to the relationship of the adverse 
experience to treatment.   
6. Reporting of Pregnancy: If a participant becomes pregnant during the study, treatment 
will be discontinued (i.e., no additional dose of study vaccine will be given) and the 
participant will be encouraged to continue to have regularly scheduled follow-up 
visits and evaluations.  The occurrence of pregnancy, and the outcome of any 
pregnancy, in a subject treated with study vaccine, must be reported to the sponsor 
(Etubics), and to the IRB.   
 
10.6. CTCAE Term (AE description) and Grade:   
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting.  All 
appropriate treatment areas should have access to a copy of the CTCAE version 4.0.  A copy of 
the CTCAE version 4.0 can be downloaded from the CTEP web site (http://ctep.cancer.gov).  

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The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each 
AE based on the following guideline: 
Grade 1 
Mild AE 
Grade 2 
Moderate AE 
Grade 3 
Severe AE 
Grade 4 
Life-threatening or disabling AE 
Grade 5 
Death related to AE 
10.7. Serious Adverse Event Reporting 
Events are classified as SERIOUS if they meet any of the following criteria [per the US 
Code of Federal Regulations (CFR) 21 CFR 312.32 and the recommendations of the 
International Conference on Harmonization (ICH)]: 
An SAE is any sign, symptom or medical condition that emerges during the study or 
during a post-study follow-up period that 1) was not present at the start of the study and is not a 
chronic condition that is part of the patient’s medical history, OR 2) was present at the start of 
the study or as part of the patient’s medical history but worsened in severity and/or frequency 
during study participation, AND that meets any of the following regulatory serious criteria: 
 any death 
 any life-threatening event, i.e., an event that places the patient, in the view of the 
investigator, at immediate risk of death from the event as it occurred (does not 
include an event that, had it occurred in a more severe form, might have caused 
death) 
 any event that requires or prolongs in-patient hospitalization 
 any event that results in persistent or significant disability/incapacity 
 any congenital anomaly/birth defect diagnosed in a child of a patient who 
participated in this study and received investigational drug 
 other medically important events that in the opinion of the investigator may 
jeopardize the patient or may require intervention to prevent one of the other 
outcomes listed in the definition above (e.g. allergic bronchospasm requiring 
intensive treatment in an emergency room, convulsions occurring at home that do 
not require in-patient hospitalization, any blood dyscrasias, or the development of 
drug dependency or drug abuse). 
 
Procedures for adverse event reporting 
 
  1.  PI notified by medical staff of a SAE 
 
PI: Michael Morse, MD 
            Address: Duke University Medical Center 
Seeley Mudd Building  
Box 3233, Durham, NC 27710 
 
Telephone: 1-919-681-3480 
 
Fax: 1-919-681-7970 
Pager 1-919-970-5626 
 
Email: michael.morse@duke.edu 

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2. PI calls sponsor to report an unexpected SAE associated with the use of the drug 
 
 
Sponsor: Carol Jones, Vice President of Administration 
 
Address: 410 West Harrison Street, Suite 100, Seattle, WA 981119 
 
Telephone: 206-838-5110 ext. 102 
 
Cell: 1-206-818-2985 
 
Fax: 1-206-838-2978 
 
Email: cj@etubics.com 
 
  3.  Carol Jones reports the SAE to one of the following in this order: 
 
      A.  Chief Scientific Officer: Frank Jones, PhD  
 
Address: 410 West Harrison Street, Suite 100, Seattle, WA 98119  
 
Telephone: 206-838-5110 ext. 101 
 
Cell: 206-818-2857 
 
Fax: 206-838-2978 
 
Email: frj@etubics.com 
      B.  Laboratory Manager:  Joseph Balint, PhD 
 
Address: 410 West Harrison Street, Suite 100, Seattle, WA 98119 
Telephone: 206-838-5110 ext. 107 
Fax:  206-838-2978 
 
Email: joe@etubics.com 
      C.  Vice President Research: Elizabeth S. Gabitzsch 
 
Address: 410 West Harrison Street, Suite 100, Seattle, WA 98119 
Telephone: 206-838-5110 ext. 103 
Cell: 970-402-2598 
Fax:  206-838-2978 
 
Email: beth@etubics.com 
 
 
4. Contacted person in three (3) above notifies the FDA on MedWatch 3200A form. 
a. If the SAE results in death or is life-threatening, report the SAE to the FDA within 7 days 
b. All other SAEs must be reported to FDA within 15 days 
 
5. If the SAE requires input from a physician then the Acting Medical Director is consulted: 
 
Herbert K. Lyerly, MD 
 
      Telephone: 919-684-5613 
      Fax:  919-684-5653 
 
Email: rberenson@gmail.com 
 
All SAE reports will be recorded on the Duke IRB Adverse Event Reporting form and 
will be reviewed and signed by the Principal Investigator.  Only adverse events that are deemed 
to be serious, unexpected and related or possibly related to the research must be reported to the 
IRB (this is in accordance with Duke’s IRB reporting policy). All reportable events will be 
forwarded to the IRB via campus mail or fax: 
 
 
 

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IRB: 
Duke Medical Center Institutional Review Board: 
Hock Plaza, 4th floor 
2424 Erwin Road 
Box 2991 
Durham, NC  27705 
Fax: 919-668-5125 
 
In accordance with FDA regulations and ICH guidelines, investigators will be notified of the 
occurrence of new, serious, unexpected adverse events associated with the use of the study 
medication (i.e. there is a reasonable possibility that the adverse event may have been caused by 
the drug) within 15 calendar days via a written report.  It is the responsibility of the investigator 
to promptly inform the relevant Institutional Review Board (IRB) of these new adverse 
events/risks to patients, in accordance with 21 CFR 312.66.  It is also the responsibility of the 
investigator and the sponsor (Etubics) in conducting gene transfer research to promptly inform 
the NIH Office of Biotechnology Activities (OBA) and relevant Scientific Review Board of 
these new adverse events/risks to patients, in accordance with NIH Guidelines for Research 
Involving Recombinant DNA Molecules, in particular Appendix M.  It is the responsibility of the 
sponsor (Etubics) to report these serious adverse events to the FDA.  The SAE report will be 
forwarded to the FDA after recording the event data via the FDA MedWatch form 3500A.   
 
MedWatch 3500A Reporting Guidelines: 
In addition to completing appropriate patient demographic and suspect medication 
information, the report should include the following information within the Event Description 
(section 5) of the MedWatch 3500A form: 
Treatment regimen (dosing frequency, combination therapy) 
Protocol description (and number, if assigned) 
Description of event, severity, treatment, and outcome, if known 
Supportive laboratory results and diagnostics 
Investigator’s assessment of the relationship of the adverse event to each investigational 
product and suspect medication 
Follow-up information:   
Additional information may be added to a previously submitted report by any of the 
following methods: 
 Adding to the original MedWatch 3500A report and submitting it as follow-up 
 Adding supplemental summary information and submitting it as follow-up with the 
original MedWatch 3500A form  
 Summarizing new information and faxing it with a cover letter including patient 
identifiers (i.e. D.O.B., initials, patient number), protocol description and number, if 
assigned, suspect drug, brief adverse event description, and notation that additional or 
follow-up information is being submitted  (The patient identifiers are important so that 
the new information is added to the correct initial report.) 
 
 

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10.8. Assessing Causality: 
Investigators are required to assess whether there is a reasonable possibility that study 
medications caused or contributed to an adverse event.  The following general guidance may be 
used. 
Yes: 
if the temporal relationship of the clinical event to study drug administration makes a 
causal relationship possible, and other drugs, therapeutic interventions or underlying 
conditions do not provide a sufficient explanation for the observed event. 
No: 
if the temporal relationship of the clinical event to study drug administration makes a 
causal relationship unlikely, or other drugs, therapeutic interventions or underlying 
conditions provide a sufficient explanation for the observed event. 
10.9. Safety Reporting Requirements for IND Holders 
In accordance with 21 CFR 212.32, sponsor-investigators of studies conducted under an 
IND must comply with following safety reporting requirements:  
 
a. Expedited IND Safety Reports: 
7 Calendar-Day Telephone or Fax Report:   
The sponsor is required to notify the FDA of any fatal or life-threatening adverse event 
that is unexpected and assessed by the investigator to be possibly related to the use of the 
investigational product.   An unexpected adverse event is one that is not already described in the 
Investigator’s Brochure.  Such reports are to be telephoned or faxed to the FDA within 
7 calendar days of first learning of the event.   
15 Calendar-Day Written Report:   
The sponsor is also required to notify the FDA and all participating investigators, in a 
written IND Safety Report, of any serious, unexpected AE that is considered possibly related to 
the investigational product.  An unexpected adverse event is one that is not already described in 
the Investigator Brochure. 
Written IND Safety Reports should include an Analysis of Similar Events in accordance 
with regulation 21 CFR § 312.32.  All safety reports previously filed with the IND concerning 
similar events should be analyzed.  The new report should contain comments on the significance 
of the new event in light of the previous, similar reports.   
Written IND safety reports with Analysis of Similar Events are to be submitted to the 
FDA and all participating investigators within 15 calendar days of first learning of the event.  
The FDA prefers these reports on a MedWatch 3500A Form but alternative formats are 
acceptable (e.g. summary letter). 
 

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b. IND Annual Reports 
In accordance with the regulation 21 CFR § 312.32, the sponsor shall within 60 days of 
the anniversary date that the IND went into effect submit a brief report of the progress of the 
investigation.  Please refer to Code of Federal Regulations, 21 CFR § 312.32 for a list of the 
elements required for the annual report.   
 
c. Data and Safety Monitoring  
Data will be collected by: the principal investigator, co-investigators, and the protocol 
coordinator.  The protocol coordinator under the supervision of the principal investigator will 
report the AEs. The data will be audited by the CPC and Etubics’ CRA.  
 
11. REFERENCES 
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of 
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cytotoxic 
T 
lymphocyte 
epitopes 
from 

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38 
 
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factor, in patients with carcinoembryonic antigen-expressing carcinomas. J Clin Oncol 
23:720-731. 

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Protocol Version 1.1, December 21, 2009 
 
40 
 
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immunity and achieves tumor eradication. Hum Gene Ther 11:53-65. 
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Molecular Therapeutics Program 
Protocol Version 2.0, 13 April 2010 
 
Molecular Therapeutics Program  
1 
 
A PHASE I/II STUDY OF ACTIVE IMMUNOTHERAPY WITH Ad5 [E1-, E2b-]-
CEA(6D)  
VACCINE 
(ETBX-011) 
IN 
PATIENTS 
WITH 
ADVANCED 
OR 
METASTATIC MALIGNANCIES EXPRESSING CEA  
 
Principal Investigator: 
 
Michael Morse, M.D. 
 
 
 
 
 
Duke University Medical Center 
 
 
Agents Used in This Study:  
Ad5 [E1-, E2b-]-CEA(6D)  (ETBX-011) 

Molecular Therapeutics Program 
Protocol Version 2.0, 13 April 2010 
 
Molecular Therapeutics Program  
2 
 
Names and addresses of key study personnel: 
Study Chairman and Principal Investigator 
Name:  Michael Morse, MD 
Address: Duke University Medical Center 
Box 3233, Durham, NC 27710 
Telephone:  (919) 681-3480 
Fax:  (919) 681-7970 
Email: michael.morse@duke.edu 
Bioassay Oversight/Laboratory Oversight 
Name:  Timothy Clay, PhD 
Address: Duke University Medical Center 
Box 2606, Durham, NC 27710 
Telephone:  (919) 684-0350 
Fax:  (919) 681-7970 
Email: clay0017@c.duke.edu 
Biostatistician  
Name:  Donna Niedzwiecki, PhD 
Address: Duke University Medical Center 
Box 3958, Durham, NC 27710 
Telephone: (919) 681-5030 
Fax:  (919) 691-8028 
E-mail: donna.niedzwiecki@duke.edu 
Other Applicable Staff 
Title:  Acting Medical Director  
Name: Ron Berenson, MD  
Address: 410 West Harrison Street, 
Seattle, WA. 98119  
Telephone: 206-790-1094 
Fax:(206) 838-2978 
Email: rberenson@gmail.com 
Pharmacist or Person Responsible for Drug 
Accountability       
Name: Cheryl Morgan 
Address: Morris Pharmacy, Duke University 
Medical Center, Trent Drive, 
Durham, NC 27710 
Telephone:  (919) 668-0657 
Fax: (919) 668-3895 
Email: cheryl.morgan@duke.edu 
Other Applicable Staff: 
Title:  CEO and CSO, Etubics Corporation 
Name:  Frank R. Jones, Ph.D. 
Address: Etubics Corporation 
   410 West Harrison Street 
   Seattle, WA 981119 
Telephone: 206-838-5110 Ext 101 
Fax:  206-838-2978 
Email: frj@etubics.com 
Other Consultants: 
H. Kim Lyerly, MD, Duke University 
Andy Amalfitano, DO, PhD, Michigan State 
University 
Elizabeth Gabitzsch, Etubics Corporation 
Raj Dua, Ph.D., Etubics Corporation 
 

Molecular Therapeutics Program 
Protocol Version 2.0, 13 April 2010 
 
Molecular Therapeutics Program  
3 
 
 
TABLE OF CONTENT 
 
 
 
 
 
 
 
 
 
 
 
Page Number 
 
 
1. Protocol Summary …………………………………………………..  4 
 
2. Study Objectives …………………………………………………….  6 
 
3. Background and Significance ……………………………………….  6 
 
4. Patient Selection …………………………………………………….. 15 
 
5. Pre-Treatment Evaluation …………………………………………… 19 
 
6. Treatment Plan ………………………………………………………. 20 
 
7. Treatment Evaluation ………………………………………………... 25 
 
8. Statistical Considerations ……………………………………………. 28 
 
9. Patient Withdrawal …………………………………………………... 29 
 
10. Study Conduct and Ethical and Regulatory Considerations …………. 29 
 
11.  References …………………………………………………………… 37 
 
12.  Appendix …………………………………………………………….. 43 
 

Molecular Therapeutics Program 
Protocol Version 2.0, 13 April 2010 
 
Molecular Therapeutics Program  
4 
 
1. PROTOCOL SUMMARY 
Title 
A PHASE I/II STUDY OF ACTIVE IMMUNOTHERAPY WITH 
Ad5 [E1-, E2b-]-CEA(6D)  VACCINE (ETBX-011) IN PATIENTS 
WITH 
ADVANCED 
OR 
METASTATIC 
MALIGNANCIES 
EXPRESSING CEA 
Objectives 
a) The primary objective of this protocol is to determine the safety of 
immunization with Ad5 [E1-, E2B-]-CEA(6D), in patients with 
advanced or metastatic CEA-expressing malignancies.  
b) The secondary objectives are to evaluate CEA-specific immune 
responses to the immunizations and to obtain preliminary data on 
clinical response rate. 
Major Inclusion/ 
Exclusion Criteria 
Patients with a histologically confirmed diagnosis of metastatic 
malignancy who were previously treated with standard therapy known to 
have a possible survival benefit or refused such therapy.  The tumor must 
express CEA as defined by any of the following: immunohistochemical 
staining (at least 50% of the tumor with at least moderate intensity of 
staining), or a tumor known to be universally CEA positive (i.e. colon 
and rectal cancer). In addition, only colorectal adenocarcinomas (for 
those with colorectal cancers) can be enrolled. Patients will not be treated 
until 4 or more weeks after any prior chemotherapy or radiation therapy, 
but may be receiving non-cytotoxic targeted therapy (bevacizumab, 
cetuximab, trastuzumab, erlotinib, or gefitinib) or hormonal therapy.  
They must not have a history of autoimmune disease, serious intercurrent 
chronic or acute illness, active hepatitis, serologic evidence for HIV, or 
be receiving steroid or immunosuppressive therapy.  All patients must be 
≥ 21 years old and have an ECOG Performance Status of 0 or 1. Pregnant 
women and nursing mothers are excluded.  
Study Design 
Phase I/II study with three dosage levels of Ad5 [E1-, E2B-]-CEA(6D)  
vaccine (phase I component), and the maximally tolerated dose of Ad5 
[E1-, E2B-]-CEA(6D)  vaccine (phase II component).  The study drug is 
Ad5 [E1-, E2B-]-CEA(6D) given by subcutaneous (SQ) injection every 
3 weeks for 3 immunizations.  The following procedures will occur: 
1) Peripheral blood draw of 90 mL for immune analysis 
2) Cohort 1: Three patients will receive Ad5 [E1-, E2B-]-CEA(6D)  
at a dose of 1 x 109 particles SQ in 0.5 mL every 3 weeks for 
3 immunizations.  Assessment of dose-limiting toxicities (DLT) 
for dose escalation will be made after all patients in this cohort 
have had a study visit at least 3 weeks after receiving their first 
dose of vaccine.  If there are no DLT, defined as any Grade 2, 3 
or 4 immediate hypersensitivity reactions or neurological toxicity, 
other Grade 3 or 4 allergic or major organ toxicity, or Grade 4 

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fever, that may possibly be associated with the immunization), 
then patients may begin enrolling into cohort 2.  If there is 1 
DLT, then an additional 3 patients will be enrolled at this dosage 
level. Assessment of DLT for dose escalation will be made after 
the 3 additional patients have had a study visit at least 3 weeks 
after receiving their first dose of vaccine.  If none of these latter 3 
patients have DLT (i.e., 1 DLT in the 6 total patients), then 
patients may begin enrolling into cohort 2. If 2 patients have DLT 
at this lowest dosage level, dosing will be de-escalated to 1 x 108 
particles. 
3) Cohort 2: Three patients will receive Ad5 [E1-, E2B-]-CEA(6D)  at a 
dose of 1 x 1010 particles SQ in 0.5 mL every 3 weeks for 
3 immunizations.  Assessment of DLT for dose escalation will be 
made after all patients in this cohort have had a study visit at least 
3 weeks after receiving their first dose of vaccine.  If there are no 
DLT, then patients may begin enrolling into cohort 3.  If there is 1 
DLT then an additional 3 patients will be enrolled at this dosage 
level. Assessment of DLT for dose escalation will be made after the 3 
additional patients have had a study visit at least 3 weeks after 
receiving their first dose of vaccine.  If none of these latter 3 patients 
have DLT, then patients may begin enrolling into cohort 3. 
4) Cohort 3: Six patients will receive Ad5 [E1-, E2B-]-CEA(6D)  at a 
dose of 1 x 1011 particles SQ in 0.7 mL every 3 weeks for 
3 immunizations.  Assessment of DLT for proceeding to phase II 
enrollment will be made after all patients in this cohort have had a 
study visit at least 3 weeks after receiving their first dose of vaccine.  
If there is 0 or 1 DLT, then patients may begin enrolling into the 
phase II portion of the study.  
5) Phase II cohort: An additional 12 patients will receive Ad5 [E1-, 
E2B-]-CEA(6D) at the maximally tolerated dose every 3 weeks for 
3 immunizations.  
6) Patients will have 90 mL peripheral blood drawn prior to each 
immunization and at Week 9 to determine whether there is an effect 
on the immune response at specific time points during the study 
and/or after a specific number of immunizations. 
7) Time to progression will be measured using CT scans performed as 
per standard of care (approximately 3 month intervals). 
Risks/toxicities 
Potential risks associated with the vaccine include anaphylaxis, fever, 
skin reaction, autoimmunity (colitis), and hepatic insufficiency.   
Number of Patients 
Planned: 24 evaluable patients (plus up to 12 replacements); may require 
30-42 patients if DLT occur. 
Duration of Study 
6 months after the last patient is enrolled; approximately 2 years total 
Criteria for 
Evaluation 
Toxicity will be assessed using CTC toxicity criteria.  CEA-specific 
immune response will be measured by ELISpot.  Time to recurrence will 

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For the following common cancers, the following eligibility criteria apply: 
• Colorectal cancer: Must have received and progressed through at least one 
line of palliative chemotherapy consisting of one of the following regimens: 
- 
Palliative chemotherapy for metastatic colorectal cancer with 
5-fluorouracil (or capecitabine) and oxaliplatin. 
- 
Palliative chemotherapy for metastatic colorectal cancer with 
5-fluorouracil (or capecitabine) and irinotecan. 
- 
Palliative chemotherapy regimen for metastatic colorectal cancer that 
includes bevacizumab. 
- 
Colorectal cancer patients currently receiving palliative single-agent 
bevacizumab or cetuximab will be eligible for this trial and may 
continue these therapies concomitant with study treatment (if they 
have been on these single therapies for at least 3 months). 
• Breast cancer: Must have received and progressed through at least one line of 
chemotherapy for metastatic breast cancer consisting of one of the following 
regimens: 
- 
Palliative anthracycline- or taxane-based chemotherapy 
- 
Patients with tumors that over express HER2 (IHC 3+ or FISH+) must 
have received and progressed through at least one line of palliative 
therapy that combines trastuzumab with chemotherapy.  
- 
Breast cancer patients currently receiving palliative endocrine therapy 
or single-agent trastuzumab will be eligible for this trial and may 
continue these therapies concomitant with study treatment (if they 
have been on these single therapies for at least 3 months). 
- 
Patients who have been treated or offered the option of treatment with 
Bevacizumab (option clearly stated in the Consent Form). 
- 
Patients who have been treated or offered the option of treatment with 
Lapatinib (option clearly stated in the Consent Form). 
• Lung cancer: Must have received and progressed through chemotherapy for 
metastatic disease consisting of one of the following regimens: 
- 
Palliative platinum-based (cisplatin or carboplatin) chemotherapy if 
the patient has not received chemotherapy previously. 
- 
Palliative taxane-based (docetaxel or paclitaxel) or vinorelbine 
chemotherapy if the patient has received chemotherapy previously. 
- 
Lung cancer patients currently receiving palliative single-agent 
erlotinib or gefitinib will be eligible for this trial and may continue 
these therapies concomitant with study treatment (if they have been on 
these single therapies for at least 3 months). 
• Pancreatic cancer: Must have received and progressed through chemotherapy 
including gemcitabine. 

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- 
Pancreatic cancer patients currently receiving palliative single-agent 
erlotinib will be eligible for this trial and may continue this therapy 
concomitant with study treatment (if they have been on this single 
therapy for at least 3 months). 
• 
For other malignancies, if a first line therapy with survival or palliative benefit 
exists, it should have been administered and there should have been 
progressive disease. 
• 
Patients who have received and progressed through first-line palliative 
chemotherapy must be advised regarding second-line therapy before being 
enrolled on this investigational study.  
4.1.4. 
ECOG 0 or 1 performance status 
4.1.5. 
Estimated life expectancy > 3 months.. 
4.1.6. 
Age ≥ 21 years, but <75. 
4.1.7. 
Adequate hematologic function, with WBC ≥ 3000/microliter, hemoglobin 
≥ 9 g/dL (may transfuse or use erythropoietin to achieve this level), platelets 
≥ 75,000/microliter; PT-INR <1.5, PTT <1.5X ULN 
4.1.8. 
Adequate renal and hepatic function, with serum creatinine < 1.5 mg/dL, bilirubin 
< 1.5 mg/dL (except for Gilbert’s syndrome which will allow bilirubin 
≤ 2.0 mg/dL), ALT and AST ≤ 2.5 x upper limit of normal. 
4.1.9. 
Patients who have received prior CEA-targeted immunotherapy are eligible for 
this trial, if this treatment was discontinued at least 3 months prior to enrollment. 
4.1.10. Patients who are taking medications that do not have a known history of 
immunosuppression are eligible for this trial. 
4.1.11. Ability to understand and provide signed informed consent that fulfills 
Institutional Review Board’s guidelines. 
4.1.12.    Ability to return to Duke University Medical Center for adequate follow-up, as         
required by this protocol. 
4.2. Criteria for Patient Exclusion 
4.2.1  
Patients with concurrent cytotoxic chemotherapy or radiation therapy should be 
excluded. There are no exclusions based on the number of prior chemotherapy, 
biologic, hormonal, or experimental regimens. Except for the permitted 
concomitant therapies (bevacizumab, cetuximab, trastuzumab, erlotinib, gefitinib, 
or hormonal therapy which patients must have been on for at least 3 months at the 
time of enrollment if they intend to continue them with the vaccine), there must 
be at least 3 months between any prior CEA-targeted immunotherapy and study 
treatment and at least 4 weeks between any other prior therapy (including 
radiotherapy) and study treatment.  Patients must have recovered from all acute 
toxicities from prior treatment. 
4.2.2. 
Patients with a history of brain metastases will not be permitted 

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4.2.3.  
Patients with a history of autoimmune disease, such as but not restricted to, 
inflammatory bowel disease, systemic lupus erythematosus, ankylosing 
spondylitis, scleroderma, or multiple sclerosis.  Autoimmune related thyroid 
disease and vitiligo are permitted. 
4.2.4. 
Patients with serious intercurrent chronic or acute illness, such as cardiac disease 
(NYHA class III or IV), hepatic disease, or other illness considered by the 
Principal Investigator as unwarranted high risk for investigational drug treatment. 
4.2.5. 
Patients with a medical or psychological impediment to probable compliance with 
the protocol should be excluded. 
4.2.6. 
Concurrent (or within the last 5 years) second malignancy other than 
non-melanoma skin cancer, cervical carcinoma in situ, controlled superficial 
bladder cancer, or other carcinoma in situ that has been treated. 
4.2.7. 
Presence of an active acute or chronic infection including: a urinary tract 
infection, HIV (as determined by ELISA and confirmed by Western Blot) or viral 
hepatitis (as determined by HBsAg and Hepatitis C serology).  Patients with HIV 
are excluded based on immuno-suppression, which may render them unable to 
respond to the vaccine; patients with chronic hepatitis are excluded because of 
concern that hepatitis could be exacerbated by the injections.  Patients with active 
CMV disease will be excluded, but CMV seropositive patients will be eligible. 
4.2.8. 
Patients on steroid therapy (or other immuno-suppressives, such as azathioprine 
or cyclosporin A) are excluded on the basis of potential immune suppression.  
Patients must have had 6 weeks of discontinuation of any steroid therapy (except 
that used as pre-medication for chemotherapy or contrast-enhanced studies) prior 
to enrollment. 
4.2.9. 
Patients with allergies to any component of the vaccine will be excluded from the 
protocol. 
4.2.10. Pregnant and nursing women should be excluded from the protocol since this 
research may have unknown and harmful effects on an unborn child or on young 
children.  If the patient is sexually active, the patient must agree to use a 
medically acceptable form of birth control while receiving treatment and for a 
period of 4 months following the last vaccination therapy. It is not known whether 
the treatment used in this study could affect the sperm and could potentially harm 
a child that may be fathered while on this study. 
4.2.11. Patients with acute or chronic skin disorders that will interfere with injection into 
the skin of the extremities or subsequent assessment of potential skin reactions 
will be excluded. 
4.2.12. Patients will be allowed warfarin 1mg po qd for port prophylaxis but not full dose 
warfarin or low molecular weight heparin. 
4.2.13 
Patients with metastatic disease that is determined to be resectable will be 
excluded. 

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4.3. Accrual 
We expect to accrue a minimum of 24 evaluable patients (plus up to 12 replacements 
for patients removed from the study prior to completion of the assigned vaccine 
schedule for any reason other than toxicity).  The study may require 30-42 patients if 
DLT occur that necessitate re-dosing at a lower dosage levels (see section 6 for a 
description of the dose escalation criteria). 
 
4.4 Assignment of study number: Patients will be assigned study numbers in order of their 
screening using the following: ETBX-011-xxx. 
• Assignment of study day: Day 0 is the day of the first immunization. The second 
immunization is at Day 21. 
 
5. PRE-TREATMENT EVALUATION 
(See also Schema in Appendix 1.) The following pre-treatment evaluations will be completed 
within 1 month (+/- 2 weeks) before starting study treatment: 
• History and physical exam, to include ECOG Performance Score and review of inclusion 
and exclusion criteria 
• ß-HCG for women with childbearing potential 
• Hematological, biochemical and immunological tests: 
CBC with differential 
PT INR and PTT 
Na, K, Cl, CO2, BUN, creatinine, Ca, total protein, albumin, total bilirubin, alkaline 
phosphatase, AST, ALT and glucose 
Urinalysis 
• Infectious Disease 
HIV antibody, Hepatitis BsAg, Hepatitis C serology, CMV serology 
• ECG 
• Biological Markers: 
Serum will be obtained to measure antibodies to CEA and the neutralizing antibodies to 
Ad vector, and other available serum markers (e.g., CEA  or CA15-3) will be reviewed. 
• Archive Samples: 
An additional 20 mL of blood may be drawn during the first clinic visit, when the patient 
history and physical exam are conducted, at the discretion of the immune monitoring 
laboratory, and serum stored for later analysis of immune responses. 
• Imaging studies: 
CT or MRI scans of the chest, abdomen, brain, and/or pelvis will be requested within 1 
month (±2 weeks) before starting study treatment to document the presence and size of 

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any measurable metastatic disease that might present.  CT and MRI are the best currently 
available and reproducible methods to measure target lesions selected for response 
assessment.  Conventional CT and MRI should be performed with cuts of 10 mm or less 
in slice thickness contiguously.  Spiral CT should be performed using a 5 mm contiguous 
reconstruction algorithm.  This applies to tumors in the chest, abdomen, and pelvis. 
 
6. TREATMENT PLAN 
In the phase I component, patients will be enrolled into successive dosage level cohorts 
of 3 or 6 patients and monitored for dose-limiting toxicity (DLT).  
 DLT (based on CTCAE4.0 criteria) is defined as any Grade 2, 3 or 4 immediate 
hypersensitivity reactions, Grade 3 or 4 fever that may possibly be associated with the 
immunization, Grade ≥2 autoimmune events except for vitilgo or fever for less than 2 days and 
less than <101.5 ºF, Grade ≥2 allergic reactions (grade 2 is defined as generalized urticaria), or 
Grade ≥3 non-hematologic toxicity.  
During dose escalation through the first three patients of cohort 3, there will be a 
minimum of 1 week between enrolling successive patients.  If no DLT have been observed at 
this point, then further enrollment can occur in cohort 3 and phase II component without the 
1-week waiting period.  Between dosage levels, assessment of DLT for dose escalation will be 
made after all patients in a cohort have had a study visit at least 3 weeks after receiving their first 
dose of vaccine and all the available safety data and laboratory results have been reviewed by the 
Principle Investigator. If DLT occurs in <33% of patients in a given dosage level cohort, 
progression to the next dosage level will proceed.  If DLT occurs in ≥33% of patients in a given 
cohort, the next lower dosage level will be defined as the maximum tolerated dose (MTD).  If 
DLT occurs in <33% of patients in the highest dosage level tested, that dosage level will be 
defined as the MTD.  In phase II, 12 additional patients will be enrolled at the MTD.  In phase II, 
if at any time the rate of DLT in patients enrolled at the MTD (for the phase I and phase II 
cohorts combined) is ≥33%, the MTD will be re-defined as the next lower dosage level, and 
phase II will proceed with enrollment of additional patients at this lower dosage level.  
Additional details of this dose escalation and de-escalation plan are provided below and in 
Figures 3A, 3B and Table 3.  
1) Phase I: Cohort 1: Three patients will receive Ad5 [E1-, E2B-]-CEA(6D) at a dose of 1 x 
109 particles in 0.5 mL subcutaneously (SQ) in the same thigh every 3 weeks for 
3 immunizations. Immunizations should be separated by 5 cm.  Assessment of DLT for 
dose escalation will be made after all patients in this cohort have had a study visit at least 
3 weeks after receiving their first dose of vaccine.  If there are no DLT (as defined 
above), then patients may begin enrolling into cohort 2.  If there is 1 DLT then an 
additional 3 patients will be enrolled at this dosage level. Assessment of DLT for dose 
escalation will be made after the 3 additional patients have had a study visit at least 3 
weeks after receiving their first dose of vaccine.  If none of these latter 3 patients have 
DLT, then patients may begin enrolling into cohort 2.  If 2 patients have DLT at this 
lowest dosage level, dosing will de-escalated to 1 x 108 particles. 

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2) Cohort 2: Three patients will receive Ad5 [E1-, E2B-]-CEA(6D) at a dose of 1 x 1010 
particles in 0.5 mL SQ in the same thigh every 3 weeks for 3 immunizations.  
Immunizations should be separated by 5 cm.  Assessment of DLT for dose escalation will 
be made after all patients in this cohort have had a study visit at least 3 weeks after 
receiving their first dose of vaccine.  If there are no DLT, then patients may begin 
enrolling into cohort 3.  If there is 1 DLT then an additional 3 patients will be enrolled at 
this dosage level. Assessment of DLT for dose escalation will be made after the 3 
additional patients have had a study visit at least 3 weeks after receiving their first dose of 
vaccine.  If none of these latter 3 patients have DLT, then patients may begin enrolling 
into cohort 3.  If 2 patients have DLT at this dosage level, the dosage level in cohort 1 
will be considered the MTD.  If only 3 patients were enrolled in cohort 1, an additional 3 
patients will be enrolled at that dosage before proceeding to phase II. 
3) Cohort 3: Six patients will receive Ad5 [E1-, E2B-]-CEA(6D)  at a dose of 1 x 1011 
particles in 0.7  mL SQ in the same thigh every 3  weeks for 3 immunizations.  
Immunizations should be separated by 5 cm.  Assessment of DLT for proceeding to 
phase II enrollment will be made after all patients in this cohort have had a study visit at 
least 3 weeks after receiving their first dose of vaccine.  If there is 0 or 1 DLT, then this 
dosage level will be considered the MTD and patients may begin enrolling into the phase 
II portion of the study.  If 2 patients have DLT at this dosage level, the dosage level in 
cohort 2 will be considered the MTD.  If only 3 patients were enrolled in cohort 2, an 
additional 3 patients will be enrolled at that dosage before proceeding to phase II. 
4) Phase II cohort: After the MTD is established, an additional 12 patients will receive Ad5 
[E1-, E2B-]-CEA(6D) at the MTD every 3 weeks for 3 immunizations. 
 
Note: if during accrual of patients in the phase II cohort, DLT occurs at a sufficient rate 
such that the rate of DLT amongst the total number of patients (those treated at MTD in 
phase I and those in phase II) is ≥33%, then phase II will be restarted at the dosage level 
which is one level below the prior MTD.  
5) Patients will have 90 mL peripheral blood drawn prior to each immunization and 
approximately 3 weeks after the third immunization (Week 9) to determine whether there 
is an effect on the immune response at specific time points during the study and/or after a 
specific number of immunizations. 
6) Time to progression will be measured using CT scans performed at approximately 
3 month intervals (based on clinical standard of care). 
7) For all patients, if scheduling conflicts arise, the scheduled 3-week interval between 
immunizations may be modified so that the interval between immunizations is between 
20 and 28 days (3 weeks -1 day to 3 weeks +7 days).  If the second and/or third 
immunization is delayed, the subsequent immunizations should occur no earlier than 
20 days after the previous immunization. 
9) The following safety events will trigger a temporary suspension of study vaccinations: 
a) If ≥33% of patients in the phase II cohort experience DLT at dosage level 1 (i.e.,1 x 
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b) If one or more patients develop a Grade 4 allergic reaction without a clear 
attributable cause, other than study vaccine 
c) Death not attributed to disease. 
 
Assessment of these halting rules is a review of cumulative events for all study 
participants, and should not be confused with reasons for delaying or terminating the 
immunization schedule of any individual patient. 
The Scientific Monitoring Subcommittee of the Cancer Protocol Committee (CPC) will 
fully review all available safety data, consult with the principal investigator, medical 
monitor and the FDA as needed, before determining if resuming vaccinations is 
appropriate.  If it is determined that study vaccinations can resume, the halting rules will 
apply to each subsequent event that meets the criteria described above. 
Vaccinations may also be suspended for safety concerns other than those described above 
if, in the judgment of the principal investigator or sponsor, participant safety is 
threatened. 
6.1. Study Stopping Rules 
- 
Death possibly related to the study agent. 
- 
Two Grade 4 toxicity events that are possibly/probably related to the study agent 
 

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Figure 3A 
 

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Figure 3B. 
 
 
Table 3. Calculation of rates of DLT during patient accrual in phase I and phase II 
# evaluable 
for toxicity 
1,2,3 
4,5,6 
7,8,9 
10,11,12 
13,14,15 
16,17,18 
# with DLT 
to be ≥33% 
1 
2 
3 
4 
5 
6 
 

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6.2. Pharmaceutical Information 
6.1.1 Dosage and Administration 
 
Patients will receive Ad5 [E1-, E2B-]-CEA(6D) at a dose of 1 x 109, or 1 x 1010,    
particles subcutaneously (SQ) in 0.5 mL of a buffered saline solution every 3 
weeks for 3 immunizations and patients who receive 1x1011 VP will receive 
Ad5[E1-, E2b-]-CEA(6D) in 0.7 mL of ARM formulation buffer SQ every 3 
weeks for 3 immunizations. 
 
6.1.2 How Supplied 
ETBX-011 will be provided in a frozen state in a 2ml vial with a fill volume of 
0.5 ml of extractable vaccine which contains 1X1011 total virus particles. The 
volume of injection for 1x1011 virus particles is 0.5 mL. The lower doses will be 
produced by dilution in 0.9% saline using the following directions. The product 
should be stored at </= –20°C until used. 
 
Instructions for dose preparation: 
1.  To administer 1x10e9 virus particles by subcutaneous injection: 
From a 5.0mL vial of 0.9% sterile saline remove 0.05mL of fluid which leaves 
4.95mL. Then remove 0.05mL from the vial labeled ETBX-011 and deliver this 
volume into the 5mL sterile saline vial. Mix the contents by inverting the 5mL 
diluted drug. Then with draw 0.5mL of diluted drug and deliver to the patient by 
subcutaneous injection (detailed description of dose preparation is described in 
the packaging insert). 
 
2. To administer 1x10e10 virus particles by subcutaneous injection: 
From a 5.0mL vial of 0.9% sterile saline remove 0.5mL of fluid which leaves 
4.5mL. Then remove 0.5mL from the vial labeled ETBX-011 and deliver this 
volume into the 5mL sterile saline vial. Mix the contents by inverting the 5mL 
diluted drug. Then with draw 0.5mL of diluted drug and deliver to the patient by 
subcutaneous injection (detailed description of dose preparation is described in 
the packaging insert). 
 
3. To administer 1x10e11 virus particles by subcutaneous injection: 
Withdraw 0.5mL of contents from vial and administer each subject without any 
further manipulation. 
 
 
6.1.3 Disposal of Unused Vaccine 

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Unless other arrangements are agreed in writing, all unused vaccine should be 
delivered to Dr. Tim Clay at Duke University Medical Center for disposal at or before the 
completion of the clinical study. 
7. TREATMENT EVALUATION 
7.1. Short-Term Evaluation During and After Active Immunotherapy  
On vaccine administration days, blood will be drawn before administration.  Evaluations 
will also be conducted for patients who discontinue from the study if they have received any 
treatment.  The investigator will determine the degree of evaluation based on the patient's 
condition and/or reason for discontinuation from the study. 
7.1.1 General Evaluations (each visit for immunization) 
General evaluations include medical history, ECOG performance status, and 
complete physical examination with weight.  Any other treatments, medications, 
biologics, or blood products that the patient is receiving or has received since the 
last visit will be recorded.  Patients will remain in the clinic for approximately 
30 minutes following receipt of vaccine to monitor for any adverse reactions.  Local 
and systemic reactogenicity after each dose of vaccine will be assessed daily for 3 
days (on the day of immunization and 2 days thereafter) using diary cards to report 
symptoms and a ruler to measure local reactogenicity. 
7.1.2 Hematological and Biochemical Assessment 
Blood chemistry and hematology, including CBC with differential, Na, K, Cl, CO2, 
BUN, creatinine, Ca, total protein, albumin, total bilirubin, alkaline phosphatase, 
AST, ALT and glucose will be drawn at Week 0,3,6,9, at discontinuation of 
treatment (if treatment is discontinued early), and as clinically indicated. 
7.1.3 Biological Markers 
Serum (5ml) to measure antibodies to CEA and the Ad5 vector will be obtained at 
Week 0, approximately 3 weeks after the last immunization (approximately 
Week 12), and every 3 months thereafter. 
7.1.4 Immunological Assessment 
Peripheral blood (90) will be drawn prior to each immunization and approximately 
3 weeks after the last immunization to determine whether there is an effect on the 
immune response at specific time points during the study and/or after a specific 
number of immunizations.  Peripheral blood mononuclear cells (PBMC) will be 
assayed for T cell responses to CEA using ELISPOT at all time points, plus 
proliferation assays, multi-parameter flow cytometric analysis, and cytoxicity 
assays, if possible and at the discretion of the investigator.  Plasma will be archived 
from the initial and Week 9 blood draws for evaluating antibody levels. 
7.1.5 Imaging Studies 

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CT or MRI scans of the chest, abdomen, and/or pelvis, will be requested (but not 
required) within 1-4 weeks after the third dose of vaccine.  At a minimum, the same 
imaging modality of the same portion of the body should be performed at each time 
point. 
7.1.6: Ad 5 neutralizing Ab assessment 
Serum will be sent to Etubics for Ad5 neutralizing level determination 
 
7.2. Long-Term Follow-Up 
Patients will be requested to continue long-term follow-up at Duke University 
Medical Center every 3 months for 1 year, while on the study (i.e., have not 
progressed or been removed from the study for other reasons). At each visit, a 
medical history and physical exam and labs (Blood chemistry and hematology, 
including CBC with differential, Na, K, Cl, CO2, BUN, creatinine, Ca, total protein, 
albumin, total bilirubin, alkaline phosphatase, AST, ALT and glucose) will be 
drawn. 
At each visit, 40-90 mL of peripheral blood for immune analysis may be drawn, if 
there was previous evidence of an immune response or at the discretion of the 
investigator. 
7.3. Management of Intercurrent Events 
7.3.1 Concomitant Medications 
Patients will be removed from the protocol treatment if they initiate concomitant 
chemotherapeutic agents, corticosteroids, or other immunosuppressive agents, or 
other forms of immunotherapy.  After meeting the inclusion criteria, all other 
medications deemed appropriate for the patient, by the investigator, may be 
administered to the patient.  All medications and changes in medication during 
treatment will be recorded.  Hormonal therapy and bisphosphonates may be 
continued in breast cancer patients if they have been stable on the agents for at least 
1 month prior to enrollment. 
7.3.2 Adverse Events 
7.3.2.1 Toxicity will be graded according to the NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 (which can be downloaded from 
the CTEP web site (http://ctep.cancer.gov).)  Dose-limiting toxicity (DLT) is 
defined in section 6. 
7.3.2.2 Possible side effects from immunization may include local effects (pain, 
tenderness, rednesss or swelling), systemic effects (malaise, fatigue, myalgia, 
arthralgia, headache, nausea, vomiting, chills or fever), and allergic reactions 
such as hives, rash or anaphylactic reactions.  Induction of auto-immunity, 
manifest as arthritis, serositis, nephritis, thyroiditis, colitis, neutropenia, etc., 
is theoretically possible, but has not been observed in our prior CEA vaccine 

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studies.  Also, liver function test abnormalities and liver failure are 
theoretically possible. 
7.3.3 Treatment of Toxicity 
For acute allergic reactions, use of diphenhydramine 25-50 mg IV, corticosteroids 
(Solumedrol 100 mg), and epinephrine (1:1000, 0.3-1 mL sq) should be considered.  
These medications are available in the clinical setting where the vaccine will be 
administered.  For auto-immunity, corticosteroids (prednisone 0.5-1 mg/kg/d) 
should be considered.  Clinical assessment of other targets, such as thyroid, 
arthritis, urticaria, or proteinuria, for auto-immunity and serum sickness like 
antigen-antibody complex disease, will also be performed as indicated. 
7.3.4 Active Immunotherapy will be Discontinued for: 
7.3.4.1 Life-threatening anaphylactic reactions related to active immunotherapy 
7.3.4.2 Dose-limiting toxicity related to active immunotherapy 
7.3.4.3 Disease progression (by RECIST criteria).  Patients will be offered 
referral to a medical oncologist at Duke University Medical Center for 
discussion of other treatment options, and for continued medical care.   
7.3.4.3.1 
Disease progression prior to completing the 3 study 
immunizations: In the event that a patient undergoes reimaging studies 
prior to the completion of their 3 study immunizations and is found to 
have disease progression, they will be permitted to continue on the study 
as long as the progression has been 50% or less by RECIST criteria. 
If a patient is removed from the study prior to completion of the assigned vaccine 
schedule for any reason other than toxicity, that patient will be replaced, in order to 
obtain data to help determine the toxicity of the immunizations. We will allow up to 3 
replacements per cohort (Phase I, Dose levels 1 and 2; Phase II, MTD). 
8. STATISTICAL CONSIDERATIONS 
8.1. Safety:  
We will evaluate safety continuously in a cohort.  We will make our overall assessment 
of whether to escalate to the next dose level at least 3 weeks after the last patient in the previous 
cohort has received their first injection.  This will be performed by medical monitor and the 
principle investigator.  A note to file will be generated following assessment and filed in study 
binder.  A dosage level will be considered safe if <33% patients treated at a dose level 
experience dose-limiting toxicity (i.e., 0 of 3, ≤1 of 6, ≤3 of 12, or ≤5 of 18 patients).  Dose-
limiting toxicity is defined in section 6.  Safety will be evaluated in 3 or 6 patients at each dosage 
level in phase I.   Safety will continue to be monitored among additional patients treated at the 
MTD in phase II.  A patient will be considered evaluable for safety if treated with at least one 
immunization.  DLTs will be observed through 9 weeks to accommodate safety evaluation of all 
3 product doses. 

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8.2. Rate of Immune Response:  
We will determine the percentage of patients with a positive immune response.  We 
define a positive immune response by ELISpot as described at the 2002 Society of Biologic 
Therapy Workshop on “Immunologic Monitoring of Cancer Vaccine Therapy”, i.e. a T cell 
response is considered positive if the mean number of spots adjusted for background in six wells 
with antigen exceeds the number of spots in six control wells by 10 and the difference between 
single values of the six wells containing antigen and the six control wells is statistically 
significant at a level of p ≤ 0.05 using the Student’s t test.  Immunogenicity assays will occur 
prior to each immunization and at week 12.  Immune response will be assessed among the 18 
patients treated at the MTD (12 in phase I and 12 in Phase II).  The therapy will be considered of 
further interest if 9 of 18 patients treated at the MTD dose exhibit an immune response as 
defined above.  Meeting this criterion establishes that the immune response rate is at least 33% 
with approximately 90% confidence.  At significance level 0.1 there is 82% power to test the null 
hypothesis that the immune response rate is ≤ 0.33 versus the alternative that the immune 
response rate is ≥ 0.58.  The magnitude of response will also be described.  A patient will be 
considered evaluable for immune response if they receive at least 3 immunizations. 
8.3. Determination of Clinical Response 
Among patients with measurable/evaluable disease, response determination will be made 
according to the RECIST criteria: 
Complete Response (CR): 
Disappearance of target lesion, confirmed at 4    
weeks 
Partial Response (PR): 
30% decrease in longest dimension of target lesion, 
confirmed at 4 weeks 
Stable Disease (SD): 
 
Neither PR nor PD 
Progressive Disease (PD): 
20% increase in longest dimension of target lesion; 
no CR, PR, or SD documented before increased 
disease. 
The exact binomial confidence interval for the proportion of subjects with a clinical 
response of CR or PR will be calculated. 
9. PATIENT WITHDRAWAL 
Patients may be removed from the study for the following reasons: 
• Dose-limiting toxicity, as defined in section 6.   
• Patient voluntarily decides to withdraw. 
• Patient non-compliance with the study protocol. 
• Intercurrent disease which in the opinion of the patient’s treating physician would 
affect the ability of the patient to continue on the clinical study.  
In the event of a withdrawal due to toxicity, patients will be requested to have safety 
evaluations performed as per protocol for one year duration. This may include having up to 90 
mL of blood drawn for immunologic testing. 

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10. STUDY CONDUCT AND ETHICAL AND REGULATORY CONSIDERATIONS 
10.1. Departure from the Protocol 
There should be no departure from the protocol if at all possible.  If an emergency occurs 
that requires departure from this protocol, the investigator or other physician in attendance in 
such an emergency will, if circumstances and time permit, contact the principal investigator 
(Dr. Michael Morse) or in his absence, Dr. H. Kim Lyerly, immediately by telephone 
(Page operator 919 684-8111).  Such contacts with the principal investigator will be made to 
permit a decision as to whether or not the patient will be continued on the study.  Such 
departures need to be clearly documented and reported to the IRB and the sponsor (Etubics) by 
the principal investigator. 
10.2. Informed Consent 
In accordance with guidelines in the Federal Register, Vol. 48, No. 17, 1982, pp. 8951-2, 
all patients are required to sign a statement of informed consent.  This phase I/II study involves 
research that presents risk, but holds the prospect of direct benefit to the individual patient 
(46.405-45 Code of the Federal Regulations part 46).  The investigator will report to the IRB and 
the sponsor (Etubics) will report to FDA changes in the research protocol and all unanticipated 
problems involving risks to human patients and others, and no changes will be made in the 
research activity without IRB approval. 
10.3. Institutional Review 
This study must be approved by the Institutional Review Board (IRB).  IRB approval of 
the protocol and the informed consent form for this study must be given in writing.  The IRB 
must also approve any significant changes to the protocol as well as a change of principal 
investigator.  Records of all study review and approval documents must be kept on file by the 
investigator and are subject to FDA inspection during or after completion of the study.  Adverse 
events must be reported to the IRB.  The IRB will receive notification of the completion of the 
study and final report within three months of study completion or termination.  The investigator 
must maintain an accurate and complete record of all submissions made to the IRB, including a 
list of all reports and documents submitted. 
 
10.4. Documentation and Monitoring 
Data will be collected for all patients.  Accurate completion of the computer data forms 
for all patients is the responsibility of the investigator.   
 
10.4.1 Case Report Forms 
Case Report Forms (CRFs) are used to record study data and are an integral part of the 
study and subsequent reports.  Therefore, all reports must be legible and complete.  All forms 
should be filled out using a black ballpoint pen.  Errors should be lined out but not obliterated 
and the correction inserted, initialed, and dated by the principal investigator, co-investigators, 
study coordinator, or data manager.  A Case Report Form must be completed and signed by the 

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principal investigator for each patient enrolled, including those removed from the study for any 
reason.  The reason for removal must be noted on the Final Report Form by the investigator for 
each patient.  Case Report Forms must be kept current to reflect patient status at each phase 
during the course of the study.  Patients are not to be identified on case report forms by name; 
appropriate coded identification and patient initials must be used.  The investigator must keep a 
separate log of patient names and addresses.  This log is subject to FDA inspection.  Because of 
the potential for errors, inaccuracies, and illegibility in transcribing data onto case report forms, 
originals of laboratory and other test results must be kept on file with patient's case report form 
or clinical chart.  Case report forms and copies of test results must be available at all times for 
inspection by the FDA.   
 
10.4.2 Maintenance of Study Documentation 
The following will be maintained: 
a. Case Report Forms - which must be kept legible, accurate, and up-to-date. 
b. Patient Files/Signed Informed Consent - which substantiates the data entered 
on the case report forms for all required test and evaluation procedures and 
verifies that the patient has signed an informed consent to enter the study. 
c. Patient Exclusion Record - which should reflect the reason any patient was 
screened and found ineligible for the study. 
d. Monitoring Log - listing dates of monitor visits. 
e. Regulatory Documents - including protocol, investigator brochure, FDA Form 
1572, CVs, IRB correspondence, IRB approval/renewals and IRB approved 
consent form. 
f. Adverse Experience Report Form - which should explain any serious or 
unexpected adverse experiences. 
All study documentation pertaining to the conduct of the study must be kept on file by the 
investigator for a period of 2 years following the date a marketing application is approved for the 
drug for the indication for which it is being investigated; or, if no application is to be filed or if 
the application is not approved for such indication, until 2 years after the investigation is 
discontinued and FDA is notified.  The sponsor will notify the investigator if a marketing 
application is approved or if the investigation is discontinued and the FDA notified. 
10.5. Monitoring of the Protocol 
Protocol data and safety will be monitored by the Scientific Monitoring Subcommittee of 
the Cancer Protocol Committee (CPC) with the following plan: 
1.  Purpose:  This is a phase I/II clinical study with more than minimal risk and as such 
will be monitored for the occurrence of a greater frequency of AEs. 
2.  Monitoring: Up to 24 patients will be enrolled.  The principal investigator will 
continuously monitor the study.  The principal investigator will review the data and 
safety of the study after the enrollment of three patients in cohort 1, after enrollment 
of three patients in cohort 2, and after enrollment of six patients in cohort 3.  Formal, 
independent monitoring by CPC will occur after enrollment of the three patients in 

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cohort 1 and again after enrollment of three patients in cohort 2; then a scientific 
progress review will occur yearly, assuming a result of “satisfactory” on the initial 
review.  The exceptions are as follows:  If more than one patient experiences a Grade 
4 or greater allergic reaction, the principal investigator will request a monitoring 
review by CPC.  If at any time, more than 50% of patients experience a Grade 3 or 4 
major organ toxicity, we will request a monitoring review by CPC. 
3.  Description of Monitoring:  Adverse event reports will be reviewed with tabulation of 
all Grade 2, 3 or 4 toxicity.  
4. Toxicity:  see section 7.3.2 of the protocol.  
5. Reporting Adverse Events: An adverse experience is any adverse change from the 
study patient's baseline (pre-treatment) condition, including any clinical or laboratory 
test abnormality that occurs during the course of the proposed clinical study after 
treatment has started.  All adverse experiences that are classified as serious as 
described in section 10.7 of the protocol should be reported to the sponsor (Etubics) 
by telephone or fax within 24 hours, and reported in writing to the sponsor (etubics) 
within 72 hours.  All study-related deaths should be reported to the IRB within 24 
hours; all other serious adverse experiences should be reported to the IRB within 5 
business days. All deaths, whether considered study-related or not, must also be 
reported immediately to the principal investigator, with a copy of the autopsy report 
and the death certificate.  All adverse experiences will be recorded on the Adverse 
Experience Case Report Form.  This report form should include severity, duration, 
outcome, and the investigator's judgment as to the relationship of the adverse 
experience to treatment.   
6. Reporting of Pregnancy: If a participant becomes pregnant during the study, treatment 
will be discontinued (i.e., no additional dose of study vaccine will be given) and the 
participant will be encouraged to continue to have regularly scheduled follow-up 
visits and evaluations.  The occurrence of pregnancy, and the outcome of any 
pregnancy, in a subject treated with study vaccine, must be reported to the sponsor 
(Etubics), and to the IRB.   
 
10.6. CTCAE Term (AE description) and Grade:   
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting.  All 
appropriate treatment areas should have access to a copy of the CTCAE version 4.0.  A copy of 
the CTCAE version 4.0 can be downloaded from the CTEP web site (http://ctep.cancer.gov).  
The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each 
AE based on the following guideline: 
Grade 1 
Mild AE 
Grade 2 
Moderate AE 
Grade 3 
Severe AE 
Grade 4 
Life-threatening or disabling AE 
Grade 5 
Death related to AE 

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10.7. Serious Adverse Event Reporting 
Events are classified as SERIOUS if they meet any of the following criteria [per the US 
Code of Federal Regulations (CFR) 21 CFR 312.32 and the recommendations of the 
International Conference on Harmonization (ICH)]: 
An SAE is any sign, symptom or medical condition that emerges during the study or 
during a post-study follow-up period that 1) was not present at the start of the study and is not a 
chronic condition that is part of the patient’s medical history, OR 2) was present at the start of 
the study or as part of the patient’s medical history but worsened in severity and/or frequency 
during study participation, AND that meets any of the following regulatory serious criteria: 
• any death 
• any life-threatening event, i.e., an event that places the patient, in the view of the 
investigator, at immediate risk of death from the event as it occurred (does not 
include an event that, had it occurred in a more severe form, might have caused 
death) 
• any event that requires or prolongs in-patient hospitalization 
• any event that results in persistent or significant disability/incapacity 
• any congenital anomaly/birth defect diagnosed in a child of a patient who 
participated in this study and received investigational drug 
• other medically important events that in the opinion of the investigator may 
jeopardize the patient or may require intervention to prevent one of the other 
outcomes listed in the definition above (e.g. allergic bronchospasm requiring 
intensive treatment in an emergency room, convulsions occurring at home that do 
not require in-patient hospitalization, any blood dyscrasias, or the development of 
drug dependency or drug abuse). 
 
Procedures for adverse event reporting 
 
  1.  PI notified by medical staff of a SAE 
 
PI: Michael Morse, MD 
            Address: Duke University Medical Center 
Seeley Mudd Building  
Box 3233, Durham, NC 27710 
 
Telephone: 1-919-681-3480 
 
Fax: 1-919-681-7970 
Pager 1-919-970-5626 
 
Email: michael.morse@duke.edu 
 
2. PI calls sponsor to report an unexpected SAE associated with the use of the drug 
 
 
Sponsor: Carol Jones, Vice President of Administration 
 
Address: 410 West Harrison Street, Suite 100, Seattle, WA 981119 
 
Telephone: 206-838-5110 ext. 102 
 
Cell: 1-206-818-2985 
 
Fax: 1-206-838-2978 

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Email: cj@etubics.com 
 
  3.  Carol Jones reports the SAE to one of the following in this order: 
 
      A.  Chief Scientific Officer: Frank Jones, PhD  
 
Address: 410 West Harrison Street, Suite 100, Seattle, WA 98119  
 
Telephone: 206-838-5110 ext. 101 
 
Cell: 206-818-2857 
 
Fax: 206-838-2978 
 
Email: frj@etubics.com 
      B.  Laboratory Manager:  Joseph Balint, PhD 
 
Address: 410 West Harrison Street, Suite 100, Seattle, WA 98119 
Telephone: 206-838-5110 ext. 107 
Fax:  206-838-2978 
 
Email: joe@etubics.com 
      C.  Vice President Research: Elizabeth S. Gabitzsch 
 
Address: 410 West Harrison Street, Suite 100, Seattle, WA 98119 
Telephone: 206-838-5110 ext. 103 
Cell: 970-402-2598 
Fax:  206-838-2978 
 
Email: beth@etubics.com 
 
 
4. Contacted person in three (3) above notifies the FDA on MedWatch 3200A form. 
a. If the SAE results in death or is life-threatening, report the SAE to the FDA within 7 days 
b. All other SAEs must be reported to FDA within 15 days 
 
5. 
If the SAE requires input from a physician then the Acting Medical Director is consulted: 
 
Ron Berenson, MD 
 
     Telephone: 206-790-1094 
     Fax:  206-838-2978 
 
Email: rberenson@gmail.com 
 
All SAE reports will be recorded on the Duke IRB Adverse Event Reporting form and 
will be reviewed and signed by the Principal Investigator.  Only adverse events that are deemed 
to be serious, unexpected and related or possibly related to the research must be reported to the 
IRB (this is in accordance with Duke’s IRB reporting policy). All reportable events will be 
forwarded to the IRB via campus mail or fax: 
 
IRB: 
Duke Medical Center Institutional Review Board: 
Hock Plaza, 4th floor 
2424 Erwin Road 
Box 2991 
Durham, NC  27705 
Fax: 919-668-5125 
 
 

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In accordance with FDA regulations and ICH guidelines, investigators will be notified of the 
occurrence of new, serious, unexpected adverse events associated with the use of the study 
medication (i.e. there is a reasonable possibility that the adverse event may have been caused by 
the drug) within 15 calendar days via a written report.  It is the responsibility of the investigator 
to promptly inform the relevant Institutional Review Board (IRB) of these new adverse 
events/risks to patients, in accordance with 21 CFR 312.66.  It is also the responsibility of the 
investigator and the sponsor (Etubics) in conducting gene transfer research to promptly inform 
the NIH Office of Biotechnology Activities (OBA) and relevant Scientific Review Board of 
these new adverse events/risks to patients, in accordance with NIH Guidelines for Research 
Involving Recombinant DNA Molecules, in particular Appendix M.  It is the responsibility of the 
sponsor (Etubics) to report these serious adverse events to the FDA.  The SAE report will be 
forwarded to the FDA after recording the event data via the FDA MedWatch form 3500A.   
 
MedWatch 3500A Reporting Guidelines: 
In addition to completing appropriate patient demographic and suspect medication 
information, the report should include the following information within the Event Description 
(section 5) of the MedWatch 3500A form: 
Treatment regimen (dosing frequency, combination therapy) 
Protocol description (and number, if assigned) 
Description of event, severity, treatment, and outcome, if known 
Supportive laboratory results and diagnostics 
Investigator’s assessment of the relationship of the adverse event to each investigational 
product and suspect medication 
Follow-up information:   
Additional information may be added to a previously submitted report by any of the 
following methods: 
• Adding to the original MedWatch 3500A report and submitting it as follow-up 
• Adding supplemental summary information and submitting it as follow-up with the 
original MedWatch 3500A form  
• Summarizing new information and faxing it with a cover letter including patient 
identifiers (i.e. D.O.B., initials, patient number), protocol description and number, if 
assigned, suspect drug, brief adverse event description, and notation that additional or 
follow-up information is being submitted  (The patient identifiers are important so that 
the new information is added to the correct initial report.) 
 
 
10.8. Assessing Causality: 
Investigators are required to assess whether there is a reasonable possibility that study 
medications caused or contributed to an adverse event.  The following general guidance may be 
used. 

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Yes: 
if the temporal relationship of the clinical event to study drug administration makes a 
causal relationship possible, and other drugs, therapeutic interventions or underlying 
conditions do not provide a sufficient explanation for the observed event. 
No: 
if the temporal relationship of the clinical event to study drug administration makes a 
causal relationship unlikely, or other drugs, therapeutic interventions or underlying 
conditions provide a sufficient explanation for the observed event. 
10.9. Safety Reporting Requirements for IND Holders 
In accordance with 21 CFR 212.32, sponsor-investigators of studies conducted under an 
IND must comply with following safety reporting requirements:  
 
a. Expedited IND Safety Reports: 
7 Calendar-Day Telephone or Fax Report:   
The sponsor is required to notify the FDA of any fatal or life-threatening adverse event 
that is unexpected and assessed by the investigator to be possibly related to the use of the 
investigational product.   An unexpected adverse event is one that is not already described in the 
Investigator’s Brochure.  Such reports are to be telephoned or faxed to the FDA within 
7 calendar days of first learning of the event.   
15 Calendar-Day Written Report:   
The sponsor is also required to notify the FDA and all participating investigators, in a 
written IND Safety Report, of any serious, unexpected AE that is considered possibly related to 
the investigational product.  An unexpected adverse event is one that is not already described in 
the Investigator Brochure. 
Written IND Safety Reports should include an Analysis of Similar Events in accordance 
with regulation 21 CFR § 312.32.  All safety reports previously filed with the IND concerning 
similar events should be analyzed.  The new report should contain comments on the significance 
of the new event in light of the previous, similar reports.   
Written IND safety reports with Analysis of Similar Events are to be submitted to the 
FDA and all participating investigators within 15 calendar days of first learning of the event.  
The FDA prefers these reports on a MedWatch 3500A Form but alternative formats are 
acceptable (e.g. summary letter). 
 
b. IND Annual Reports 
In accordance with the regulation 21 CFR § 312.32, the sponsor shall within 60 days of 
the anniversary date that the IND went into effect submit a brief report of the progress of the 
investigation.  Please refer to Code of Federal Regulations, 21 CFR § 312.32 for a list of the 
elements required for the annual report.   
 
c. Data and Safety Monitoring  
Data will be collected by: the principal investigator, co-investigators, and the protocol 
coordinator.  The protocol coordinator under the supervision of the principal investigator will 
report the AEs. The data will be audited by the CPC and Etubics’ CRA.  
 

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Hodges, B.L., Serra, D., Hu, H., Begy, C.A., Chamberlain, J.S., and Amalfitano, A. 2000. 
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Arthur, J.F., Butterfield, L.H., Roth, M.D., Bui, L.A., Kiertscher, S.M., Lau, R., Dubinett, 
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36. 
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Brossart, P., Goldrath, A.W., Butz, E.A., Martin, S., and Bevan, M.J. 1997. Virus-
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melanoma-specific cytotoxic T lymphocytes by dendritic cells transduced with a MART-
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Bregni, M., Shammah, S., Malaffo, F., Di Nicola, M., Milanesi, M., Magni, M., 
Matteucci, P., Ravagnani, F., Jordan, C.T., Siena, S., et al. 1998. Adenovirus vectors for 
gene transduction into mobilized blood CD34+ cells. Gene Ther 5:465-472. 
40. 
Dietz, A.B., and Vuk-Pavlovic, S. 1998. High efficiency adenovirus-mediated gene 
transfer to human dendritic cells. Blood 91:392-398. 
41. 
Ishida, T., Chada, S., Stipanov, M., Nadaf, S., Ciernik, F.I., Gabrilovich, D.I., and 
Carbone, D.P. 1999. Dendritic cells transduced with wild-type p53 gene elicit potent anti-
tumour immune responses. Clin Exp Immunol 117:244-251. 
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Ribas, A., Butterfield, L.H., McBride, W.H., Jilani, S.M., Bui, L.A., Vollmer, C.M., Lau, 
R., Dissette, V.B., Hu, B., Chen, A.Y., et al. 1997. Genetic immunization for the 
melanoma antigen MART-1/Melan-A using recombinant adenovirus-transduced murine 
dendritic cells. Cancer Res 57:2865-2869. 
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Wan, Y., Bramson, J., Carter, R., Graham, F., and Gauldie, J. 1997. Dendritic cells 
transduced with an adenoviral vector encoding a model tumor-associated antigen for 
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Wan, Y., Emtage, P., Foley, R., Carter, R., and Gauldie, J. 1999. Murine dendritic cells 
transduced with an adenoviral vector expressing a defined tumor antigen can overcome 
anti-adenovirus neutralizing immunity and induce effective tumor regression. Int J Oncol 
14:771-776. 
45. 
Miller, P.W., Sharma, S., Stolina, M., Butterfield, L.H., Luo, J., Lin, Y., Dohadwala, M., 
Batra, R.K., Wu, L., Economou, J.S., et al. 2000. Intratumoral administration of 
adenoviral interleukin 7 gene-modified dendritic cells augments specific antitumor 
immunity and achieves tumor eradication. Hum Gene Ther 11:53-65. 
46. 
Lu, L., Gambotto, A., Lee, W.C., Qian, S., Bonham, C.A., Robbins, P.D., and Thomson, 
A.W. 1999. Adenoviral delivery of CTLA4Ig into myeloid dendritic cells promotes their 
in vitro tolerogenicity and survival in allogeneic recipients. Gene Ther 6:554-563. 
47. 
Rea, D., Schagen, F.H., Hoeben, R.C., Mehtali, M., Havenga, M.J., Toes, R.E., Melief, 
C.J., and Offringa, R. 1999. Adenoviruses activate human dendritic cells without 
polarization toward a T-helper type 1-inducing subset. J Virol 73:10245-10253. 
48. 
Hirschowitz, E.A., Weaver, J.D., Hidalgo, G.E., and Doherty, D.E. 2000. Murine 
dendritic cells infected with adenovirus vectors show signs of activation. Gene Ther 
7:1112-1120. 

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49. 
Loser, P., Jennings, G.S., Strauss, M., and Sandig, V. 1998. Reactivation of the 
previously silenced cytomegalovirus major immediate-early promoter in the mouse liver: 
involvement of NFkappaB. J Virol 72:180-190. 
50. 
Morelli, A.E., Larregina, A.T., Ganster, R.W., Zahorchak, A.F., Plowey, J.M., 
Takayama, T., Logar, A.J., Robbins, P.D., Falo, L.D., and Thomson, A.W. 2000. 
Recombinant adenovirus induces maturation of dendritic cells via an NF-kappaB-
dependent pathway. J Virol 74:9617-9628. 
51. 
Jonuleit, H., Tüting, T., Steitz, J., Brück, J., Giesecke, A., Steinbrink, K., Knop, J., and 
Enk, A.H. 2000. Efficient transduction of mature CD83+ dendritic cells using 
recombinant adenovirus suppressed T cell stimulatory capacity. Gene Ther 7:249-254. 
52. 
Tillman, B.W., Hayes, T.L., DeGruijl, T.D., Douglas, J.T., and Curiel, D.T. 2000. 
Adenoviral vectors targeted to CD40 enhance the efficacy of dendritic cell-based 
vaccination against human papillomavirus 16-induced tumor cells in a murine model. 
Cancer Res 60:5456-5463. 
53. 
Shiver, J.W., Fu, T.M., Chen, L., Casimiro, D.R., Davies, M.E., Evans, R.K., Zhang, 
Z.Q., Simon, A.J., Trigona, W.L., Dubey, S.A., et al. 2002. Replication-incompetent 
adenoviral vaccine vector elicits effective anti-immunodeficiency-virus immunity. Nature 
415:331-335. 
54. 
Yang, Z.Y., Wyatt, L.S., Kong, W.P., Moodie, Z., Moss, B., and Nabel, G.J. 2003. 
Overcoming immunity to a viral vaccine by DNA priming before vector boosting. J Virol 
77:799-803. 
55. 
Casimiro, D.R., Chen, L., Fu, T.M., Evans, R.K., Caulfield, M.J., Davies, M.E., Tang, A., 
Chen, M., Huang, L., Harris, V., et al. 2003. Comparative immunogenicity in rhesus 
monkeys of DNA plasmid, recombinant vaccinia virus, and replication-defective 
adenovirus vectors expressing a human immunodeficiency virus type 1 gag gene. J Virol 
77:6305-6313. 
56. 
Chirmule, N., Propert, K., Magosin, S., Qian, Y., Qian, R., and Wilson, J. 1999. Immune 
responses to adenovirus and adeno-associated virus in humans. Gene Ther 6:1574-1583. 
57. 
Hartigan-O'Connor, D., Barjot, C., Salvatori, G., and Chamberlain, J.S. 2002. Generation 
and growth of gutted adenoviral vectors. Methods Enzymol 346:224-246. 
58. 
Harui, A., Roth, M.D., Kiertscher, S.M., Mitani, K., and Basak, S.K. 2004. Vaccination 
with helper-dependent adenovirus enhances the generation of transgene-specific CTL. 
Gene Ther 11:1617-1626. 
59. 
Morral, N., Parks, R.J., Zhou, H., Langston, C., Schiedner, G., Quinones, J., Graham, 
F.L., Kochanek, S., and Beaudet, A.L. 1998. High doses of a helper-dependent adenoviral 
vector yield supraphysiological levels of alpha1-antitrypsin with negligible toxicity. Hum 
Gene Ther 9:2709-2716. 
60. 
DelloRusso, C., Scott, J.M., Hartigan-O'Connor, D., Salvatori, G., Barjot, C., Robinson, 
A.S., Crawford, R.W., Brooks, S.V., and Chamberlain, J.S. 2002. Functional correction 
of adult mdx mouse muscle using gutted adenoviral vectors expressing full-length 
dystrophin. Proc Natl Acad Sci U S A 99:12979-12984. 
61. 
Reddy, P.S., Sakhuja, K., Ganesh, S., Yang, L., Kayda, D., Brann, T., Pattison, S., 
Golightly, D., Idamakanti, N., Pinkstaff, A., et al. 2002. Sustained human factor VIII 

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expression in hemophilia A mice following systemic delivery of a gutless adenoviral 
vector. Mol Ther 5:63-73. 
62. 
Amalfitano, A., Hauser, M.A., Hu, H., Serra, D., Begy, C.R., and Chamberlain, J.S. 1998. 
Production and characterization of improved adenovirus vectors with the E1, E2b, and E3 
genes deleted. J Virol 72:926-933. 
63. 
Hartigan-O'Connor, D., Kirk, C.J., Crawford, R., Mulé, J.J., and Chamberlain, J.S. 2001. 
Immune evasion by muscle-specific gene expression in dystrophic muscle. Mol Ther 
4:525-533. 
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Moorhead, J.W., Clayton, G.H., Smith, R.L., and Schaack, J. 1999. A replication-
incompetent adenovirus vector with the preterminal protein gene deleted efficiently 
transduces mouse ears. J Virol 73:1046-1053. 
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Nazir, S.A., and Metcalf, J.P. 2005. Innate immune response to adenovirus. J Investig 
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Schaack, J. 2005. Induction and inhibition of innate inflammatory responses by 
adenovirus early region proteins. Viral Immunol 18:79-88. 
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Schaack, J., Bennett, M.L., Colbert, J.D., Torres, A.V., Clayton, G.H., Ornelles, D., and 
Moorhead, J. 2004. E1A and E1B proteins inhibit inflammation induced by adenovirus. 
Proc Natl Acad Sci U S A 101:3124-3129. 
 
 

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Names and addresses of key study personnel: 
Study Chairman and Principal Investigator 
Name:  Michael Morse, MD 
Address: Duke University Medical Center 
Box 3233, Durham, NC 27710 
Telephone:  (919) 681-3480 
Fax:  (919) 681-7970 
Email: michael.morse@duke.edu 
 
Name:  Kent Weinhold, PhD 
Address: Duke Center for AIDS Research 
204 SORF, LaSalle St. 
 Box 2926 
Duke University Medical Center 
Durham, NC 27710-2926 
Telephone:  (919) 684-5572 
Fax:  (919) 684-4288 
Email: kjw@duke.edu 
Biostatistician  
Name:  Donna Niedzwiecki, PhD 
Address: Duke University Medical Center 
Box 3958, Durham, NC 27710 
Telephone: (919) 681-5030 
Fax:  (919) 691-8028 
E-mail: donna.niedzwiecki@duke.edu 
Other Applicable Staff 
Title:  Acting Medical Director  
Name: H. Kim Lyerly, MD  
Address: Duke Comprehensive Cancer Center, 
Duke University Medical Center, Durham, NC 
27710 
Telephone: (919) 684-5613 
Fax: (919) 684-5653 
Email: lyerl001@mc.duke.edu 
Pharmacist or Person Responsible for Drug 
Accountability       
Name: Cheryl Morgan 
Address: Morris Pharmacy, Duke University 
Medical Center, Trent Drive, 
Durham, NC 27710 
Telephone:  (919) 668-0657 
Fax: (919) 668-3895 
Email: cheryl.morgan@duke.edu 
Other Applicable Staff: 
Title:  CEO and CSO, Etubics Corporation 
Name:  Frank R. Jones, Ph.D. 
Address: Etubics Corporation 
   410 West Harrison Street 
   Seattle, WA 981119 
Telephone: 206-838-5110 Ext 101 
Fax:  206-838-2978 
Email: frj@etubics.com 
Other Consultants: 
Andy Amalfitano, DO, PhD, Michigan State 
University 
Elizabeth Gabitzsch, Etubics Corporation 
Raj Dua, Ph.D., Etubics Corporation 
Diane Lickey, RN, Etubics Coprporation 
 

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TABLE OF CONTENT 
 
 
 
 
 
 
 
 
 
 
 
Page Number 
 
 
1. Protocol Summary …………………………………………………..  4 
 
2. Study Objectives …………………………………………………….  6 
 
3. Background and Significance ……………………………………….  6 
 
4. Patient Selection …………………………………………………….. 15 
 
5. Pre-Treatment Evaluation …………………………………………… 19 
 
6. Treatment Plan ………………………………………………………. 20 
 
7. Treatment Evaluation ………………………………………………... 25 
 
8. Statistical Considerations ……………………………………………. 28 
 
9. Patient Withdrawal …………………………………………………... 29 
 
10. Study Conduct and Ethical and Regulatory Considerations …………. 29 
 
11.  References …………………………………………………………… 37 
 
12.  Appendix …………………………………………………………….. 43 
 

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1. PROTOCOL SUMMARY 
Title 
A PHASE I/II STUDY OF ACTIVE IMMUNOTHERAPY WITH 
Ad5 [E1-, E2b-]-CEA(6D)  VACCINE (ETBX-011) IN PATIENTS 
WITH 
ADVANCED 
OR 
METASTATIC 
MALIGNANCIES 
EXPRESSING CEA 
Objectives 
a) The primary objective of this protocol is to determine the safety of 
immunization with Ad5 [E1-, E2B-]-CEA(6D), in patients with 
advanced or metastatic CEA-expressing malignancies.  
b) The secondary objectives are to evaluate CEA-specific immune 
responses to the immunizations and to obtain preliminary data on 
clinical response rate. 
Major Inclusion/ 
Exclusion Criteria 
Patients with a histologically confirmed diagnosis of metastatic 
malignancy who were previously treated with standard therapy known to 
have a possible survival benefit or refused such therapy.  The tumor must 
express CEA as defined by any of the following: immunohistochemical 
staining, (at least 50% of the tumor with at least moderate intensity of 
staining) , or a tumor known to be universally CEA positive (i.e. colon 
and rectal cancer).  In addition, only colorectal adenocarcinomas (for 
those with colorectal cancer) can be enrolled. Patients will not be treated 
until 4 or more weeks after any prior chemotherapy or radiation therapy, 
but may be receiving non-cytotoxic targeted therapy (bevacizumab, 
cetuximab, trastuzumab, erlotinib, or gefitinib) or hormonal therapy.  
They must not have a history of autoimmune disease, serious intercurrent 
chronic or acute illness, active hepatitis, serologic evidence for HIV, or 
be receiving steroid or immunosuppressive therapy.  All patients must be 
>21 years old and have an Karnofsky Performance Score of 70% or 
higher. Pregnant women and nursing mothers are excluded.  
Study Design 
Phase I/II study with three dosage levels of Ad5 [E1-, E2B-]-CEA(6D)  
vaccine (phase I component), and the maximally tolerated dose of Ad5 
[E1-, E2B-]-CEA(6D)  vaccine (phase II component).  The study drug is 
Ad5 [E1-, E2B-]-CEA(6D) given by subcutaneous (SQ) injection every 
3 weeks for 3 immunizations.  The following procedures will occur: 
1) Peripheral blood draw of 90 mL for immune analysis 
2) Cohort 1: Three patients will receive Ad5 [E1-, E2B-]-CEA(6D)  at a 
dose of 1 x 109 particles SQ in 0.5 mL every 3 weeks for 
3 immunizations.  Assessment of dose-limiting toxicities (DLT) for 
dose escalation will be made after all patients in this cohort have had 
a study visit at least 3 weeks after receiving their first dose of 
vaccine.  If there are no DLT, defined as any Grade 2, 3 or 4 
immediate hypersensitivity reactions or neurological toxicity, other 
Grade 3 or 4 allergic or major organ toxicity, or Grade 4 fever, that 

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may possibly be associated with the immunization), then patients may 
begin enrolling into cohort 2.  If there is 1 DLT, then an additional 3 
patients will be enrolled at this dosage level. Assessment of DLT for 
dose escalation will be made after the 3 additional patients have had a 
study visit at least 3 weeks after receiving their first dose of vaccine.  
If none of these latter 3 patients have DLT (i.e., 1 DLT in the 6 total 
patients), then patients may begin enrolling into cohort 2. If 2 patients 
have DLT at the lowest dosage level, dosing will be de-escalated to 
1x108 particles.  
3) Cohort 2: Three patients will receive Ad5 [E1-, E2B-]-CEA(6D)  at a 
dose of 1 x 1010 particles SQ in 0.5 mL every 3 weeks for 
3 immunizations.  Assessment of DLT for dose escalation will be 
made after all patients in this cohort have had a study visit at least 
3 weeks after receiving their first dose of vaccine.  If there are no 
DLT, then patients may begin enrolling into cohort 3.  If there is 1 
DLT then an additional 3 patients will be enrolled at this dosage 
level. Assessment of DLT for dose escalation will be made after the 3 
additional patients have had a study visit at least 3 weeks after 
receiving their first dose of vaccine.  If none of these latter 3 patients 
have DLT, then patients may begin enrolling into cohort 3. 
4) Cohort 3: Six patients will receive Ad5 [E1-, E2B-]-CEA(6D)  at a 
dose of 1 x 1011 particles SQ in 0.5 mL every 3 weeks for 
3 immunizations.  Assessment of DLT for proceeding to phase II 
enrollment will be made after all patients in this cohort have had a 
study visit at least 3 weeks after receiving their first dose of vaccine.  
If there is 0 or 1 DLT, then patients may begin enrolling into the 
phase II portion of the study.  
5) Phase II cohort: An additional 12 patients will receive Ad5 [E1-, 
E2B-]-CEA(6D) at the maximally tolerated dose every 3 weeks for 
3 immunizations.  
6) Patients will have 90 mL peripheral blood drawn prior to each 
immunization and at Week 9 to determine whether there is an effect 
on the immune response at specific time points during the study 
and/or after a specific number of immunizations. 
7) Time to progression will be measured using CT scans performed as 
per standard of care (approximately 3 month intervals). 
Risks/toxicities 
Potential risks associated with the vaccine include anaphylaxis, fever, 
skin reaction, autoimmunity (colitis), and hepatic insufficiency.   
Number of Patients 
Planned: 24 evaluable patients (plus up to 12 replacements); may require 
30-42 patients if DLT occur. 
Duration of Study 
6 months after the last patient is enrolled; approximately 2 years total 
Criteria for 
Evaluation 
Toxicity will be assessed using CTC toxicity criteria.  CEA-specific 
immune response will be measured in the peripheral blood.  Time to 
recurrence will be determined by RECIST criteria. 

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Statistical Analysis 
Safety: We will evaluate safety in each cohort at least 3 weeks after the 
last patient in the previous cohort has received their first injection.  A 
dosing scheme will be considered safe if <33% of patients treated at a 
dosage level experience DLT (e.g., 0 of 3, ≤1 of 6, ≤3 of 12 or ≤5 of 18 
patients).  A patient will be considered evaluable for safety if treated with 
at least one immunization. 
Rate of immune response:  We will determine the percentage of patients 
with a positive immune response.  We define a positive immune response 
by ELISpot as described at the 2002 Society of Biologic Therapy 
Workshop on “Immunologic Monitoring of Cancer Vaccine Therapy”, 
i.e. a T cell response is considered positive if the mean number of spots 
in six wells with antigen exceeds the number of spots in six control wells 
by 10 and the difference between single values of the six wells 
containing antigen and the six control wells is statistically significant at a 
level of p ≤ 0.05 using the Student’s t test.  Immunogenicity assays will 
occur prior to each immunization and at week 12.  Immune response will 
be assessed at the MTD.  An observed immune response in 9 of 18 
patients will be considered sufficient evidence of immune response to 
justify further investigation.  Meeting this criterion establishes that the 
immune response rate is at least 33% with approximately 90% 
confidence.  The magnitude of response will also be described.  A patient 
will be considered evaluable for immune response if they receive at least 
3 immunizations. 
  
2. STUDY OBJECTIVES 
a) The primary objective of this protocol is to determine the safety of immunization with 
Ad5 [E1-, E2B-]-CEA(6D)  in patients with advanced or metastatic CEA-expressing 
malignancies.  
b) The secondary objectives are to evaluate CEA-specific immune response to the 
immunizations and obtain preliminary data on response rate. 
3. BACKGROUND AND SIGNIFICANCE 
 
 
 
 
 
  
 
 
 
  
 

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For the following common cancers, the following eligibility criteria apply: 
 Colorectal cancer: Must have received and progressed through at least one 
line of palliative chemotherapy consisting of one of the following regimens: 
- 
Palliative chemotherapy for metastatic colorectal cancer with 
5-fluorouracil (or capecitabine) and oxaliplatin. 
- 
Palliative chemotherapy for metastatic colorectal cancer with 
5-fluorouracil (or capecitabine) and irinotecan. 
- 
Palliative chemotherapy regimen for metastatic colorectal cancer that 
includes bevacizumab. 
- 
Colorectal cancer patients currently receiving palliative single-agent 
bevacizumab or cetuximab will be eligible for this trial and may 
continue these therapies concomitant with study treatment (if they 
have been on these single agent therapies for at least 3 months). 
 Breast cancer: Must have received and progressed through at least one line of 
chemotherapy for metastatic breast cancer consisting of one of the following 
regimens: 
- 
Palliative anthracycline- or taxane-based chemotherapy 
- 
Patients with tumors that over express HER2 (IHC 3+ or FISH+) must 
have received and progressed through at least one line of palliative 
therapy that combines trastuzumab with chemotherapy.  
- 
Breast cancer patients currently receiving palliative endocrine therapy 
or single-agent trastuzumab will be eligible for this trial and may 
continue these therapies concomitant with study treatment (if they 
have been on these single agent therapies for at least 3 months). 
- 
Patients who have been treated or offered the options of treatment with 
Bevacizumab (option clearly stated in the consent form). 
- 
Patients who have been treated or offered the options of treatment with 
Lapatinib (option clearly stated in the consent form). 
 Lung cancer: Must have received and progressed through chemotherapy for 
metastatic disease consisting of one of the following regimens: 
- 
Palliative platinum-based (cisplatin or carboplatin) chemotherapy if 
the patient has not received chemotherapy previously. 
- 
Palliative taxane-based (docetaxel or paclitaxel) or vinorelbine 
chemotherapy if the patient has received chemotherapy previously. 
- 
Lung cancer patients currently receiving palliative single-agent 
erlotinib or gefitinib will be eligible for this trial and may continue 
these therapies concomitant with study treatment (if they have been on 
these single agent therapies for at least 3 months). 
 Pancreatic cancer: Must have received and progressed through chemotherapy 
including gemcitabine. 

Molecular Therapeutics Program 
 
 
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- 
Pancreatic cancer patients currently receiving palliative single-agent 
erlotinib will be eligible for this trial and may continue this therapy 
concomitant with study treatment (if they have been on this single 
agent therapy for at least 3 months). 
 
For other malignancies, if a first line therapy with survival or palliative benefit 
exists, it should have been administered and there should have been 
progressive disease. 
 
Patients who have received and progressed through first-line palliative 
chemotherapy must be advised regarding second-line therapy before being 
enrolled on this investigational study.  
4.1.4. 
Karnofsky performance score of 70% or higher  
4.1.5. 
Estimated life expectancy > 3 months.. 
4.1.6. 
Age ≥ 21 years, but <75. 
4.1.7. 
Adequate hematologic function, with WBC ≥ 3000/microliter, hemoglobin 
≥ 9 g/dL (it is acceptable to have had prior transfusion), platelets 
≥ 75,000/microliter; PT-INR <1.5, PTT <1.5X ULN 
4.1.8. 
Adequate renal and hepatic function, with serum creatinine < 1.5 mg/dL, bilirubin 
< 1.5 mg/dL (except for Gilbert’s syndrome which will allow bilirubin 
≤ 2.0 mg/dL), ALT and AST ≤ 2.5 x upper limit of normal. 
4.1.9. 
Patients who have received prior CEA-targeted immunotherapy are eligible for 
this trial, if this treatment was discontinued at least 3 months prior to enrollment. 
4.1.10. Patients who are taking medications that do not have a known history of 
immunosuppression are eligible for this trial. 
4.1.11. Ability to understand and provide signed informed consent that fulfills 
Institutional Review Board’s guidelines. 
4.1.12.    Ability to return to Duke University Medical Center for adequate follow-up, as         
required by this protocol. 
4.2. Criteria for Patient Exclusion 
4.2.1  
Patients with concurrent cytotoxic chemotherapy or radiation therapy should be 
excluded. There are no exclusions based on the number of prior chemotherapy, 
biologic, hormonal, or experimental regimens. Except for the permitted 
concomitant therapies (bevacizumab, cetuximab, trastuzumab, erlotinib, gefitinib, 
or hormonal therapy which patients must have been on for at least 3 months at the 
time of enrollment if they intend to continue them with the vaccine), there must 
be at least 3 months between any prior CEA-targeted immunotherapy and study 
treatment and at least 4 weeks between any other prior therapy (including 
radiotherapy) and study treatment.  Patients must have recovered to grade 1 acute 
toxicities from prior treatment. 
4.2.2. 
Patients with a history of or current brain metastases will not be permitted 

Molecular Therapeutics Program 
 
 
18 
 
4.2.3.  
Patients with a history of autoimmune disease, such as but not restricted to, 
inflammatory bowel disease, systemic lupus erythematosus, ankylosing 
spondylitis, scleroderma, or multiple sclerosis.  Autoimmune related thyroid 
disease and vitiligo are permitted. 
4.2.4. 
Patients with serious intercurrent chronic or acute illness, such as cardiac disease 
(NYHA class III or IV), hepatic disease, or other illness considered by the 
Principal Investigator as unwarranted high risk for investigational drug treatment. 
4.2.5. 
Patients with a medical or psychological impediment to probable compliance with 
the protocol should be excluded. 
4.2.6. 
Concurrent (or within the last 5 years) second malignancy other than 
non-melanoma skin cancer, cervical carcinoma in situ, controlled superficial 
bladder cancer, or other carcinoma in situ that has been treated. 
4.2.7. 
Presence of an active acute or chronic infection including: a urinary tract 
infection, HIV (as determined by ELISA and confirmed by Western Blot) or viral 
hepatitis (as determined by HBsAg and Hepatitis C serology).  Patients with HIV 
are excluded based on immuno-suppression, which may render them unable to 
respond to the vaccine; patients with chronic hepatitis are excluded because of 
concern that hepatitis could be exacerbated by the injections.  Patients with active 
CMV disease will be excluded, but CMV seropositive patients will be eligible. 
4.2.8. 
Patients on steroid therapy (or other immuno-suppressives, such as azathioprine 
or cyclosporin A) are excluded on the basis of potential immune suppression.  
Patients must have had 6 weeks of discontinuation of any steroid therapy (except 
that used as pre-medication for chemotherapy or contrast-enhanced studies) prior 
to enrollment. 
4.2.9. 
4.2.9. Pregnant and nursing women should be excluded from the protocol since 
this research may have unknown and harmful effects on an unborn child or on 
young children.  If the patient is sexually active, the patient must agree to use a 
medically acceptable form of birth control while receiving treatment and for a 
period of 4 months following the last vaccination therapy. It is not known whether 
the treatment used in this study could affect the sperm and could potentially harm 
a child that may be fathered while on this study. 
4.2.10. Patients with acute or chronic skin disorders that will interfere with injection into 
the skin of the extremities or subsequent assessment of potential skin reactions 
will be excluded. 
4.2.11. Patients will be allowed warfarin 1mg po qd other than for port prophylaxis. 
4.2.12. Patients with metastatic disease which is determined to be resectable will be 
excluded. 
4.3. Accrual 
We expect to accrue a minimum of 24 evaluable patients (plus up to 12 replacements 
for patients removed from the study prior to completion of the assigned vaccine 
schedule for any reason other than toxicity).  The study may require 30-42 patients if 

Molecular Therapeutics Program 
 
 
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DLT occur that necessitate re-dosing at a lower dosage levels (see section 6 for a 
description of the dose escalation criteria). 
 
4.4 Assignment of study number: Patients will be assigned study numbers in order of their 
screening using the following: ETBX-011- 001, 002, 003 etc. including screened patients. 
 Assignment of study day: Day 0 is the day of the first immunization. The second 
immunization is at Day 21. 
 
5. PRE-TREATMENT EVALUATION 
(See also Schema in Appendix 1.) The following pre-treatment evaluations will be completed 
within 1 month (+/- 2 weeks) before starting study treatment: 
 History and physical exam, to include Karnofsky Performance Score and review of 
inclusion and exclusion criteria 
 ß-HCG for women with childbearing potential 
 Hematological, biochemical and immunological tests: 
CBC with differential 
PT INR and PTT 
Na, K, Cl, CO2, BUN, creatinine, Ca, total protein, albumin, total bilirubin, alkaline 
phosphatase, AST, ALT and glucose 
Urinalysis 
 Infectious Disease 
HIV antibody, Hepatitis BsAg, Hepatitis C serology, CMV serology 
 Anti Nuclear Antibody (ANA) 
 Biological Markers: 
Serum will be obtained to measure antibodies to CEA and the neutralizing antibodies to 
Ad5 vector, and other available serum markers (e.g., CEA or CA15-3) may be reviewed. 
 Archive Sample 
 20 mL of blood may be drawn during the first clinic visit, when the patient history and 
physical exam are conducted, at the discretion of the immune monitoring laboratory, and 
serum stored for later analysis of immune responses. 
 Imaging studies: 
CT or MRI scans of the chest, abdomen, brain, and/or pelvis will be requested within 1 
month (±2 weeks) before starting study treatment to document the presence and size of 
any measurable metastatic disease that might present.  CT and MRI are the best currently 
available and reproducible methods to measure target lesions selected for response 
assessment.  Conventional CT and MRI should be performed with cuts of 10 mm or less 
in slice thickness contiguously.  Spiral CT should be performed.  This applies to tumors 
in the chest, abdomen, and pelvis. 

Molecular Therapeutics Program 
 
 
20 
 
 
6. TREATMENT PLAN 
In the phase I component, patients will be enrolled into successive dosage level cohorts 
of 3 or 6 patients and monitored for dose-limiting toxicity (DLT).  
 DLT (based on CTCAE4.0 criteria) is defined as any Grade 2, 3 or 4 immediate 
hypersensitivity reactions, Grade 3 or 4 fever that may possibly be associated with the 
immunization, Grade ≥2 autoimmune events except for vitilgo or fever for less than 2 days and 
less than <101.5 ºF, Grade ≥2 allergic reactions (grade 2 is defined as generalized urticaria as 
defined by version 4 CTC guide), or Grade ≥3 non-hematologic toxicity.  
During dose escalation through the first three patients of cohort 3, there will be a 
minimum of 1 week between enrolling successive patients.  The first patient will be called to 
check on their condition prior to enrolling the second patient since patients can be enrolled after 
1 week of initiation of cohort 3. If no DLT have been observed at this point, then further 
enrollment can occur in cohort 3 and phase II component without the 1-week waiting period.  
Between dosage levels, assessment of DLT for dose escalation will be made after all patients in a 
cohort have had a study visit at least 3 weeks after receiving their first dose of vaccine and all the 
available safety data and laboratory results have been reviewed by the Principle Investigator. If 
DLT occurs in <33% of patients in a given dosage level cohort, progression to the next dosage 
level will proceed.  If DLT occurs in ≥33% of patients in a given cohort, the next lower dosage 
level will be defined as the maximum tolerated dose (MTD).  If DLT occurs in <33% of patients 
in the highest dosage level tested, that dosage level will be defined as the MTD.  In phase II, 12 
additional patients will be enrolled at the MTD.  In phase II, if at any time the rate of DLT in 
patients enrolled at the MTD (for the phase I and phase II cohorts combined) is ≥33%, the MTD 
will be re-defined as the next lower dosage level, and phase II will proceed with enrollment of 
additional patients at this lower dosage level.  Additional details of this dose escalation and 
de-escalation plan are provided below and in Figures 3A, 3B and Table 3.  

Molecular Therapeutics Program 
 
 
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1) Phase I: Cohort 1: Three patients will receive Ad5 [E1-, E2B-]-CEA(6D)  at a dose of 1 x 
109 particles in 0.5 mL subcutaneously (SQ) in the same thigh every 3 weeks for 
3 immunizations. Immunizations should be separated by 5 cm.  Diary card to record any 
adverse reactions for 2 days after treatment (24 hours and 48 hours post injection) will be 
given to each patient at the first treatment along with a ruler. Patient can fax (# 919-684-
2311) the completed diary form prior to next appointment date. The diary card will be 
placed in the patient file and a copy given to the Principal Investigator for his records. 
Assessment of DLT for dose escalation will be made after all patients in this cohort have 
had a study visit at least 3 weeks after receiving their first dose of vaccine.  If there are no 
DLT (as defined above), then patients may begin enrolling into cohort 2.  If there is 1 
DLT then an additional 3 patients will be enrolled at this dosage level. Assessment of 
DLT for dose escalation will be made after the 3 additional patients have had a study visit 
at least 3 weeks after receiving their first dose of vaccine.  If none of these latter 3 
patients have DLT, then patients may begin enrolling into cohort 2.  If 2 patients have 
DLT at this lowest dosage level, dosing will be de-escalated to 1x108 particles. and a new 
cohort instituted. 
2) Cohort 2: Three patients will receive Ad5 [E1-, E2B-]-CEA(6D) at a dose of 1 x 1010 
particles in 0.5 mL SQ in the same thigh every 3 weeks for 3 immunizations.  
Immunizations site should be separated by 5 cm.  Assessment of DLT for dose escalation 
will be made after all patients in this cohort have had a study visit at least 3 weeks after 
receiving their first dose of vaccine.  If there are no DLT, then patients may begin 
enrolling into cohort 3.  If there is 1 DLT then an additional 3 patients will be enrolled at 
this dosage level. Assessment of DLT for dose escalation will be made after the 3 
additional patients have had a study visit at least 3 weeks after receiving their first dose of 
vaccine.  If none of these latter 3 patients have DLT, then patients may begin enrolling 
into cohort 3.  If 2 patients have DLT at this dosage level, the dosage level in cohort 1 
will be considered the MTD.  If only 3 patients were enrolled in cohort 1, an additional 3 
patients will be enrolled at that dosage before proceeding to phase II. 
3) Cohort 3: Six patients will receive Ad5 [E1-, E2B-]-CEA(6D)  at a dose of 1 x 1011 
particles in 0.5  mL SQ in the same thigh every 3  weeks for 3 immunizations.  
Immunizations site should be separated by 5 cm.  Assessment of DLT for proceeding to 
phase II enrollment will be made after all patients in this cohort have had a study visit at 
least 3 weeks after receiving their first dose of vaccine.  If there is 0 or 1 DLT, then this 
dosage level will be considered the MTD and patients may begin enrolling into the phase 
II portion of the study.  If 2 patients have DLT at this dosage level, the dosage level in 
cohort 2 will be considered the MTD.  If only 3 patients were enrolled in cohort 2, an 
additional 3 patients will be enrolled at that dosage before proceeding to phase II. 
4) Phase II cohort: After the MTD is established, an additional 12 patients will receive Ad5 
[E1-, E2B-]-CEA(6D) at the MTD every 3 weeks for 3 immunizations. 
 
Note: if during accrual of patients in the phase II cohort, DLT occurs at a sufficient rate 
such that the rate of DLT amongst the total number of patients (those treated at MTD in 

Molecular Therapeutics Program 
 
 
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phase I and those in phase II) is ≥33%, then phase II will be restarted at the dosage level 
which is one level below the prior MTD.  
5) Patients will have 90 mL peripheral blood drawn prior to each immunization and 
approximately 3 weeks after the third immunization (Week 9) to determine whether there 
is an effect on the immune response at specific time points during the study and/or after a 
specific number of immunizations. 
6) Time to progression will be measured using CT scans performed at approximately 
3 month intervals (based on clinical standard of care). 
7) For all patients, if scheduling conflicts arise, the scheduled 3-week interval between 
immunizations may be modified so that the interval between immunizations is between 
20 and 28 days (3 weeks -1 day to 3 weeks +7 days).  If the second and/or third 
immunization is delayed, the subsequent immunizations should occur no earlier than 
20 days after the previous immunization. 
9) The following safety events will trigger a temporary suspension of study vaccinations: 
a) If ≥33% of patients in the phase II cohort experience DLT at dosage level 1 (i.e.,1 x 
109 particles) 
b) If one or more patients develop a Grade 4 allergic reaction without a clear 
attributable cause, other than study vaccine 
c) Death not attributed to disease. 
 
Assessment of these halting rules is a review of cumulative events for all study 
participants, and should not be confused with reasons for delaying or terminating the 
immunization schedule of any individual patient. 
The Scientific Monitoring Subcommittee of the Cancer Protocol Committee (CPC) will 
fully review all available safety data, consult with the principal investigator, medical 
monitor and the FDA as needed, before determining if resuming vaccinations is 
appropriate.  If it is determined that study vaccinations can resume, the halting rules will 
apply to each subsequent event that meets the criteria described above. 
Vaccinations may also be suspended for safety concerns other than those described above 
if, in the judgment of the principal investigator or sponsor, participant safety is 
threatened. 
6.1. Study Stopping Rules 
- 
Death possibly related to the study agent. 
- 
Two patients having a Grade 4 toxicity event that is possibly/probably related to 
the study agent. 
 
 

Molecular Therapeutics Program 
 
 
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Figure 3B. 
 
Table 3. Calculation of rates of DLT during patient accrual in phase I and phase II 
# evaluable 
for toxicity 
1,2,3 
4,5,6 
7,8,9 
10,11,12 
13,14,15 
16,17,18 
# with DLT 
to be ≥33% 
1 
2 
3 
4 
5 
6 
 
Phase II cohort 
N=12  
(monitor DLT rate for phase I  
and phase II cohorts at this 
dose level combined) 
DLT > 33% at any point  
(see table) 
DLT 
<33% 
Complete accrual 
If phase II is 
at dosage  
level 3 
Restart phase II  
at dosage  
level 2 
If phase II is 
at dosage  
level 2 
Restart phase II  
at dosage  
level 1 
If phase II is 
at dosage  
level 1 
Stop and 
Re-evaluate 
study 

Molecular Therapeutics Program 
 
 
25 
 
6.2. Pharmaceutical Information 
6.1.1 Dosage and Administration 
 
Patients will receive Ad5 [E1-, E2B-]-CEA(6D) at a dose of 1 x 109, or 1 x 1010,    
particles subcutaneously (SQ) in 0.5 mL of a buffered saline solution every 3 
weeks for 3 immunizations and patients who receive 1x1011 VP will receive 
Ad5[E1-, E2b-]-CEA(6D) in 0.5 mL of ARM formulation buffer SQ every 3 
weeks for 3 immunizations. 
 
6.1.2 How Supplied 
ETBX-011 will be provided in a frozen state in a 2ml vial with a fill volume of 
0.5 ml of extractable vaccine which contains 1X1011 total virus particles. The 
volume of injection for 1x1011 virus particles is 0.5 mL. The lower doses will be 
produced by dilution in 0.9% saline using the following directions. The product 
should be stored at </= –20°C until used. 
 
Instructions for dose preparation:  
A detailed description of dose preparation is described in the study IPHP and 
clinic SOP. 
 
1.  To administer 1x10e9 virus particles by subcutaneous injection: 
Perform 2 serial dilutions of vialed vaccine as follows: 
Draw 4.5 mL of sterile saline into a syringe.  Using a second syringe, withdraw 0.5 
mL of previously thawed ETBX-011 from the supplied vial.  Remove the needle 
from syringe containing the 4.5 mL saline, and inject the 0.5 mL of ETBX-011 from 
the second syringe into the syringe containing saline.  Mix. This new solution has a 
concentration 2 x 1010 vp/ml. 
Use a new sterile syringe with a needle and repeat above procedure. Withdraw 4.5 
mL of sterile saline.  In the second syringe withdraw 0.5 mL from the syringe 
containing 2 x 1010 vp/ml.  Remove the needle from the syringe containing the 4.5 
mL saline, and inject the 0.5 mL of 2 x 1010vp/mL from the second syringe. 
Place a new needle on the 10-mL syringe (Syringe C from Step 9 above) and mix 
the two solutions.  This solution now has a concentration 2 x 109 vp/mL (1 x 109 vp 
per 0.5 mL). 
Label a new 1-mL sterile syringe ETBX-011, 1 x 109 vp and withdraw 0.5 mL from 
the syringe containing 2 x 109 vp/mL.  This prepared vaccine (ETBX-011, 1 x 109 
vp) can be kept at room temperature for four hours prior to administering to the 
patient. 
 
2. To administer 1x10e10 virus particles by subcutaneous injection: 
Draw 4.5 mL of sterile saline into a syringe.  Using a second syringe, withdraw 0.5 
mL of previously thawed ETBX-011 from the supplied vial.  Remove the needle 
from syringe containing the 4.5 mL saline, and inject the 0.5 mL of ETBX-011 from 

Molecular Therapeutics Program 
 
 
26 
 
the second syringe into the syringe containing saline.  Mix. This new solution has a 
concentration 2 x 1010 vp/ml.  
Label a new 1-mL sterile syringe ETBX-011, 1 x 1010 vp and withdraw 0.5 mL from 
the syringe containing 2 x 1010 vp/mL.  This prepared vaccine (ETBX-011, 1 x 1010 
vp) can be kept at room temperature for four hours prior to administering to the 
patient. 
 
3. To administer 1x10e11 virus particles by subcutaneous injection: 
Withdraw 0.5mL of contents from vial and administer each subject without any 
further manipulation. 
 
 
6.1.3 Disposal of Unused Vaccine 
Unless other arrangements are agreed in writing, all unused vaccine should be 
delivered to Dr. Joe Balint, at Etubics Corporation  for disposal at or before the completion of the 
clinical study. 
7. TREATMENT EVALUATION 
7.1. Short-Term Evaluation During and After Active Immunotherapy  
On vaccine administration days, blood will be drawn before administration.  Evaluations 
will also be conducted for patients who discontinue from the study if they have received any 
treatment.  The investigator will determine the degree of evaluation based on the patient's 
condition and/or reason for discontinuation from the study. 
7.1.1 General Evaluations (each visit for immunization) 
General evaluations include medical history, Karnofsky performance status, and 
complete physical examination with weight.  Any other treatments, medications, 
biologics, or blood products that the patient is receiving or has received since the 
last visit will be recorded.  Patients will remain in the clinic for approximately 
30 minutes following receipt of vaccine to monitor for any adverse reactions.  Local 
and systemic reactogenicity after each dose of vaccine will be assessed daily for 3 
days (on the day of immunization and 2 days thereafter) using diary cards to report 
symptoms and a ruler to measure local reactogenicity. 
7.1.2 Hematological and Biochemical Assessment 
Blood chemistry and hematology, including CBC with differential, Na, K, Cl, CO2, 
BUN, creatinine, Ca, total protein, albumin, total bilirubin, alkaline phosphatase, 
AST, ALT and glucose will be drawn at Week 0,3,6,9, at discontinuation of 
treatment (if treatment is discontinued early), and as clinically indicated. 
7.1.3 Biological Markers 

Molecular Therapeutics Program 
 
 
27 
 
Serum (5ml) to measure antibodies to CEA and the Ad5 vector will be obtained at 
Week 0, approximately 3 weeks after the last immunization (approximately 
Week 12), and every 3 months thereafter. 
7.1.4 Immunological Assessment 
Peripheral blood (90mL) will be drawn prior to each immunization and 
approximately 3 weeks after the last immunization to determine whether there is an 
effect on the immune response at specific time points during the study and/or after a 
specific number of immunizations.  Peripheral blood mononuclear cells (PBMC) 
will be assayed for T cell responses to CEA using ELISPOT at all time points, plus 
proliferation assays, multi-parameter flow cytometric analysis, and cytoxicity 
assays, if possible and at the discretion of the investigator.  Serum will be archived 
from each blood draw for evaluating antibody levels. 
7.2. Long-Term Follow-Up 
Patients will be requested to continue long-term follow-up at Duke University 
Medical Center every 3 months for 1 year, while on the study (i.e., have not 
progressed or been removed from the study for other reasons). At each visit, a 
medical history and physical exam and labs (Blood chemistry and hematology, 
including CBC with differential, Na, K, Cl, CO2, BUN, creatinine, Ca, total protein, 
albumin, total bilirubin, alkaline phosphatase, AST, ALT and glucose) will be 
drawn. 
At each visit, 40-90 mL of peripheral blood for immune analysis may be drawn, if 
there was previous evidence of an immune response or at the discretion of the 
investigator. 
7.3. Management of Intercurrent Events 
7.3.1 Concomitant Medications 
Patients will be removed from the protocol treatment if they initiate concomitant 
chemotherapeutic agents, corticosteroids, or other immunosuppressive agents, or 
other forms of immunotherapy.  After meeting the inclusion criteria, all other 
medications deemed appropriate for the patient, by the investigator, may be 
administered to the patient.  All medications and changes in medication during 
treatment will be recorded.  Hormonal therapy and bisphosphonates may be 
continued in breast cancer patients if they have been stable on the agents for at least 
1 month prior to enrollment. 
7.3.2 Adverse Events 
7.3.2.1 Toxicity will be graded according to the NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 (which can be downloaded from 

Molecular Therapeutics Program 
 
 
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the CTEP web site (http://ctep.cancer.gov).)  Dose-limiting toxicity (DLT) is 
defined in section 6. 
7.3.2.2 Possible side effects from immunization may include local effects (pain, 
tenderness, rednesss or swelling), systemic effects (malaise, fatigue, myalgia, 
arthralgia, headache, nausea, vomiting, chills or fever), and allergic reactions 
such as hives, rash or anaphylactic reactions.  Induction of auto-immunity, 
manifest as arthritis, serositis, nephritis, thyroiditis, colitis, neutropenia, etc., 
is theoretically possible, but has not been observed in our prior CEA vaccine 
studies.  Also, liver function test abnormalities and liver failure are 
theoretically possible. 
7.3.3 Treatment of Toxicity 
For acute allergic reactions, use of diphenhydramine 25-50 mg IV, corticosteroids 
(Solumedrol 100 mg), and epinephrine (1:1000, 0.3-1 mL sq) should be considered.  
These medications are available in the clinical setting where the vaccine will be 
administered.  For auto-immunity, corticosteroids (prednisone 0.5-1 mg/kg/d) 
should be considered.  Clinical assessment of other targets, such as thyroid, 
arthritis, urticaria, or proteinuria, for auto-immunity and serum sickness like 
antigen-antibody complex disease, will also be performed as indicated. 
7.3.4 Active Immunotherapy will be Discontinued for: 
7.3.4.1 Life-threatening anaphylactic reactions related to active immunotherapy 
7.3.4.2 Dose-limiting toxicity related to active immunotherapy 
7.3.4.3 Disease progression (by RECIST criteria).  Patients will be offered 
referral to a medical oncologist at Duke University Medical Center for 
discussion of other treatment options, and for continued medical care.   
7.3.4.3.1 
Disease progression prior to completing the 3 study 
immunizations: In the event that a patient undergoes reimaging studies 
prior to the completion of their 3 study immunizations and is found to 
have disease progression, they will be permitted to continue on the study 
as long as the progression has been 50% or less by RECIST criteria.  
 
If a patient is removed from the study prior to completion of the assigned vaccine 
schedule for any reason other than toxicity, that patient will be replaced, in order to 
obtain data to help determine the toxicity of the immunizations. We will allow up to 3 
replacements per cohort (Phase I, Dose levels 1 and 2; Phase II, MTD). 
8. STATISTICAL CONSIDERATIONS 
8.1. Safety:  
We will evaluate safety continuously in a cohort.  We will make our overall assessment 
of whether to escalate to the next dose level at least 3 weeks after the last patient in the previous 
cohort has received their first injection.  This decision will be made by the medical monitor and 

Molecular Therapeutics Program 
 
 
29 
 
the Principle Investigator.  A note will be generated following the assessment decision and filed 
in study binder.  A dosage level will be considered safe if <33% patients treated at a dose level 
experience dose-limiting toxicity (i.e., 0 of 3, 1 of 6, 3 of 12, or 5 of 18 patients).  Dose-
limiting toxicity is defined in section 6.  Safety will be evaluated in 3 or 6 patients at each dosage 
level in phase I.   Safety will continue to be monitored among additional patients treated at the 
MTD in phase II.  A patient will be considered evaluable for safety if treated with at least one 
immunization.  DLTs will be observed through 9 weeks to accommodate safety evaluation of all 
3 product doses. 
8.2. Rate of Immune Response:  
Immune responses against CEA will be evaluated from the peripheral blood of 
patients from among the following studies at the discretion of the Principle Investigator 
(ELISpot, cytokine flow cytometry, and antibody responses). We will determine the 
percentage of patients with a positive immune response.  We define a positive immune response 
by ELISpot as described at the 2002 Society of Biologic Therapy Workshop on “Immunologic 
Monitoring of Cancer Vaccine Therapy”, i.e. a T cell response is considered positive if the 
mean number of spots adjusted for background in six wells with antigen exceeds the number of 
spots in six control wells by 10 and the difference between single values of the six wells 
containing antigen and the six control wells is statistically significant at a level of p ≤ 0.05 using 
the Student’s t test.  Immunogenicity assays will occur prior to each immunization and at week 
12.  Immune response will be assessed among the 18 patients treated at the MTD (12 in phase I 
and 12 in Phase II).  The therapy will be considered of further interest if 9 of 18 patients treated 
at the MTD dose exhibit an immune response as defined above.  Meeting this criterion 
establishes that the immune response rate is at least 33% with approximately 90% confidence.  
At significance level 0.1 there is 82% power to test the null hypothesis that the immune response 
rate is ≤ 0.33 versus the alternative that the immune response rate is ≥ 0.58.  The magnitude of 
response will also be described.  A patient will be considered evaluable for immune response if 
they receive at least 3 immunizations. 
8.3. Determination of Clinical Response 
Among patients with measurable/evaluable disease, response determination will be made 
according to the RECIST criteria: 
Complete Response (CR): 
Disappearance of target lesion, confirmed at 4    
weeks 
Partial Response (PR): 
30% decrease in longest dimension of target lesion, 
confirmed at 4 weeks 
Stable Disease (SD): 
 
Neither PR nor PD 
Progressive Disease (PD): 
20% increase in longest dimension of target lesion; 
no CR, PR, or SD documented before increased 
disease. 
The exact binomial confidence interval for the proportion of subjects with a clinical 
response of CR or PR will be calculated. 

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9. PATIENT WITHDRAWAL 
Patients may be removed from the study for the following reasons: 
 Dose-limiting toxicity, as defined in section 6.   
 Patient voluntarily decides to withdraw. 
 Patient non-compliance with the study protocol. 
 Intercurrent disease which in the opinion of the patient’s treating physician would 
affect the ability of the patient to continue on the clinical study.  
In the event of withdrawal due to toxicity, a patient will be requested to have safety 
evaluations performed as per the protocol for a one year duration post treatment. This may 
include having up to 90 mL of blood drawn for immunologic testing.. 
10. STUDY CONDUCT AND ETHICAL AND REGULATORY CONSIDERATIONS 
10.1. Departure from the Protocol 
There should be no departure from the protocol if at all possible.  If an emergency occurs 
that requires departure from this protocol, the investigator or other physician in attendance in 
such an emergency will, if circumstances and time permit, contact the principal investigator 
(Dr. Michael Morse) or in his absence, Dr. H. Kim Lyerly, immediately by telephone 
(Page operator 919 684-8111).  Such contacts with the principal investigator will be made to 
permit a decision as to whether or not the patient will be continued on the study.  Such 
departures need to be clearly documented and reported to the IRB and the sponsor (Etubics) by 
the principal investigator. 
10.2. Informed Consent 
In accordance with guidelines in the Federal Register, Vol. 48, No. 17, 1982, pp. 8951-2, 
all patients are required to sign a statement of informed consent.  This phase I/II study involves 
research that presents risk, but holds the prospect of direct benefit to the individual patient 
(46.405-45 Code of the Federal Regulations part 46).  The investigator will report to the IRB and 
the sponsor (Etubics) will report to FDA changes in the research protocol and all unanticipated 
problems involving risks to human patients and others, and no changes will be made in the 
research activity without IRB approval. 
10.3. Institutional Review 
This study must be approved by the Institutional Review Board (IRB).  IRB approval of 
the protocol and the informed consent form for this study must be given in writing.  The IRB 
must also approve any significant changes to the protocol as well as a change of principal 
investigator.  Records of all study review and approval documents must be kept on file by the 
investigator and are subject to FDA inspection during or after completion of the study.  Adverse 
events must be reported to the IRB.  The IRB will receive notification of the completion of the 
study and final report within three months of study completion or termination.  The investigator 

Molecular Therapeutics Program 
 
 
31 
 
must maintain an accurate and complete record of all submissions made to the IRB, including a 
list of all reports and documents submitted. 
 
10.4. Documentation and Monitoring 
Data will be collected for all patients.  Accurate completion of the computer data forms 
for all patients is the responsibility of the investigator.   
 
10.4.1 Case Report Forms 
Case Report Forms (CRFs) are used to record study data and are an integral part of the 
study and subsequent reports.  Therefore, all reports must be legible and complete.  All forms 
should be filled out using a black ballpoint pen.  Errors should be lined out but not obliterated 
and the correction inserted, initialed, and dated by the principal investigator, co-investigators, 
study coordinator, or data manager.  A Case Report Form must be completed and signed by the 
principal investigator for each patient enrolled, including those removed from the study for any 
reason.  The reason for removal must be noted on the Final Report Form by the investigator for 
each patient.  Case Report Forms must be kept current to reflect patient status at each phase 
during the course of the study.  Patients are not to be identified on case report forms by name; 
appropriate coded identification and patient initials must be used.  The investigator must keep a 
separate log of patient names and addresses.  This log is subject to FDA inspection.  Because of 
the potential for errors, inaccuracies, and illegibility in transcribing data onto case report forms, 
originals of laboratory and other test results must be kept on file with patient's case report form 
or clinical chart.  Case report forms and copies of test results must be available at all times for 
inspection by the FDA.   
 
10.4.2 Maintenance of Study Documentation 
The following will be maintained: 
a. Case Report Forms - which must be kept legible, accurate, and up-to-date. 
b. Patient Files/Signed Informed Consent - which substantiates the data entered 
on the case report forms for all required test and evaluation procedures and 
verifies that the patient has signed an informed consent to enter the study. 
c. Patient Exclusion Record - which should reflect the reason any patient was 
screened and found ineligible for the study. 
d. Monitoring Log - listing dates of monitor visits. 
e. Regulatory Documents - including protocol, investigator brochure, FDA Form 
1572, CVs, IRB correspondence, IRB approval/renewals and IRB approved 
consent form. 
f. Adverse Experience Report Form - which should explain any serious or 
unexpected adverse experiences. 
All study documentation pertaining to the conduct of the study must be kept on file by the 
investigator for a period of 2 years following the date a marketing application is approved for the 
drug for the indication for which it is being investigated; or, if no application is to be filed or if 

Molecular Therapeutics Program 
 
 
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the application is not approved for such indication, until 2 years after the investigation is 
discontinued and FDA is notified.  The sponsor will notify the investigator if a marketing 
application is approved or if the investigation is discontinued and the FDA notified. 
10.5. Monitoring of the Protocol 
Protocol data and safety will be monitored by the Scientific Monitoring Subcommittee of 
the Cancer Protocol Committee (CPC) with the following plan: 
1.  Purpose:  This is a phase I/II clinical study with more than minimal risk and as such 
will be monitored for the occurrence of a greater frequency of AEs. 
2.  Monitoring: Up to 24 patients will be enrolled.  The principal investigator will 
continuously monitor the study.  The principal investigator will review the data and 
safety of the study after the enrollment of three patients in cohort 1, after enrollment 
of three patients in cohort 2, and after enrollment of six patients in cohort 3.  Formal, 
independent monitoring by CPC will occur after enrollment of the three patients in 
cohort 1 and again after enrollment of three patients in cohort 2; then a scientific 
progress review will occur yearly, assuming a result of “satisfactory” on the initial 
review.  The exceptions are as follows:  If more than one patient experiences a Grade 
4 or greater allergic reaction, the principal investigator will request a monitoring 
review by CPC.  If at any time, more than 50% of patients experience a Grade 3 or 4 
major organ toxicity, we will request a monitoring review by CPC. 
3.  Description of Monitoring:  Adverse event reports will be reviewed with tabulation of 
all Grade 2, 3 or 4 toxicity.  
4. Toxicity:  see section 7.3.2 of the protocol.  
5. Reporting Adverse Events: An adverse experience is any adverse change from the 
study patient's baseline (pre-treatment) condition, including any clinical or laboratory 
test abnormality that occurs during the course of the proposed clinical study after 
treatment has started.  All adverse experiences that are classified as serious as 
described in section 10.7 of the protocol should be reported to the sponsor (Etubics) 
by telephone or fax within 24 hours, and reported in writing to the sponsor (etubics) 
within 72 hours.  All study-related deaths should be reported to the IRB within 24 
hours; all other serious adverse experiences should be reported to the IRB within 5 
business days. All deaths, whether considered study-related or not, must also be 
reported immediately to the principal investigator, with a copy of the autopsy report 
and the death certificate.  All adverse experiences will be recorded on the Adverse 
Experience Case Report Form.  This report form should include severity, duration, 
outcome, and the investigator's judgment as to the relationship of the adverse 
experience to treatment.   
6. Reporting of Pregnancy: If a participant becomes pregnant during the study, treatment 
will be discontinued (i.e., no additional dose of study vaccine will be given) and the 
participant will be encouraged to continue to have regularly scheduled follow-up 
visits and evaluations.  The occurrence of pregnancy, and the outcome of any 
pregnancy, in a subject treated with study vaccine, must be reported to the sponsor 
(Etubics), and to the IRB.   

Molecular Therapeutics Program 
 
 
33 
 
 
10.6. CTCAE Term (AE description) and Grade:   
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting.  All 
appropriate treatment areas should have access to a copy of the CTCAE version 4.0.  A copy of 
the CTCAE version 4.0 can be downloaded from the CTEP web site (http://ctep.cancer.gov).  
The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each 
AE based on the following guideline: 
Grade 1 
Mild AE 
Grade 2 
Moderate AE 
Grade 3 
Severe AE 
Grade 4 
Life-threatening or disabling AE 
Grade 5 
Death related to AE 
10.7. Serious Adverse Event Reporting 
Events are classified as SERIOUS if they meet any of the following criteria [per the US 
Code of Federal Regulations (CFR) 21 CFR 312.32 and the recommendations of the 
International Conference on Harmonization (ICH)]: 
An SAE is any sign, symptom or medical condition that emerges during the study or 
during a post-study follow-up period that 1) was not present at the start of the study and is not a 
chronic condition that is part of the patient’s medical history, OR 2) was present at the start of 
the study or as part of the patient’s medical history but worsened in severity and/or frequency 
during study participation, AND that meets any of the following regulatory serious criteria: 
 any death 
 any life-threatening event, i.e., an event that places the patient, in the view of the 
investigator, at immediate risk of death from the event as it occurred (does not 
include an event that, had it occurred in a more severe form, might have caused 
death) 
 any event that requires or prolongs in-patient hospitalization 
 any event that results in persistent or significant disability/incapacity 
 any congenital anomaly/birth defect diagnosed in a child of a patient who 
participated in this study and received investigational drug 
 other medically important events that in the opinion of the investigator may 
jeopardize the patient or may require intervention to prevent one of the other 
outcomes listed in the definition above (e.g. allergic bronchospasm requiring 
intensive treatment in an emergency room, convulsions occurring at home that do 
not require in-patient hospitalization, any blood dyscrasias, or the development of 
drug dependency or drug abuse). 
 
Procedures for adverse event reporting 
 
  1.  PI notified by medical staff of a SAE 

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PI: Michael Morse, MD 
            Address: Duke University Medical Center 
Seeley Mudd Building  
Box 3233, Durham, NC 27710 
 
Telephone: 1-919-681-3480 
 
Fax: 1-919-681-7970 
Pager 1-919-970-5626 
 
Email: michael.morse@duke.edu 
 
2. PI calls sponsor to report an unexpected SAE associated with the use of the drug 
 
 
Sponsor: Carol Jones, Vice President of Administration 
 
Address: 410 West Harrison Street, Suite 100, Seattle, WA 981119 
 
Telephone: 206-838-5110 ext. 102 
 
Cell: 1-206-818-2985 
 
Fax: 1-206-838-2978 
 
Email: cj@etubics.com 
 
  3.  Carol Jones reports the SAE to one of the following in this order: 
 
      A.  Chief Scientific Officer: Frank Jones, PhD  
 
Address: 410 West Harrison Street, Suite 100, Seattle, WA 98119  
 
Telephone: 206-838-5110 ext. 101 
 
Cell: 206-818-2857 
 
Fax: 206-838-2978 
 
Email: frj@etubics.com 
      B.  Laboratory Manager:  Joseph Balint, PhD 
 
Address: 410 West Harrison Street, Suite 100, Seattle, WA 98119 
Telephone: 206-838-5110 ext. 107 
Fax:  206-838-2978 
 
Email: joe@etubics.com 
      C.  Vice President Research: Elizabeth S. Gabitzsch 
 
Address: 410 West Harrison Street, Suite 100, Seattle, WA 98119 
Telephone: 206-838-5110 ext. 103 
Cell: 970-402-2598 
Fax:  206-838-2978 
 
Email: beth@etubics.com 
 
 
4. Contacted person in three (3) above notifies the FDA on MedWatch 3200A form. 
a. If the SAE results in death or is life-threatening, report the SAE to the FDA within 7 days 
b. All other SAEs must be reported to FDA within 15 days 
 
5. 
If the SAE requires input from a physician then the Acting Medical Director is consulted: 
 
 
 
      
H. Kim Lyerly, MD  
Telephone: (919) 684-5613 
Fax: (919) 684-5653 

Molecular Therapeutics Program 
 
 
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Email: lyerl001@mc.duke.edu 
 
 
All SAE reports will be recorded on the Duke IRB Adverse Event Reporting form and 
will be reviewed and signed by the Principal Investigator.  Only adverse events that are deemed 
to be serious, unexpected and related or possibly related to the research must be reported to the 
IRB (this is in accordance with Duke’s IRB reporting policy). All reportable events will be 
forwarded to the IRB via campus mail or fax: 
 
IRB: 
Duke Medical Center Institutional Review Board: 
Hock Plaza, 4th floor 
2424 Erwin Road 
Box 2991 
Durham, NC  27705 
Fax: 919-668-5125 
 
 
In accordance with FDA regulations and ICH guidelines, investigators will be notified of the 
occurrence of new, serious, unexpected adverse events associated with the use of the study 
medication (i.e. there is a reasonable possibility that the adverse event may have been caused by 
the drug) within 15 calendar days via a written report.  It is the responsibility of the investigator 
to promptly inform the relevant Institutional Review Board (IRB) of these new adverse 
events/risks to patients, in accordance with 21 CFR 312.66.  It is also the responsibility of the 
investigator and the sponsor (Etubics) in conducting gene transfer research to promptly inform 
the NIH Office of Biotechnology Activities (OBA) and relevant Scientific Review Board of 
these new adverse events/risks to patients, in accordance with NIH Guidelines for Research 
Involving Recombinant DNA Molecules, in particular Appendix M.  It is the responsibility of the 
sponsor (Etubics) to report these serious adverse events to the FDA.  The SAE report will be 
forwarded to the FDA after recording the event data via the FDA MedWatch form 3500A.   
 
MedWatch 3500A Reporting Guidelines: 
In addition to completing appropriate patient demographic and suspect medication 
information, the report should include the following information within the Event Description 
(section 5) of the MedWatch 3500A form: 
Treatment regimen (dosing frequency, combination therapy) 
Protocol description (and number, if assigned) 
Description of event, severity, treatment, and outcome, if known 
Supportive laboratory results and diagnostics 
Investigator’s assessment of the relationship of the adverse event to each investigational 
product and suspect medication 
Follow-up information:   
Additional information may be added to a previously submitted report by any of the 
following methods: 

Molecular Therapeutics Program 
 
 
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 Adding to the original MedWatch 3500A report and submitting it as follow-up 
 Adding supplemental summary information and submitting it as follow-up with the 
original MedWatch 3500A form  
 Summarizing new information and faxing it with a cover letter including patient 
identifiers (i.e. D.O.B., initials, patient number), protocol description and number, if 
assigned, suspect drug, brief adverse event description, and notation that additional or 
follow-up information is being submitted  (The patient identifiers are important so that 
the new information is added to the correct initial report.) 
 
 
10.8. Assessing Causality: 
Investigators are required to assess whether there is a reasonable possibility that study 
medications caused or contributed to an adverse event.  The following general guidance may be 
used. 
Yes: 
if the temporal relationship of the clinical event to study drug administration makes a 
causal relationship possible, and other drugs, therapeutic interventions or underlying 
conditions do not provide a sufficient explanation for the observed event. 
No: 
if the temporal relationship of the clinical event to study drug administration makes a 
causal relationship unlikely, or other drugs, therapeutic interventions or underlying 
conditions provide a sufficient explanation for the observed event. 
10.9. Safety Reporting Requirements for IND Holders 
In accordance with 21 CFR 212.32, sponsor-investigators of studies conducted under an 
IND must comply with following safety reporting requirements:  
 
a. Expedited IND Safety Reports: 
7 Calendar-Day Telephone or Fax Report:   
The sponsor is required to notify the FDA of any fatal or life-threatening adverse event 
that is unexpected and assessed by the investigator to be possibly related to the use of the 
investigational product.   An unexpected adverse event is one that is not already described in the 
Investigator’s Brochure.  Such reports are to be telephoned or faxed to the FDA within 
7 calendar days of first learning of the event.   
15 Calendar-Day Written Report:   
The sponsor is also required to notify the FDA and all participating investigators, in a 
written IND Safety Report, of any serious, unexpected AE that is considered possibly related to 
the investigational product.  An unexpected adverse event is one that is not already described in 
the Investigator Brochure. 
Written IND Safety Reports should include an Analysis of Similar Events in accordance 
with regulation 21 CFR § 312.32.  All safety reports previously filed with the IND concerning 
similar events should be analyzed.  The new report should contain comments on the significance 
of the new event in light of the previous, similar reports.   

Molecular Therapeutics Program 
 
 
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Written IND safety reports with Analysis of Similar Events are to be submitted to the 
FDA and all participating investigators within 15 calendar days of first learning of the event.  
The FDA prefers these reports on a MedWatch 3500A Form but alternative formats are 
acceptable (e.g. summary letter). 
 
b. IND Annual Reports 
In accordance with the regulation 21 CFR § 312.32, the sponsor shall within 60 days of 
the anniversary date that the IND went into effect submit a brief report of the progress of the 
investigation.  Please refer to Code of Federal Regulations, 21 CFR § 312.32 for a list of the 
elements required for the annual report.   
 
c. Data and Safety Monitoring  
Data will be collected by: the principal investigator, co-investigators, and the protocol 
coordinator.  The protocol coordinator under the supervision of the principal investigator will 
report the AEs. The data will be audited by the CPC and Etubics’ CRA.  
 
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Miller, P.W., Sharma, S., Stolina, M., Butterfield, L.H., Luo, J., Lin, Y., Dohadwala, M., 
Batra, R.K., Wu, L., Economou, J.S., et al. 2000. Intratumoral administration of 
adenoviral interleukin 7 gene-modified dendritic cells augments specific antitumor 
immunity and achieves tumor eradication. Hum Gene Ther 11:53-65. 
46. 
Lu, L., Gambotto, A., Lee, W.C., Qian, S., Bonham, C.A., Robbins, P.D., and Thomson, 
A.W. 1999. Adenoviral delivery of CTLA4Ig into myeloid dendritic cells promotes their 
in vitro tolerogenicity and survival in allogeneic recipients. Gene Ther 6:554-563. 
47. 
Rea, D., Schagen, F.H., Hoeben, R.C., Mehtali, M., Havenga, M.J., Toes, R.E., Melief, 
C.J., and Offringa, R. 1999. Adenoviruses activate human dendritic cells without 
polarization toward a T-helper type 1-inducing subset. J Virol 73:10245-10253. 
48. 
Hirschowitz, E.A., Weaver, J.D., Hidalgo, G.E., and Doherty, D.E. 2000. Murine 
dendritic cells infected with adenovirus vectors show signs of activation. Gene Ther 
7:1112-1120. 
49. 
Loser, P., Jennings, G.S., Strauss, M., and Sandig, V. 1998. Reactivation of the 
previously silenced cytomegalovirus major immediate-early promoter in the mouse liver: 
involvement of NFkappaB. J Virol 72:180-190. 
50. 
Morelli, A.E., Larregina, A.T., Ganster, R.W., Zahorchak, A.F., Plowey, J.M., 
Takayama, T., Logar, A.J., Robbins, P.D., Falo, L.D., and Thomson, A.W. 2000. 
Recombinant adenovirus induces maturation of dendritic cells via an NF-kappaB-
dependent pathway. J Virol 74:9617-9628. 
51. 
Jonuleit, H., Tüting, T., Steitz, J., Brück, J., Giesecke, A., Steinbrink, K., Knop, J., and 
Enk, A.H. 2000. Efficient transduction of mature CD83+ dendritic cells using 
recombinant adenovirus suppressed T cell stimulatory capacity. Gene Ther 7:249-254. 
52. 
Tillman, B.W., Hayes, T.L., DeGruijl, T.D., Douglas, J.T., and Curiel, D.T. 2000. 
Adenoviral vectors targeted to CD40 enhance the efficacy of dendritic cell-based 
vaccination against human papillomavirus 16-induced tumor cells in a murine model. 
Cancer Res 60:5456-5463. 
53. 
Shiver, J.W., Fu, T.M., Chen, L., Casimiro, D.R., Davies, M.E., Evans, R.K., Zhang, 
Z.Q., Simon, A.J., Trigona, W.L., Dubey, S.A., et al. 2002. Replication-incompetent 
adenoviral vaccine vector elicits effective anti-immunodeficiency-virus immunity. Nature 
415:331-335. 
54. 
Yang, Z.Y., Wyatt, L.S., Kong, W.P., Moodie, Z., Moss, B., and Nabel, G.J. 2003. 
Overcoming immunity to a viral vaccine by DNA priming before vector boosting. J Virol 
77:799-803. 
55. 
Casimiro, D.R., Chen, L., Fu, T.M., Evans, R.K., Caulfield, M.J., Davies, M.E., Tang, A., 
Chen, M., Huang, L., Harris, V., et al. 2003. Comparative immunogenicity in rhesus 
monkeys of DNA plasmid, recombinant vaccinia virus, and replication-defective 
adenovirus vectors expressing a human immunodeficiency virus type 1 gag gene. J Virol 
77:6305-6313. 
56. 
Chirmule, N., Propert, K., Magosin, S., Qian, Y., Qian, R., and Wilson, J. 1999. Immune 
responses to adenovirus and adeno-associated virus in humans. Gene Ther 6:1574-1583. 
57. 
Hartigan-O'Connor, D., Barjot, C., Salvatori, G., and Chamberlain, J.S. 2002. Generation 
and growth of gutted adenoviral vectors. Methods Enzymol 346:224-246. 

Molecular Therapeutics Program 
 
 
42 
 
58. 
Harui, A., Roth, M.D., Kiertscher, S.M., Mitani, K., and Basak, S.K. 2004. Vaccination 
with helper-dependent adenovirus enhances the generation of transgene-specific CTL. 
Gene Ther 11:1617-1626. 
59. 
Morral, N., Parks, R.J., Zhou, H., Langston, C., Schiedner, G., Quinones, J., Graham, 
F.L., Kochanek, S., and Beaudet, A.L. 1998. High doses of a helper-dependent adenoviral 
vector yield supraphysiological levels of alpha1-antitrypsin with negligible toxicity. Hum 
Gene Ther 9:2709-2716. 
60. 
DelloRusso, C., Scott, J.M., Hartigan-O'Connor, D., Salvatori, G., Barjot, C., Robinson, 
A.S., Crawford, R.W., Brooks, S.V., and Chamberlain, J.S. 2002. Functional correction 
of adult mdx mouse muscle using gutted adenoviral vectors expressing full-length 
dystrophin. Proc Natl Acad Sci U S A 99:12979-12984. 
61. 
Reddy, P.S., Sakhuja, K., Ganesh, S., Yang, L., Kayda, D., Brann, T., Pattison, S., 
Golightly, D., Idamakanti, N., Pinkstaff, A., et al. 2002. Sustained human factor VIII 
expression in hemophilia A mice following systemic delivery of a gutless adenoviral 
vector. Mol Ther 5:63-73. 
62. 
Amalfitano, A., Hauser, M.A., Hu, H., Serra, D., Begy, C.R., and Chamberlain, J.S. 1998. 
Production and characterization of improved adenovirus vectors with the E1, E2b, and E3 
genes deleted. J Virol 72:926-933. 
63. 
Hartigan-O'Connor, D., Kirk, C.J., Crawford, R., Mulé, J.J., and Chamberlain, J.S. 2001. 
Immune evasion by muscle-specific gene expression in dystrophic muscle. Mol Ther 
4:525-533. 
64. 
Moorhead, J.W., Clayton, G.H., Smith, R.L., and Schaack, J. 1999. A replication-
incompetent adenovirus vector with the preterminal protein gene deleted efficiently 
transduces mouse ears. J Virol 73:1046-1053. 
65. 
Nazir, S.A., and Metcalf, J.P. 2005. Innate immune response to adenovirus. J Investig 
Med 53:292-304. 
66. 
Schaack, J. 2005. Induction and inhibition of innate inflammatory responses by 
adenovirus early region proteins. Viral Immunol 18:79-88. 
67. 
Schaack, J., Bennett, M.L., Colbert, J.D., Torres, A.V., Clayton, G.H., Ornelles, D., and 
Moorhead, J. 2004. E1A and E1B proteins inhibit inflammation induced by adenovirus. 
Proc Natl Acad Sci U S A 101:3124-3129. 
 
 

Molecular Therapeutics Program 
 
 
43 
 
11. APPENDIX 1 – SCHEMA  
Procedure / Test 
Pre-
treatment a 
Week  
0 a 
Week  
3 b 
Week  
6 b 
Week  
9 
Months 6, 
9, etc. c 
Off 
Treatment 
H & P 
X 
X 
X 
X 
X 
X 
X 
Karnofsky Status  
X 
X 
X 
X 
X 
X 
X 
-HCG 
X 
 
 
 
 
 
 
CBC & diff 
X 
X 
X 
X 
X 
X 
X 
PT/PTT 
X 
 
 
 
 
 
 
Chemistries/LFTS 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
 
 
 
 
 
ANA 
X 
 
 
 
X 
 
X 
HIV 
X 
 
 
 
 
 
 
Immune Monitoring 
X 
X 
X 
X 
X 
  X d 
X 
Biological Markers 
X 
X 
 
 
X 
X 
X 
MRI/CT Scan 
X 
 
 
 
  X e 
X 
X 
Immunization 
 
X 
X 
X 
 
    
 
 
Notes:  H & P = history & physical examination, Karnofsky = performance score of 70% or higher, -HCG 
= human chorionic gonadotrophin pregnancy test, CBC & diff = complete blood count and white blood 
cell differential, ANA = antinuclear antibody, HIV = human immunodeficiency virus antibodyMRI/CT = 
magnetic resonance imaging/computed tomography. 
a CEA and or other biological markers and with tumor that are universally CEA positive testing for 
biomarkers will be performed at the discretion of PI  
b Immunizations may be performed -1 to +7 days after the specified week.  Subsequent immunizations 
should be 3 weeks afterwards and keep to the every 3 week interval.  
c Follow-up evaluations to be performed every 3 months after the Week 9 visit. 
d Immune monitoring if there was evidence of an immune response or at the discretion of the immune 
monitoring laboratory. 
e MRI/CT scan to be requested 1-4 weeks after the third immunization.  
 
 
 

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A PHASE I/II STUDY OF ACTIVE IMMUNOTHERAPY WITH Ad5 [E1-, E2b-]-
CEA(6D)  VACCINE (ETBX-011) IN PATIENTS WITH ADVANCED OR 
METASTATIC MALIGNANCIES EXPRESSING CEA 
 
 
 
 
STUDY PRODUCT: 
 
 
Ad5 [E1-, E2b-]-CEA(6D)  (ETBX-011) 
 
 
STUDY SPONSOR:  
 
 
Etubics Corporation 
    
 
 
 
 
410 West Harrison Street 
    
 
 
 
 
Seattle, WA 98119 
 
 
PRINCIPLE INVESTIGATOR:   
Michael Morse 
 
 
 
 
 
 
Duke University Medical Center 
 
 
 
 
 
 
Box 3233, Durham, NC  27710 
 
 
ACTING MEDICAL DIRECTOR: 
H. Kim Lyerly, MD 
 
 
 
 
 
 
Duke Comprehensive Cancer Center 
 
 
 
 
 
 
Duke University Medical Center 
 
 
 
 
 
 
Durham, NC  27710 
 
 
CO-INVESTIGATOR: 
 
 
Arvind Chaudhry, MD 
 
 
 
 
 
 
Medical Oncology Associates, PS 
 
 
 
 
 
 
6001 N. Mayfair St. 
 
 
 
 
 
 
Spokane, WA  99208 
 
 
Original Protocol: 
 
 
 
Version 1.1, December 21, 2009 
Amendment 1: 
 
 
 
Version 2.1, May 14, 2010 
Amendment 2: 
 
 
 
Version 2.1, August 31, 2010 
 
 
 

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TABLE OF CONTENT 
 
 
 
 
 
 
 
 
 
 
 
Page Number 
 
1. Protocol Summary …………………………………………………..  4 
 
2. Study Objectives …………………………………………………….  6 
 
3. Background and Significance ……………………………………….  6 
 
4. Patient Selection …………………………………………………….. 15 
 
5. Pre-Treatment Evaluation …………………………………………… 19 
 
6. Treatment Plan ………………………………………………………. 20 
 
7. Treatment Evaluation ………………………………………………... 25 
 
8. Statistical Considerations ……………………………………………. 28 
 
9. Patient Withdrawal …………………………………………………... 29 
 
10. Study Conduct and Ethical and Regulatory Considerations …………. 29 
 
11.  References …………………………………………………………… 37 
 
12.  Appendix …………………………………………………………….. 43 
 

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1. PROTOCOL SUMMARY 
 
Title 
A PHASE I/II STUDY OF ACTIVE IMMUNOTHERAPY WITH 
Ad5 [E1-, E2b-]-CEA(6D)  VACCINE (ETBX-011) IN PATIENTS 
WITH 
ADVANCED 
OR 
METASTATIC 
MALIGNANCIES 
EXPRESSING CEA 
Objectives 
a) The primary objective of this protocol is to determine the safety of 
immunization with Ad5 [E1-, E2B-]-CEA(6D), in patients with 
advanced or metastatic CEA-expressing malignancies.  
b) The secondary objectives are to evaluate CEA-specific immune 
responses to the immunizations and to obtain preliminary data on 
clinical response rate. 
Major Inclusion/ 
Exclusion Criteria 
Patients with a histologically confirmed diagnosis of metastatic 
malignancy who were previously treated with standard therapy known to 
have a possible survival benefit or refused such therapy.  The tumor must 
express CEA as defined by immunohistochemical staining (at least 50% 
of the tumor with at least moderate intensity of staining) or a tumor 
known to be universally CEA positive (i.e. colon and rectal cancer). If 
colorectal cancer, pathologic or clinical confirmation of adenocarcinoma 
is required. Patients will not be treated until 4 or more weeks after any 
prior chemotherapy or radiation therapy, but may be receiving non-
cytotoxic targeted therapy (bevacizumab, cetuximab, trastuzumab, 
erlotinib, or gefitinib) or hormonal therapy.  They must not have a 
history of autoimmune disease, serious intercurrent chronic or acute 
illness, active hepatitis, serologic evidence for HIV, or be receiving 
steroid or immunosuppressive therapy.  All patients must be >21 years 
old and have a Karnofsky Performance Score  of 70% or higher. 
Pregnant women and nursing mothers are excluded.  
Study Design 
Phase I/II study with three dosage levels of Ad5 [E1-, E2B-]-CEA(6D)  
vaccine (phase I component), and the Maximally Tolerated Dose (MTD) 
of Ad5 [E1-, E2B-]-CEA(6D)  vaccine (phase II component).  The study 
drug is Ad5 [E1-, E2B-]-CEA(6D) given by subcutaneous (SQ) injection 
every 3 weeks for 3 immunizations.  The following procedures will 
occur: 
1) Peripheral blood draw (90 mL) for immune analysis. 
2) Cohort 1: Three patients will receive Ad5 [E1-, E2B-]-CEA(6D)  at a 
dose of 1 x 109 particles SQ in 0.5 mL every 3 weeks for 
3 immunizations.  Assessment of dose-limiting toxicities (DLT) for 
dose escalation will be made after all patients in this cohort have had 
a study visit at least 3 weeks after receiving their first dose of 
vaccine.  If there are no DLT, defined as any Grade 2, 3 or 4 
immediate hypersensitivity reactions, Grade 3 or 4 fever that may 
possibly be associated with the immunization, Grade ≥2 autoimmune 
events except for vitiligo or fever for less than 2 days and less than 
101.5 ºF, Grade ≥2 allergic reactions (grade 2 is defined as 
generalized urticaria as defined by NCI Common Terminology 

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Criteria for Adverse Events (CTCAE version 4.0), or Grade ≥3 non-
hematologic toxicity, then patients may begin enrolling into cohort 2.  
If there is 1 DLT, then an additional 3 patients will be enrolled at this 
dosage level. Assessment of DLT for dose escalation will be made 
after the 3 additional patients have had a study visit at least 3 weeks 
after receiving their first dose of vaccine.  If none of these latter 3 
patients have DLT (i.e., 1 DLT in the 6 total patients), then patients 
may begin enrolling into cohort 2. If 2 patients have DLT at the 
lowest dosage level, dosing will be de-escalated to 1x108 particles.  
3)  Cohort 2: Three patients will receive Ad5 [E1-, E2B-]-CEA(6D)  at a 
dose of 1 x 1010 particles SQ in 0.5 mL every 3 weeks for 
3 immunizations.  Assessment of DLT for dose escalation will be 
made after all patients in this cohort have had a study visit at least 
3 weeks after receiving their first dose of vaccine.  If there are no 
DLT, then patients may begin enrolling into cohort 3.  If there is 1 
DLT then an additional 3 patients will be enrolled at this dosage 
level. Assessment of DLT for dose escalation will be made after the 3 
additional patients have had a study visit at least 3 weeks after 
receiving their first dose of vaccine.  If none of these latter 3 patients 
have DLT, then patients may begin enrolling into cohort 3. 
4) Cohort 3: Six patients will receive Ad5 [E1-, E2B-]-CEA(6D)  at a 
dose of 1 x 1011 particles SQ in 0.5 mL every 3 weeks for 
3 immunizations.  Assessment of DLT for proceeding to phase II 
enrollment will be made after all patients in this cohort have had a 
study visit at least 3 weeks after receiving their first dose of vaccine.  
If there is 0 or 1 DLT, then patients may begin enrolling into the 
phase II portion of the study.  
5) Phase II Cohort: An additional 12 patients will receive Ad5 [E1-, 
E2B-]-CEA(6D) at the MTD every 3 weeks for 3 immunizations.  
6) Patients will have 90 mL peripheral blood drawn prior to each 
immunization and at week 9 to determine whether there is an effect 
on the immune response at specific time points during the study 
and/or after a specific number of immunizations. 
7) Time to progression will be measured using MRI/CT scans 
performed as per standard of care (approximately 3 month intervals). 
Risks/Toxicities 
Potential risks associated with the vaccine include anaphylaxis, fever, 
skin reaction, autoimmunity (colitis), and hepatic insufficiency.   
Number of Patients 
Planned: 24 evaluable patients (plus up to 12 replacements); may require 
30-42 patients if DLT occur. 
Duration of Study 
6 months after the last patient is enrolled; approximately 2 years total. 
Criteria for 
Evaluation 
Toxicity will be assessed using CTCAE version 4.0.  CEA-specific 
immune response will be measured in the peripheral blood.  Time to 
recurrence will be determined by RECIST criteria. 
Statistical Analysis 
Safety: We will evaluate safety in each cohort at least 3 weeks after the 
last patient in the previous cohort has received their first injection.  A 
dosing scheme will be considered safe if <33% of patients treated at a 

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4. PATIENT SELECTION 
 
4.1. Criteria for Patient Eligibility 
4.1.1. 
Histologically confirmed diagnosis of malignancy expressing CEA.  Because this 
is a safety and immunogenicity study, patients are NOT required to have 
measurable or evaluable disease by Response Evaluation Criteria in Solid Tumors 
(RECIST).  
4.1.2. 
For all tumor types other than colorectal, the tumor must express CEA as defined 
by immunohistochemical staining (at least 50% of the tumor with at least 
moderate intensity of staining) or a tumor known to be universally CEA positive 
(i.e. colon and rectal cancer). If colorectal cancer then, pathologic or clinical 
confirmation of adenocarcinoma is required.  
4.1.3. 
Patients must have received treatment with standard therapy known to have a 
possible overall survival benefit.  
For the following common cancers, the following eligibility criteria apply: 
• Colorectal cancer: Must have received and progressed through at least one 
line of palliative chemotherapy consisting of one of the following regimens: 
- 
Palliative chemotherapy for metastatic colorectal cancer with 
5-fluorouracil (or capecitabine) and oxaliplatin. 
- 
Palliative chemotherapy for metastatic colorectal cancer with 
5-fluorouracil (or capecitabine) and irinotecan. 
- 
Palliative chemotherapy regimen for metastatic colorectal cancer that 
includes bevacizumab. 
- 
Colorectal cancer patients currently receiving palliative single-agent 
bevacizumab or cetuximab will be eligible for this trial and may 
continue these therapies concomitant with study treatment (if they 
have been on these single agent therapies for at least 3 months). 
• Breast cancer: Must have received and progressed through at least one line of 
chemotherapy for metastatic breast cancer consisting of one of the following 
regimens: 
- 
Palliative anthracycline- or taxane-based chemotherapy 
- 
Patients with tumors that over express HER2 (IHC 3+ or FISH+) must 
have received and progressed through at least one line of palliative 
therapy that combines trastuzumab with chemotherapy.  
- 
Breast cancer patients currently receiving palliative endocrine therapy 
or single-agent trastuzumab will be eligible for this trial and may 
continue these therapies concomitant with study treatment (if they 
have been on these single agent therapies for at least 3 months). 
- 
Patients who have been treated or offered the options of treatment with 
Bevacizumab (option clearly stated in the consent form). 
- 
Patients who have been treated or offered the options of treatment with 
Lapatinib (option clearly stated in the consent form). 
• Lung cancer: Must have received and progressed through chemotherapy for 
metastatic disease consisting of one of the following regimens: 
- 
Palliative platinum-based (cisplatin or carboplatin) chemotherapy if 
the patient has not received chemotherapy previously. 

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- 
Palliative taxane-based (docetaxel or paclitaxel) or vinorelbine 
chemotherapy if the patient has received chemotherapy previously. 
- 
Lung cancer patients currently receiving palliative single-agent 
erlotinib or gefitinib will be eligible for this trial and may continue 
these therapies concomitant with study treatment (if they have been on 
these single agent therapies for at least 3 months). 
• Pancreatic cancer: Must have received and progressed through chemotherapy 
including gemcitabine. 
- 
Pancreatic cancer patients currently receiving palliative single-agent 
erlotinib will be eligible for this trial and may continue this therapy 
concomitant with study treatment (if they have been on this single 
agent therapy for at least 3 months). 
• 
For other malignancies, if a first line therapy with survival or palliative benefit 
exists, it should have been administered and there should have been 
progressive disease. 
• 
Patients who have received and progressed through first-line palliative 
chemotherapy must be advised regarding second-line therapy before being 
enrolled on this investigational study.  
4.1.4. 
Karnofsky performance score  of 70% or higher  
4.1.5. 
Estimated life expectancy > 3 months 
4.1.6. 
Age ≥ 21 years, but < 75 
4.1.7. 
Adequate hematologic function, with WBC ≥ 3000/microliter, hemoglobin 
≥ 9 g/dL (it is acceptable to have had prior transfusion), platelets 
≥ 75,000/microliter; PT-INR <1.5, PTT <1.5X ULN 
4.1.8. 
Adequate renal and hepatic function, with serum creatinine < 1.5 mg/dL, bilirubin 
< 1.5 mg/dL (except for Gilbert’s syndrome which will allow bilirubin 
≤ 2.0 mg/dL), ALT and AST ≤ 2.5 x upper limit of normal. 
4.1.9. 
Patients who have received prior CEA-targeted immunotherapy are eligible for  
  
this trial, if this treatment was discontinued at least 3 months prior to enrollment. 
4.1.10. Patients who are taking medications that do not have a known history of 
immunosupression are eligible for this trial. 
4.1.11. Ability to understand and provide signed informed consent that fulfills 
Institutional Review Board’s guidelines. 
4.1.12. Ability to return to the clinical site for adequate follow-up, as required by this 
protocol. 
 
4.2. Criteria for Patient Exclusion 
4.2.1  
Patients with concurrent cytotoxic chemotherapy or radiation therapy should be 
excluded. There are no exclusions based on the number of prior chemotherapy, 
biologic, hormonal, or experimental regimens. Except for the permitted 
concomitant therapies (bevacizumab, cetuximab, trastuzumab, erlotinib, gefitinib, 
or hormonal therapy which patients must have been on for at least 3 months at the 
time of enrollment if they intend to continue them with the vaccine), there must 
be at least 3 months between any prior CEA-targeted immunotherapy and study 
treatment and at least 4 weeks between any other prior therapy (including 

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radiotherapy) and study treatment.  Patients must have recovered to grade 1 acute 
toxicities from prior treatment. 
4.2.2. 
Patients with a history of or current brain metastases will not be permitted. 
4.2.3.  
Patients with a history of autoimmune disease, such as but not restricted to, 
inflammatory bowel disease, systemic lupus erythematosus, ankylosing 
spondylitis, scleroderma, or multiple sclerosis.  Autoimmune related thyroid 
disease and vitiligo are permitted. 
4.2.4. 
Patients with serious intercurrent chronic or acute illness, such as cardiac disease 
(NYHA class III or IV), hepatic disease, or other illness considered by the 
Principal Investigator as unwarranted high risk for investigational drug treatment. 
4.2.5. 
Patients with a medical or psychological impediment to probable compliance with 
the protocol should be excluded. 
4.2.6. 
Concurrent (or within the last 5 years) second malignancy other than 
non-melanoma skin cancer, cervical carcinoma in situ, controlled superficial 
bladder cancer, or other carcinoma in situ that has been treated. 
4.2.7. 
Presence of an active acute or chronic infection including: a urinary tract 
infection, HIV (as determined by ELISA and confirmed by Western Blot).  
Patients with HIV are excluded based on immuno-suppression, which may render 
them unable to respond to the vaccine; patients with chronic hepatitis are 
excluded because of concern that hepatitis could be exacerbated by the injections.   
4.2.8. 
Patients on steroid therapy (or other immuno-suppressives, such as azathioprine 
or cyclosporin A) are excluded on the basis of potential immune suppression.  
Patients must have had 6 weeks of discontinuation of any steroid therapy (except 
that used as pre-medication for chemotherapy or contrast-enhanced studies) prior 
to enrollment. 
4.2.9. 
Pregnant and nursing women should be excluded from the protocol since this 
research may have unknown and harmful effects on an unborn child or on young 
children.  If the patient is sexually active, the patient must agree to use a 
medically acceptable form of birth control while receiving treatment and for a 
period of 4 months following the last vaccination therapy. It is not known whether 
the treatment used in this study could affect the sperm and could potentially harm 
a child that may be fathered while on this study. 
4.2.10. Patients with acute or chronic skin disorders that will interfere with injection into 
the skin of the extremities or subsequent assessment of potential skin reactions 
will be excluded. 
4.2.11. Patients will be allowed warfarin 1mg po qd other than for port prophylaxis. 
4.2.11. Patients with metastatic disease which is determined to be resectable will be 
excluded. 
 
4.3. Accrual 
We expect to accrue a minimum of 24 evaluable patients (plus up to 12 replacements 
for patients removed from the study prior to completion of the assigned vaccine 
schedule for any reason other than toxicity).  The study may require 30-42 patients if 
DLT occur that necessitate re-dosing at a lower dosage levels (Refer to Protocol 
Section 6 for a description of the dose escalation criteria). 
 

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4.4 
Assignment of study number 
Patients will be assigned study numbers in order of their screening using the following: 
ETBX-011- 001, 002, 003 etc. including screened patients. 
• Assignment of study day: Day 0 is the day of the first immunization. The second 
immunization is at Day 21. 
 
5. PRE-TREATMENT EVALUATION 
 
The following pre-treatment evaluations will be completed within 1 month (+/- 2 weeks) 
before starting study treatment: (Refer to Appendix 1 - Schema) 
 
• History and physical exam, to include Karnofsky Performance Score  and review of 
inclusion and exclusion criteria 
• ß-HCG for women with childbearing potential 
• Hematological and Biochemical Tests: 
o CBC with differential 
o PT, INR and PTT 
o Na, K, Cl, CO2, BUN, creatinine, Ca, total protein, albumin, total bilirubin, 
alkaline phosphatase, AST, ALT and glucose 
• Urinalysis 
• HIV Antibody 
• Anti Nuclear Antibody (ANA) 
• Biological Markers: 
o Serum will be obtained to measure antibodies to CEA and the neutralizing 
antibodies to Ad5 vector and sent to Etubics Corporation for determination. 
Other available serum markers (e.g., CEA or CA15-3) will be reviewed if  determined 
and  available.   
o  
• Immunologic Evaluation/Archive Sample: 
o Blood should be drawn during the first clinic visit for immunologic evaluation 
and/or archiving. . 
• Imaging Studies: 
o 
Brain CT scan or MRI is required within 6 weeks of starting study treatment. 
o 
Available CT scans or MRI of the chest, abdomen, and/or pelvis will be reviewed.  
Imaging studies within 6 weeks of starting study treatment is preferred,  but is not 
required.  
 
6. TREATMENT PLAN 
 
In the phase I component, patients will be enrolled into successive dosage level cohorts 
of 3 or 6 patients and monitored for dose-limiting toxicity (DLT).  
 
 DLT (Based on NCI CTCAE version 4.0) is defined as any Grade 2, 3 or 4 immediate 
hypersensitivity reactions, Grade 3 or 4 fever that may possibly be associated with the 
immunization, Grade ≥2 autoimmune events except for vitiligo or fever for less than 2 days and 

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less than 101.5 ºF, Grade ≥2 allergic reactions (grade 2 is defined as generalized urticaria as 
defined by CTCAE version 4.0), or Grade ≥3 non-hematologic toxicity.  
 
During dose escalation through the first three patients of cohort 3, there will be a 
minimum of 1 week between enrolling successive patients.  The first patient will be called to 
check on their condition prior to enrolling the second patient since patients can be enrolled after 
1 week of initiation of cohort 3. If no DLT have been observed at this point, then further 
enrollment can occur in cohort 3 and phase II component without the 1-week waiting period.  
Between dosage levels, assessment of DLT for dose escalation will be made after all patients in a 
cohort have had a study visit at least 3 weeks after receiving their first dose of vaccine and all the 
available safety data and laboratory results have been reviewed. If DLT occurs in <33% of 
patients in a given dosage level cohort, progression to the next dosage level will proceed.  If 
DLT occurs in ≥33% of patients in a given cohort, the next lower dosage level will be defined as 
the maximum tolerated dose (MTD).  If DLT occurs in <33% of patients in the highest dosage 
level tested, that dosage level will be defined as the MTD.  In phase II, 12 additional patients will 
be enrolled at the MTD.  In phase II, if at any time the rate of DLT in patients enrolled at the 
MTD (for the phase I and phase II cohorts combined) is ≥33%, the MTD will be re-defined as 
the next lower dosage level, and phase II will proceed with enrollment of additional patients at 
this lower dosage level.  Additional details of this dose escalation and de-escalation plan are 
provided below and in Figures 3A, 3B and Table 3.  
 
1) Phase I: Cohort 1: Three patients will receive Ad5 [E1-, E2B-]-CEA(6D)  at a dose of 1 x 
109 particles in 0.5 mL subcutaneously (SQ) in the same thigh every 3 weeks for 
3 immunizations. Immunizations should be separated by 5 cm.  A diary card will be 
given to each subject at the first treatment along with a ruler to record any adverse 
reactions for 2 days after treatment (24 hours and 48 hours post injection). The diary card 
will be placed in the study file.  Assessment of DLT for dose escalation will be made 
after all patients in this cohort have had a study visit at least 3 weeks after receiving their 
first dose of vaccine.  If there are no DLT (as defined above), then patients may begin 
enrolling into cohort 2.  If there is 1 DLT then an additional 3 patients will be enrolled at 
this dosage level. Assessment of DLT for dose escalation will be made after the 3 
additional patients have had a study visit at least 3 weeks after receiving their first dose of 
vaccine.  If none of these latter 3 patients have DLT, then patients may begin enrolling 
into cohort 2.  If 2 patients have DLT at this lowest dosage level, dosing will be de-
escalated to 1x108 particles and a new cohort of 3 patients instituted. 
 
2)  Cohort 2: Three patients will receive Ad5 [E1-, E2B-]-CEA(6D) at a dose of 1 x 1010 
particles in 0.5 mL SQ in the same thigh every 3 weeks for 3 immunizations.  
Immunizations site should be separated by 5 cm.  A diary card will be given to each 
subject at the first treatment along with a ruler to record any adverse reactions for 2 days 
after treatment (24 hours and 48 hours post injection). The diary card will be placed in 
the study file.  Assessment of DLT for dose escalation will be made after all patients in 
this cohort have had a study visit at least 3 weeks after receiving their first dose of 
vaccine.  If there are no DLT, then patients may begin enrolling into cohort 3.  If there is 
1 DLT then an additional 3 patients will be enrolled at this dosage level. Assessment of 
DLT for dose escalation will be made after the 3 additional patients have had a study visit 

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at least 3 weeks after receiving their first dose of vaccine.  If none of these latter 3 
patients have DLT, then patients may begin enrolling into cohort 3.  If 2 patients have 
DLT at this dosage level, the dosage level in cohort 1 will be considered the MTD.  If 
only 3 patients were enrolled in cohort 1, an additional 3 patients will be enrolled at that 
dosage before proceeding to phase II. 
 
3) Cohort 3: Six patients will receive Ad5 [E1-, E2B-]-CEA(6D)  at a dose of 1 x 1011 
particles in 0.5  mL SQ in the same thigh every 3  weeks for 3 immunizations.  
Immunizations site should be separated by 5 cm.  A diary card will be given to each 
subject at the first treatment along with a ruler to record any adverse reactions for 2 days 
after treatment (24 hours and 48 hours post injection). The diary card will be placed in 
the study file.  Assessment of DLT for proceeding to phase II enrollment will be made 
after all patients in this cohort have had a study visit at least 3 weeks after receiving their 
first dose of vaccine.  If there is 0 or 1 DLT, then this dosage level will be considered the 
MTD and patients may begin enrolling into the phase II portion of the study.  If 2 patients 
have DLT at this dosage level, the dosage level in cohort 2 will be considered the MTD.  
If only 3 patients were enrolled in cohort 2, an additional 3 patients will be enrolled at 
that dosage before proceeding to phase II. 
 
4) Phase II cohort: After the MTD is established, an additional 12 patients will receive Ad5 
[E1-, E2B-]-CEA(6D) at the MTD every 3 weeks for 3 immunizations. 
 
 
 
Note: if during accrual of patients in the phase II cohort, DLT occurs at a sufficient rate 
such that the rate of DLT amongst the total number of patients (those treated at MTD in 
phase I and those in phase II) is ≥33%, then phase II will be restarted at the dosage level 
which is one level below the prior MTD.  
 
5) Patients will have 90 mL peripheral blood drawn prior to each immunization and 
approximately 3 weeks after the third immunization (Week 9) to determine whether there 
is an effect on the immune response at specific time points during the study and/or after a 
specific number of immunizations. 
 
6) Time to progression will be measured using CT scans performed at approximately 
3 month intervals (based on clinical standard of care). 
 
7) For all patients, if scheduling conflicts arise, the scheduled 3-week interval between 
immunizations may be modified so that the interval between immunizations is between 
20 and 28 days (3 weeks -1 day to 3 weeks +7 days).  If the second and/or third 
immunization is delayed, the subsequent immunizations should occur no earlier than 
20 days after the previous immunization. 
 
8) The following safety events will trigger a temporary suspension of study vaccinations: 
 
a) If ≥33% of patients in the phase II cohort experience DLT at dosage level 1 (i.e.,1 x 
109 particles) 

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b) If one or more patients develop a Grade 4 allergic reaction without a clear 
attributable cause, other than study vaccine 
c) Death not attributed to disease. 
 
Assessment of these halting rules is a review of cumulative events for all study 
participants, and should not be confused with reasons for delaying or terminating the 
immunization schedule of any individual patient. 
 
Etubics Corporation will fully review all available safety data, consult with the principal 
investigator, medical monitor and the FDA as needed, before determining if resuming 
vaccinations is appropriate.  If it is determined that study vaccinations can resume, the 
halting rules will apply to each subsequent event that meets the criteria described above. 
Vaccinations may also be suspended for safety concerns other than those described above 
if, in the judgment of the principal investigator or sponsor, participant safety is 
threatened. 
 
6.1. Study Stopping Rules 
- 
Death possibly related to the study agent. 
- 
Two patients having a Grade 4 toxicity event that is possibly/probably related to 
the study agent. 
 

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Figure 3A. 
 

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Figure 3B. 
 
 
 
Table 3. Calculation of rates of DLT during patient accrual in phase I and phase II 
# evaluable 
for toxicity 
1,2,3 
4,5,6 
7,8,9 
10,11,12 
13,14,15 
16,17,18 
# with DLT 
to be ≥33% 
1 
2 
3 
4 
5 
6 
 

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6.2. Pharmaceutical Information 
6.1.1 Dosage and Administration 
Patients will receive Ad5 [E1-, E2B-]-CEA(6D) at a dose of 1 x 109, or 1 x 1010,  or 
1x1011 virus particles (vp)  per immunization ain 0.5 mL of sterile saline   SQ every 3 weeks for 
3 immunizations. 
 
6.1.2 How Supplied 
ETBX-011 will be provided in a frozen state in a 2ml vial with a fill volume of 0.5 ml of 
extractable vaccine which contains 1X1011 total virus particles. The volume of injection for 
1x1011 virus particles is 0.5 mL. The lower doses will be produced by dilution in 0.9% saline 
using the following directions. The product should be stored at </= –20°C until used. 
 
Instructions for dose preparation:  
Cohort 1: To administer 1x10e9 virus particles by subcutaneous injection, perform 2 serial 
dilutions of vialed vaccine as follows: 
1. Draw 4.5 mL of sterile saline into a syringe.   
2. Using a second syringe, withdraw 0.5 mL of previously thawed ETBX-011 from the supplied 
vial.   
3. Remove the needle from syringe containing the 4.5 mL saline, and inject the 0.5 mL of 
ETBX-011 from the second syringe into the syringe containing saline.   
4. Mix. This new solution has a concentration 2 x 1010 vp/ml. 
5. Use a new sterile syringe with a needle and repeat above procedure.  
6. Withdraw 4.5 mL of sterile saline.   
7. In the second syringe withdraw 0.5 mL from the syringe containing 2 x 1010 vp/ml.   
8. Remove the needle from the syringe containing the 4.5 mL saline, and inject the 0.5 mL of 2 
x 1010vp/mL from the second syringe. 
9.  Place a new needle on the 10-mL syringe from Step 8 above  and mix the two solutions.  
This solution now has a concentration 2 x 109 vp/mL (1 x 109 vp per 0.5 mL). 
10. Label a new 1-mL sterile syringe ETBX-011, 1 x 109 vp and withdraw 0.5 mL from the 
syringe containing 2 x 109 vp/mL.  This prepared vaccine (ETBX-011, 1 x 109 vp) can be 
kept at room temperature for four hours prior to administering to the patient. 
 
Cohort 2: To administer 1x10e10 virus particles by subcutaneous injection: 
1. Draw 4.5 mL of sterile saline into a syringe.   
2. Using a second syringe, withdraw 0.5 mL of previously thawed ETBX-011 from the supplied 
vial.   
3. Remove the needle from syringe containing the 4.5 mL saline, and inject the 0.5 mL of 
ETBX-011 from the second syringe into the syringe containing saline.   
4. Mix. This new solution has a concentration 2 x 1010 vp/ml.  
5. Label a new 1-mL sterile syringe ETBX-011, 1 x 1010 vp and withdraw 0.5 mL from the 
syringe containing 2 x 1010 vp/mL.  This prepared vaccine (ETBX-011, 1 x 1010 vp) can be 
kept at room temperature for four hours prior to administering to the patient. 
 
Cohort 3: To administer 1x10e11 virus particles by subcutaneous injection: 
1.  Withdraw 0.5mL of contents from a previously thawed ETBX-011 from the supplied vial 
and administer to each subject without any further manipulation. 
 

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6.1.3 Disposal of Unused Vaccine 
Unless other arrangements are agreed in writing, all unused vaccine should be delivered 
to Dr. Joe Balint, at Etubics Corporation for disposal at or before the completion of the clinical 
study. 
 
7. TREATMENT EVALUATION 
 
7.1. Short-Term Evaluation During and After Active Immunotherapy  
On vaccine administration days, blood will be drawn before administration.  Evaluations 
will also be conducted for patients who discontinue from the study if they have received any 
treatment. The investigator will determine the degree of evaluation based on the patient's 
condition and/or reason for discontinuation from the study. 
 
7.1.1 General Evaluations  
Weeks 0, 3, 6 (Immunization Visits): 
General evaluations include medical history, Karnofsky performance status , and 
complete physical examination with weight by the attending physician.  Any other 
treatments, medications, biologics, or blood products that the patient is receiving or has 
received since the last visit will be recorded.  Patients will remain in the clinic for 
approximately 30 minutes following receipt of vaccine to monitor for any adverse 
reactions.  Local and systemic reactogenicity after each dose of vaccine will be assessed 
daily for 3 days (on the day of immunization and 2 days thereafter) using diary cards to 
report symptoms and a ruler to measure local reactogenicity. 
 
Week 9:   
General evaluations include medical history, Karnofsky performance status, and 
complete physical examination with weight by attending physician.  Any other 
treatments, medications, biologics, or blood products that the patient is receiving or has 
received since the last visit will be recorded.  Immunization injection sites will be 
assessed. 
 
7.1.2 Hematological and Biochemical Assessment 
Weeks 0, 3, 6 (Immunization Visits): 
Blood will be drawn to perform chemistry and hematology, including CBC with 
differential, Na, K, Cl, CO2, BUN, creatinine, Ca, total protein, albumin, total bilirubin, 
alkaline phosphatase, AST, ALT and glucose.  
 
Week 9:   
Blood will be drawn to perform chemistry and hematology, including CBC with 
differential, Na, K, Cl, CO2, BUN, creatinine, Ca, total protein, albumin, total bilirubin, 
alkaline phosphatase, AST, ALT, glucose and ANA.  
 
7.1.3 Biological Markers 
Weeks 0 and 9:   

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Serum (5ml) to measure antibodies to CEA and the Ad5 vector will be obtained and send 
to Etubics Corporation for determination.  Biomarkers (e.g., CEA or CA15-3) will be 
reviewed if determined and  available.   
 
 
7.1.4 Immunological Assessment 
Weeks 0, 3, 6, and 9:   
Peripheral blood (90mL) will be drawn prior to each immunization and approximately 3 
weeks after the last immunization to determine whether there is an effect on the immune 
response at specific time points during the study and/or after a specific number of 
immunizations.  Peripheral blood mononuclear cells (PBMC) will be assayed for T cell 
responses to CEA using ELISPOT at all time points, plus proliferation assays, multi-
parameter flow cytometric analysis, and cytoxicity assays, if possible and at the 
discretion of the investigator.  Serum from each blood draw will be archived and sent to 
Etubics Corporation for Ad5 neutralizing level determination.  
 
 
7.2. Long-Term Follow-Up 
Patients will be requested to continue long-term follow-up every 3 months for 1 year, 
while on the study (i.e., have not progressed or been removed from the study for other 
reasons). At each visit, a medical history and physical exam and the following lab tests  
will be performed: blood chemistry and hematology, including CBC with differential, Na, 
K, Cl, CO2, BUN, creatinine, Ca, total protein, albumin, total bilirubin, alkaline 
phosphatase, AST, ALT and glucose. At each visit, peripheral blood (40-90 mL) should  
be drawn for immune analysis if there is previous evidence of an immune response or at 
the discretion of the investigator. 
 
7.3. Management of Intercurrent Events 
7.3.1 Concomitant Medications 
Patients will be removed from the protocol treatment if they initiate concomitant 
chemotherapeutic agents, corticosteroids, or other immunosuppressive agents, or other 
forms of immunotherapy.  After meeting the inclusion criteria, all other medications 
deemed appropriate for the patient, by the investigator, may be administered to the 
patient.  All medications and changes in medication during treatment will be recorded.  
Hormonal therapy and bisphosphonates may be continued in breast cancer patients if they 
have been stable on the agents for at least 1 month prior to enrollment. 
 
7.3.2 Adverse Events 
7.3.2.1 Toxicity will be graded according to the NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 (which can be downloaded from 
the CTEP web site (http://ctep.cancer.gov).)  DLT is defined in Protocol 
Section 6. 
7.3.2.2 Possible side effects from immunization may include local effects (pain, 
tenderness, rednesss or swelling), systemic effects (malaise, fatigue, myalgia, 
arthralgia, headache, nausea, vomiting, chills or fever), and allergic reactions 
such as hives, rash or anaphylactic reactions.  Induction of auto-immunity, 

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manifest as arthritis, serositis, nephritis, thyroiditis, colitis, neutropenia, etc., 
is theoretically possible, but has not been observed in our prior CEA vaccine 
studies.  Also, liver function test abnormalities and liver failure are 
theoretically possible. 
 
7.3.3 Treatment of Toxicity 
For acute allergic reactions, use of diphenhydramine 25-50 mg IV, corticosteroids 
(Solumedrol 100 mg), and epinephrine (1:1000, 0.3-1 mL sq) should be considered.  
These medications are available in the clinical setting where the vaccine will be 
administered.  For auto-immunity, corticosteroids (prednisone 0.5-1 mg/kg/d) should be 
considered.  Clinical assessment of other targets, such as thyroid, arthritis, urticaria, or 
proteinuria, for auto-immunity and serum sickness like antigen-antibody complex 
disease, will also be performed as indicated. 
 
7.3.4 Active Immunotherapy will be Discontinued for: 
7.3.4.1 Life-threatening anaphylactic reactions related to active immunotherapy 
7.3.4.2 DLT related to active immunotherapy 
7.3.4.3 Disease progression (by RECIST criteria).  Patients will be offered 
referral to a medical oncologist for discussion of other treatment options, 
and for continued medical care.   
7.3.4.3.1 
Disease progression prior to completing the 3 study 
 
immunizations:  
 
In the event that a patient undergoes reimaging studies prior to the 
 
completion of their 3 study immunizations and is found to have 
 
disease progression, they will be permitted to continue on the study 
 
as long as the progression has been 50% or less by RECIST 
 
criteria.  
 
If a patient is removed from the study prior to completion of the assigned vaccine 
schedule for any reason other than toxicity, that patient will be replaced, in order to 
obtain data to help determine the toxicity of the immunizations. We will allow up to 3 
replacements per cohort (Phase I, Dose levels 1 and 2; Phase II, MTD). 
 
8. STATISTICAL CONSIDERATIONS 
8.1. Safety  
We will evaluate safety continuously in a cohort.  We will make our overall assessment 
of whether to escalate to the next dose level at least 3 weeks after the last patient in the previous 
cohort has received their first injection.  This decision will be made by the medical monitor and 
the Principal Investigator.  A note will be generated following the assessment decision and filed 
in study binder.  A dosage level will be considered safe if <33% patients treated at a dose level 
experience DLT (i.e., 0 of 3, ≤1 of 6, ≤3 of 12, or ≤5 of 18 patients).  DLT is defined in Protocol 
Section 6.  Safety will be evaluated in 3 or 6 patients at each dosage level in phase I.   Safety will 
continue to be monitored among additional patients treated at the MTD in phase II.  A patient 
will be considered evaluable for safety if treated with at least one immunization.  DLTs will be 
observed through 9 weeks to accommodate safety evaluation of all 3 product doses. 

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8.2. Rate of Immune Response  
Immune responses against CEA will be evaluated from the peripheral blood of patients 
from among the following studies at the discretion of the Principal Investigator (ELISpot, 
cytokine flow cytometry, and antibody responses). We will determine the percentage of patients 
with a positive immune response.  We define a positive immune response by ELISpot as 
described at the 2002 Society of Biologic Therapy Workshop on “Immunologic Monitoring of 
Cancer Vaccine Therapy”, i.e. a T cell response is considered positive if the mean number of 
spots adjusted for background in six wells with antigen exceeds the number of spots in six 
control wells by 10 and the difference between single values of the six wells containing antigen 
and the six control wells is statistically significant at a level of p ≤ 0.05 using the Student’s t test.  
Immunogenicity assays will occur prior to each immunization and at week 12.  Immune response 
will be assessed among the 18 patients treated at the MTD (12 in phase I and 12 in Phase II).  
The therapy will be considered of further interest if 9 of 18 patients treated at the MTD dose 
exhibit an immune response as defined above.  Meeting this criterion establishes that the immune 
response rate is at least 33% with approximately 90% confidence.  At significance level 0.1 there 
is 82% power to test the null hypothesis that the immune response rate is ≤ 0.33 versus the 
alternative that the immune response rate is ≥ 0.58.  The magnitude of response will also be 
described.  A patient will be considered evaluable for immune response if they receive at least 3 
immunizations. 
 
8.3. Determination of Clinical Response 
Among patients with measurable/evaluable disease, response determination will be made 
according to the RECIST criteria: 
Complete Response (CR): 
Disappearance of target lesion, confirmed at 4    
weeks 
Partial Response (PR): 
30% decrease in longest dimension of target lesion, 
confirmed at 4 weeks 
Stable Disease (SD): 
 
Neither PR nor PD 
Progressive Disease (PD): 
20% increase in longest dimension of target lesion; 
no CR, PR, or SD documented before increased 
disease. 
The exact binomial confidence interval for the proportion of subjects with a clinical 
response of CR or PR will be calculated. 
 
9. PATIENT WITHDRAWAL 
Patients may be removed from the study for the following reasons: 
• DLT as defined in Protocol Section 6.   
• Patient voluntarily decides to withdraw. 
• Patient non-compliance with the study protocol. 
• Intercurrent disease which in the opinion of the patient’s treating physician would 
affect the ability of the patient to continue on the clinical study.  
In the event of withdrawal due to toxicity, a patient will be requested to have safety 
evaluations performed as per the protocol for a one year duration post treatment. This may 
include having up to 90 mL of blood drawn for immunologic testing. 
 

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10. STUDY CONDUCT AND ETHICAL AND REGULATORY CONSIDERATIONS 
 
10.1. Departure from the Protocol 
There should be no departure from the protocol if at all possible.  If an emergency occurs 
that requires departure from this protocol, the investigator or other physician in attendance in 
such an emergency will, if circumstances and time permit, contact the principal investigator, or 
in his absence, Dr. H. Kim Lyerly, Acting Medical Director, immediately by telephone (919) 
684-8111  (paging operator). Such contacts with the principal investigator will be made to permit 
a decision as to whether or not the patient will be continued on the study.  Such departures need 
to be clearly documented and reported to the Institutional Review Board (IRB) and the Etubics 
Corporation by the principal investigator. 
 
10.2. Informed Consent 
In accordance with guidelines in the Federal Register, Vol. 48, No. 17, 1982, pp. 8951-2, 
all patients are required to sign a statement of informed consent.  This phase I/II study involves 
research that presents risk, but holds the prospect of direct benefit to the individual patient 
(46.405-45 Code of the Federal Regulations part 46).  The investigator will report to the IRB and 
Etubics Corporation will report to FDA changes in the research protocol and all unanticipated 
problems involving risks to human patients and others, and no changes will be made in the 
research activity without IRB approval. 
 
10.3. Institutional Review 
This study must be approved by the site’s IRB.  IRB approval of the protocol and the 
informed consent form for this study must be given in writing.  The IRB must also approve any 
significant changes to the protocol as well as a change of principal investigator.  Records of all 
study review and approval documents must be kept on file by the investigator and are subject to 
FDA inspection during or after completion of the study.  Adverse events must be reported to the 
IRB.  The IRB will receive notification of the completion of the study and final report within 
three months of study completion or termination.  The investigator must maintain an accurate 
and complete record of all submissions made to the IRB, including a list of all reports and 
documents submitted. 
 
10.4. Documentation and Monitoring 
Data will be collected for all patients signing consent.  Accurate completion of the 
computer data forms for all patients is the responsibility of the investigator.   
 
10.4.1 Case Report Forms 
Case Report Forms (CRFs) are used to record study data and are an integral part of the 
study and subsequent reports.  Therefore, all reports must be legible and complete.  All forms 
should be filled out using a black ballpoint pen.  Errors should be lined out but not obliterated 
and the correction inserted, initialed, and dated by the principal investigator, co-investigators, 
study coordinator, or data manager.  A CRF must be completed and signed by the principal 
investigator for each patient enrolled, including those removed from the study for any reason.  
The reason for removal must be noted on the Final Report Form by the investigator for each 
patient.  CRFs must be kept current to reflect patient status at each phase during the course of the 
study.  Patients are not to be identified on CRFs by name; appropriate coded identification and 

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patient initials must be used.  The investigator must keep a separate log of patient names and 
addresses.  This log is subject to FDA inspection.  Because of the potential for errors, 
inaccuracies, and illegibility in transcribing data onto CRFs, originals of laboratory and other test 
results must be kept on file with patient's CRFs or clinical chart.  CRFs and copies of test results 
must be available at all times for inspection by the FDA.   
 
10.4.2 Maintenance of Study Documentation 
The following will be maintained: 
a. Case Report Forms - which must be kept legible, accurate, and up-to-date. 
b. Patient Files/Signed Informed Consent - which substantiates the data entered 
on the case report forms for all required test and evaluation procedures and 
verifies that the patient has signed an informed consent to enter the study. 
c. Patient Exclusion Record - which should reflect the reason any patient was 
screened and found ineligible for the study. 
d. Monitoring Log - listing dates of monitor visits. 
e. Regulatory Documents - including protocol, investigator brochure, FDA Form 
1572, CVs, IRB correspondence, IRB approval/renewals and IRB approved 
consent form. 
f. Adverse Event Report Form - which should explain any serious or unexpected 
adverse experiences. 
All study documentation pertaining to the conduct of the study must be kept on file by the 
investigator for a period of 2 years following the date a marketing application is approved for the 
drug for the indication for which it is being investigated; or, if no application is to be filed or if 
the application is not approved for such indication, until 2 years after the investigation is 
discontinued and FDA is notified.  The sponsor will notify the investigator if a marketing 
application is approved or if the investigation is discontinued and the FDA notified. 
 
10.5. Monitoring of the Protocol 
A Etubics Corporation representative will conduct a site initiation visit and will review 
protocol documents with the investigators and their staff. During the study, the Etubics monitor 
will visit the site regularly to check the completeness of study files, the accuracy of data entries 
on the CRFs, and adherence to the protocol and to Good Clinical Practice (GCP).  Key study 
personnel must be available to assist the monitor during these visits. The investigator must 
maintain source documents for each subject in the study. The investigator must also keep the 
original informed consent form signed by every patient.  The investigator must give the monitor 
access to all relevant source documents to verify data entries on CRFs.  No information in source 
documents about the identity of subjects will be disclosed. 
 
This is a phase I/II clinical study with more than minimal risk and as such will be monitored for 
the occurrence of a greater frequency of adverse events (AEs).  The principal investigator will 
continuously monitor the data and safety of all subjects enrolled. All grades of toxicities will be 
recorded.   
 
Safety assessments will consist of monitoring all AEs including serious adverse events (SAEs), 
the regular monitoring of hematology, serum chemistry, and routine monitoring of vital signs 
and physical condition.  AE monitoring should occur from the time of informed consent to 30 

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days after the last dose of study drug. For those subjects who discontinue study participation 
prior to receiving study drug, AE and SAEs will be collected through the time of discontinuation.   
 
Toxicity will be assessed using the NCI CTCAE version 4.0.  Refer to Protocol Section 7.3.2. 
 
An AE is any adverse change from the study patient’s baseline (pretreatment) condition, 
including any clinical or laboratory test abnormality that occurs during the course of the 
proposed clinical study after treatment has started.   
 
Events are classified as SERIOUS if they meet any of the following criteria [per the US Code of 
Federal Regulations (CFR) 21 CFR 312.32 and the recommendations of the International 
Conference on Harmonization (ICH)]: 
 
An SAE is any sign, symptom or medical condition that emerges during the study or during a 
post-study follow-up period that 1) was not present at the start of the study and is not a chronic 
condition that is part of the patient’s medical history, OR 2) was present at the start of the study 
or as part of the patient’s medical history but worsened in severity and/or frequency during study 
participation, AND that meets any of the following regulatory serious criteria: 
 
• any death 
• any life-threatening event, i.e., an event that places the patient, in the view of the 
investigator, at immediate risk of death from the event as it occurred (does not 
include an event that, had it occurred in a more severe form, might have caused 
death) 
• any event that requires or prolongs in-patient hospitalization 
• any event that results in persistent or significant disability/incapacity 
• any congenital anomaly/birth defect diagnosed in a child of a patient who 
participated in this study and received investigational drug 
• other medically important events that in the opinion of the investigator may 
jeopardize the patient or may require intervention to prevent one of the other 
outcomes listed in the definition above (e.g. allergic bronchospasm requiring 
intensive treatment in an emergency room, convulsions occurring at home that do 
not require in-patient hospitalization, any blood dyscrasias, or the development of 
drug dependency or drug abuse). 
 
10.6. CTCAE Term (AE description) and Grade   
The descriptions and grading scales found in the revised NCI CTCAE version 4.0 will be 
utilized for AE reporting. A copy can be downloaded from the CTEP web site 
(http://ctep.cancer.gov).   
 
The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for 
each AE based on the following guideline: 
 
Grade 1 
Mild AE 
Grade 2 
Moderate AE 
Grade 3 
Severe AE 

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Grade 4 
Life-threatening or disabling AE 
Grade 5 
Death related to AE 
 
10.7. Assessing Causality 
Investigators are required to assess whether there is a reasonable possibility that study 
medications caused or contributed to an adverse event.  The following general guidance may be 
used. 
Yes: 
if the temporal relationship of the clinical event to study drug administration makes a 
causal relationship possible, and other drugs, therapeutic interventions or underlying 
conditions do not provide a sufficient explanation for the observed event. 
No: 
if the temporal relationship of the clinical event to study drug administration makes a 
causal relationship unlikely, or other drugs, therapeutic interventions or underlying 
conditions provide a sufficient explanation for the observed event. 
 
10.8. Serious Adverse Event Reporting 
All AEs that are classified as serious, unexpected and related or possibly related, will be 
recorded on the MedWatch 3500A form and reported within 24 hours of learning of the event to 
Etubics Corporation.  The form should be completed as much as possible but should not be held 
until all information is available. Additional information and/or corrections may be submitted as 
they are obtained. The investigator will follow SAEs until resolution, a return to baseline 
condition or stabilization or 30 days after the last subject is enrolled whichever occurs first. 
SAEs that are ongoing at the time of clinical database closure will be recorded as unresolved.  
All study-related deaths should be reported to the IRB within 24 hours; all other serious adverse 
experiences should be reported to the IRB within 5 business days. All deaths, whether considered 
study-related or not, must also be reported immediately to Etubics Corporation, with a copy of 
the autopsy report and the death certificate.   
 
MedWatch 3500A Reporting Guidelines: 
In addition to completing appropriate patient demographic and suspect medication 
information, the report should include the following information within the Event Description 
(section 5) of the MedWatch 3500A form: 
 
• Treatment regimen (dosing frequency, combination therapy) 
• Protocol description (and number, if assigned) 
• Description of event, severity, treatment, and outcome, if known 
• Supportive laboratory results and diagnostics 
• Investigator’s assessment of the relationship of the adverse event to each investigational 
product and suspect medication 
 
Follow-up information:  
 Additional information may be added to a previously submitted report by any of the 
following methods: 
• Adding to the original MedWatch 3500A report and submitting it as follow-up 
• Adding supplemental summary information and submitting it as follow-up with the 
original MedWatch 3500A form  

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• Summarizing new information and faxing it with a cover letter including patient 
identifiers (i.e. D.O.B., initials, patient number), protocol description and number, if 
assigned, suspect drug, brief adverse event description, and notation that additional or 
follow-up information is being submitted  (The patient identifiers are important so that 
the new information is added to the correct initial report.) 
 
Reporting of Pregnancy:  
If a participant becomes pregnant during the study, treatment will be discontinued (i.e., 
no additional dose of study vaccine will be given) and the participant will be encouraged to 
continue to have regularly scheduled follow-up visits and evaluations.  The occurrence of 
pregnancy, and the outcome of any pregnancy, in a subject treated with study vaccine, must be 
reported to the Etubics Corporation and to the IRB.   
 
Procedures for SAE Reporting: 
1. Medical staff/study team notifies principal investigator of SAE. MedWatch 3500A is 
completed. 
 
2. Principal Investigator calls Etubics Corpration to report the SAE and faxes the completed 
MedWatch 3500A to: 
 
 
 
Carol Jones, Vice President of Administration 
 
Address: 410 West Harrison Street, Suite 100, Seattle, WA 981119 
 
Telephone: 206-838-5110 ext. 102 
 
Cell: (206) 818-2985 
 
Fax: (206) 838-2978 
 
Email: cj@etubics.com 
 
3.   Carol Jones reports the SAE to one of the following in this order: 
 
 
A.   Chief Scientific Officer: Frank Jones, PhD  
 
Address: 410 West Harrison Street, Suite 100, Seattle, WA 98119  
 
Telephone: 206-838-5110 ext. 101 
 
Cell: (206) 818-2857 
 
Fax: (206) 838-2978 
 
Email: frj@etubics.com 
 
B.  Laboratory Manager:  Joseph Balint, PhD 
 
Address: 410 West Harrison Street, Suite 100, Seattle, WA 98119 
 
Telephone: (206) 838-5110 ext. 107 
 
Fax:  (206) 838-2978 
 
Email: joe@etubics.com 
 
 
 
 
 

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C.  Vice President Research: Elizabeth S. Gabitzsch 
 
Address: 410 West Harrison Street, Suite 100, Seattle, WA 98119 
 
Telephone: (206) 838-5110 ext. 103 
 
Cell: (970) 402-2598 
 
Fax:  (206) 838-2978 
 
Email: beth@etubics.com 
 
 
4.  Contacted person in three (3) above notifies the FDA via MedWatch 3500A form. 
 
a. If the SAE results in death or is life-threatening, SAE report will be submitted to the 
FDA within 7 days 
b. All other SAEs must be reported to the FDA within 15 days 
 
5. All SAE will require input from a physician, the Acting Medical Director will be consulted: 
 
  
H. Kim Lyerly, MD  
Telephone: (919) 684-5613 or (919)684-8111 (paging operator) 
Fax: (919) 684-5653 
Email: lyerl001@mc.duke.edu 
 
6. SAEs will be reported to the IRB according to the site’s IRB guidelines.   
 
In accordance with FDA regulations and ICH guidelines, investigators will be notified of the 
occurrence of new, serious, unexpected adverse events associated with the use of the study 
medication (i.e. there is a reasonable possibility that the AE may have been caused by the drug) 
within 15 calendar days via a written report.  It is the responsibility of the investigator to 
promptly inform the relevant IRB of these new adverse events/risks to patients, in accordance 
with 21 CFR 312.66.  It is the responsibility of Etubics Corporation to promptly inform the NIH 
Office of Biotechnology Activities (OBA) and relevant Scientific Review Board of these new 
adverse events/risks to patients, in accordance with NIH Guidelines for Research Involving 
Recombinant DNA Molecules, in particular Appendix M.  It is the responsibility of the Etubics 
Corporation to report these SAEs to the FDA.  The SAE report will be forwarded to the FDA 
after recording the event data via the FDA MedWatch form 3500A.   
 
10.9. Safety Reporting Requirements  
In accordance with 21 CFR 212.32, the sponsor of studies conducted under an IND must 
comply with following safety reporting requirements:  
 
a. Expedited IND Safety Reports: 
 
7 Calendar-Day Telephone or Fax Report:   
The sponsor is required to notify the FDA of any fatal or life-threatening adverse event 
that is unexpected and assessed by the investigator to be possibly related to the use of the 
investigational product.   An unexpected adverse event is one that is not already described in the 
Investigator’s Brochure.  Such reports are to be telephoned or faxed to the FDA within 
7 calendar days of first learning of the event.   

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15 Calendar-Day Written Report:   
The sponsor is also required to notify the FDA and all participating investigators, in a 
written IND Safety Report, of any serious, unexpected AE that is considered possibly related to 
the investigational product.  An unexpected adverse event is one that is not already described in 
the Investigator Brochure. 
Written IND Safety Reports should include an Analysis of Similar Events in accordance 
with regulation 21 CFR § 312.32.  All safety reports previously filed with the IND concerning 
similar events should be analyzed.  The new report should contain comments on the significance 
of the new event in light of the previous, similar reports.   
Written IND safety reports with Analysis of Similar Events are to be submitted to the 
FDA and all participating investigators within 15 calendar days of first learning of the event.  
The FDA prefers these reports on a MedWatch 3500A Form but alternative formats are 
acceptable (e.g. summary letter). 
 
b. IND Annual Reports 
In accordance with the regulation 21 CFR § 312.32, the sponsor shall within 60 days of 
the anniversary date that the IND went into effect submit a brief report of the progress of the 
investigation.   
 
c. Data and Safety Monitoring  
Data will be collected by the principal investigator, co-investigators, and the protocol 
coordinator.  The protocol coordinator under the supervision of the principal investigator will 
report the AEs. The data will be audited by Etubics Corporation.  

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Hartigan-O'Connor, D., Kirk, C.J., Crawford, R., Mulé, J.J., and Chamberlain, J.S. 2001. 
Immune evasion by muscle-specific gene expression in dystrophic muscle. Mol Ther 
4:525-533. 
64. 
Moorhead, J.W., Clayton, G.H., Smith, R.L., and Schaack, J. 1999. A replication-
incompetent adenovirus vector with the preterminal protein gene deleted efficiently 
transduces mouse ears. J Virol 73:1046-1053. 
65. 
Nazir, S.A., and Metcalf, J.P. 2005. Innate immune response to adenovirus. J Investig 
Med 53:292-304. 
66. 
Schaack, J. 2005. Induction and inhibition of innate inflammatory responses by 
adenovirus early region proteins. Viral Immunol 18:79-88. 

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67. 
Schaack, J., Bennett, M.L., Colbert, J.D., Torres, A.V., Clayton, G.H., Ornelles, D., and 
Moorhead, J. 2004. E1A and E1B proteins inhibit inflammation induced by adenovirus. 
Proc Natl Acad Sci U S A 101:3124-3129. 
 
 

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A PHASE I/II STUDY OF ACTIVE IMMUNOTHERAPY WITH Ad5 [E1-, E2b-]-
CEA(6D)  VACCINE (ETBX-011) IN PATIENTS WITH ADVANCED OR 
METASTATIC MALIGNANCIES EXPRESSING CEA 
 
 
 
 
STUDY PRODUCT: 
 
 
Ad5 [E1-, E2b-]-CEA(6D)  (ETBX-011) 
 
 
STUDY SPONSOR:  
 
 
Etubics Corporation 
    
 
 
 
 
410 West Harrison Street 
    
 
 
 
 
Seattle, WA 98119 
 
 
PRINCIPAL INVESTIGATOR:   
Michael Morse 
 
 
 
 
 
 
Duke University Medical Center 
 
 
 
 
 
 
Box 3233, Durham, NC  27710 
 
 
Original Protocol: 
 
 
 
Version 1.1, December 21, 2009 
Amendment 1: 
 
 
 
Version 2.0, 13 April 2010 
Amendment 2: 
 
 
 
Version 2.1, May 14, 2010 
Amendment 3: 
 
 
 
Version 2.1, August 31, 2010 
Amendment 4: 
 
 
 
Version 3.1, June 20, 2011 
 
 
 

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TABLE OF CONTENT 
 
 
 
 
 
 
 
 
 
 
 
Page Number 
 
1. Protocol Summary …………………………………………………..  3 
 
2. Study Objectives ……………………………………………………. 5 
 
3. Background and Significance ……………………………………….  5 
 
4. Patient Selection …………………………………………………….. 14 
 
5. Pre-Treatment Evaluation …………………………………………… 17 
 
6. Treatment Plan ………………………………………………………. 17 
 
7. Treatment Evaluation ………………………………………………... 24 
 
8. Statistical Considerations ……………………………………………. 27 
 
9. Patient Withdrawal …………………………………………………... 28 
 
10. Study Conduct and Ethical and Regulatory Considerations …………. 28 
 
11.  References …………………………………………………………… 35 
 
12.  Appendix …………………………………………………………….. 41 
 

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1. PROTOCOL SUMMARY 
 
Title 
A PHASE I/II STUDY OF ACTIVE IMMUNOTHERAPY WITH 
Ad5 [E1-, E2b-]-CEA(6D)  VACCINE (ETBX-011) IN PATIENTS 
WITH 
ADVANCED 
OR 
METASTATIC 
MALIGNANCIES 
EXPRESSING CEA 
Objectives 
a) The primary objective of this protocol is to determine the safety of 
immunization with Ad5 [E1-, E2B-]-CEA(6D), in patients with 
advanced or metastatic CEA-expressing malignancies.  
b) The secondary objectives are to evaluate CEA-specific immune 
responses to the immunizations and to obtain preliminary data on 
clinical response rate. 
Major Inclusion/ 
Exclusion Criteria 
Patients with a histologically confirmed diagnosis of metastatic 
malignancy who were previously treated with standard therapy known to 
have a possible survival benefit or refused such therapy.  The tumor must 
express CEA as defined by immunohistochemical staining (at least 50% 
of the tumor with at least moderate intensity of staining) or a tumor 
known to be universally CEA positive (i.e. colon and rectal cancer). If 
colorectal cancer, pathologic or clinical confirmation of adenocarcinoma 
is required. Patients will not be treated until 4 or more weeks after any 
prior chemotherapy or radiation therapy, but may be receiving non-
cytotoxic targeted therapy (bevacizumab, cetuximab, panitumumab,  
trastuzumab, lapatinib, erlotinib, or gefitinib) or hormonal therapy.  They 
must not have a history of autoimmune disease, serious intercurrent 
chronic or acute illness, active hepatitis, serologic evidence for HIV, or 
be receiving chronic steroid or immunosuppressive therapy.  All patients 
must be >21 years old and have a Karnofsky Performance Score  of 70% 
or higher. Pregnant women and nursing mothers are excluded.  
Study Design 
Phase I/II study with three dosage levels of Ad5 [E1-, E2B-]-CEA(6D)  
vaccine (phase I component), and the Maximally Tolerated Dose (MTD) 
of Ad5 [E1-, E2B-]-CEA(6D)  vaccine (phase II component).  The study 
drug is Ad5 [E1-, E2B-]-CEA(6D) given by subcutaneous (SQ) injection 
every 3 weeks for 3 immunizations.  The following procedures will 
occur: 
1) Peripheral blood draw (90 mL) for immune analysis. 
2) Cohort 1: Three patients will receive Ad5 [E1-, E2B-]-CEA(6D)  at a 
dose of 1 x 109 particles SQ in 0.5 mL every 3 weeks for 
3 immunizations.  Assessment of dose-limiting toxicities (DLT) for 
dose escalation will be made after all patients in this cohort have had 
a study visit at least 3 weeks after receiving their first dose of 
vaccine.  If there are no DLT, defined as any Grade 2, 3 or 4 
immediate hypersensitivity reactions, Grade 3 or 4 fever that may 
possibly be associated with the immunization, Grade ≥2 autoimmune 
events except for vitiligo or fever for less than 2 days and less than 
101.5 ºF, Grade ≥2 allergic reactions (grade 2 is defined as 
generalized urticaria as defined by NCI Common Terminology 

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Criteria for Adverse Events (CTCAE version 4.0), or Grade ≥3 non-
hematologic toxicity, then patients may begin enrolling into cohort 2.  
If there is 1 DLT, then an additional 3 patients will be enrolled at this 
dosage level. Assessment of DLT for dose escalation will be made 
after the 3 additional patients have had a study visit at least 3 weeks 
after receiving their first dose of vaccine.  If none of these latter 3 
patients have DLT (i.e., 1 DLT in the 6 total patients), then patients 
may begin enrolling into cohort 2. If 2 patients have DLT at the 
lowest dosage level, dosing will be de-escalated to 1x108 particles.  
3)  Cohort 2: Three patients will receive Ad5 [E1-, E2B-]-CEA(6D)  at a 
dose of 1 x 1010 particles SQ in 0.5 mL every 3 weeks for 
3 immunizations.  Assessment of DLT for dose escalation will be 
made after all patients in this cohort have had a study visit at least 
3 weeks after receiving their first dose of vaccine.  If there are no 
DLT, then patients may begin enrolling into cohort 3.  If there is 1 
DLT then an additional 3 patients will be enrolled at this dosage 
level. Assessment of DLT for dose escalation will be made after the 3 
additional patients have had a study visit at least 3 weeks after 
receiving their first dose of vaccine.  If none of these latter 3 patients 
have DLT, then patients may begin enrolling into cohort 3. 
4) Cohort 3: Six patients will receive Ad5 [E1-, E2B-]-CEA(6D)  at a 
dose of 1 x 1011 particles SQ in 0.5 mL every 3 weeks for 
3 immunizations.  Assessment of DLT for proceeding to phase II 
enrollment will be made after all patients in this cohort have had a 
study visit at least 3 weeks after receiving their first dose of vaccine.  
If there is 0 or 1 DLT, then patients may begin enrolling into the 
phase II portion of the study.  
5) Phase II Cohort (Cohort 4): An additional 12 patients will receive 
Ad5 [E1-, E2B-]-CEA(6D) at the MTD every 3 weeks for 
3 immunizations.  
6) Cohort 5: Beginning after the third dose of ETBX-011 for the 12th 
patient in cohort 4, enrollment in an additional higher dose cohort 
will be permitted. Six patients will receive Ad5 [E1-, E2B-]-
CEA(6D)  at a dose of 5x1011 particles SQ in 2.5 mL every 3 weeks 
for 3 immunizations.  Assessment of DLT will be made after all 
patients in this cohort have had all 3 injections and been observed for 
at least 30 days after the last injection.  If there are 0-1 DLT, then this 
will be declared the maximum feasible dose. If there are 2 or more 
DLT, then 1 x 1011 particles will be declared the MTD. 
7) Patients will have 90 mL peripheral blood drawn prior to each 
immunization and at week 9 to determine whether there is an effect 
on the immune response at specific time points during the study 
and/or after a specific number of immunizations. 
8) Time to progression will be measured using MRI/CT scans 
performed as per standard of care (approximately 3 month intervals). 
Risks/Toxicities 
Potential risks associated with the vaccine include anaphylaxis, fever, 

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4.1. Criteria for Patient Eligibility 
4.1.1. 
Histologically confirmed diagnosis of malignancy expressing CEA.  Because this 
is a safety and immunogenicity study, patients are NOT required to have 
measurable or evaluable disease by Response Evaluation Criteria in Solid Tumors 
(RECIST).  
4.1.2. 
For all tumor types other than colorectal, the tumor must express CEA as defined 
by immunohistochemical staining (at least 50% of the tumor with at least 
moderate intensity of staining) or a tumor known to be universally CEA positive 
(i.e. colon and rectal cancer). If colorectal cancer then, pathologic or clinical 
confirmation of adenocarcinoma is required.  
4.1.3. 
Patients must have received treatment with standard therapy known to have a 
possible overall survival benefit.  
For the following common cancers, the following eligibility criteria apply: 
• Colorectal cancer: Must have received and progressed through at least one 
line of palliative chemotherapy consisting of one of the following regimens: 
- 
Palliative chemotherapy for metastatic colorectal cancer with 
5-fluorouracil (or capecitabine) and oxaliplatin. 
- 
Palliative chemotherapy for metastatic colorectal cancer with 
5-fluorouracil (or capecitabine) and irinotecan. 
- 
Palliative chemotherapy regimen for metastatic colorectal cancer that 
includes bevacizumab. 
- 
Colorectal cancer patients currently receiving palliative single-agent 
bevacizumab or cetuximab will be eligible for this trial and may 
continue these therapies concomitant with study treatment (if they 
have been on these single agent therapies for at least 3 months). 
• Breast cancer: Must have received and progressed through at least one line of 
chemotherapy for metastatic breast cancer consisting of one of the following 
regimens: 
- 
Palliative anthracycline- or taxane-based chemotherapy 
- 
Patients with tumors that over express HER2 (IHC 3+ or FISH+) must 
have received and progressed through at least one line of palliative 
therapy that combines trastuzumab with chemotherapy.  
- 
Breast cancer patients currently receiving palliative endocrine therapy 
or single-agent trastuzumab will be eligible for this trial and may 
continue these therapies concomitant with study treatment (if they 
have been on these single agent therapies for at least 3 months). 
- 
Patients who have been treated or offered the options of treatment with 
Bevacizumab (option clearly stated in the consent form). 
- 
Patients who have been treated or offered the options of treatment with 
Lapatinib (option clearly stated in the consent form). 
• Lung cancer: Must have received and progressed through chemotherapy for 
metastatic disease consisting of one of the following regimens: 
- 
Palliative platinum-based (cisplatin or carboplatin) chemotherapy if 
the patient has not received chemotherapy previously. 
- 
Palliative taxane-based (docetaxel or paclitaxel) or vinorelbine 
chemotherapy if the patient has received chemotherapy previously. 

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- 
Lung cancer patients currently receiving palliative single-agent 
erlotinib or gefitinib will be eligible for this trial and may continue 
these therapies concomitant with study treatment (if they have been on 
these single agent therapies for at least 3 months). 
• Pancreatic cancer: Must have received and progressed through chemotherapy 
including gemcitabine. 
- 
Pancreatic cancer patients currently receiving palliative single-agent 
erlotinib will be eligible for this trial and may continue this therapy 
concomitant with study treatment (if they have been on this single 
agent therapy for at least 3 months). 
• 
For other malignancies, if a first line therapy with survival or palliative benefit 
exists, it should have been administered and there should have been 
progressive disease. 
• 
Patients who have received and progressed through first-line palliative 
chemotherapy must be advised regarding second-line therapy before being 
enrolled on this investigational study.  
4.1.4. 
Karnofsky performance score  of 70% or higher  
4.1.5. 
Estimated life expectancy > 3 months 
4.1.6. 
Age ≥ 21 years, but < 75 
4.1.7. 
Adequate hematologic function, with WBC ≥ 3000/microliter, hemoglobin 
≥ 9 g/dL (it is acceptable to have had prior transfusion), platelets 
≥ 75,000/microliter; PT-INR <1.5 (unless patient is receiving warfarin in which 
case PT-INR must be <3), PTT <1.5X ULN 
4.1.8. 
Adequate renal and hepatic function, with serum creatinine < 1.5 mg/dL, bilirubin 
< 1.5 mg/dL (except for Gilbert’s syndrome which will allow bilirubin 
≤ 2.0 mg/dL), ALT and AST ≤ 2.5 x upper limit of normal. 
4.1.9. 
Patients who have received prior CEA-targeted immunotherapy are eligible for  
  
this trial, if this treatment was discontinued at least 3 months prior to enrollment. 
4.1.10. Patients who are taking medications that do not have a known history of 
immunosupression are eligible for this trial. 
4.1.11. Ability to understand and provide signed informed consent that fulfills 
Institutional Review Board’s guidelines. 
4.1.12. Ability to return to the clinical site for adequate follow-up, as required by this 
protocol. 
 
4.2. Criteria for Patient Exclusion 
4.2.1  
Patients with concurrent cytotoxic chemotherapy or radiation therapy should be 
excluded. There are no exclusions based on the number of prior chemotherapy, 
biologic, hormonal, or experimental regimens. Except for the permitted 
concomitant therapies (bevacizumab, cetuximab, panitumumab, trastuzumab, 
lapatinib, erlotinib, gefitinib, or hormonal therapy which patients must have been 
on for at least 3 months at the time of enrollment if they intend to continue them 
with the vaccine), there must be at least 3 months between any prior CEA-
targeted immunotherapy and study treatment and at least 4 weeks between any 
other prior therapy (including radiotherapy) and study treatment.  Patients must 
have recovered to grade 1 acute toxicities from prior treatment. 

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4.2.2. 
Patients with a history of or current brain metastases will not be permitted. 
4.2.3.  
Patients with a history of autoimmune disease, such as but not restricted to, 
inflammatory bowel disease, systemic lupus erythematosus, ankylosing 
spondylitis, scleroderma, or multiple sclerosis.  Autoimmune related thyroid 
disease and vitiligo are permitted. 
4.2.4. 
Patients with serious intercurrent chronic or acute illness, such as cardiac disease 
(NYHA class III or IV), hepatic disease, or other illness considered by the 
Principal Investigator as unwarranted high risk for investigational drug treatment. 
4.2.5. 
Patients with a medical or psychological impediment to probable compliance with 
the protocol should be excluded. 
4.2.6. 
Concurrent (or within the last 5 years) second malignancy other than 
non-melanoma skin cancer, cervical carcinoma in situ, controlled superficial 
bladder cancer, or other carcinoma in situ that has been treated. 
4.2.7. 
Presence of an active acute or chronic infection including: a urinary tract 
infection, HIV (as determined by ELISA and confirmed by Western Blot).  
Patients with HIV are excluded based on immuno-suppression, which may render 
them unable to respond to the vaccine; patients with chronic hepatitis are 
excluded because of concern that hepatitis could be exacerbated by the injections.   
4.2.8. 
Patients on chronic steroid therapy (or other immuno-suppressives, such as 
azathioprine or cyclosporin A) are excluded on the basis of potential immune 
suppression.  Patients must have had 6 weeks of discontinuation of any steroid 
therapy (except that used as pre-medication for chemotherapy or contrast-
enhanced studies or for acute treatment (<5 days) of intercurrent medical 
condition such as a gout flare) prior to enrollment. 
4.2.9. 
Pregnant and nursing women should be excluded from the protocol since this 
research may have unknown and harmful effects on an unborn child or on young 
children.  If the patient is sexually active, the patient must agree to use a 
medically acceptable form of birth control while receiving treatment and for a 
period of 4 months following the last vaccination therapy. It is not known whether 
the treatment used in this study could affect the sperm and could potentially harm 
a child that may be fathered while on this study. 
4.2.10. Patients with acute or chronic skin disorders that will interfere with injection into 
the skin of the extremities or subsequent assessment of potential skin reactions 
will be excluded. 
4.2.11. Patients with metastatic disease which is determined to be resectable must have 
been referred to a surgeon for consideration of resection. 
 
4.3. Accrual 
We expect to accrue a minimum of 24 evaluable patients (plus up to 12 replacements 
for patients removed from the study prior to completion of the assigned vaccine 
schedule for any reason other than toxicity).  The study may require 30-42 patients if 
DLT occur that necessitate re-dosing at a lower dosage levels (Refer to Protocol 
Section 6 for a description of the dose escalation criteria). 
 
4.4 
Assignment of study number 

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Patients will be assigned study numbers in order of their screening using a site specific 
sequential numbering system, e.g.,: ETBX-011- 001, 002, 003 etc. including screened 
patients. 
• Assignment of study day: Day 0 is the day of the first immunization. The second 
immunization is at Day 21. 
 
5. PRE-TREATMENT EVALUATION 
 
The following pre-treatment evaluations will be completed within 1 month (+/- 2 weeks) 
before starting study treatment: (Refer to Appendix 1 - Schema) 
 
• History and physical exam, to include Karnofsky Performance Score  and review of 
inclusion and exclusion criteria 
• ß-HCG for women with childbearing potential 
• Hematological and Biochemical Tests: 
o CBC with differential 
o PT, INR and PTT 
o Na, K, Cl, CO2, BUN, creatinine, Ca, total protein, albumin, total bilirubin, 
alkaline phosphatase, AST, ALT and glucose 
• Urinalysis 
• HIV Antibody 
• Anti Nuclear Antibody (ANA) 
• Biological Markers: 
o Serum will be obtained to measure antibodies to CEA and the neutralizing 
antibodies to Ad5 vector and sent to Etubics Corporation for determination. 
o Other available serum markers (e.g., CEA or CA15-3) will be reviewed if 
 
determined and  available.   
• Immunologic Evaluation/Archive Sample: 
o Blood may be drawn during the first clinic visit (after consent is signed) for 
immunologic evaluation and/or archiving.  
• Imaging Studies: 
o 
Brain CT scan or MRI is required within 6 weeks of starting study treatment. 
o 
Available CT scans or MRI of the chest, abdomen, and/or pelvis will be reviewed.  
Imaging studies within 6 weeks of starting study treatment is preferred,  but is not 
required.  
 
6. TREATMENT PLAN 
 
Patients will be enrolled into successive dosage level cohorts of 3 or 6 patients and 
monitored for dose-limiting toxicity (DLT).  
 
 DLT (Based on NCI CTCAE version 4.0) is defined as any Grade 2, 3 or 4 immediate 
hypersensitivity reactions, Grade 3 or 4 fever that may possibly be associated with the 
immunization, Grade ≥2 autoimmune events except for vitiligo or fever for less than 2 days and 

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less than 101.5 ºF, Grade ≥2 allergic reactions (grade 2 is defined as generalized urticaria as 
defined by CTCAE version 4.0), or Grade ≥3 non-hematologic toxicity.  
 
During dose escalation through the first three patients of cohort 3, there will be a 
minimum of 1 week between enrolling successive patients.  The first patient will be called to 
check on their condition prior to enrolling the second patient since patients can be enrolled after 
1 week of initiation of cohort 3. If no DLT have been observed at this point, then further 
enrollment can occur in cohort 3 and phase II component (Cohort 4) without the 1-week waiting 
period.  Between dosage levels, through Cohort 3, assessment of DLT for dose escalation will be 
made after all patients in a cohort have had a study visit at least 3 weeks after receiving their first 
dose of vaccine and all the available safety data and laboratory results have been reviewed. 
Patients in cohort 5 may begin injections once all patients in cohort 4 have had at least their first 
injections and all patients in cohort 3 have had a study visit at least 3 weeks after receiving their 
first dose of vaccine. If DLT occurs in <33% of patients in a given dosage level cohort, 
progression to the next dosage level will proceed.  If DLT occurs in ≥33% of patients in a given 
cohort, the next lower dosage level will be defined as the maximum tolerated dose (MTD).  If 
DLT occurs in <33% of patients in the highest dosage level tested, that dosage level will be 
defined as the MTD.  In phase II (Cohort 4) and Cohort 5, if at any time the rate of DLT in 
patients enrolled is ≥33%, the MTD will be re-defined as the next lower dosage level.  
Additional details of this dose escalation and de-escalation plan are provided below and in 
Figures 3A, 3B and Table 3.  
 
1) Phase I: Cohort 1: Three patients will receive Ad5 [E1-, E2B-]-CEA(6D)  at a dose of 1 x 
109 particles in 0.5 mL subcutaneously (SQ) in the same thigh every 3 weeks for 
3 immunizations. Immunizations should be separated by 5 cm.  A diary card will be 
given to each subject at the first treatment along with a ruler to record any adverse 
reactions for 2 days after treatment (24 hours and 48 hours post injection). The diary card 
will be placed in the study file.  Assessment of DLT for dose escalation will be made 
after all patients in this cohort have had a study visit at least 3 weeks after receiving their 
first dose of vaccine.  If there are no DLT (as defined above), then patients may begin 
enrolling into cohort 2.  If there is 1 DLT then an additional 3 patients will be enrolled at 
this dosage level. Assessment of DLT for dose escalation will be made after the 3 
additional patients have had a study visit at least 3 weeks after receiving their first dose of 
vaccine.  If none of these latter 3 patients have DLT, then patients may begin enrolling 
into cohort 2.  If 2 patients have DLT at this lowest dosage level, dosing will be de-
escalated to 1x108 particles and a new cohort of 3 patients instituted. 
 
2)  Cohort 2: Three patients will receive Ad5 [E1-, E2B-]-CEA(6D) at a dose of 1 x 1010 
particles in 0.5 mL SQ in the same thigh every 3 weeks for 3 immunizations.  
Immunizations site should be separated by 5 cm.  A diary card will be given to each 
subject at the first treatment along with a ruler to record any adverse reactions for 2 days 
after treatment (24 hours and 48 hours post injection). The diary card will be placed in 
the study file.  Assessment of DLT for dose escalation will be made after all patients in 
this cohort have had a study visit at least 3 weeks after receiving their first dose of 
vaccine.  If there are no DLT, then patients may begin enrolling into cohort 3.  If there is 
1 DLT then an additional 3 patients will be enrolled at this dosage level. Assessment of 

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DLT for dose escalation will be made after the 3 additional patients have had a study visit 
at least 3 weeks after receiving their first dose of vaccine.  If none of these latter 3 
patients have DLT, then patients may begin enrolling into cohort 3.  If 2 patients have 
DLT at this dosage level, the dosage level in cohort 1 will be considered the MTD.  If 
only 3 patients were enrolled in cohort 1, an additional 3 patients will be enrolled at that 
dosage before proceeding to the next cohort. 
 
3) Cohort 3: Six patients will receive Ad5 [E1-, E2B-]-CEA(6D)  at a dose of 1 x 1011 
particles in 0.5  mL SQ in the same thigh every 3  weeks for 3 immunizations.  
Immunizations site should be separated by 5 cm.  A diary card will be given to each 
subject at the first treatment along with a ruler to record any adverse reactions for 2 days 
after treatment (24 hours and 48 hours post injection). The diary card will be placed in 
the study file.  Assessment of DLT for proceeding to phase II enrollment (Cohort 4) will 
be made after all patients in this cohort have had a study visit at least 3 weeks after 
receiving their first dose of vaccine.  If there is 0 or 1 DLT, then subjects may enroll in 
Cohort 4.  If 2 patients have DLT at this dosage level, the dosage level in cohort 2 will be 
considered the MTD.  If only 3 patients were enrolled in cohort 2, an additional 3 patients 
will be enrolled at that dosage before proceeding to the next level. 
 
4) Phase II cohort (Cohort 4): After the MTD is established, an additional 12 patients will 
receive Ad5 [E1-, E2B-]-CEA(6D) at the MTD every 3 weeks for 3 immunizations. 
 
 
 
Note: if during accrual of patients in the phase II cohort, DLT occurs at a sufficient rate 
such that the rate of DLT amongst the total number of patients (those treated at MTD in 
phase I and those in phase II) is ≥33%, then phase II will be restarted at the dosage level 
which is one level below the prior MTD.  
 
5) Cohort 5: Six patients will receive Ad5 [E1-, E2B-]-CEA(6D) at a dose of 5x1011 
particles SQ in 2.5 mL every 3 weeks for 3 immunizations.  Assessment of DLT will be 
made after all patients in this cohort have had all 3 injections and been observed for at 
least 30 days after the last injection.  If there are 0-1 DLT, then this will be declared the 
maximum feasible dose. If there are 2 or more DLT, then 1x1011 particles will be 
declared the MTD.  
 
6) Patients will have 90 mL peripheral blood drawn prior to each immunization and 
approximately 3 weeks after the third immunization (Week 9) to determine whether there 
is an effect on the immune response at specific time points during the study and/or after a 
specific number of immunizations. 
 
7) Time to progression will be measured using CT scans performed at approximately 
3 month intervals (based on clinical standard of care). 
 
8) For all patients, if scheduling conflicts arise, the scheduled 3-week interval between 
immunizations may be modified so that the interval between immunizations is between 
20 and 28 days (3 weeks -1 day to 3 weeks +7 days).  If the second and/or third 

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immunization is delayed, the subsequent immunizations should occur no earlier than 
20 days after the previous immunization. 
 
9) The following safety events will trigger a temporary suspension of study vaccinations: 
 
a) If one or more patients develop a Grade 4 allergic reaction without a clear 
attributable cause, other than study vaccine 
b) Death not attributed to disease. 
 
Assessment of these halting rules is a review of cumulative events for all study 
participants, and should not be confused with reasons for delaying or terminating the 
immunization schedule of any individual patient. 
 
Etubics Corporation will fully review all available safety data, consult with the principal 
investigator, medical monitor and the FDA as needed, before determining if resuming 
vaccinations is appropriate.  If it is determined that study vaccinations can resume, the 
halting rules will apply to each subsequent event that meets the criteria described above. 
Vaccinations may also be suspended for safety concerns other than those described above 
if, in the judgment of the principal investigator or sponsor, participant safety is 
threatened. 
 
6.1. Study Stopping Rules 
- 
Death possibly related to the study agent. 
- 
Two patients having a Grade 4 toxicity event that is possibly/probably related to 
the study agent. 
 

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Figure 3A. 
 
 
 
 
 
 
 
 
 
 
 
 

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Figure 3B. 
 
 
 
 
Table 3. Calculation of rates of DLT during patient accrual in phase I and phase II 
# evaluable 
for toxicity 
1,2,3 
4,5,6 
7,8,9 
10,11,12 
13,14,15 
16,17,18 
# with DLT 
to be ≥33% 
1 
2 
3 
4 
5 
6 
 

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6.2. Pharmaceutical Information 
6.2.1 Dosage and Administration 
Patients will receive Ad5 [E1-, E2B-]-CEA(6D) at a dose of 1 x 109, 1 x 1010,  or 1 x 1011 
virus particles (vp)  per immunization in 0.5 mL of sterile saline SQ every 3 weeks for 3 
immunizations. The 5th cohort will receive Ad5 [E1-, E2B-]-CEA(6D) at a dose of 1 x 109, or 1 x 
1010,  or 1 x 1011 virus particles (vp)  per immunization in 0.5 mL of sterile saline  SQ every 3 
weeks for 3 immunizations. 
 
6.2.2 How Supplied 
ETBX-011 will be provided in a frozen state in a 2ml vial with a fill volume of 0.5 ml of 
extractable vaccine which contains 1x1011 total virus particles. The volume of injection for 
1x1011 virus particles is 0.5 mL. The lower doses will be produced by dilution in 0.9% saline 
using the following directions. The product should be stored at </= –20°C until used. 
 
Instructions for dose preparation:  
Cohort 1: To administer 1x10e9 virus particles by subcutaneous injection, perform 2 serial 
dilutions of vialed vaccine as follows: 
1. Draw 4.5 mL of sterile saline into a syringe.   
2. Using a second syringe, withdraw 0.5 mL of previously thawed ETBX-011 from the supplied 
vial.   
3. Remove the needle from syringe containing the 4.5 mL saline, and inject the 0.5 mL of 
ETBX-011 from the second syringe into the syringe containing saline.   
4. Mix. This new solution has a concentration 2 x 1010 vp/ml. 
5. Use a new sterile syringe with a needle and repeat above procedure.  
6. Withdraw 4.5 mL of sterile saline.   
7. In the second syringe withdraw 0.5 mL from the syringe containing 2 x 1010 vp/ml.   
8. Remove the needle from the syringe containing the 4.5 mL saline, and inject the 0.5 mL of 2 
x 1010vp/mL from the second syringe. 
9.  Place a new needle on the 10-mL syringe from Step 8 above  and mix the two solutions.  
This solution now has a concentration 2 x 109 vp/mL (1 x 109 vp per 0.5 mL). 
10. Label a new 1-mL sterile syringe ETBX-011, 1 x 109 vp and withdraw 0.5 mL from the 
syringe containing 2 x 109 vp/mL.  This prepared vaccine (ETBX-011, 1 x 109 vp) can be 
kept at room temperature for four hours prior to administering to the patient. 
 
Cohort 2: To administer 1x10e10 virus particles by subcutaneous injection: 
1. Draw 4.5 mL of sterile saline into a syringe.   
2. Using a second syringe, withdraw 0.5 mL of previously thawed ETBX-011 from the supplied 
vial.   
3. Remove the needle from syringe containing the 4.5 mL saline, and inject the 0.5 mL of 
ETBX-011 from the second syringe into the syringe containing saline.   
4. Mix. This new solution has a concentration 2 x 1010 vp/ml.  
5. Label a new 1-mL sterile syringe ETBX-011, 1 x 1010 vp and withdraw 0.5 mL from the 
syringe containing 2 x 1010 vp/mL.  This prepared vaccine (ETBX-011, 1 x 1010 vp) can be 
kept at room temperature for four hours prior to administering to the patient. 
 
 
 

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Cohort 3 and 4: To administer 1x10e11 virus particles by subcutaneous injection: 
1.  Withdraw 0.5mL of contents from the previously thawed, supplied ETBX-011 from the vial 
and administer to each subject without any further manipulation. 
 
Cohort 5: To administer 5x10e11 virus particles by subcutaneous injection: 
      1.  Withdraw 0.5mL of contents from each of 5 previously thawed ETBX-011 vials (total 
volume 2.5ml) and administer to each subject without any further manipulation. 
 
6.2.3 Disposal of Unused Vaccine 
Unless other arrangements are agreed in writing, all unused vaccine should be delivered 
to Dr. Joe Balint, at Etubics Corporation for disposal at or before the completion of the clinical 
study. 
 
7. TREATMENT EVALUATION 
 
7.1. Short-Term Evaluation During and After Active Immunotherapy  
On vaccine administration days, blood will be drawn before administration.  Evaluations 
will also be conducted for patients who discontinue from the study if they have received any 
treatment. The investigator will determine the degree of evaluation based on the patient's 
condition and/or reason for discontinuation from the study. 
 
7.1.1 General Evaluations  
Weeks 0, 3, 6 (Immunization Visits): 
General evaluations include medical history, Karnofsky performance status , and 
complete physical examination with weight by the attending physician.  Any other 
treatments, medications, biologics, or blood products that the patient is receiving or has 
received since the last visit will be recorded.  Patients will remain in the clinic for 
approximately 30 minutes following receipt of vaccine to monitor for any adverse 
reactions.  Local and systemic reactogenicity after each dose of vaccine will be assessed 
daily for 3 days (on the day of immunization and 2 days thereafter) using diary cards to 
report symptoms and a ruler to measure local reactogenicity. 
 
Week 9:   
General evaluations include medical history, Karnofsky performance status, and 
complete physical examination with weight by attending physician.  Any other 
treatments, medications, biologics, or blood products that the patient is receiving or has 
received since the last visit will be recorded.  Immunization injection sites will be 
assessed. 
 
7.1.2 Hematological and Biochemical Assessment 
Weeks 0, 3, 6 (Immunization Visits): 
Blood will be drawn to perform chemistry and hematology, including CBC with 
differential, Na, K, Cl, CO2, BUN, creatinine, Ca, total protein, albumin, total bilirubin, 
alkaline phosphatase, AST, ALT and glucose.  
 
 

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Week 9:   
Blood will be drawn to perform chemistry and hematology, including CBC with 
differential, Na, K, Cl, CO2, BUN, creatinine, Ca, total protein, albumin, total bilirubin, 
alkaline phosphatase, AST, ALT, glucose and ANA.  
 
7.1.3 Biological Markers 
Weeks 0 and 9:   
Serum (5ml) to measure antibodies to CEA and the Ad5 vector will be obtained and send 
to Etubics Corporation for determination.  Biomarkers (e.g., CEA or CA15-3) will be 
reviewed if determined and  available.   
 
 
7.1.4 Immunological Assessment 
Weeks 0, 3, 6, and 9:   
Peripheral blood (90mL) will be drawn prior to each immunization and approximately 3 
weeks after the last immunization to determine whether there is an effect on the immune 
response at specific time points during the study and/or after a specific number of 
immunizations.  Peripheral blood mononuclear cells (PBMC) will be assayed for T cell 
responses to CEA using ELISPOT at all time points, plus proliferation assays, multi-
parameter flow cytometric analysis, and cytoxicity assays, if possible and at the 
discretion of the investigator.  Serum from each blood draw will be archived and sent to 
Etubics Corporation for Ad5 neutralizing level determination.  
 
 
7.2. Long-Term Follow-Up 
Patients will be requested to continue long-term follow-up every 3 months for 1 year. At 
each visit, a medical history and physical exam and the following lab tests  will be 
performed: blood chemistry and hematology, including CBC with differential, Na, K, Cl, 
CO2, BUN, creatinine, Ca, total protein, albumin, total bilirubin, alkaline phosphatase, 
AST, ALT and glucose.  
 
At each visit, 40-90 mL of peripheral blood should be drawn for immune analysis, if 
there was previous evidence of an immune response or at the discretion of the 
investigator.  Available serum markers (e.g., CEA, CA15-3) will be reviewed. 
 
7.3. Management of Intercurrent Events 
7.3.1 Concomitant Medications 
Patients will be removed from the protocol treatment if they initiate concomitant 
chemotherapeutic agents, corticosteroids, or other immunosuppressive agents, or other 
forms of immunotherapy.  After meeting the inclusion criteria, all other medications 
deemed appropriate for the patient, by the investigator, may be administered to the 
patient.  All medications and changes in medication during treatment will be recorded.  
Hormonal therapy and bisphosphonates may be continued in breast cancer patients if they 
have been stable on the agents for at least 1 month prior to enrollment. 

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7.3.2 Adverse Events 
7.3.2.1 Toxicity will be graded according to the NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 (which can be downloaded from 
the CTEP web site (http://ctep.cancer.gov).)  DLT is defined in Protocol 
Section 6. 
7.3.2.2 Possible side effects from immunization may include local effects (pain, 
tenderness, rednesss or swelling), systemic effects (malaise, fatigue, myalgia, 
arthralgia, headache, nausea, vomiting, chills or fever), and allergic reactions 
such as hives, rash or anaphylactic reactions.  Induction of auto-immunity, 
manifest as arthritis, serositis, nephritis, thyroiditis, colitis, neutropenia, etc., 
is theoretically possible, but has not been observed in our prior CEA vaccine 
studies.  Also, liver function test abnormalities and liver failure are 
theoretically possible. 
 
7.3.3 Treatment of Toxicity 
For acute allergic reactions, use of diphenhydramine 25-50 mg IV, corticosteroids 
(Solumedrol 100 mg), and epinephrine (1:1000, 0.3-1 mL sq) should be considered.  
These medications are available in the clinical setting where the vaccine will be 
administered.  For auto-immunity, corticosteroids (prednisone 0.5-1 mg/kg/d) should be 
considered.  Clinical assessment of other targets, such as thyroid, arthritis, urticaria, or 
proteinuria, for auto-immunity and serum sickness like antigen-antibody complex 
disease, will also be performed as indicated. 
 
7.3.4 Active Immunotherapy will be Discontinued for: 
7.3.4.1 Life-threatening anaphylactic reactions related to active immunotherapy 
7.3.4.2 DLT related to active immunotherapy 
7.3.4.3 Disease progression (by RECIST criteria).  Patients will be offered 
referral to a medical oncologist for discussion of other treatment options, 
and for continued medical care.   
7.3.4.3.1 
Disease progression prior to completing the 3 study 
 
immunizations:  
 
In the event that a patient undergoes reimaging studies prior to the 
 
completion of their 3 study immunizations and is found to have 
 
disease progression, they will be permitted to continue on the study 
 
as long as the progression has been 50% or less by RECIST 
 
criteria.  
 
If a patient is removed from the study prior to completion of the assigned vaccine 
schedule for any reason other than toxicity, that patient will be replaced, in order to 
obtain data to help determine the toxicity of the immunizations. We will allow up to 3 
replacements per cohort (Phase I, Dose levels 1 and 2; Phase II, MTD). 
 

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8. STATISTICAL CONSIDERATIONS 
8.1. Safety  
We will evaluate safety continuously in a cohort.  We will make our overall assessment 
of whether to escalate to the next dose level at least 3 weeks after the last patient in the previous 
cohort has received their first injection.  This decision will be made by the medical monitor and 
the Principal Investigator.  A note will be generated following the assessment decision and filed 
in study binder.  A dosage level will be considered safe if <33% patients treated at a dose level 
experience DLT (i.e., 0 of 3, ≤1 of 6, ≤3 of 12, or ≤5 of 18 patients).  DLT is defined in Protocol 
Section 6.  Safety will be evaluated in 3 or 6 patients at each dosage level in phase I.   Safety will 
continue to be monitored among additional patients treated at the MTD in phase II.  A patient 
will be considered evaluable for safety if treated with at least one immunization.  DLTs will be 
observed through 9 weeks to accommodate safety evaluation of all 3 product doses. 
8.2. Rate of Immune Response  
Immune responses against CEA will be evaluated from the peripheral blood of patients 
from among the following studies at the discretion of the Principal Investigator (ELISpot, 
cytokine flow cytometry, and antibody responses). We will determine the percentage of patients 
with a positive immune response.  We define a positive immune response by ELISpot as 
described at the 2002 Society of Biologic Therapy Workshop on “Immunologic Monitoring of 
Cancer Vaccine Therapy”, i.e. a T cell response is considered positive if the mean number of 
spots adjusted for background in six wells with antigen exceeds the number of spots in six 
control wells by 10 and the difference between single values of the six wells containing antigen 
and the six control wells is statistically significant at a level of p ≤ 0.05 using the Student’s t test.  
Immunogenicity assays will occur prior to each immunization and at week 12.  Immune response 
will be assessed among the 18 patients treated at the MTD (12 in phase I and 12 in Phase II).  
The therapy will be considered of further interest if 9 of 18 patients treated at the MTD dose 
exhibit an immune response as defined above.  Meeting this criterion establishes that the immune 
response rate is at least 33% with approximately 90% confidence.  At significance level 0.1 there 
is 82% power to test the null hypothesis that the immune response rate is ≤ 0.33 versus the 
alternative that the immune response rate is ≥ 0.58.  The magnitude of response will also be 
described.  A patient will be considered evaluable for immune response if they receive at least 3 
immunizations. 
 
8.3. Determination of Clinical Response 
Among patients with measurable/evaluable disease, response determination will be made 
according to the RECIST criteria: 
Complete Response (CR): 
Disappearance of target lesion, confirmed at 4    
weeks 
Partial Response (PR): 
30% decrease in longest dimension of target lesion, 
confirmed at 4 weeks 
Stable Disease (SD): 
 
Neither PR nor PD 
Progressive Disease (PD): 
20% increase in longest dimension of target lesion; 
no CR, PR, or SD documented before increased 
disease. 
The exact binomial confidence interval for the proportion of subjects with a clinical 
response of CR or PR will be calculated. 
 

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9. PATIENT WITHDRAWAL 
Patients may be removed from the study for the following reasons: 
• DLT as defined in Protocol Section 6.   
• Patient voluntarily decides to withdraw. 
• Patient non-compliance with the study protocol. 
• Intercurrent disease which in the opinion of the patient’s treating physician would 
affect the ability of the patient to continue on the clinical study.  
In the event of withdrawal due to toxicity, a patient will be requested to have safety 
evaluations performed as per the protocol for a one year duration post treatment. This may 
include having up to 90 mL of blood drawn for immunologic testing. 
 
10. STUDY CONDUCT AND ETHICAL AND REGULATORY CONSIDERATIONS 
 
10.1. Departure from the Protocol 
There should be no departure from the protocol if at all possible.  If an emergency occurs 
that requires departure from this protocol, the investigator or other physician in attendance in 
such an emergency will, if circumstances and time permit, contact the principal investigator, or 
in his absence, Dr. H. Kim Lyerly, Acting Medical Director, immediately by telephone (919) 
684-8111  (paging operator). Such contacts with the principal investigator will be made to permit 
a decision as to whether or not the patient will be continued on the study.  Such departures need 
to be clearly documented and reported to the Institutional Review Board (IRB) and the Etubics 
Corporation by the principal investigator. 
 
10.2. Informed Consent 
In accordance with guidelines in the Federal Register, Vol. 48, No. 17, 1982, pp. 8951-2, 
all patients are required to sign a statement of informed consent.  This phase I/II study involves 
research that presents risk, but holds the prospect of direct benefit to the individual patient 
(46.405-45 Code of the Federal Regulations part 46).  The investigator will report to the IRB and 
Etubics Corporation will report to FDA changes in the research protocol and all unanticipated 
problems involving risks to human patients and others, and no changes will be made in the 
research activity without IRB approval. 
 
10.3. Institutional Review 
This study must be approved by the site’s IRB.  IRB approval of the protocol and the 
informed consent form for this study must be given in writing.  The IRB must also approve any 
significant changes to the protocol as well as a change of principal investigator.  Records of all 
study review and approval documents must be kept on file by the investigator and are subject to 
FDA inspection during or after completion of the study.  Adverse events must be reported to the 
IRB.  The IRB will receive notification of the completion of the study and final report within 
three months of study completion or termination.  The investigator must maintain an accurate 
and complete record of all submissions made to the IRB, including a list of all reports and 
documents submitted. 
 
10.4. Documentation and Monitoring 
Data will be collected for all patients signing consent.  Accurate completion of the 
computer data forms for all patients is the responsibility of the investigator.   

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10.4.1 Case Report Forms 
Case Report Forms (CRFs) are used to record study data and are an integral part of the 
study and subsequent reports.  Therefore, all reports must be legible and complete.  All forms 
should be filled out using a black ballpoint pen.  Errors should be lined out but not obliterated 
and the correction inserted, initialed, and dated by the principal investigator, co-investigators, 
study coordinator, or data manager.  A CRF must be completed and signed by the principal 
investigator for each patient enrolled, including those removed from the study for any reason.  
The reason for removal must be noted on the Final Report Form by the investigator for each 
patient.  CRFs must be kept current to reflect patient status at each phase during the course of the 
study.  Patients are not to be identified on CRFs by name; appropriate coded identification and 
patient initials must be used.  The investigator must keep a separate log of patient names and 
addresses.  This log is subject to FDA inspection.  Because of the potential for errors, 
inaccuracies, and illegibility in transcribing data onto CRFs, originals of laboratory and other test 
results must be kept on file with patient's CRFs or clinical chart.  CRFs and copies of test results 
must be available at all times for inspection by the FDA.   
 
10.4.2 Maintenance of Study Documentation 
The following will be maintained: 
a. Case Report Forms - which must be kept legible, accurate, and up-to-date. 
b. Patient Files/Signed Informed Consent - which substantiates the data entered 
on the case report forms for all required test and evaluation procedures and 
verifies that the patient has signed an informed consent to enter the study. 
c. Patient Exclusion Record - which should reflect the reason any patient was 
screened and found ineligible for the study. 
d. Monitoring Log - listing dates of monitor visits. 
e. Regulatory Documents - including protocol, investigator brochure, FDA Form 
1572, CVs, IRB correspondence, IRB approval/renewals and IRB approved 
consent form. 
f. Adverse Event Report Form - which should explain any serious or unexpected 
adverse experiences. 
All study documentation pertaining to the conduct of the study must be kept on file by the 
investigator for a period of 2 years following the date a marketing application is approved for the 
drug for the indication for which it is being investigated; or, if no application is to be filed or if 
the application is not approved for such indication, until 2 years after the investigation is 
discontinued and FDA is notified.  The sponsor will notify the investigator if a marketing 
application is approved or if the investigation is discontinued and the FDA notified. 
 
10.5. Monitoring of the Protocol 
A Etubics Corporation representative will conduct a site initiation visit and will review 
protocol documents with the investigators and their staff. During the study, the Etubics monitor 
will visit the site regularly to check the completeness of study files, the accuracy of data entries 
on the CRFs, and adherence to the protocol and to Good Clinical Practice (GCP).  Key study 
personnel must be available to assist the monitor during these visits. The investigator must 
maintain source documents for each subject in the study. The investigator must also keep the 
original informed consent form signed by every patient.  The investigator must give the monitor 

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access to all relevant source documents to verify data entries on CRFs.  No information in source 
documents about the identity of subjects will be disclosed. 
 
This is a phase I/II clinical study with more than minimal risk and as such will be monitored for 
the occurrence of a greater frequency of adverse events (AEs).  The principal investigator will 
continuously monitor the data and safety of all subjects enrolled. All grades of toxicities will be 
recorded.   
 
Safety assessments will consist of monitoring all AEs including serious adverse events (SAEs), 
the regular monitoring of hematology, serum chemistry, and routine monitoring of vital signs 
and physical condition.  AE monitoring should occur from the time of informed consent to 30 
days after the last dose of study drug. For those subjects who discontinue study participation 
prior to receiving study drug, AE and SAEs will be collected through the time of discontinuation.   
 
Toxicity will be assessed using the NCI CTCAE version 4.0.  Refer to Protocol Section 7.3.2. 
 
An AE is any adverse change from the study patient’s baseline (pretreatment) condition, 
including any clinical or laboratory test abnormality that occurs during the course of the 
proposed clinical study after treatment has started.   
 
Events are classified as SERIOUS if they meet any of the following criteria [per the US Code of 
Federal Regulations (CFR) 21 CFR 312.32 and the recommendations of the International 
Conference on Harmonization (ICH)]: 
 
An SAE is any sign, symptom or medical condition that emerges during the study or during a 
post-study follow-up period that 1) was not present at the start of the study and is not a chronic 
condition that is part of the patient’s medical history, OR 2) was present at the start of the study 
or as part of the patient’s medical history but worsened in severity and/or frequency during study 
participation, AND that meets any of the following regulatory serious criteria: 
 
• any death 
• any life-threatening event, i.e., an event that places the patient, in the view of the 
investigator, at immediate risk of death from the event as it occurred (does not 
include an event that, had it occurred in a more severe form, might have caused 
death) 
• any event that requires or prolongs in-patient hospitalization 
• any event that results in persistent or significant disability/incapacity 
• any congenital anomaly/birth defect diagnosed in a child of a patient who 
participated in this study and received investigational drug 
• other medically important events that in the opinion of the investigator may 
jeopardize the patient or may require intervention to prevent one of the other 
outcomes listed in the definition above (e.g. allergic bronchospasm requiring 
intensive treatment in an emergency room, convulsions occurring at home that do 
not require in-patient hospitalization, any blood dyscrasias, or the development of 
drug dependency or drug abuse). 
 

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10.6. CTCAE Term (AE description) and Grade   
The descriptions and grading scales found in the revised NCI CTCAE version 4.0 will be 
utilized for AE reporting. A copy can be downloaded from the CTEP web site 
(http://ctep.cancer.gov).   
 
The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for 
each AE based on the following guideline: 
 
Grade 1 
Mild AE 
Grade 2 
Moderate AE 
Grade 3 
Severe AE 
Grade 4 
Life-threatening or disabling AE 
Grade 5 
Death related to AE 
 
10.7. Assessing Causality 
Investigators are required to assess whether there is a reasonable possibility that study 
medications caused or contributed to an adverse event.  The following general guidance may be 
used. 
Yes: 
if the temporal relationship of the clinical event to study drug administration makes a 
causal relationship possible, and other drugs, therapeutic interventions or underlying 
conditions do not provide a sufficient explanation for the observed event. 
No: 
if the temporal relationship of the clinical event to study drug administration makes a 
causal relationship unlikely, or other drugs, therapeutic interventions or underlying 
conditions provide a sufficient explanation for the observed event. 
 
10.8. Serious Adverse Event Reporting 
All AEs that are classified as serious, unexpected and related or possibly related, will be 
recorded on the MedWatch 3500A form and reported within 24 hours of learning of the event to 
Etubics Corporation.  The form should be completed as much as possible but should not be held 
until all information is available. Additional information and/or corrections may be submitted as 
they are obtained. The investigator will follow SAEs until resolution, a return to baseline 
condition or stabilization or 30 days after the last subject is enrolled whichever occurs first. 
SAEs that are ongoing at the time of clinical database closure will be recorded as unresolved.   
 
All study-related deaths should be reported to the IRB within 24 hours; all other serious 
adverse experiences should be reported to the IRB within 5 business days. All deaths, whether 
considered study-related or not, must also be reported immediately to Etubics Corporation, 
additional information may be requested from the treating institution. Deaths believed to be 
related to disease progression will not be reported to the FDA as SAEs, as these deaths are an 
anticipated outcome of the disease; however, all deaths will be reported to the FDA in the annual 
reports.  
 
MedWatch 3500A Reporting Guidelines: 
In addition to completing appropriate patient demographic and suspect medication 
information, the report should include the following information within the Event Description 
(section 5) of the MedWatch 3500A form: 

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• Treatment regimen (dosing frequency, combination therapy) 
• Protocol description (and number, if assigned) 
• Description of event, severity, treatment, and outcome, if known 
• Supportive laboratory results and diagnostics 
• Investigator’s assessment of the relationship of the adverse event to each investigational 
product and suspect medication 
 
Follow-up information:  
 Additional information may be added to a previously submitted report by any of the 
following methods: 
• Adding to the original MedWatch 3500A report and submitting it as follow-up 
• Adding supplemental summary information and submitting it as follow-up with the 
original MedWatch 3500A form  
• Summarizing new information and faxing it with a cover letter including patient 
identifiers (i.e. D.O.B., initials, patient number), protocol description and number, if 
assigned, suspect drug, brief adverse event description, and notation that additional or 
follow-up information is being submitted  (The patient identifiers are important so that 
the new information is added to the correct initial report.) 
 
Reporting of Pregnancy:  
If a participant becomes pregnant during the study, treatment will be discontinued (i.e., 
no additional dose of study vaccine will be given) and the participant will be encouraged to 
continue to have regularly scheduled follow-up visits and evaluations.  The occurrence of 
pregnancy, and the outcome of any pregnancy, in a subject treated with study vaccine, must be 
reported to the Etubics Corporation and to the IRB.   
 
Procedures for SAE Reporting: 
1. Medical staff/study team notifies principal investigator of SAE. MedWatch 3500A is 
completed. 
 
2. Principal Investigator calls Etubics Corpration to report the SAE and faxes the completed 
MedWatch 3500A to: 
 
 
 
Carol Jones, Vice President of Administration 
 
Address: 410 West Harrison Street, Suite 100, Seattle, WA 981119 
 
Telephone: 206-838-5110 ext. 102 
 
Cell: (206) 818-2985 
 
Fax: (206) 838-2978 
 
Email: cj@etubics.com 
 
3.   Carol Jones reports the SAE to one of the following in this order: 
 
 
A.   Chief Scientific Officer: Frank Jones, PhD  
 
Address: 410 West Harrison Street, Suite 100, Seattle, WA 98119  
 
Telephone: 206-838-5110 ext. 101 

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Cell: (206) 818-2857 
 
Fax: (206) 838-2978 
 
Email: frj@etubics.com 
 
B.  Laboratory Manager:  Joseph Balint, PhD 
 
Address: 410 West Harrison Street, Suite 100, Seattle, WA 98119 
 
Telephone: (206) 838-5110 ext. 107 
 
Fax:  (206) 838-2978 
 
Email: joe@etubics.com 
 
C.  Vice President Research: Elizabeth S. Gabitzsch 
 
Address: 410 West Harrison Street, Suite 100, Seattle, WA 98119 
 
Telephone: (206) 838-5110 ext. 103 
 
Cell: (970) 402-2598 
 
Fax:  (206) 838-2978 
 
Email: beth@etubics.com 
 
 
4.  Contacted person in three (3) above notifies the FDA via MedWatch 3500A form. 
 
a. If the SAE results in death or is life-threatening, SAE report will be submitted to the 
FDA within 7 days 
b. All other SAEs must be reported to the FDA within 15 days 
 
5. All SAE will require input from a physician, the Acting Medical Director will be consulted: 
 
  
H. Kim Lyerly, MD  
Telephone: (919) 684-5613 or (919)684-8111 (paging operator) 
Fax: (919) 684-5653 
Email: lyerl001@mc.duke.edu 
 
6. SAEs will be reported to the IRB according to the site’s IRB guidelines.   
 
In accordance with FDA regulations and ICH guidelines, investigators will be notified of the 
occurrence of new, serious, unexpected adverse events associated with the use of the study 
medication (i.e. there is a reasonable possibility that the AE may have been caused by the drug) 
within 15 calendar days via a written report.  It is the responsibility of the investigator to 
promptly inform the relevant IRB of these new adverse events/risks to patients, in accordance 
with 21 CFR 312.66.  It is the responsibility of Etubics Corporation to promptly inform the NIH 
Office of Biotechnology Activities (OBA) and relevant Scientific Review Board of these new 
adverse events/risks to patients, in accordance with NIH Guidelines for Research Involving 
Recombinant DNA Molecules, in particular Appendix M.  It is the responsibility of the Etubics 
Corporation to report these SAEs to the FDA.  The SAE report will be forwarded to the FDA 
after recording the event data via the FDA MedWatch form 3500A.   
 

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10.9. Safety Reporting Requirements  
In accordance with 21 CFR 312.32, the sponsor of studies conducted under an IND must 
comply with following safety reporting requirements:  
 
a. Expedited IND Safety Reports: 
 
7 Calendar-Day Telephone or Fax Report:   
The sponsor is required to notify the FDA of any fatal or life-threatening adverse event 
that is unexpected and assessed by the investigator to be possibly related to the use of the 
investigational product.   An unexpected adverse event is one that is not already described in the 
Investigator’s Brochure.  Such reports are to be telephoned or faxed to the FDA within 
7 calendar days of first learning of the event.   
 
15 Calendar-Day Written Report:   
The sponsor is also required to notify the FDA and all participating investigators, in a 
written IND Safety Report, of any serious, unexpected AE that is considered possibly related to 
the investigational product.  An unexpected adverse event is one that is not already described in 
the Investigator Brochure. 
Written IND Safety Reports should include an Analysis of Similar Events in accordance 
with regulation 21 CFR § 312.32.  All safety reports previously filed with the IND concerning 
similar events should be analyzed.  The new report should contain comments on the significance 
of the new event in light of the previous, similar reports.   
Written IND safety reports with Analysis of Similar Events are to be submitted to the 
FDA and all participating investigators within 15 calendar days of first learning of the event.  
The FDA prefers these reports on a MedWatch 3500A Form but alternative formats are 
acceptable (e.g. summary letter). 
 
b. IND Annual Reports 
In accordance with the regulation 21 CFR § 312.32, the sponsor shall within 60 days of 
the anniversary date that the IND went into effect submit a brief report of the progress of the 
investigation.   
 
c. Data and Safety Monitoring  
Data will be collected by the principal investigator, co-investigators, and the protocol 
coordinator.  The protocol coordinator under the supervision of the principal investigator will 
report the AEs. The data will be audited by Etubics Corporation.  

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11. REFERENCES 
1. 
Berinstein, N.L. 2002. Carcinoembryonic antigen as a target for therapeutic anticancer 
vaccines: a review. J Clin Oncol 20:2197-2207. 
2. 
Tsang, K.Y., Zaremba, S., Nieroda, C.A., Zhu, M.Z., Hamilton, J.M., and Schlom, J. 
1995. Generation of human cytotoxic T cells specific for human carcinoembryonic 
antigen epitopes from patients immunized with recombinant vaccinia-CEA vaccine. J 
Natl Cancer Inst 87:982-990. 
3. 
Tsang, K.Y., Zhu, M., Nieroda, C.A., Correale, P., Zaremba, S., Hamilton, J.M., Cole, 
D., Lam, C., and Schlom, J. 1997. Phenotypic stability of a cytotoxic T-cell line directed 
against an immunodominant epitope of human carcinoembryonic antigen. Clin Cancer 
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4. 
Ras, E., van der Burg, S.H., Zegveld, S.T., Brandt, R.M., Kuppen, P.J., Offringa, R., 
Warnarr, S.O., van de Velde, C.J., and Melief, C.J. 1997. Identification of potential HLA-
A *0201 restricted CTL epitopes derived from the epithelial cell adhesion molecule (Ep-
CAM) and the carcinoembryonic antigen (CEA). Hum Immunol 53:81-89. 
5. 
Zaremba, S., Barzaga, E., Zhu, M., Soares, N., Tsang, K.Y., and Schlom, J. 1997. 
Identification of an enhancer agonist cytotoxic T lymphocyte peptide from human 
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6. 
Kawashima, I., Hudson, S.J., Tsai, V., Southwood, S., Takesako, K., Appella, E., Sette, 
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7. 
Zhu, M.Z., Marshall, J., Cole, D., Schlom, J., and Tsang, K.Y. 2000. Specific cytolytic T-
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antigen class I epitopes that are more potent and immunogenic than wild-type peptide. J 
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Kass, E., Panicali, D.L., Mazzara, G., Schlom, J., and Greiner, J.W. 2001. 
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Marshall, J.L., Hawkins, M.J., Tsang, K.Y., Richmond, E., Pedicano, J.E., Zhu, M.Z., 
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25. 
von Mehren, M., Arlen, P., Tsang, K.Y., Rogatko, A., Meropol, N., Cooper, H.S., Davey, 
M., McLaughlin, S., Schlom, J., and Weiner, L.M. 2000. Pilot study of a dual gene 
recombinant avipox vaccine containing both carcinoembryonic antigen (CEA) and B7.1 
transgenes in patients with recurrent CEA-expressing adenocarcinomas. Clin Cancer Res 
6:2219-2228. 

Protocol Version 3.1, June 20, 2011 
 
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26. 
von Mehren, M., Davey, M., and McLaughlin, S. 2000. Phase I study of vaccine therapy 
with ALVAC-CEA B7.1 and GM-CSF in patients with advanced CEA-expressing 
cancers (abstr 1883). In Proc Am Soc Clin Oncol 480a. 
27. 
von Mehren, M., Arlen, P., Gulley, J., Rogatko, A., Cooper, H.S., Meropol, N.J., 
Alpaugh, R.K., Davey, M., McLaughlin, S., Beard, M.T., et al. 2001. The influence of 
granulocyte macrophage colony-stimulating factor and prior chemotherapy on the 
immunological response to a vaccine (ALVAC-CEA B7.1) in patients with metastatic 
carcinoma. Clin Cancer Res 7:1181-1191. 
28. 
Hörig, H., Lee, D.S., Conkright, W., Divito, J., Hasson, H., LaMare, M., Rivera, A., Park, 
D., Tine, J., Guito, K., et al. 2000. Phase I clinical trial of a recombinant canarypoxvirus 
(ALVAC) vaccine expressing human carcinoembryonic antigen and the B7.1 co-
stimulatory molecule. Cancer Immunol Immunother 49:504-514. 
29. 
Marshall, J.L., Hoyer, R.J., Toomey, M.A., Faraguna, K., Chang, P., Richmond, E., 
Pedicano, J.E., Gehan, E., Peck, R.A., Arlen, P., et al. 2000. Phase I study in advanced 
cancer patients of a diversified prime-and-boost vaccination protocol using recombinant 
vaccinia virus and recombinant nonreplicating avipox virus to elicit anti-
carcinoembryonic antigen immune responses. J Clin Oncol 18:3964-3973. 
30. 
Slack, R., Ley, L., and Chang, P. 2001. Association between CEA-specific T cell 
responses following treatment wiht vaccinia CEA and survival in patients with CEA 
bearing cancers (abstr 1086). In Proc Am Soc Clin Oncol 272a. 
31. 
Marshall, J.L., Gulley, J.L., Arlen, P.M., Beetham, P.K., Tsang, K.Y., Slack, R., Hodge, 
J.W., Doren, S., Grosenbach, D.W., Hwang, J., et al. 2005. Phase I study of sequential 
vaccinations with fowlpox-CEA(6D)-TRICOM alone and sequentially with vaccinia-
CEA(6D)-TRICOM, with and without granulocyte-macrophage colony-stimulating 
factor, in patients with carcinoembryonic antigen-expressing carcinomas. J Clin Oncol 
23:720-731. 
32. 
Hu, H., Serra, D., and Amalfitano, A. 1999. Persistence of an [E1-, polymerase-] 
adenovirus vector despite transduction of a neoantigen into immune-competent mice. 
Hum Gene Ther 10:355-364. 
33. 
Hodges, B.L., Evans, H.K., Everett, R.S., Ding, E.Y., Serra, D., and Amalfitano, A. 2001. 
Adenovirus vectors with the 100K gene deleted and their potential for multiple gene 
therapy applications. J Virol 75:5913-5920. 
34. 
Hodges, B.L., Serra, D., Hu, H., Begy, C.A., Chamberlain, J.S., and Amalfitano, A. 2000. 
Multiply deleted [E1, polymerase-, and pTP-] adenovirus vector persists despite deletion 
of the preterminal protein. J Gene Med 2:250-259. 
35. 
Arthur, J.F., Butterfield, L.H., Roth, M.D., Bui, L.A., Kiertscher, S.M., Lau, R., Dubinett, 
S., Glaspy, J., McBride, W.H., and Economou, J.S. 1997. A comparison of gene transfer 
methods in human dendritic cells. Cancer Gene Ther 4:17-25. 
36. 
Diao, J., Smythe, J.A., Smyth, C., Rowe, P.B., and Alexander, I.E. 1999. Human PBMC-
derived dendritic cells transduced with an adenovirus vectorinduce cytotoxic T-
lymphocyte responses against a vector-encoded antigen in vitro. Gene Ther 6:845-853. 
37. 
Brossart, P., Goldrath, A.W., Butz, E.A., Martin, S., and Bevan, M.J. 1997. Virus-
mediated delivery of antigenic epitopes into dendritic cells as a means to induce CTL. J 
Immunol 158:3270-3276. 
38. 
Butterfield, L.H., Jilani, S.M., Chakraborty, N.G., Bui, L.A., Ribas, A., Dissette, V.B., 
Lau, R., Gamradt, S.C., Glaspy, J.A., McBride, W.H., et al. 1998. Generation of 

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melanoma-specific cytotoxic T lymphocytes by dendritic cells transduced with a MART-
1 adenovirus. J Immunol 161:5607-5613. 
39. 
Bregni, M., Shammah, S., Malaffo, F., Di Nicola, M., Milanesi, M., Magni, M., 
Matteucci, P., Ravagnani, F., Jordan, C.T., Siena, S., et al. 1998. Adenovirus vectors for 
gene transduction into mobilized blood CD34+ cells. Gene Ther 5:465-472. 
40. 
Dietz, A.B., and Vuk-Pavlovic, S. 1998. High efficiency adenovirus-mediated gene 
transfer to human dendritic cells. Blood 91:392-398. 
41. 
Ishida, T., Chada, S., Stipanov, M., Nadaf, S., Ciernik, F.I., Gabrilovich, D.I., and 
Carbone, D.P. 1999. Dendritic cells transduced with wild-type p53 gene elicit potent anti-
tumour immune responses. Clin Exp Immunol 117:244-251. 
42. 
Ribas, A., Butterfield, L.H., McBride, W.H., Jilani, S.M., Bui, L.A., Vollmer, C.M., Lau, 
R., Dissette, V.B., Hu, B., Chen, A.Y., et al. 1997. Genetic immunization for the 
melanoma antigen MART-1/Melan-A using recombinant adenovirus-transduced murine 
dendritic cells. Cancer Res 57:2865-2869. 
43. 
Wan, Y., Bramson, J., Carter, R., Graham, F., and Gauldie, J. 1997. Dendritic cells 
transduced with an adenoviral vector encoding a model tumor-associated antigen for 
tumor vaccination. Hum Gene Ther 8:1355-1363. 
44. 
Wan, Y., Emtage, P., Foley, R., Carter, R., and Gauldie, J. 1999. Murine dendritic cells 
transduced with an adenoviral vector expressing a defined tumor antigen can overcome 
anti-adenovirus neutralizing immunity and induce effective tumor regression. Int J Oncol 
14:771-776. 
45. 
Miller, P.W., Sharma, S., Stolina, M., Butterfield, L.H., Luo, J., Lin, Y., Dohadwala, M., 
Batra, R.K., Wu, L., Economou, J.S., et al. 2000. Intratumoral administration of 
adenoviral interleukin 7 gene-modified dendritic cells augments specific antitumor 
immunity and achieves tumor eradication. Hum Gene Ther 11:53-65. 
46. 
Lu, L., Gambotto, A., Lee, W.C., Qian, S., Bonham, C.A., Robbins, P.D., and Thomson, 
A.W. 1999. Adenoviral delivery of CTLA4Ig into myeloid dendritic cells promotes their 
in vitro tolerogenicity and survival in allogeneic recipients. Gene Ther 6:554-563. 
47. 
Rea, D., Schagen, F.H., Hoeben, R.C., Mehtali, M., Havenga, M.J., Toes, R.E., Melief, 
C.J., and Offringa, R. 1999. Adenoviruses activate human dendritic cells without 
polarization toward a T-helper type 1-inducing subset. J Virol 73:10245-10253. 
48. 
Hirschowitz, E.A., Weaver, J.D., Hidalgo, G.E., and Doherty, D.E. 2000. Murine 
dendritic cells infected with adenovirus vectors show signs of activation. Gene Ther 
7:1112-1120. 
49. 
Loser, P., Jennings, G.S., Strauss, M., and Sandig, V. 1998. Reactivation of the 
previously silenced cytomegalovirus major immediate-early promoter in the mouse liver: 
involvement of NFkappaB. J Virol 72:180-190. 
50. 
Morelli, A.E., Larregina, A.T., Ganster, R.W., Zahorchak, A.F., Plowey, J.M., 
Takayama, T., Logar, A.J., Robbins, P.D., Falo, L.D., and Thomson, A.W. 2000. 
Recombinant adenovirus induces maturation of dendritic cells via an NF-kappaB-
dependent pathway. J Virol 74:9617-9628. 
51. 
Jonuleit, H., Tüting, T., Steitz, J., Brück, J., Giesecke, A., Steinbrink, K., Knop, J., and 
Enk, A.H. 2000. Efficient transduction of mature CD83+ dendritic cells using 
recombinant adenovirus suppressed T cell stimulatory capacity. Gene Ther 7:249-254. 
52. 
Tillman, B.W., Hayes, T.L., DeGruijl, T.D., Douglas, J.T., and Curiel, D.T. 2000. 
Adenoviral vectors targeted to CD40 enhance the efficacy of dendritic cell-based 

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vaccination against human papillomavirus 16-induced tumor cells in a murine model. 
Cancer Res 60:5456-5463. 
53. 
Shiver, J.W., Fu, T.M., Chen, L., Casimiro, D.R., Davies, M.E., Evans, R.K., Zhang, 
Z.Q., Simon, A.J., Trigona, W.L., Dubey, S.A., et al. 2002. Replication-incompetent 
adenoviral vaccine vector elicits effective anti-immunodeficiency-virus immunity. Nature 
415:331-335. 
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Yang, Z.Y., Wyatt, L.S., Kong, W.P., Moodie, Z., Moss, B., and Nabel, G.J. 2003. 
Overcoming immunity to a viral vaccine by DNA priming before vector boosting. J Virol 
77:799-803. 
55. 
Casimiro, D.R., Chen, L., Fu, T.M., Evans, R.K., Caulfield, M.J., Davies, M.E., Tang, A., 
Chen, M., Huang, L., Harris, V., et al. 2003. Comparative immunogenicity in rhesus 
monkeys of DNA plasmid, recombinant vaccinia virus, and replication-defective 
adenovirus vectors expressing a human immunodeficiency virus type 1 gag gene. J Virol 
77:6305-6313. 
56. 
Chirmule, N., Propert, K., Magosin, S., Qian, Y., Qian, R., and Wilson, J. 1999. Immune 
responses to adenovirus and adeno-associated virus in humans. Gene Ther 6:1574-1583. 
57. 
Hartigan-O'Connor, D., Barjot, C., Salvatori, G., and Chamberlain, J.S. 2002. Generation 
and growth of gutted adenoviral vectors. Methods Enzymol 346:224-246. 
58. 
Harui, A., Roth, M.D., Kiertscher, S.M., Mitani, K., and Basak, S.K. 2004. Vaccination 
with helper-dependent adenovirus enhances the generation of transgene-specific CTL. 
Gene Ther 11:1617-1626. 
59. 
Morral, N., Parks, R.J., Zhou, H., Langston, C., Schiedner, G., Quinones, J., Graham, 
F.L., Kochanek, S., and Beaudet, A.L. 1998. High doses of a helper-dependent adenoviral 
vector yield supraphysiological levels of alpha1-antitrypsin with negligible toxicity. Hum 
Gene Ther 9:2709-2716. 
60. 
DelloRusso, C., Scott, J.M., Hartigan-O'Connor, D., Salvatori, G., Barjot, C., Robinson, 
A.S., Crawford, R.W., Brooks, S.V., and Chamberlain, J.S. 2002. Functional correction 
of adult mdx mouse muscle using gutted adenoviral vectors expressing full-length 
dystrophin. Proc Natl Acad Sci U S A 99:12979-12984. 
61. 
Reddy, P.S., Sakhuja, K., Ganesh, S., Yang, L., Kayda, D., Brann, T., Pattison, S., 
Golightly, D., Idamakanti, N., Pinkstaff, A., et al. 2002. Sustained human factor VIII 
expression in hemophilia A mice following systemic delivery of a gutless adenoviral 
vector. Mol Ther 5:63-73. 
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Amalfitano, A., Hauser, M.A., Hu, H., Serra, D., Begy, C.R., and Chamberlain, J.S. 1998. 
Production and characterization of improved adenovirus vectors with the E1, E2b, and E3 
genes deleted. J Virol 72:926-933. 
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Immune evasion by muscle-specific gene expression in dystrophic muscle. Mol Ther 
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64. 
Moorhead, J.W., Clayton, G.H., Smith, R.L., and Schaack, J. 1999. A replication-
incompetent adenovirus vector with the preterminal protein gene deleted efficiently 
transduces mouse ears. J Virol 73:1046-1053. 
65. 
Nazir, S.A., and Metcalf, J.P. 2005. Innate immune response to adenovirus. J Investig 
Med 53:292-304. 
66. 
Schaack, J. 2005. Induction and inhibition of innate inflammatory responses by 
adenovirus early region proteins. Viral Immunol 18:79-88. 

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67. 
Schaack, J., Bennett, M.L., Colbert, J.D., Torres, A.V., Clayton, G.H., Ornelles, D., and 
Moorhead, J. 2004. E1A and E1B proteins inhibit inflammation induced by adenovirus. 
Proc Natl Acad Sci U S A 101:3124-3129. 
 
 

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11. APPENDIX 1 – SCHEMA  
 
Procedure / Test 
Pre-
treatment  
Week  
0  
Week  
3  
Week  
6  
Week  
9 
Months 6, 
9, etc. i 
Off 
Treatment 
H & P 
X 
X 
X 
X 
X 
X 
X 
Karnofsky Status  
X 
X 
X 
X 
X 
X 
X 
-HCG a 
X 
 
 
 
 
 
 
CBC with diff 
X 
X 
X 
X 
X 
X 
X 
PT-INR, PTT 
X 
 
 
 
 
 
 
Chemistries 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
 
 
 
 
 
ANA 
X 
 
 
 
X 
 
X 
HIV 
X 
 
 
 
 
 
 
Immune Monitoring b 
  X b 
X 
X 
X 
X 
  X b 
X b 
Antibodies to 
CEA/Ad5 Vector c  
 
X 
 
 
X 
 
 
Biological Markers d 
(i.e. CEA, CA15-3)  
X d 
 
 
 
X d 
X d 
X d 
Brain MRI/CT Scan e  
X 
 
 
 
 
 
 
MRI/CT Scan f 
Xf 
 
 
 
Xf 
Xf 
Xf 
Immunization g 
 
X 
X 
X 
 
    
 
AE Assessment h 
X 
X 
X 
X 
X 
 
 
Key: H & P = history & physical examination, KPS = Karnofsky Performance Score, -HCG = human chorionic 
gonadotrophin pregnancy test; CBC & diff = complete blood count and white blood cell differential, Chemistries = 
Na, K, Cl, CO2, BUN, creatinine, Ca, total protein, albumin, total bilirubin, alkaline phosphatase, AST, ALT and 
glucose; ANA = antinuclear antibody, HIV = human immunodeficiency virus antibody, MRI/CT = magnetic 
resonance imaging/computed tomography; AE = Adverse Event 
 
Notes: 
a  -HCG performed on women of childbearing potential 
b Immune monitoring drawn during the first clinic visit at the discretion of the investigator/immune 
monitoring laboratory,  prior to each immunization and approximately 3 weeks after the last immunization, 
and will be repeated at the discretion of the investigator/immune monitoring laboratory. 
c  Serum obtained for antibodies to CEA and Ad5 vector weeks 0 and 9.  
d  Available serum markers (e.g., CEA or CA15-3) reviewed as available.  
e  Brain CT scan or MRI required within 6 weeks of starting study treatment. 
f  Available CT scans or MRI of the chest, abdomen, and/or pelvis reviewed.  Imaging studies within 6 weeks 
of starting study treatment is preferred, however is not required. Repeat imaging conducted according to 
standard of care. 
g   Immunizations may be modified so that the interval is between 20 and 28 days (3 weeks -1 day to 3 weeks 
+7 days).  If the second and/or third immunization is delayed, the subsequent immunizations should occur no 
earlier than 20 days after the previous immunization. 
h  AE monitoring from the time of informed consent to 30 days after the last dose of study drug. 
i  Follow-up evaluations requested every 3 months for 1 year, while on the study.  
 
 
 
 
 
 
 

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A PHASE I/II STUDY OF ACTIVE IMMUNOTHERAPY WITH Ad5 [E1-, E2b-]-
CEA(6D)  VACCINE (ETBX-011) IN PATIENTS WITH ADVANCED OR 
METASTATIC MALIGNANCIES EXPRESSING CEA 
 
 
 
 
STUDY PRODUCT: 
 
 
Ad5 [E1-, E2b-]-CEA(6D)  (ETBX-011) 
 
 
STUDY SPONSOR:  
 
 
Etubics Corporation 
    
 
 
 
 
410 West Harrison Street, Suite 100 
    
 
 
 
 
Seattle, WA 98119 
 
 
PRINCIPAL INVESTIGATOR:   
Gerald Messerschmidt, MD  
 
 
 
 
 
 
Etubics Corporation 
 
 
 
 
 
 
410 West Harrison Street, Suite 100 
 
 
 
 
 
 
Seattle, WA 98119 
 
 
Original Protocol: 
 
 
 
Version 1.1, December 21, 2009 
Amendment 1: 
 
 
 
Version 2.0, 13 April 2010 
Amendment 2: 
 
 
 
Version 2.1, May 14, 2010 
Amendment 3: 
 
 
 
Version 2.1, August 31, 2010 
Amendment 4: 
 
 
 
Version 3.1, June 20, 2011 
Amendment 5: 
 
 
 
Version 3.2, September 23, 2015 
 
 
 
 

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Page 2 of 42 
 
TABLE OF CONTENT 
 
 
 
 
 
 
 
 
 
 
 
Page Number 
 
1. Protocol Summary …………………………………………………..  3 
 
2. Study Objectives ……………………………………………………. 6 
 
3. Background and Significance ……………………………………….  6 
 
4. Patient Selection …………………………………………………….. 14 
 
5. Pre-Treatment Evaluation …………………………………………… 17 
 
6. Treatment Plan ………………………………………………………. 18 
 
7. Treatment Evaluation ………………………………………………... 25 
 
8. Statistical Considerations ……………………………………………. 28 
 
9. Patient Withdrawal …………………………………………………... 29 
 
10. Study Conduct and Ethical and Regulatory Considerations …………. 29 
 
11.  References …………………………………………………………… 36 
 
12.  Appendix …………………………………………………………….. 42 
 

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1. PROTOCOL SUMMARY 
 
Title 
A PHASE I/II STUDY OF ACTIVE IMMUNOTHERAPY WITH 
Ad5 [E1-, E2b-]-CEA(6D)  VACCINE (ETBX-011) IN PATIENTS 
WITH 
ADVANCED 
OR 
METASTATIC 
MALIGNANCIES 
EXPRESSING CEA 
Objectives 
a) The primary objective of this protocol is to determine the safety of 
immunization with Ad5 [E1-, E2b-]-CEA(6D), in patients with 
advanced or metastatic CEA-expressing malignancies.  
b) The secondary objectives are to evaluate CEA-specific immune 
responses to the immunizations and to obtain preliminary data on 
clinical response rate. 
Major Inclusion/ 
Exclusion Criteria 
Patients with a histologically confirmed diagnosis of metastatic 
malignancy who were previously treated with standard therapy known to 
have a possible survival benefit or refused such therapy.  The tumor must 
express CEA as defined by immunohistochemical staining (at least 50% 
of the tumor with at least moderate intensity of staining) or a tumor known 
to be universally CEA positive (i.e. colon and rectal cancer). If colorectal 
cancer, pathologic or clinical confirmation of adenocarcinoma is required. 
Patients will not be treated until 4 or more weeks after any prior 
chemotherapy or radiation therapy, but may be receiving non-cytotoxic 
targeted therapy (bevacizumab, cetuximab, panitumumab,  trastuzumab, 
lapatinib, erlotinib, or gefitinib) or hormonal therapy.  They must not have 
a history of autoimmune disease, serious intercurrent chronic or acute 
illness, active hepatitis, serologic evidence for HIV, or be receiving 
chronic steroid or immunosuppressive therapy.  All patients must be >21 
years old and have a Karnofsky Performance Score  of 70% or higher. 
Pregnant women and nursing mothers are excluded.  
Study Design 
Phase I/II study with three dosage levels of Ad5 [E1-, E2b-]-CEA(6D)  
vaccine (phase I component), and the Maximally Tolerated Dose (MTD) 
of Ad5 [E1-, E2b-]-CEA(6D)  vaccine (phase II component).  The study 
drug is Ad5 [E1-, E2b-]-CEA(6D) given by subcutaneous (SQ) injection 
every 3 weeks for 3 immunizations.  The following procedures will occur: 
1) Cohort 1: Three patients will receive Ad5 [E1-, E2b-]-CEA(6D)  at a 
dose of 1 x 109 particles SQ in 0.5 mL every 3 weeks for 
3 immunizations.  Assessment of dose-limiting toxicities (DLT) for 
dose escalation will be made after all patients in this cohort have had a 
study visit at least 3 weeks after receiving their first dose of vaccine.  
If there are no DLT, defined as any Grade 2, 3 or 4 immediate 
hypersensitivity reactions, Grade 3 or 4 fever that may possibly be 
associated with the immunization, Grade ≥2 autoimmune events 
except for vitiligo or fever for less than 2 days and less than 101.5 ºF, 
Grade ≥2 allergic reactions (grade 2 is defined as generalized urticaria 
as defined by NCI Common Terminology Criteria for Adverse Events 
(CTCAE version 4.0), or Grade ≥3 non-hematologic toxicity, then 
patients may begin enrolling into cohort 2.  If there is 1 DLT, then an 

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additional 3 patients will be enrolled at this dosage level. Assessment 
of DLT for dose escalation will be made after the 3 additional patients 
have had a study visit at least 3 weeks after receiving their first dose of 
vaccine.  If none of these latter 3 patients have DLT (i.e., 1 DLT in the 
6 total patients), then patients may begin enrolling into cohort 2. If 2 
patients have DLT at the lowest dosage level, dosing will be de-
escalated to 1x108 particles.  
2)  Cohort 2: Three patients will receive Ad5 [E1-, E2b-]-CEA(6D)  at a 
dose of 1 x 1010 particles SQ in 0.5 mL every 3 weeks for 
3 immunizations.  Assessment of DLT for dose escalation will be made 
after all patients in this cohort have had a study visit at least 3 weeks 
after receiving their first dose of vaccine.  If there are no DLT, then 
patients may begin enrolling into cohort 3.  If there is 1 DLT then an 
additional 3 patients will be enrolled at this dosage level. Assessment 
of DLT for dose escalation will be made after the 3 additional patients 
have had a study visit at least 3 weeks after receiving their first dose of 
vaccine.  If none of these latter 3 patients have DLT, then patients may 
begin enrolling into cohort 3. 
3) Cohort 3: Six patients will receive Ad5 [E1-, E2b-]-CEA(6D)  at a dose 
of 1 x 1011 particles SQ in 0.5 mL every 3 weeks for 3 immunizations.  
Assessment of DLT for proceeding to phase II enrollment will be made 
after all patients in this cohort have had a study visit at least 3 weeks 
after receiving their first dose of vaccine.  If there is 0 or 1 DLT, then 
patients may begin enrolling into the phase II portion of the study.  
4) Phase II Cohort (Cohort 4): An additional 12 patients will receive Ad5 
[E1-, E2B-]-CEA(6D) at the MTD every 3 weeks for 3 immunizations.  
5) Cohort 5: Beginning after the third dose of ETBX-011 for the 12th 
patient in cohort 4, enrollment in an additional higher dose cohort will 
be permitted. Six patients will receive Ad5 [E1-, E2b-]-CEA(6D)  at a 
dose of 5x1011 particles SQ in 2.5 mL every 3 weeks for 
3 immunizations.  Assessment of DLT will be made after all patients 
in this cohort have had all 3 injections and been observed for at least 
30 days after the last injection.  If there are 0-1 DLT, then this will be 
declared the maximum feasible dose. If there are 2 or more DLT, then 
1 x 1011 particles will be declared the MTD. 
6) Cohort 6: Up to ten (10) will receive Ad5 [E1-, E2b-]-CEA(6D) at a 
dose of 5x1011 particles SQ in 1.0 mL every 3 weeks for 3 
immunizations. Patients will be permitted to receive booster doses of 
Ad5 [E1-, E2b-]-CEA(6D) every 3 months for a period of one year 
following the first 3 treatments. In the event that a qualified patient 
undergoes reimaging prior to the completion of their initial 3 study 
immunizations and is found to have disease progression, the patient 
should continue on the immunization protocol because this could be a 
“flare reaction” associated with the vaccine which may be an 
inflammatory response.  Patients will be required to have MRI/CT scans 
performed prior to initiation of treatment, at 3 month intervals +/- 1 

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month for 12 months or if the investigator believes signs or symptoms 
are suggestive of progression or relapse.  All patients will be followed 
for overall survival for a period of 24 months from initiation of 
treatment. 
7) Patients will have 90 mL peripheral blood drawn prior to each 
immunization and at week 9 to determine whether there is an effect on 
the immune response at specific time points during the study and/or 
after a specific number of immunizations. 
8) Time to progression will be measured using MRI/CT scans performed 
as per standard of care (approximately 3 month intervals). 
Risks/Toxicities 
Potential risks associated with the vaccine include anaphylaxis, fever, skin 
reaction, autoimmunity (colitis), and hepatic insufficiency.   
Number of Patients 
Planned: 30 evaluable patients (plus up to 12 replacements) plus an 
additional 10 patients from cohort 6; may require 40-52 patients if DLT 
occur. 
Duration of Study 
6 months after the last patient is enrolled; approximately 2 years total. 
Criteria for 
Evaluation 
Toxicity will be assessed using CTCAE version 4.0.  CEA-specific 
immune response will be measured in the peripheral blood.  Time to 
recurrence will be determined by RECIST criteria. 
Statistical Analysis 
Safety: We will evaluate safety in each cohort at least 3 weeks after the 
last patient in the previous cohort has received their first injection.  A 
dosing scheme will be considered safe if <33% of patients treated at a 
dosage level experience DLT (e.g., 0 of 3, ≤1 of 6, ≤3 of 12 or ≤5 of 18 
patients).  A patient will be considered evaluable for safety if treated with 
at least one immunization. 
Rate of immune response:  We will determine the percentage of patients 
with a positive immune response.  We define a positive immune response 
by ELISpot as described at the 2002 Society of Biologic Therapy 
Workshop on “Immunologic Monitoring of Cancer Vaccine Therapy”, i.e. 
a T cell response is considered positive if the mean number of spots in six 
wells with antigen exceeds the number of spots in six control wells by 10 
and the difference between single values of the six wells containing 
antigen and the six control wells is statistically significant at a level of p ≤ 
0.05 using the Student’s t test.  Immunogenicity assays will occur prior to 
each immunization and at week 9.  Immune response will be assessed at 
the MTD.  An observed immune response in 9 of 18 patients will be 
considered sufficient evidence of immune response to justify further 
investigation.  Meeting this criterion establishes that the immune response 
rate is at least 33% with approximately 90% confidence.  The magnitude 
of response will also be described.  A patient will be considered evaluable 
for immune response if they receive at least 3 immunizations. 
  
2. STUDY OBJECTIVES 
 

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a) The primary objective of this protocol is to determine the safety of immunization with Ad5 
[E1-, E2b-]-CEA(6D)  in patients with advanced or metastatic CEA-expressing 
malignancies.  
b) The secondary objectives are to evaluate CEA-specific immune response to the 
immunizations and obtain preliminary data on response rate. 
 
3. BACKGROUND AND SIGNIFICANCE 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 

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4. PATIENT SELECTION 
 
4.1. Criteria for Patient Eligibility 
4.1.1. 
Histologically confirmed diagnosis of malignancy expressing CEA.  Because this 
is a safety and immunogenicity study, patients are NOT required to have 
measurable or evaluable disease by Response Evaluation Criteria in Solid Tumors 
(RECIST).  
4.1.2. 
For all tumor types other than colorectal, the tumor must express CEA as defined 
by immunohistochemical staining (at least 50% of the tumor with at least moderate 
intensity of staining) or a tumor known to be universally CEA positive (i.e. colon 
and rectal cancer). If colorectal cancer then, pathologic or clinical confirmation of 
adenocarcinoma is required.  
4.1.3. 
Patients must have received treatment with standard therapy known to have a 
possible overall survival benefit.  
For the following common cancers, the following eligibility criteria apply: 
 Colorectal cancer: Must have received and progressed through at least one line 
of palliative chemotherapy consisting of one of the following regimens: 
- 
Palliative chemotherapy for metastatic colorectal cancer with 
5-fluorouracil (or capecitabine) and oxaliplatin. 
- 
Palliative chemotherapy for metastatic colorectal cancer with 
5-fluorouracil (or capecitabine) and irinotecan. 
- 
Palliative chemotherapy regimen for metastatic colorectal cancer that 
includes bevacizumab. 
- 
Colorectal cancer patients currently receiving palliative single-agent 
bevacizumab or cetuximab will be eligible for this trial and may 
continue these therapies concomitant with study treatment (if they have 
been on these single agent therapies for at least 3 months). 
 Breast cancer: Must have received and progressed through at least one line of 
chemotherapy for metastatic breast cancer consisting of one of the following 
regimens: 
- 
Palliative anthracycline- or taxane-based chemotherapy 
- 
Patients with tumors that over express HER2 (IHC 3+ or FISH+) must 
have received and progressed through at least one line of palliative 
therapy that combines trastuzumab with chemotherapy.  
- 
Breast cancer patients currently receiving palliative endocrine therapy 
or single-agent trastuzumab will be eligible for this trial and may 
continue these therapies concomitant with study treatment (if they have 
been on these single agent therapies for at least 3 months). 

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- 
Patients who have been treated or offered the options of treatment with 
bevacizumab (option clearly stated in the consent form). 
- 
Patients who have been treated or offered the options of treatment with 
lapatinib (option clearly stated in the consent form). 
 Lung cancer: Must have received and progressed through chemotherapy for 
metastatic disease consisting of one of the following regimens: 
- 
Palliative platinum-based (cisplatin or carboplatin) chemotherapy if the 
patient has not received chemotherapy previously. 
- 
Palliative taxane-based (docetaxel or paclitaxel) or vinorelbine 
chemotherapy if the patient has received chemotherapy previously. 
- 
Lung cancer patients currently receiving palliative single-agent erlotinib 
or gefitinib will be eligible for this trial and may continue these therapies 
concomitant with study treatment (if they have been on these single 
agent therapies for at least 3 months). 
 Pancreatic cancer: Must have received and progressed through chemotherapy 
including gemcitabine. 
- 
Pancreatic cancer patients currently receiving palliative single-agent 
erlotinib will be eligible for this trial and may continue this therapy 
concomitant with study treatment (if they have been on this single agent 
therapy for at least 3 months). 
 
For other malignancies, if a first line therapy with survival or palliative benefit 
exists, it should have been administered and there should have been progressive 
disease. 
 
Patients who have received and progressed through first-line palliative 
chemotherapy must be advised regarding second-line therapy before being 
enrolled on this investigational study.  
4.1.4. 
Karnofsky performance score  of 70% or higher  
4.1.5. 
Estimated life expectancy > 3 months 
4.1.6. 
Age ≥ 21 years, but < 75 
4.1.7. 
Adequate hematologic function, with WBC ≥ 3000/microliter, hemoglobin 
≥ 9 g/dL (it is acceptable to have had prior transfusion), platelets 
≥ 75,000/microliter; PT-INR <1.5 (unless patient is receiving warfarin in which 
case PT-INR must be <3), PTT <1.5X ULN 
4.1.8. 
Adequate renal and hepatic function, with serum creatinine < 1.5 mg/dL, bilirubin 
< 1.5 mg/dL (except for Gilbert’s syndrome which will allow bilirubin 
≤ 2.0 mg/dL), ALT and AST ≤ 2.5 x upper limit of normal. 
4.1.9. 
Patients who have received prior CEA-targeted immunotherapy are eligible for  
  
this trial, if this treatment was discontinued at least 3 months prior to enrollment. 
4.1.10. Patients who are taking medications that do not have a known history of 
immunosupression are eligible for this trial. 
4.1.11. Ability to understand and provide signed informed consent that fulfills Institutional 
Review Board’s guidelines. 
4.1.12. Ability to return to the clinical site for adequate follow-up, as required by this 
protocol. 

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4.2. Criteria for Patient Exclusion 
4.2.1  
Patients with concurrent cytotoxic chemotherapy or radiation therapy should be 
excluded. There are no exclusions based on the number of prior chemotherapy, 
biologic, hormonal, or experimental regimens. Except for the permitted 
concomitant therapies (bevacizumab, cetuximab, panitumumab, trastuzumab, 
lapatinib, erlotinib, gefitinib, or hormonal therapy which patients must have been 
on for at least 3 months at the time of enrollment if they intend to continue them 
with the vaccine), there must be at least 3 months between any prior CEA-targeted 
immunotherapy and study treatment and at least 4 weeks between any other prior 
therapy (including radiotherapy) and study treatment.  Patients must have recovered 
to grade 1 acute toxicities from prior treatment. 
4.2.2. 
Patients with a history of or current brain metastases will not be permitted. 
4.2.3.  
Patients with a history of autoimmune disease, such as but not restricted to, 
inflammatory bowel disease, systemic lupus erythematosus, ankylosing 
spondylitis, scleroderma, or multiple sclerosis.  Autoimmune related thyroid 
disease and vitiligo are permitted. 
4.2.4. 
Patients with serious intercurrent chronic or acute illness, such as cardiac disease 
(NYHA class III or IV), hepatic disease, or other illness considered by the Principal 
Investigator as unwarranted high risk for investigational drug treatment. 
4.2.5. 
Patients with a medical or psychological impediment to probable compliance with 
the protocol should be excluded. 
4.2.6. 
Concurrent (or within the last 5 years) second malignancy other than 
non-melanoma skin cancer, cervical carcinoma in situ, controlled superficial 
bladder cancer, or other carcinoma in situ that has been treated. 
4.2.7. 
Presence of an active acute or chronic infection including: a urinary tract infection, 
HIV (as determined by ELISA and confirmed by Western Blot).  Patients with HIV 
are excluded based on immuno-suppression, which may render them unable to 
respond to the vaccine; patients with chronic hepatitis are excluded because of 
concern that hepatitis could be exacerbated by the injections.   
4.2.8. 
Patients on chronic steroid therapy (or other immuno-suppressives, such as 
azathioprine or cyclosporin A) are excluded on the basis of potential immune 
suppression.  Patients must have had 6 weeks of discontinuation of any steroid 
therapy (except that used as pre-medication for chemotherapy or contrast-enhanced 
studies or for acute treatment (<5 days) of intercurrent medical condition such as a 
gout flare) prior to enrollment. 
4.2.9. 
Pregnant and nursing women should be excluded from the protocol since this 
research may have unknown and harmful effects on an unborn child or on young 
children.  If the patient is sexually active, the patient must agree to use a medically 
acceptable form of birth control while receiving treatment and for a period of 4 
months following the last vaccination therapy. It is not known whether the 
treatment used in this study could affect the sperm and could potentially harm a 
child that may be fathered while on this study. 
4.2.10. Patients with acute or chronic skin disorders that will interfere with injection into 
the skin of the extremities or subsequent assessment of potential skin reactions will 
be excluded. 

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4.2.11. Patients with metastatic disease which is determined to be resectable must have 
been referred to a surgeon for consideration of resection. 
 
4.3. Accrual 
We expect to accrue a minimum of 24 evaluable patients (plus up to 12 replacements for 
patients removed from the study prior to completion of the assigned vaccine schedule for 
any reason other than toxicity).  The study may require 30-42 patients if DLT occur that 
necessitate re-dosing at a lower dosage levels (Refer to Protocol Section 6 for a 
description of the dose escalation criteria). 
 
4.4 
Assignment of study number 
Patients will be assigned study numbers in order of their screening using a site specific 
sequential numbering system, e.g.,: ETBX-011- 001, 002, 003 etc. including screened 
patients. 
 Assignment of study day: Day 0 is the day of the first immunization. The second 
immunization is at Day 21. 
 
5. PRE-TREATMENT EVALUATION 
 
The following pre-treatment evaluations will be completed within 1 month (+/- 2 weeks) 
before starting study treatment: (Refer to Appendix 1 - Schema) 
 
 History and physical exam, to include Karnofsky Performance Score  and review of 
inclusion and exclusion criteria 
 ß-HCG for women with childbearing potential 
 Hematological and Biochemical Tests: 
o CBC with differential 
o PT, INR and PTT 
o Na, K, Cl, CO2, BUN, creatinine, Ca, total protein, albumin, total bilirubin, alkaline 
phosphatase, AST, ALT and glucose 
 
Urinalysis 
 
HIV Antibody 
 
Anti Nuclear Antibody (ANA) 
 Biological Markers: 
o Serum will be obtained to measure antibodies to CEA and the neutralizing 
antibodies to Ad5 vector and sent to Etubics Corporation for determination. 
o Other available serum markers (e.g., CEA or CA15-3) will be reviewed if 
 
determined and  available.   
 Immunologic Evaluation/Archive Sample: 
o Blood may be drawn during the first clinic visit (after consent is signed) for 
immunologic evaluation and/or archiving.  
 Imaging Studies: 
o 
Brain CT scan or MRI is required within 6 weeks of starting study treatment. 

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o 
Available CT scans or MRI of the chest, abdomen, and/or pelvis will be reviewed.  
Imaging studies within 6 weeks of starting study treatment is preferred,  but is not 
required.  
 
6. TREATMENT PLAN 
 
Patients will be enrolled into successive dosage level cohorts of 3 or 6 patients and 
monitored for dose-limiting toxicity (DLT).  
 
 DLT (Based on NCI CTCAE version 4.0) is defined as any Grade 2, 3 or 4 immediate 
hypersensitivity reactions, Grade 3 or 4 fever that may possibly be associated with the 
immunization, Grade ≥2 autoimmune events except for vitiligo or fever for less than 2 days and 
less than 101.5 ºF, Grade ≥2 allergic reactions (grade 2 is defined as generalized urticaria as 
defined by CTCAE version 4.0), or Grade ≥3 non-hematologic toxicity.  
 
During dose escalation through the first three patients of cohort 3, there will be a minimum 
of 1 week between enrolling successive patients.  The first patient will be called to check on their 
condition prior to enrolling the second patient since patients can be enrolled after 1 week of 
initiation of cohort 3. If no DLT have been observed at this point, then further enrollment can occur 
in cohort 3 and phase II component (Cohort 4) without the 1-week waiting period.  Between dosage 
levels, through Cohort 3, assessment of DLT for dose escalation will be made after all patients in 
a cohort have had a study visit at least 3 weeks after receiving their first dose of vaccine and all 
the available safety data and laboratory results have been reviewed. Patients in cohort 5 may begin 
injections once all patients in cohort 4 have had at least their first injections and all patients in 
cohort 3 have had a study visit at least 3 weeks after receiving their first dose of vaccine. If DLT 
occurs in <33% of patients in a given dosage level cohort, progression to the next dosage level will 
proceed.  If DLT occurs in ≥33% of patients in a given cohort, the next lower dosage level will be 
defined as the maximum tolerated dose (MTD).  If DLT occurs in <33% of patients in the highest 
dosage level tested, that dosage level will be defined as the MTD.  In phase II (Cohort 4) and 
Cohort 5, if at any time the rate of DLT in patients enrolled is ≥33%, the MTD will be re-defined 
as the next lower dosage level.  Additional details of this dose escalation and de-escalation plan 
are provided below and in Figures 3A, 3B and Table 3.  
 

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1) Phase I: Cohort 1: Three patients will receive Ad5 [E1-, E2b-]-CEA(6D)  at a dose of 1 x 
109 particles in 0.5 mL subcutaneously (SQ) in the same thigh every 3 weeks for 
3 immunizations. Immunizations should be separated by 5 cm.  A diary card will be given 
to each subject at the first treatment along with a ruler to record any adverse reactions for 
2 days after treatment (24 hours and 48 hours post injection). The diary card will be placed 
in the study file.  Assessment of DLT for dose escalation will be made after all patients in 
this cohort have had a study visit at least 3 weeks after receiving their first dose of vaccine.  
If there are no DLT (as defined above), then patients may begin enrolling into cohort 2.  If 
there is 1 DLT then an additional 3 patients will be enrolled at this dosage level. 
Assessment of DLT for dose escalation will be made after the 3 additional patients have 
had a study visit at least 3 weeks after receiving their first dose of vaccine.  If none of these 
latter 3 patients have DLT, then patients may begin enrolling into cohort 2.  If 2 patients 
have DLT at this lowest dosage level, dosing will be de-escalated to 1x108 particles and a 
new cohort of 3 patients instituted. 
 
2)  Cohort 2: Three patients will receive Ad5 [E1-, E2b-]-CEA(6D) at a dose of 1 x 1010 
particles in 0.5 mL SQ in the same thigh every 3 weeks for 3 immunizations.  
Immunizations site should be separated by 5 cm.  A diary card will be given to each subject 
at the first treatment along with a ruler to record any adverse reactions for 2 days after 
treatment (24 hours and 48 hours post injection). The diary card will be placed in the study 
file.  Assessment of DLT for dose escalation will be made after all patients in this cohort 
have had a study visit at least 3 weeks after receiving their first dose of vaccine.  If there 
are no DLT, then patients may begin enrolling into cohort 3.  If there is 1 DLT then an 
additional 3 patients will be enrolled at this dosage level. Assessment of DLT for dose 
escalation will be made after the 3 additional patients have had a study visit at least 3 weeks 
after receiving their first dose of vaccine.  If none of these latter 3 patients have DLT, then 
patients may begin enrolling into cohort 3.  If 2 patients have DLT at this dosage level, the 
dosage level in cohort 1 will be considered the MTD.  If only 3 patients were enrolled in 
cohort 1, an additional 3 patients will be enrolled at that dosage before proceeding to the 
next cohort. 
 
3) Cohort 3: Six patients will receive Ad5 [E1-, E2b-]-CEA(6D)  at a dose of 1 x 1011 particles 
in 0.5  mL SQ in the same thigh every 3  weeks for 3 immunizations.  Immunizations site 
should be separated by 5 cm.  A diary card will be given to each subject at the first treatment 
along with a ruler to record any adverse reactions for 2 days after treatment (24 hours and 
48 hours post injection). The diary card will be placed in the study file.  Assessment of 
DLT for proceeding to phase II enrollment (Cohort 4) will be made after all patients in this 
cohort have had a study visit at least 3 weeks after receiving their first dose of vaccine.  If 
there is 0 or 1 DLT, then subjects may enroll in Cohort 4.  If 2 patients have DLT at this 
dosage level, the dosage level in cohort 2 will be considered the MTD.  If only 3 patients 
were enrolled in cohort 2, an additional 3 patients will be enrolled at that dosage before 
proceeding to the next level. 
 
4) Phase II cohort (Cohort 4): After the MTD is established, an additional 12 patients will 
receive Ad5 [E1-, E2b-]-CEA(6D) at the MTD every 3 weeks for 3 immunizations. 
 
 

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Note: if during accrual of patients in the phase II cohort, DLT occurs at a sufficient rate 
such that the rate of DLT amongst the total number of patients (those treated at MTD in 
phase I and those in phase II) is ≥33%, then phase II will be restarted at the dosage level 
which is one level below the prior MTD.  
 
5) Cohort 5: Six patients will receive Ad5 [E1-, E2b-]-CEA(6D) at a dose of 5x1011 particles 
SQ in 2.5 mL every 3 weeks for 3 immunizations.  Assessment of DLT will be made after 
all patients in this cohort have had all 3 injections and been observed for at least 30 days 
after the last injection.  If there are 0-1 DLT, then this will be declared the maximum 
feasible dose. If there are 2 or more DLT, then 1x1011 particles will be declared the MTD.  
 
6) Cohort 6: Up to ten (10) patients will receive Ad5 [E1-, E2b-]-CEA(6D) at a dose of 5x1011 
particles SQ in 1.0 mL every 3 weeks for 3 immunizations. Patients will be permitted to 
receive booster doses of Ad5 [E1-, E2b-]-CEA(6D) every 3 months for a period of two 
years following the first 3 treatments. In the event that a qualified patient undergoes 
reimaging prior to the completion of their initial 3 study immunizations and is found to 
have disease progression, the patient should continue on the immunization protocol 
because this could be a “flare reaction” associated with the vaccine which may be an 
inflammatory response.  Patients will be required to have MRI/CT scans performed prior 
to initiation of treatment, at 3 month intervals +/- 1 month for 12 months or if the 
investigator believes signs or symptoms are suggestive of progression or relapse.  All 
patients will be followed for overall survival for a period of 24 months from initiation of 
treatment. 
 
7) Patients will have 90 mL peripheral blood drawn prior to each immunization and 
approximately 3 weeks after the third immunization (Week 9) to determine whether there 
is an effect on the immune response at specific time points during the study and/or after a 
specific number of immunizations. 
 
8) Time to progression will be measured using CT scans performed at approximately 3 month 
intervals (based on clinical standard of care). 
 
9) For all patients, if scheduling conflicts arise, the scheduled 3-week interval between 
immunizations may be modified so that the interval between immunizations is between 20 
and 28 days (3 weeks -1 day to 3 weeks +7 days).  If the second and/or third immunization 
is delayed, the subsequent immunizations should occur no earlier than 20 days after the 
previous immunization. 
 
10) The following safety events will trigger a temporary suspension of study vaccinations: 
 
a) If one or more patients develop a Grade 4 allergic reaction without a clear attributable 
cause, other than study vaccine 
b) Death not attributed to disease. 
 

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Assessment of these halting rules is a review of cumulative events for all study participants, 
and should not be confused with reasons for delaying or terminating the immunization 
schedule of any individual patient. 
 
Etubics Corporation will fully review all available safety data, consult with the principal 
investigator, medical monitor and the FDA as needed, before determining if resuming 
vaccinations is appropriate.  If it is determined that study vaccinations can resume, the 
halting rules will apply to each subsequent event that meets the criteria described above. 
Vaccinations may also be suspended for safety concerns other than those described above 
if, in the judgment of the principal investigator or sponsor, participant safety is threatened. 
 
6.1. Study Stopping Rules 
- 
Death possibly related to the study agent. 
- 
Two patients having a Grade 4 toxicity event that is possibly/probably related to 
the study agent. 
 

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immunization in 1.0 mL SQ every 3 weeks for 3 immunizations and each additional boost will be 
delivered at the same dose. 
 
6.2.2 How Supplied 
ETBX-011 will be provided in a frozen state in a 2ml vial with a fill volume of 0.5 ml of 
extractable vaccine which contains 1x1011 total virus particles. The volume of injection for 1x1011 
virus particles is 0.5 mL. The lower doses will be produced by dilution in 0.9% saline using the 
following directions. For cohort 6, ETBX-011 will be provided in a frozen state in a 2ml vial with 
a fill volume of 1.0 ml of extractable vaccine which contains 5x1011 total virus particles. The 
volume of injection for 5x1011 virus particles is 1.0 mL. The product should be stored at –20°C 
until used. 
 
Instructions for dose preparation:  
Cohort 1: To administer 1x109 virus particles by subcutaneous injection, perform 2 serial 
dilutions of vialed vaccine as follows: 
1. Draw 4.5 mL of sterile saline into a syringe.   
2. Using a second syringe, withdraw 0.5 mL of previously thawed ETBX-011 from the supplied 
vial.   
3. Remove the needle from syringe containing the 4.5 mL saline, and inject the 0.5 mL of 
ETBX-011 from the second syringe into the syringe containing saline.   
4. Mix. This new solution has a concentration 2 x 1010 vp/ml. 
5. Use a new sterile syringe with a needle and repeat above procedure.  
6. Withdraw 4.5 mL of sterile saline.   
7. In the second syringe withdraw 0.5 mL from the syringe containing 2 x 1010 vp/ml.   
8. Remove the needle from the syringe containing the 4.5 mL saline, and inject the 0.5 mL of 2 
x 1010vp/mL from the second syringe. 
9.  Place a new needle on the 10-mL syringe from Step 8 above  and mix the two solutions.  
This solution now has a concentration 2 x 109 vp/mL (1 x 109 vp per 0.5 mL). 
10. Label a new 1-mL sterile syringe ETBX-011, 1 x 109 vp and withdraw 0.5 mL from the 
syringe containing 2 x 109 vp/mL.  This prepared vaccine (ETBX-011, 1 x 109 vp) can be 
kept at room temperature for four hours prior to administering to the patient. 
 
Cohort 2: To administer 1x1010 virus particles by subcutaneous injection: 
1. Draw 4.5 mL of sterile saline into a syringe.   
2. Using a second syringe, withdraw 0.5 mL of previously thawed ETBX-011 from the supplied 
vial.   
3. Remove the needle from syringe containing the 4.5 mL saline, and inject the 0.5 mL of 
ETBX-011 from the second syringe into the syringe containing saline.   
4. Mix. This new solution has a concentration 2 x 1010 vp/ml.  
5. Label a new 1-mL sterile syringe ETBX-011, 1 x 1010 vp and withdraw 0.5 mL from the 
syringe containing 2 x 1010 vp/mL.  This prepared vaccine (ETBX-011, 1 x 1010 vp) can be 
kept at room temperature for four hours prior to administering to the patient. 
 
Cohort 3 and 4: To administer 1x1011 virus particles by subcutaneous injection: 
1.  Withdraw 0.5mL of contents from the previously thawed, supplied ETBX-011 from the vial 
and administer to each subject without any further manipulation. 
 

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Cohort 5: To administer 5x1011 virus particles by subcutaneous injection: 
      1.  Withdraw 0.5mL of contents from each of 5 previously thawed ETBX-011 vials (total 
volume 2.5ml) and administer to each subject without any further manipulation. 
 
Cohort 6: To administer 5x1011 virus particles by subcutaneous injection: 
      1. Withdraw 1.0mL of contents from the previously thawed, supplied ETBX-011 from the 
vial and administer to each subject without any further manipulation. 
 
6.2.3 Disposal of Unused Vaccine 
Unless other arrangements are agreed in writing, all unused vaccine should be delivered to 
Dr. Joe Balint, at Etubics Corporation for disposal at or before the completion of the clinical 
study. 
 
7. TREATMENT EVALUATION 
 
7.1. Short-Term Evaluation During and After Active Immunotherapy  
On vaccine administration days, blood will be drawn before administration.  Evaluations 
will also be conducted for patients who discontinue from the study if they have received any 
treatment. The investigator will determine the degree of evaluation based on the patient's condition 
and/or reason for discontinuation from the study. 
 
7.1.1 General Evaluations  
Weeks 0, 3, 6 (Immunization Visits): 
General evaluations include medical history, Karnofsky performance status, and complete 
physical examination with weight by the attending physician.  Any other treatments, 
medications, biologics, or blood products that the patient is receiving or has received since 
the last visit will be recorded.  Patients will remain in the clinic for approximately 
30 minutes following receipt of vaccine to monitor for any adverse reactions.  Local and 
systemic reactogenicity after each dose of vaccine will be assessed daily for 3 days (on the 
day of immunization and 2 days thereafter) using diary cards to report symptoms and a 
ruler to measure local reactogenicity. 
 
Week 9:   
General evaluations include medical history, Karnofsky performance status, and complete 
physical examination with weight by attending physician.  Any other treatments, 
medications, biologics, or blood products that the patient is receiving or has received since 
the last visit will be recorded.  Immunization injection sites will be assessed. 
 
7.1.2 Hematological and Biochemical Assessment 
Weeks 0, 3, 6 (Immunization Visits): 
Blood will be drawn to perform chemistry and hematology, including CBC with 
differential, Na, K, Cl, CO2, BUN, creatinine, Ca, total protein, albumin, total bilirubin, 
alkaline phosphatase, AST, ALT and glucose.  
 
 
Week 9:   

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Blood will be drawn to perform chemistry and hematology, including CBC with 
differential, Na, K, Cl, CO2, BUN, creatinine, Ca, total protein, albumin, total bilirubin, 
alkaline phosphatase, AST, ALT, glucose and ANA.  
 
7.1.3 Biological Markers 
Weeks 0 and 9:   
Serum (5ml) to measure antibodies to CEA and the Ad5 vector will be obtained and send 
to Etubics Corporation for determination.  Biomarkers (e.g., CEA or CA15-3) will be 
reviewed if determined and available.   
 
 
7.1.4 Immunological Assessment 
Weeks 0, 3, 6, and 9:   
Peripheral blood (90mL) will be drawn prior to each immunization and approximately 3 
weeks after the last immunization to determine whether there is an effect on the immune 
response at specific time points during the study and/or after a specific number of 
immunizations.  Peripheral blood mononuclear cells (PBMC) will be assayed for T cell 
responses to CEA using ELISPOT at all time points, plus proliferation assays, multi-
parameter flow cytometric analysis, and cytoxicity assays, if possible and at the discretion 
of the investigator.  Serum from each blood draw will be archived and sent to Etubics 
Corporation for Ad5 neutralizing level determination.  
 
 
7.2. Long-Term Follow-Up 
Patients will be requested to continue long-term follow-up every 3 months for 1 year. At 
each visit, a medical history and physical exam and the following lab tests  will be 
performed: blood chemistry and hematology, including CBC with differential, Na, K, Cl, 
CO2, BUN, creatinine, Ca, total protein, albumin, total bilirubin, alkaline phosphatase, 
AST, ALT and glucose.  
 
At each visit, 40-90 mL of peripheral blood should be drawn for immune analysis, if there 
was previous evidence of an immune response or at the discretion of the investigator.  
Available serum markers (e.g., CEA, CA15-3) will be reviewed. 
 
7.3. Management of Intercurrent Events 
7.3.1 Concomitant Medications 
Patients will be removed from the protocol treatment if they initiate concomitant 
chemotherapeutic agents, corticosteroids, or other immunosuppressive agents, or other 
forms of immunotherapy.  After meeting the inclusion criteria, all other medications 
deemed appropriate for the patient, by the investigator, may be administered to the patient.  
All medications and changes in medication during treatment will be recorded.  Hormonal 
therapy and bisphosphonates may be continued in breast cancer patients if they have been 
stable on the agents for at least 1 month prior to enrollment. 

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7.3.2 Adverse Events 
7.3.2.1 Toxicity will be graded according to the NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 (which can be downloaded from the 
CTEP web site (http://ctep.cancer.gov).)  DLT is defined in Protocol Section 
6. 
7.3.2.2 Possible side effects from immunization may include local effects (pain, 
tenderness, rednesss or swelling), systemic effects (malaise, fatigue, myalgia, 
arthralgia, headache, nausea, vomiting, chills or fever), and allergic reactions 
such as hives, rash or anaphylactic reactions.  Induction of auto-immunity, 
manifest as arthritis, serositis, nephritis, thyroiditis, colitis, neutropenia, etc., 
is theoretically possible, but has not been observed in our prior CEA vaccine 
studies.  Also, liver function test abnormalities and liver failure are 
theoretically possible. 
 
7.3.3 Treatment of Toxicity 
For acute allergic reactions, use of diphenhydramine 25-50 mg IV, corticosteroids 
(Solumedrol 100 mg), and epinephrine (1:1000, 0.3-1 mL sq) should be considered.  These 
medications are available in the clinical setting where the vaccine will be administered.  
For auto-immunity, corticosteroids (prednisone 0.5-1 mg/kg/d) should be considered.  
Clinical assessment of other targets, such as thyroid, arthritis, urticaria, or proteinuria, for 
auto-immunity and serum sickness like antigen-antibody complex disease, will also be 
performed as indicated. 
 
7.3.4 Active Immunotherapy will be Discontinued for: 
7.3.4.1 Life-threatening anaphylactic reactions related to active immunotherapy 
7.3.4.2 DLT related to active immunotherapy 
7.3.4.3 Disease progression (by RECIST criteria).  Patients will be offered 
referral to a medical oncologist for discussion of other treatment options, 
and for continued medical care.   
7.3.4.3.1 
Disease progression prior to completing the 3 study 
 
immunizations:  
 
In the event that a patient undergoes reimaging studies prior to the 
 
completion of their 3 study immunizations and is found to have 
 
disease progression, they will be permitted to continue on the study 
 
as long as the progression has been 50% or less by RECIST 
 
criteria.  
 
If a patient is removed from the study prior to completion of the assigned vaccine schedule 
for any reason other than toxicity, that patient will be replaced, in order to obtain data to 
help determine the toxicity of the immunizations. We will allow up to 3 replacements per 
cohort (Phase I, Dose levels 1 and 2; Phase II, MTD). 
 

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8. STATISTICAL CONSIDERATIONS 
8.1. Safety  
We will evaluate safety continuously in a cohort.  We will make our overall assessment of 
whether to escalate to the next dose level at least 3 weeks after the last patient in the previous 
cohort has received their first injection.  This decision will be made by the medical monitor and 
the Principal Investigator.  A note will be generated following the assessment decision and filed 
in study binder.  A dosage level will be considered safe if <33% patients treated at a dose level 
experience DLT (i.e., 0 of 3, 1 of 6, 3 of 12, or 5 of 18 patients).  DLT is defined in Protocol 
Section 6.  Safety will be evaluated in 3 or 6 patients at each dosage level in phase I.   Safety will 
continue to be monitored among additional patients treated at the MTD in phase II.  A patient will 
be considered evaluable for safety if treated with at least one immunization.  DLTs will be 
observed through 9 weeks to accommodate safety evaluation of all 3 product doses. 
8.2. Rate of Immune Response  
Immune responses against CEA will be evaluated from the peripheral blood of patients 
from among the following studies at the discretion of the Principal Investigator (ELISpot, cytokine 
flow cytometry, and antibody responses). We will determine the percentage of patients with a 
positive immune response.  We define a positive immune response by ELISpot as described at the 
2002 Society of Biologic Therapy Workshop on “Immunologic Monitoring of Cancer Vaccine 
Therapy”, i.e. a T cell response is considered positive if the mean number of spots adjusted for 
background in six wells with antigen exceeds the number of spots in six control wells by 10 and 
the difference between single values of the six wells containing antigen and the six control wells 
is statistically significant at a level of p ≤ 0.05 using the Student’s t test.  Immunogenicity assays 
will occur prior to each immunization and at week 9.  Immune response will be assessed among 
the 18 patients treated at the MTD (12 in phase I and 12 in Phase II).  The therapy will be 
considered of further interest if 9 of 18 patients treated at the MTD dose exhibit an immune 
response as defined above.  Meeting this criterion establishes that the immune response rate is at 
least 33% with approximately 90% confidence.  At significance level 0.1 there is 82% power to 
test the null hypothesis that the immune response rate is ≤ 0.33 versus the alternative that the 
immune response rate is ≥ 0.58.  The magnitude of response will also be described.  A patient will 
be considered evaluable for immune response if they receive at least 3 immunizations. 
 
8.3. Determination of Clinical Response 
Among patients with measurable/evaluable disease, response determination will be made 
according to the RECIST criteria: 
Complete Response (CR): 
Disappearance of target lesion, confirmed at 4    
weeks 
Partial Response (PR): 
30% decrease in longest dimension of target lesion, 
confirmed at 4 weeks 
Stable Disease (SD): 
 
Neither PR nor PD 
Progressive Disease (PD): 
20% increase in longest dimension of target lesion; 
no CR, PR, or SD documented before increased 
disease. 
The exact binomial confidence interval for the proportion of subjects with a clinical 
response of CR or PR will be calculated. 
 

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9. PATIENT WITHDRAWAL 
Patients may be removed from the study for the following reasons: 
 DLT as defined in Protocol Section 6.   
 Patient voluntarily decides to withdraw. 
 Patient non-compliance with the study protocol. 
 Intercurrent disease which in the opinion of the patient’s treating physician would 
affect the ability of the patient to continue on the clinical study.  
In the event of withdrawal due to toxicity, a patient will be requested to have safety 
evaluations performed as per the protocol for a one year duration post treatment. This may include 
having up to 90 mL of blood drawn for immunologic testing. 
 
10. STUDY CONDUCT AND ETHICAL AND REGULATORY CONSIDERATIONS 
 
10.1. Departure from the Protocol 
There should be no departure from the protocol if at all possible.  If an emergency occurs 
that requires departure from this protocol, the investigator or other physician in attendance in such 
an emergency will, if circumstances and time permit, contact the principal investigator, or in his 
absence, Dr. Gerald Messerschmidt, Medical Director, immediately by telephone (610) 613-3882 
(cell phone). Such contacts with the principal investigator will be made to permit a decision as to 
whether or not the patient will be continued on the study.  Such departures need to be clearly 
documented and reported to the Institutional Review Board (IRB) and the Etubics Corporation by 
the principal investigator. 
 
10.2. Informed Consent 
In accordance with guidelines in the Federal Register, Vol. 48, No. 17, 1982, pp. 8951-2, 
all patients are required to sign a statement of informed consent.  This phase I/II study involves 
research that presents risk, but holds the prospect of direct benefit to the individual patient (46.405-
45 Code of the Federal Regulations part 46).  The investigator will report to the IRB and Etubics 
Corporation will report to FDA changes in the research protocol and all unanticipated problems 
involving risks to human patients and others, and no changes will be made in the research activity 
without IRB approval. 
 
10.3. Institutional Review 
This study must be approved by the site’s IRB.  IRB approval of the protocol and the 
informed consent form for this study must be given in writing.  The IRB must also approve any 
significant changes to the protocol as well as a change of principal investigator.  Records of all 
study review and approval documents must be kept on file by the investigator and are subject to 
FDA inspection during or after completion of the study.  Adverse events must be reported to the 
IRB.  The IRB will receive notification of the completion of the study and final report within three 
months of study completion or termination.  The investigator must maintain an accurate and 
complete record of all submissions made to the IRB, including a list of all reports and documents 
submitted. 
 
10.4. Documentation and Monitoring 
Data will be collected for all patients signing consent.  Accurate completion of the 
computer data forms for all patients is the responsibility of the investigator.   

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10.4.1 Case Report Forms 
Case Report Forms (CRFs) are used to record study data and are an integral part of the 
study and subsequent reports.  Therefore, all reports must be legible and complete.  All forms 
should be filled out using a black ballpoint pen.  Errors should be lined out but not obliterated and 
the correction inserted, initialed, and dated by the principal investigator, co-investigators, study 
coordinator, or data manager.  A CRF must be completed and signed by the principal investigator 
for each patient enrolled, including those removed from the study for any reason.  The reason for 
removal must be noted on the Final Report Form by the investigator for each patient.  CRFs must 
be kept current to reflect patient status at each phase during the course of the study.  Patients are 
not to be identified on CRFs by name; appropriate coded identification and patient initials must be 
used.  The investigator must keep a separate log of patient names and addresses.  This log is subject 
to FDA inspection.  Because of the potential for errors, inaccuracies, and illegibility in transcribing 
data onto CRFs, originals of laboratory and other test results must be kept on file with patient's 
CRFs or clinical chart.  CRFs and copies of test results must be available at all times for inspection 
by the FDA.   
 
10.4.2 Maintenance of Study Documentation 
The following will be maintained: 
a. Case Report Forms - which must be kept legible, accurate, and up-to-date. 
b. Patient Files/Signed Informed Consent - which substantiates the data entered on 
the case report forms for all required test and evaluation procedures and verifies 
that the patient has signed an informed consent to enter the study. 
c. Patient Exclusion Record - which should reflect the reason any patient was 
screened and found ineligible for the study. 
d. Monitoring Log - listing dates of monitor visits. 
e. Regulatory Documents - including protocol, investigator brochure, FDA Form 
1572, CVs, IRB correspondence, IRB approval/renewals and IRB approved 
consent form. 
f. Adverse Event Report Form - which should explain any serious or unexpected 
adverse experiences. 
All study documentation pertaining to the conduct of the study must be kept on file by the 
investigator for a period of 2 years following the date a marketing application is approved for the 
drug for the indication for which it is being investigated; or, if no application is to be filed or if the 
application is not approved for such indication, until 2 years after the investigation is discontinued 
and FDA is notified.  The sponsor will notify the investigator if a marketing application is approved 
or if the investigation is discontinued and the FDA notified. 
 
10.5. Monitoring of the Protocol 
An Etubics Corporation representative will conduct a site initiation visit and will review 
protocol documents with the investigators and their staff. During the study, the Etubics monitor 
will visit the site regularly to check the completeness of study files, the accuracy of data entries on 
the CRFs, and adherence to the protocol and to Good Clinical Practice (GCP).  Key study personnel 
must be available to assist the monitor during these visits. The investigator must maintain source 
documents for each subject in the study. The investigator must also keep the original informed 
consent form signed by every patient.  The investigator must give the monitor access to all relevant 

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source documents to verify data entries on CRFs.  No information in source documents about the 
identity of subjects will be disclosed. 
 
This is a phase I/II clinical study with more than minimal risk and as such will be monitored for 
the occurrence of a greater frequency of adverse events (AEs).  The principal investigator will 
continuously monitor the data and safety of all subjects enrolled. All grades of toxicities will be 
recorded.   
 
Safety assessments will consist of monitoring all AEs including serious adverse events (SAEs), 
the regular monitoring of hematology, serum chemistry, and routine monitoring of vital signs and 
physical condition.  AE monitoring should occur from the time of informed consent to 30 days 
after the last dose of study drug. For those subjects who discontinue study participation prior to 
receiving study drug, AE and SAEs will be collected through the time of discontinuation.   
 
Toxicity will be assessed using the NCI CTCAE version 4.0.  Refer to Protocol Section 7.3.2. 
 
An AE is any adverse change from the study patient’s baseline (pretreatment) condition, including 
any clinical or laboratory test abnormality that occurs during the course of the proposed clinical 
study after treatment has started.   
 
Events are classified as SERIOUS if they meet any of the following criteria [per the US Code of 
Federal Regulations (CFR) 21 CFR 312.32 and the recommendations of the International 
Conference on Harmonization (ICH)]: 
 
An SAE is any sign, symptom or medical condition that emerges during the study or during a post-
study follow-up period that 1) was not present at the start of the study and is not a chronic condition 
that is part of the patient’s medical history, OR 2) was present at the start of the study or as part of 
the patient’s medical history but worsened in severity and/or frequency during study participation, 
AND that meets any of the following regulatory serious criteria: 
 
 any death 
 any life-threatening event, i.e., an event that places the patient, in the view of the 
investigator, at immediate risk of death from the event as it occurred (does not 
include an event that, had it occurred in a more severe form, might have caused 
death) 
 any event that requires or prolongs in-patient hospitalization 
 any event that results in persistent or significant disability/incapacity 
 any congenital anomaly/birth defect diagnosed in a child of a patient who 
participated in this study and received investigational drug 
 other medically important events that in the opinion of the investigator may 
jeopardize the patient or may require intervention to prevent one of the other 
outcomes listed in the definition above (e.g. allergic bronchospasm requiring 
intensive treatment in an emergency room, convulsions occurring at home that do 
not require in-patient hospitalization, any blood dyscrasias, or the development of 
drug dependency or drug abuse). 
 

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10.6. CTCAE Term (AE description) and Grade   
The descriptions and grading scales found in the revised NCI CTCAE version 4.0 will be 
utilized for AE reporting. A copy can be downloaded from the CTEP web site 
(http://ctep.cancer.gov).   
 
The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for 
each AE based on the following guideline: 
 
Grade 1 
Mild AE 
Grade 2 
Moderate AE 
Grade 3 
Severe AE 
Grade 4 
Life-threatening or disabling AE 
Grade 5 
Death related to AE 
 
10.7. Assessing Causality 
Investigators are required to assess whether there is a reasonable possibility that study 
medications caused or contributed to an adverse event.  The following general guidance may be 
used. 
Yes: 
if the temporal relationship of the clinical event to study drug administration makes a 
causal relationship possible, and other drugs, therapeutic interventions or underlying 
conditions do not provide a sufficient explanation for the observed event. 
No: 
if the temporal relationship of the clinical event to study drug administration makes a 
causal relationship unlikely, or other drugs, therapeutic interventions or underlying 
conditions provide a sufficient explanation for the observed event. 
 
10.8. Serious Adverse Event Reporting 
All AEs that are classified as serious, unexpected and related or possibly related, will be 
recorded on the MedWatch 3500A form and reported within 24 hours of learning of the event to 
Etubics Corporation.  The form should be completed as much as possible but should not be held 
until all information is available. Additional information and/or corrections may be submitted as 
they are obtained. The investigator will follow SAEs until resolution, a return to baseline condition 
or stabilization or 30 days after the last subject is enrolled whichever occurs first. SAEs that are 
ongoing at the time of clinical database closure will be recorded as unresolved.   
 
All study-related deaths should be reported to the IRB within 24 hours; all other serious 
adverse experiences should be reported to the IRB within 5 business days. All deaths, whether 
considered study-related or not, must also be reported immediately to Etubics Corporation, 
additional information may be requested from the treating institution. Deaths believed to be related 
to disease progression will not be reported to the FDA as SAEs, as these deaths are an anticipated 
outcome of the disease; however, all deaths will be reported to the FDA in the annual reports.  
 
MedWatch 3500A Reporting Guidelines: 
In addition to completing appropriate patient demographic and suspect medication 
information, the report should include the following information within the Event Description 
(section 5) of the MedWatch 3500A form: 
 

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 Treatment regimen (dosing frequency, combination therapy) 
 Protocol description (and number, if assigned) 
 Description of event, severity, treatment, and outcome, if known 
 Supportive laboratory results and diagnostics 
 Investigator’s assessment of the relationship of the adverse event to each investigational 
product and suspect medication 
 
Follow-up information:  
 Additional information may be added to a previously submitted report by any of the 
following methods: 
 Adding to the original MedWatch 3500A report and submitting it as follow-up 
 Adding supplemental summary information and submitting it as follow-up with the 
original MedWatch 3500A form  
 Summarizing new information and faxing it with a cover letter including patient identifiers 
(i.e. D.O.B., initials, patient number), protocol description and number, if assigned, suspect 
drug, brief adverse event description, and notation that additional or follow-up information 
is being submitted  (The patient identifiers are important so that the new information is 
added to the correct initial report.) 
 
Reporting of Pregnancy:  
If a participant becomes pregnant during the study, treatment will be discontinued (i.e., no 
additional dose of study vaccine will be given) and the participant will be encouraged to continue 
to have regularly scheduled follow-up visits and evaluations.  The occurrence of pregnancy, and 
the outcome of any pregnancy, in a subject treated with study vaccine, must be reported to the 
Etubics Corporation and to the IRB.   
 
Procedures for SAE Reporting: 
1. Medical staff/study team notifies principal investigator of SAE. MedWatch 3500A is 
completed. 
 
2. Principal Investigator calls Etubics Corpration to report the SAE and faxes the completed 
MedWatch 3500A to: 
 
 
 
Carol Jones, Vice President of Administration 
 
Address: 410 West Harrison Street, Suite 100, Seattle, WA 98119 
 
Telephone: 206-838-5110 ext. 2 
 
Cell: (206) 818-2985 
 
Fax: (206) 838-2978 
 
Email: cj@etubics.com 
 
3.   Carol Jones reports the SAE to one of the following in this order: 
 
 
A.   Chief Scientific Officer: Frank Jones, PhD  
 
Address: 410 West Harrison Street, Suite 100, Seattle, WA 98119  
 
Telephone: 206-838-5110 ext. 1 
 
Cell: (206) 818-2857 

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Fax: (206) 838-2978 
 
Email: frj@etubics.com 
 
B.  Laboratory Manager:  Joseph Balint, PhD 
 
Address: 410 West Harrison Street, Suite 100, Seattle, WA 98119 
 
Telephone: (206) 838-5110 ext. 7 
 
Fax:  (206) 838-2978 
 
Email: joe@etubics.com 
 
C.  Vice President Research: Elizabeth S. Gabitzsch 
 
Address: 410 West Harrison Street, Suite 100, Seattle, WA 98119 
 
Telephone: (206) 838-5110 ext. 3 
 
Cell: (970) 402-2598 
 
Fax:  (206) 838-2978 
 
Email: beth@etubics.com 
 
 
4.  Contacted person in three (3) above notifies the FDA via MedWatch 3500A form. 
 
a. If the SAE results in death or is life-threatening, SAE report will be submitted to the 
FDA within 7 days 
b. All other SAEs must be reported to the FDA within 15 days 
 
5. All SAE will require input from a physician, the Acting Medical Director will be consulted: 
 
  
Gerald Messerschmidt, MD 
Telephone: (610) 613-3882 or (206) 838-5110 
Fax: (206) 838-2978 
Email:gerry@etubics.com 
 
6. SAEs will be reported to the IRB according to the site’s IRB guidelines.   
 
In accordance with FDA regulations and ICH guidelines, investigators will be notified of the 
occurrence of new, serious, unexpected adverse events associated with the use of the study 
medication (i.e. there is a reasonable possibility that the AE may have been caused by the drug) 
within 15 calendar days via a written report.  It is the responsibility of the investigator to promptly 
inform the relevant IRB of these new adverse events/risks to patients, in accordance with 21 CFR 
312.66.  It is the responsibility of Etubics Corporation to promptly inform the NIH Office of 
Biotechnology Activities (OBA) and relevant Scientific Review Board of these new adverse 
events/risks to patients, in accordance with NIH Guidelines for Research Involving Recombinant 
DNA Molecules, in particular Appendix M.  It is the responsibility of the Etubics Corporation to 
report these SAEs to the FDA.  The SAE report will be forwarded to the FDA after recording the 
event data via the FDA MedWatch form 3500A.   
 
10.9. Safety Reporting Requirements  
In accordance with 21 CFR 312.32, the sponsor of studies conducted under an IND must 
comply with following safety reporting requirements:  

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a. Expedited IND Safety Reports: 
 
7 Calendar-Day Telephone or Fax Report:   
The sponsor is required to notify the FDA of any fatal or life-threatening adverse event that 
is unexpected and assessed by the investigator to be possibly related to the use of the 
investigational product.   An unexpected adverse event is one that is not already described in the 
Investigator’s Brochure.  Such reports are to be telephoned or faxed to the FDA within 7 calendar 
days of first learning of the event.   
 
15 Calendar-Day Written Report:   
The sponsor is also required to notify the FDA and all participating investigators, in a 
written IND Safety Report, of any serious, unexpected AE that is considered possibly related to 
the investigational product.  An unexpected adverse event is one that is not already described in 
the Investigator Brochure. 
Written IND Safety Reports should include an Analysis of Similar Events in accordance 
with regulation 21 CFR § 312.32.  All safety reports previously filed with the IND concerning 
similar events should be analyzed.  The new report should contain comments on the significance 
of the new event in light of the previous, similar reports.   
Written IND safety reports with Analysis of Similar Events are to be submitted to the FDA 
and all participating investigators within 15 calendar days of first learning of the event.  The FDA 
prefers these reports on a MedWatch 3500A Form but alternative formats are acceptable (e.g. 
summary letter). 
 
b. IND Annual Reports 
In accordance with the regulation 21 CFR § 312.32, the sponsor shall within 60 days of the 
anniversary date that the IND went into effect submit a brief report of the progress of the 
investigation.   
 
c. Data and Safety Monitoring  
Data will be collected by the principal investigator, co-investigators, and the protocol 
coordinator.  The protocol coordinator under the supervision of the principal investigator will 
report the AEs. The data will be audited by Etubics Corporation.  

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