An Open-Label Phase 2 Efficacy Trial of the Implantation of Mouse Renal Adenocarcinoma Cell-Containing Agarose-Agarose Macrobeads in the Treatment of Patients With Treatment-Resistant, Metastatic Pancreatic or Colorectal Cancer
Phase: PHASE2
Conditions: Pancreatic Adenocarcinoma Non-resectable, Pancreatic Adenocarcinoma Metastatic, Colorectal Cancer Metastatic
Sponsor: The Rogosin Institute

 
 
 
The Rogosin Institute 
 
Protocol No.  0911010739 
 
 
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CONFIDENTIAL 
 
 
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November 12th 2014 
  
 
 
 
 
 
 
 
 
 
 
®®            ® 
                
 
 
 
 
The Rogosin Institute 
505 East 70th Street 
New York, NY  10021 
 
 
 
An Open-Label, Phase II Efficacy Trial of the Implantation of 
Mouse Renal Adenocarcinoma Cell-Containing Agarose-Agarose 
Macrobeads in the Treatment of Patients with 
Treatment-Resistant, Metastatic Pancreatic Adenocarcinoma or 
Colorectal Cancer 
 
 
 
Clinical Study Protocol Number: 0911010739 
 
 
 
IND Number:  BB-IND 10091 
 
 
 
November 12th 2014 
Amendment 11 
 
 
 
 
 
CONFIDENTIAL 
This document and its contents are the property of and confidential to The 
Rogosin Institute.  Any unauthorized copying or use of this document is prohibited. 

 
 
 
The Rogosin Institute 
 
Protocol No.  0911010739 
 
 
Version: Amendment 11 
 
 
CONFIDENTIAL 
 
 
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November 12th 2014 
  
 
 
 
 
 
 
 
 
 
PROTOCOL SYNOPSIS 
TITLE OF 
STUDY 
 
An Open-Label, Phase II Efficacy Trial of the Implantation of Mouse Renal 
Adenocarcinoma Cell-Containing Agarose-Agarose Macrobeads in the 
Treatment of Patients with Treatment-Resistant, Metastatic Pancreatic 
Adenocarcinoma or Colorectal Cancer 
Investigators/ 
Study Centers: 
 
Thomas J. Fahey,III, MD 
Nataniel Berman, MD 
Weill Cornell Medicine/The Rogosin Institute 
505/520 East 70th Street.  
New York, NY  10021 
 
Objectives: 
The primary efficacy outcome for colorectal cancer is post-implantation all-
cause mortality, where time to death is defined as the time from the first 
scan showing disease progression after completion of prior treatment (time 
of origin, T0) to death from any cause. 
 
The primary objective for pancreatic cancer is to determine the Response 
Rate (RR), at 2 weeks, 4 weeks, 8 weeks, 3 months, 6 months, 9 months, 
12 months or longer as possible, of subjects treated with macrobeads after 
they have failed standard chemotherapeutic regimens or have decided not 
to pursue standard or experimental chemotherapy for treatment-resistant, 
metastatic pancreatic adenocarcinoma. 
 
The secondary objectives for both pancreatic and colorectal cancer are 
outlined in Section 3 of this protocol. 
 
Rationale for 
Dosage: 
Based on the animal studies conducted to date, as well as the Phase I 
human trial that has enrolled 31 subjects to date, a reasonable dosage 
range (number of beads to be implanted) is 8 macrobeads per kilogram of 
body weight.  We know that 16 macrobeads per kilogram were also well-
tolerated in the Phase I human trial, but, at least with a single dose, this 
number was not seen to be any more effective than 8 macrobeads per 
kilogram. As it is planned to carry out up to four implants (over 
approximately 12 months) in this Phase II trial, each implantation will be 
carried out at the 8 macrobeads per kilogram dosage. 
Study Design: 
This is an open-label clinical trial. The clinical trial will have duration of 12 
months and involve a potential total of four macrobead implants, each no 
less than three months apart. A total of 74 subjects will be treated. After 
the formal phase of the trial is completed, subjects will be followed for life. 
The response of each subject to the intraperitoneal implantation of the 
RENCA agarose-agarose macrobeads will be measured as outlined in 
Section 3 of this protocol. 
 
Each implant will be considered as Day 0. Post implant follow-up visits will 
be done in reference to the corresponding Implantations i.e. Days 14, 30, 
60 and 90. Because much of the testing will be objective in terms of 

 
 
 
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PROTOCOL SYNOPSIS 
quantifiable clinical laboratory, bias on the part of subjects, investigators, 
and analysts should be minimized. 
Planned Sample 
Size: 
The study will enroll a total of 116 evaluable subjects with advanced 
pancreatic cancer and colorectal cancer, and implant 74 eligible patients. 
An evaluable subject is defined as a subject who completes the first 
implantation of the RENCA agarose-agarose macrobeads.  If a subject 
signs an Informed Consent and is not implanted, the subjects will not be 
classified as evaluable and will be replaced.   These subjects will be 
classified as screen failures 
Inclusion 
Criteria: 
1. Histologically-confirmed adenocarcinoma of the pancreas, colon, or 
rectum. 
2. Radiographic evidence of metastatic cancer of the colon or rectum. 
3. The subject has pancreatic cancer that is unresectable or already 
metastatic or colorectal cancer that has failed available treatment 
modalities.  
4. For the pancreas subjects, he/she may be accepted without prior 
chemotherapy or with multiple therapies that have failed. The colon 
and rectal cancer subjects must have failed available 
chemotherapy/targeted regimens.  There is no limit to the number of 
prior chemotherapeutic regimens.  
5. The subject must have evidence of progressive disease defined as at 
least one of the following: 
       a.  Progressive measurable disease: using conventional solid 
tumor criteria 
        b.  Increasing tumor markers and/or activity on PET-CT SUV 
measurement 
6. All clinically significant toxic effects (excluding alopecia) of prior 
surgery, radiotherapy, or hormonal therapy have resolved to ≤ Grade 1 
based on the NCI-CTCAE v 3.0, with the exception of peripheral 
neuropathy, which must have resolved to Grade ≤ 2. 
7. The subject has an Eastern Cooperative Oncology Group performance 
status (ECOG PS) of 0-2. 
8. The subject has adequate hematologic function (minimum 
requirements: absolute neutrophil count [ANC] ≥ 1500/mL, hemoglobin 
≥ 9 g/dL, and platelets ≥ 100,000/mL). 
9. The subject has adequate hepatic function (bilirubin ≤ 1.5 times the 
upper limit of normal (ULN)], aspartate transaminase [AST] and 
alanine transaminase [ALT] ≤ 3 times the ULN, or ≤ 5 times the ULN, if 
liver metastases are present). 
10. The subject has adequate renal function (creatinine ≤ 2.0 mg/dL). 
11. The subject has adequate coagulation function (an international 
normalized ratio [INR] ≤ 1.5 and a partial thromboplastin time [PTT] ≤ 5 
seconds above the ULN [unless on oral anticoagulant therapy]). 
Subjects receiving full-dose anticoagulation therapy are eligible 
provided they meet all other criteria, are on a stable dose of oral 
anticoagulant or low molecular weight heparin (and if on warfarin have 

 
 
 
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PROTOCOL SYNOPSIS 
a therapeutic INR between 2 and 3). 
12. The subject has a life expectancy of 6 weeks. 
13. The subject is male or female and at least 18 years of age.  For 
females, a negative pregnancy test is required. 
14. The subject agrees to use contraceptives while on study, if sexually 
active. 
15. The subject has provided signed informed consent. 
 
Exclusion 
Criteria: 
1. Any condition (cardiovascular or other), making subject an 
unacceptably high anesthetic or surgical risk based on current 
anesthesia/general surgery standards. 
2. Positive testing for HIV. 
3. Cognitive impairment sufficient to render the subject incapable of 
giving informed consent.  
4. Hypersensitivity reaction that, in the opinion of the investigators, poses 
an increased risk of an allergy to the macrobeads, particularly any 
known allergy to murine antigens or body tissues. 
5. Surgical treatment or chemotherapy within three weeks of scheduled 
macrobead implantation or within four weeks of bevacizumab (or 
similar drugs), or radiation therapy within four weeks of scheduled 
macrobead implantation. 
6. Investigational medications for their respective tumors within one 
month of baseline evaluation. 
7. The subject has inadequate hematologic function (absolute neutrophil 
count [ANC] < 1500/mL, hemoglobin < 9 g/dL, and platelets  < 
100,000/mL). 
8. The subject has inadequate hepatic function [bilirubin > 1.5 times the 
upper limit of normal (ULN)], aspartate transaminase [AST] and 
alanine transaminase [ALT] > 3 times the ULN, or > 5 times the ULN, if 
liver metastases are present). 
9. The subject has inadequate renal function (serum creatinine > 2.0 
mg/dL). 
10. The subject has inadequate coagulation function (an international 
normalized ratio [INR] > 1.5 and a partial thromboplastin time [PTT] > 5 
seconds above the ULN [unless on oral anticoagulant therapy]). 
Subjects receiving full-dose anticoagulation therapy are eligible 
provided they meet all other criteria, are on a stable dose of oral 
anticoagulant or low molecular weight heparin (and if on warfarin have 
a therapeutic INR between 2 and 3). 
11. Hepatic blood flow abnormalities: portal vein hypertension and 
thrombosis; and/or large volume of ascites. 
12. Concurrent cancer of any other type except skin cancer (excluding 
melanoma). 
13. History of allergic reactions to mouse antigen. 
14. The subject has an ongoing or active infection, symptomatic 
congestive heart failure, unstable angina pectoris, serious cardiac 

 
 
 
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PROTOCOL SYNOPSIS 
arrhythmias, (well-controlled atrial fibrillation, is permitted,) psychiatric 
illness/social situations that could interfere with the subject’s ability to 
participate in the protocol, active bleeding.  
15. As a result of the medical history, examination or blood testing, the 
investigator considers the subject unfit for the study. 
Efficacy 
Variables: 
The response of each subject to the intraperitoneal implantation of the 
RENCA agarose-agarose macrobeads will be measured after each 
implantation with respect to changes in: 
• 
Primary tumor size 
• 
Size or number of secondary/metastatic tumors 
• 
Tumor marker (such as CEA, CA 19-9 and CA-125) or other 
relevant biochemical parameters such as liver enzymes, alkaline 
phosphatase. lactic dehydrogenase 
• 
Cellular and humoral immune status 
• 
Global clinical status or rating 
• 
Activities of daily living (ADL) rating 
• 
Symptom rating/severity (including narcotic analgesic consumption’ 
visual analog pain scale; 
• 
Quality of life- EORTC 
• 
ECOG and Karnofsky Performance Status 
• 
Abdominal MRI/PET/CT scan with other imaging studies as 
appropriate for the subject’s tumor type (primary and metastatic) 
and condition 
Safety Variables: The following safety variables will be monitored to insure the safety of the 
participants in the study: 
 
• 
Complete physical examination with all vital signs 
• 
Weight  
• 
Global Clinical Assessment 
• 
EKG 
• 
Biochemical profile including appropriate tumor markers 
• 
Amylase, lipase 
• 
Complete blood count (CBC) with differential WBC 
• 
Erythrocyte sedimentation rate 
• 
C-reactive protein 
• 
Standard biochemical profile 
• 
Liver function (AST, ALT, LD, alkaline phosphatase, GGT) 
• 
Tumor markers as appropriate and available  
• 
Urinalysis 
• 
Coagulation profile (PT, INR, PTT) 
• 
Hepatitis B, C, E 
• 
HIV 
• 
Immunoglobulin levels (IgA, IgG, IgE, IgM) 
• 
Skin testing with murine epithelial antigen preparation, with positive 

 
 
 
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PROTOCOL SYNOPSIS 
and negative controls 
• 
Cellular and humoral immune function 
o T cells 
o Cytokine production 
o B cells 
o Antibodies to common bacteria and viruses (such as 
diphtheria, tetanus, mumps, rubella) 
o Quantitative IgG subclass determinations 
o NK cells count (CD16) 
Analysis of circulating tumor cells. 
• 
Ecotropic murine leukemia virus (e-MuLV) (PCR-based assay) 
• 
Ultrasound examination, if medically indicated, will include views of 
the hepatic veins and inferior vena cava to be certain that they are 
free of clots and that there is free peritoneal drainage 
Principles of 
Statistical 
Analysis: 
The critical parameters of this Phase II trial are those related to efficacy 
and safety.  Various markers, such as CEA, CA 19-9, CA125 and C-
reactive protein, amylase, liver function tests, cell counts, and cytokine 
levels, will be sampled and analyzed in relationship to their baseline 
values.   
 
Given the study design, simple population comparisons designed for small 
samples (non-normal distribution) as well as simple trend analysis for 
selected parameters will be performed.  The data from all subjects, 
including those who withdraw or are withdrawn from the study will be 
analyzed.  All data will be analyzed using SAS software. 
 
 
 

 
 
 
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TABLE OF CONTENTS 
 
1 
LIST OF ABBREVIATIONS .................................................................................................. 11 
2 
BACKGROUND ...................................................................................................................... 13 
3 
OBJECTIVES .......................................................................................................................... 18 
3.1 Objectives for the advanced colorectal cancer ....................................................................... 18 
3.1.1 Efficacy ........................................................................................................................... 18 
3.1.2 Safety .............................................................................................................................. 19 
3.1.3 Exploratory ..................................................................................................................... 19 
3.2 
Objectives for the advanced pancreatic cancer ................................................................... 19 
3.2.1 
Primary Objective ........................................................................................................ 19 
3.2.2 
Secondary Objectives .................................................................................................. 20 
3.2.3 Exploratory objectives .................................................................................................... 21 
3.3 
Rationale for Study Dosages ............................................................................................... 21 
4 
INVESTIGATIONAL PLAN ................................................................................................... 22 
4.1 
Description of Overall Study Design and Plan ................................................................... 22 
4.2 
Study Device/Biological Product ........................................................................................ 23 
4.3 
Selection of Study Population ............................................................................................. 25 
4.3.1 
Inclusion Criteria: ........................................................................................................ 25 
4.3.2 
Exclusion Criteria: ....................................................................................................... 26 
4.4 
 Screening to Exclude Subjects with Allergic Reactions to Mouse Antigens ...................... 27 
4.5 
 Treatments ......................................................................................................................... 27 
4.5.1 
Dosage Determination ................................................................................................. 27 
4.5.2 
Drug Labeling .............................................................................................................. 27 
4.6 
 Assessments ........................................................................................................................ 27 
5 
STUDY CONDUCT ................................................................................................................. 29 
5.1 
 Schedule of Assessments .................................................................................................... 29 
5.1.1 
Study Days -28 to -1: ................................................................................................... 29 
5.1.2 
Decision to Proceed with First Implantation ............................................................... 30 
5.1.3 
Study Day -28 to Study Day -1: .................................................................................. 31 
5.1.4 
Visit 1 / Study Day 0: .................................................................................................. 31 
5.1.5 
Home Care: .................................................................................................................. 31 
5.1.6 
Visit 2, Study Day 14 ± 3 days: ................................................................................... 32 
5.1.7 
Visit 3, Study Day 30 ± 5 days: ................................................................................... 33 
5.1.8 
Visit 4, Study Day 60 ± 5 days: ................................................................................... 33 
5.1.9 
Visit 5, Study Day 90 ± 5 days: ................................................................................... 34 
Decision to Proceed with Second Implantation ........................................................................... 35 

 
 
 
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5.1.10 
 Visit 6, Implant 2 / Study Day 0: .............................................................................. 35 
5.1.11 
 Visit 7, Implant 2 / Study Day 14 ± 3 days: ............................................................. 35 
5.1.12 
 Visit 8, Implant 2 / Study Day 30 ± 5 days: ............................................................. 36 
5.1.13 
 Visit 9, Implant 2 / Study Day 60 ± 5 days: ............................................................. 36 
5.1.14 
 Visit 10, Implant 2 / Study Day 90 ± 5 days: ........................................................... 37 
Decision to Proceed with Third Implantation .............................................................................. 38 
5.1.15 
 Visit 11, Implant 3 / Study Day 0: ............................................................................ 38 
5.1.16 
 Visit 12, Implant 3 / Study Day 14 ± 3 days: ........................................................... 38 
5.1.17 
 Visit 13, Implant 3 / Study Day 30 ± 5 days: ........................................................... 39 
5.1.18 
 Visit 14, Implant 3 / Study Day 60 ± 5 days: ........................................................... 39 
5.1.19 
 Visit 15, Implant 3 / Study Day 90 ± 5 days: ........................................................... 40 
Decision to Proceed with Fourth Implantation ............................................................................ 40 
5.1.20 
 Visit 16, Implant 4 / Study Day 0: ............................................................................ 41 
5.1.21 
 Visit 17, Implant 4 / Study Day 14 ± 3 days: ........................................................... 41 
5.1.22 
 Visit 18, Implant 4 / Study Day 30 ± 5 days: ........................................................... 42 
5.1.23 
 Visit 19, Implant 4 / Study Day 60 ± 5 days: ........................................................... 42 
5.1.24 
 Visit 20, Implant 4 / Study Day 90 ± 5 days: ........................................................... 43 
5.1.25 
 Visit 21, Implant 4 / Study Day 120 ± 5 days: ......................................................... 43 
5.2 
 Number of Clinical Sites .................................................................................................... 45 
5.3 
 Safety and Tolerability Assessments .................................................................................. 45 
5.4 
 Medical History ................................................................................................................. 46 
5.5 
 Physical Examination ........................................................................................................ 46 
5.6 
 Clinical Laboratory Parameters ........................................................................................ 46 
5.7 
 Appropriateness of Measurements and Assessments ......................................................... 47 
5.8 
 Progression of Disease During the Study .......................................................................... 48 
5.9 
 Rescue Program ................................................................................................................. 49 
6 
SAFETY EVALUATIONS ...................................................................................................... 49 
6.1 
Adverse Events ................................................................................................................... 49 
6.2 Classification of Adverse Events by Intensity ....................................................................... 50 
6.3 Classification of Adverse Events by Relationship to Study Drug ........................................... 50 
6.4  
Serious Adverse Events ...................................................................................................... 51 
6.5  
Stopping Rule for an Individual Subject ............................................................................ 52 
6.5.1 
Maximum Tolerated Dose/Dose Limiting Toxicity .................................................... 52 
6.6  
Premature Termination of the Study .................................................................................. 53 
6.7  
Potential Risks ................................................................................................................... 53 
6.7.1  
Procedures to minimize risks ...................................................................................... 56 
6.8  
Escape Arm (Withdrawal with/without Bead Removal) .................................................... 57 
6.9  
Treatment of Adverse Effects ............................................................................................. 58 

 
 
 
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7 
DATA MANAGEMENT AND STATISTICAL ANALYSIS ................................................ 59 
7.1 
 Determination of Sample Size ............................................................................................ 59 
7.2 
 Determination of  Response ............................................................................................... 59 
8 
STUDY MANAGEMENT ........................................................................................................ 61 
8.1 
 Recruitment and Consent Procedures ............................................................................... 61 
8.2 
 Regulatory Guidelines ....................................................................................................... 61 
8.3 
 Institutional Review Board ................................................................................................ 61 
8.4 
 Informed Consent ............................................................................................................... 61 
8.5 
 Data Monitoring and Safety Board.................................................................................... 62 
8.6 
 Study Documentation ......................................................................................................... 62 
8.7 
 Study Monitoring and Auditing .......................................................................................... 63 
8.8 
 HIPAA ................................................................................................................................ 63 
8.9 
 Retention of Records .......................................................................................................... 63 
APPENDICES ................................................................................................................................ 65 
Appendix 1 .................................................................................................................................... 65 
Name, Address, and Qualifications of Each Investigator ........................................................ 65 
Appendix 2 .................................................................................................................................... 66 
Appendix 3 ................................................................................................................................... 69 
REFERENCES ............................................................................................................................... 72 
References in Introduction: .......................................................................................................... 72 
Xenotransplantation: .................................................................................................................... 76 
Murine Leukemia Virus: .............................................................................................................. 77 
 

 
 
 
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1 LIST OF ABBREVIATIONS 
ADL 
Activities of daily living 
AE 
Adverse event 
Alk Phos 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
Beta cells 
The predominant type of cell in the islets. 
BB-IND 
Bureau of Biologics,Investigational New Drug  
CA 125 
Cancer antigen, marker for ovarian cancer 
CA 19-9 
Cancer antigen 19-9, specific marker for certain 
gastrointestinal tumors 
CBC 
Complete blood count 
Cc 
Cubic centimeter 
cc/min 
Cubic centimeter per minute 
CD133+ 
Some melanoma cells contain subset of cells 
expressing CD133+, a surface antigen 
CD44+ 
Multispecific cell adhesion molecule 
Cd16 
A cluster of differentiation found on the surface of 
natural killer cells 
CEA 
Carcinoembryonal antigen 
CT scan 
Computerized tomography 
CTCAE v3.0 
Common Terminology Criteria for Adverse Events 
DLT 
Dose limiting toxicity 
DNA 
Deoxyribosenucleic acid 
DSMB 
Data Safety Monitoring Board 
ECOG 
Eastern Collaborative Oncology Group 
EGFR 
Epidermal growth factor receptor/gene  
EKG 
Electrocardiogram 
e-MuLV DNA 
Ecotropic murine leukemia virus envelope protein 
EORTC 
European Organization for Research and Treatment 
of Cancer 
FDA 
Food and Drug Administration 
G1-S 
Stage in the cell cycle at the boundary between the 
G1 phase and the S phase. 
G2-M 
Checks for damaged DNA and unreplicated DNA  
GADD45 
A p53-regulated stress protein 
GGT 
Gamma glutamyl transpeptidase 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
HAMA 
Anti-mouse antibodies 
HER-2 
Human epidermal growth factor receptor  
HIV 
Human immunodeficiency virus 
IgA 
Immunoglobin A 
IgE 
Immunoglobin E 

 
 
 
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IgG 
Immunoglobin G 
IgM 
Immunoglobin M 
IND 
Investigational New Drug 
INR 
International Normalization Ratio 
IRB 
Institutional Review Board 
IV 
Intravenous 
kD 
KiloDalton 
Kg 
Kilogram 
Ki67 
Cell-cycle related nuclear protein; proliferation 
marker. 
LD 
Lactic dehydrogenase 
mg/dl 
Milligram per deciliter 
PM 
Micromole 
MuLV 
Murine leukemia virus 
Mm 
Millimeter 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
mTor 
Coordinates several upstream signaling pathways in 
renal tumor cells. 
MTT assay 
Laboratory test for measuring the activity of 
enzymes 
NCI 
National Cancer Institute 
NK 
Natural killer cell 
OS 
Overall survival 
p27 
Gene which lies on chromosome 12 in humans 
PCR DNA 
Method by which a few fragments of DNA can be 
duplicated 
PET scans 
Positron emission tomography 
PFS 
Progression-free survival 
PT 
Prothrombin Time 
PTT 
Partial Thromboplastin Time 
RENCA 
Renal adenocarcinoma 
RT-PCR 
Reverse transcription polymerase chain reaction 
SAE 
Serious adverse event 
T cells 
A type of blood cell that protects the body from 
infection. 
TPN 
Total parenteral nutrition 
USPHS 
United States Public Health Service 
VEGF 
Vascular endothelial growth factor 
 

 
 
 
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2 
BACKGROUND 
 
 
Treatment for cancer has traditionally consisted of three modalities: 
surgery, radiation therapy and chemotherapy.  Advances with all three modalities 
over the years have produced some long-term remissions and/or cures in certain 
types of cancer such as the leukemias, and prolonged survival for many other 
patients.  The advent of targeted, often more “biological” therapies such as 
tyrosine kinase inhibitors, inhibitors of angiogenesis, inhibitors of, and antibodies 
to, specific receptors such as mTor, HER-2, VEGF, and EGFR, has further 
changed the face of anti-cancer therapy.  Much remains to be accomplished, 
however, especially with respect to the treatment of solid tumors, including some 
of the most common and deadly cancers such as those of the lung, colon, breast, 
ovary, prostate, pancreas, and kidney.  New types of less toxic, less debilitating 
and more effective therapies are needed.  
 
Pancreatic cancer:  
Carcinoma of the pancreas has had a markedly increased incidence during 
the past several decades and ranks as the fourth leading cause of cancer death in 
the United States (American Cancer Society, 2009; Greenlee et al, 2000). Despite 
the high mortality rate associated with pancreatic cancer, its etiology is poorly 
understood.  Cancer of the exocrine pancreas is rarely curable and has an overall 
survival (OS) rate of less than 4%[Greenlee et al, 2000]. The highest cure rate 
occurs if the tumor is truly localized to the pancreas; however, this stage of the 
disease accounts for fewer than 20% of cases. For those patients with localized 
disease and small cancers (<2 cm) with no lymph node metastases and no 
extension beyond the capsule of the pancreas, complete surgical resection can 
yield actuarial 5-year survival rates of 18% to 24%. (Yeo et al, 1997). 
Improvements in imaging technology, including spiral computed tomographic 
scans, magnetic resonance imaging scans, positron emission tomographic scans, 
endoscopic ultrasound examination, and laparoscopic staging can aid in the 
diagnosis and the identification of patients with disease that is not amenable to 
resection. For patients with advanced cancers, the OS rate of all stages is less 
than 1% at 5 years with most patients dying within 1 year. 
No tumor-specific markers exist for pancreatic cancer; markers such as 
serum CA 19-9 have low specificity. Most patients with pancreatic cancer will have 
an elevated CA 19-9 at diagnosis. Following or during definitive therapy, the 
increase of CA 19-9 levels may identify patients with progressive tumor growth. 
The presence of a normal CA 19-9, however, does not preclude recurrence.  

 
 
 
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According to the National Cancer Institute 
(www.cancer.gov/cancerinfo/types/pancreatic), patients with any stage of 
pancreatic cancer can appropriately be considered candidates for clinical trials 
because of the poor response to chemotherapy, radiation therapy, and surgery as 
conventionally used.  One such trial is the gemcitabine, docetaxel, capecitabine 
(GTX) therapy being utilized at Columbia University by Dr. Robert Fine and his 
colleagues (Phase II). 
Colorectal cancer: 
In contrast to pancreatic cancer, cancer of the colon is a highly treatable 
and often curable disease when localized to the bowel. Surgery is the primary form 
of treatment and results in cure in approximately 50% of the patients. Recurrence 
following surgery is a major problem and is often the ultimate cause of death.  
The prognosis of patients with colon cancer is clearly related to the degree 
of penetration of the tumor through the bowel wall, the presence or absence of 
nodal involvement, and the presence or absence of distant metastases. Beyond 
those characteristics, elevated pretreatment serum levels of carcinoembryonic 
antigen (CEA) have a negative prognostic significance.  The fact is, however, that, 
even with good prognostic factors and aggressive chemotherapy with regimens 
such as FOLFOX and FOLFIRI, with or without the addition of bevacizumab and 
cetuximab (the latter for KRAS+ patients), many patients become resistant to 
available chemotherapies and targeted biological therapies.  In addition, the other 
surgical and ablative techniques may no longer be applicable. With liver and lung 
metastases common problems, and brain metastases less common, but 
potentially devastating, there clearly is a need for new, more effective therapeutic 
measures, especially for those patients who do have metastatic spread of their 
tumors 
Among the therapeutic possibilities currently being explored for pancreatic 
and colorectal cancer, as well as other solid tumors, those that involve cellular 
biological control mechanisms seem both promising and attractive. Many such 
modalities-- such as induction of terminal differentiation, enhancement of growth-
inhibitory (negative) feedback, selective programmed cell death (apoptosis), 
targeted insertion of viral or other genes into the proliferating cancer cell, and 
growth arrest at either the G1-S or G2-M checkpoints of the cell cycle -- all seem 
to be feasible goals with significant potential for clinical use.  Furthermore, recent 
data suggest that a subpopulation of cells within a tumor, i.e., the so-called cancer 
stem or progenitor cells, which have been described and characterized in certain 
tumor types such as those of the brain (glioma series), colon, and breast, may, in 
fact, be responsible for tumor survival, progression, resistance, and metastasis.  
Should these observations be verified, these cell populations represent a novel 
and fundamental target for anti-neoplastic therapy.  

 
 
 
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The development of truly new and more effective therapeutic approaches to 
the treatment of neoplastic disease requires a far better understanding of the 
nature of cancer than we currently have.  It is increasingly clear that cancer is not 
simply the result of a rogue, mutated cell or clone of cells exhibiting unrestricted 
proliferative and metastatic behavior.  Rather, cancer is itself a biological system, 
in a sense a kind of (undesirable) organ and/or organ system. Furthermore, cancer 
is not a entirely separate entity within the host, but rather dependent on complex 
interactions with the host as a whole and its own microenvironment, just as a 
normal organ is. The local microenvironment may, in fact, aid and abet the 
neoplastic cells, providing them with blood flow and nutrition, for example. The 
“normal” host cells in the microenvironment may not be normal at all, but may 
become incorporated into the structure and workings of the tumor.  In other words, 
the tumor is a heterogeneous collection of interdependent cells, the least desirable 
of which may be what we think of as the neoplastic cells.  Those cells, however, 
are only part of the story.  
 
The fact that cancer is, in effect, an alternative organ system, suggests that 
it should be subject to at least some of the same regulatory processes that govern 
normal, physiologic system function.  One such process, the control of proliferation 
in a normal organ, is quite strict.  Although it has long been thought that cancer 
cells and the tumors they form are not subject to the same regulatory growth-
control feedback mechanisms as are normal cells and organs, increasing evidence 
suggests that they are, in fact, subject to such regulation. Not surprisingly, an 
important signal in the growth-regulatory process for tumor cells is the mass of 
tumor present. Tumor growth slows as the mass of both primary and metastatic 
tumors increase (7-12). Surgeons, for example, have observed that surgical 
excision of part of a tumor mass can be associated with rapid re-growth of the 
remaining tumor and/or distant metastases (13,14).  De Wys (15) and Fisher et al 
(16) have demonstrated the same phenomenon in animal models of tumors.  We 
have been able to confirm this ourselves in a mouse tumor model involving the 
injection of mouse renal adenocarcinoma cells under the renal capsule. In these 
studies, removal of the primary tumor at an early stage of development of the 
malignancy has resulted in the appearance of dramatically greater numbers of 
distal metastases. Taking these various findings into account, it is not 
unreasonable to argue, as Prehn has done (17), that a promising therapeutic 
approach to the biological control of tumor growth could consist of “fooling” tumors 
into sensing that their mass is greater than it actually is, thereby slowing or halting 
tumor growth. 
 
The proposed cancer treatment to be tested in the Phase II clinical trial 
outlined in this protocol is based, at least in part, on the concept that tumor growth 

 
 
 
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can be controlled by tumor mass or signals that indicate that such mass is present.  
In this case, however, the induction of such signals is brought about not by true 
tumor mass, but rather by placing cancer cells in a proliferation-restrictive 
hydrophilic matrix composed of agarose.  In brief, cancer cells (in this case, mouse 
renal adenocarcinoma cells) placed in such a growth-restrictive matrix contained 
within the structure of a 6-8mm “macrobead’ are induced to produce and release 
signals that can inhibit the proliferation of free cancer cells of the same and 
different types (and without species specificity) both in vitro and in vivo.   
Translated into practical clinical terms, the release of such inhibitory signals from 
cancer cells in a proliferation-restrictive environment could be useful in the 
treatment of human cancers. 
 
Based on our continued laboratory and clinical studies with the macrobead 
approach to the control of the cancerous growth, we can say that the mechanisms 
by which this is achieved are more complex than the model advocated by Prehn. 
In fact, the cells that survive to function in the bead have at least some of the 
properties of cancer stem or progenitor cells.  These colonies are comprised of 
cells that secrete inhibitory factor(s), which, in turn, regulate a variety of processes 
in the freely growing cancer cells.  These affected processes include regulation of 
the cell-cycle check points (G1S and G2M), DNA synthesis/replication, cell-cell 
interactions, angiogenesis, cellular metabolism and cytoskeletal function more 
generally.  In other words, the macrobeads themselves constitute an altered, 
constrained neoplastic system with the capability of influencing the behavior of 
other, non-constrained neoplastic systems.  In vivo, these changes are achieved 
without any evident impairment to date of normal body functions, including that of 
the immune system.  In fact, data from our Phase I clinical trial show that the 
human immune system is of normal to increased activity after the beads have 
been placed.  
 
The heterogeneous renal adenocarcinoma cell population initially placed in 
the agarose matrix of the macrobead undergoes dramatic depopulation followed 
by dedifferentiation of the surviving cells.  Specifically, colonies emerge that 
contain both cells with stem cell-like properties and cells with other as yet 
undefined properties.  The latter group has features suggestive of the tumor 
“niches” that have now been described in a range of tumors.  These niches 
represent the bodies that are now postulated to be responsible for tumor 
generation and survival/perpetuation.  They are likely also to be the source of the 
cells that can break loose and form both local and distant metastases. In vivo, 
niches are composed of cells morphologically and molecularly similar to those 
seen in the macrobeads, but have the additional feature of being surrounded by an 
outer coat of fine blood vessels that both nourishes and protects them from host 
defenses, as well as possibly external therapies.  Quite apart from their biological 
importance in neoplasia, the niches represent a unique endpoint for assessing the 
anti-neoplastic efficacy of the macrobeads. 

 
 
 
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While the properties of the cancer stem cells, “niches”, and the macrobeads 
that contain them are of significant scientific interest, their precise mechanism of 
anti-tumor action has yet to be fully explored.  Genomic studies of the cells within 
the colonies in the macrobeads show striking up-regulation of certain genes such 
as CHOPP and GADD45.   One or more, or all, of the proteins produced by these 
and other genes, which can be measured by PCR, can be released into the 
medium and serve as the postulated signals to the freely-growing cancer cells. 
Whatever the outcome of this important line of research, however, there is solid 
evidence in preclinical studies that the macrobeads may yield clinically important 
results.  Preclinical studies in mouse tumor models, both in vivo and in vitro, have 
indicated statistically significant activity of the macrobeads with respect to 
suppression of tumor growth.  Studies in 45 dogs and cats with the above 
macrobeads in the treatment of a variety of spontaneous tumors including 
gastrointestinal lymphoma, prostate cancer and hepatocellular tumors have shown 
a tumor response rate of at least 50%.  Increased activity levels and weight gain 
have also characterized these animals after RENCA macrobead implantation 
consistent with an improved quality of life.  
 
New and ongoing in vitro laboratory studies with human tumor cell lines 
including those with an androgen-independent, docetaxel-resistant human 
prostate cell line have shown that the macrobeads can slow or stop the 
proliferation of these cells when no other agents are effective.  These in vitro 
studies, plus in vivo tests with the same tumor line in an immunodeficient mouse 
tumor model, add further, preclinical support to the trial proposed here. If the 
macrobeads continue to be effective after cancer cells have developed resistance 
to all currently available agents, then they could have a place in the clinical 
treatment of advanced cancers, let alone those at an earlier stage. 
 
The Phase I trial of the cancer macrobeads in the initially targeted 13 
subjects with a variety of Stage IV, end-stage, treatment-resistant epithelial-
derived tumors has enrolled and implanted 31 subjects to date, 21 more than the 
original goal of 10. It has demonstrated that the macrobeads are well tolerated 
when implanted in the human abdominal cavity for periods of up to 24 months.  
Tumor types evaluated in the safety/toxicity trial have included colorectal 
carcinoma, gall bladder cancer (cholangiocarcinoma), gastric carcinoma (schirrous 
type), pancreatic carcinoma, ovarian carcinoma, and non-small cell lung 
carcinoma.  There was no pattern of any consistent adverse effect attributable to 
the macrobeads.  Rather, the problems that did occur were attributable to the 
disease process itself.  Phase I study is closed for the subject accrual and is only 
open for data analysis. 
 

 
 
 
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3 OBJECTIVES  
 
All study objectives will be assessed in each of the two study groups to be enrolled 
in this clinical trial: subjects with advanced pancreatic cancer and subjects with 
advanced colorectal cancer. 
 
3.1 Objectives for the advanced colorectal cancer  
 
The objectives for the advanced colorectal cancer, as defined in the Statistical 
Analysis Plan (SAP), are:  
 
3.1.1 Efficacy 
 
The primary efficacy outcome is post-implantation all-cause mortality, where time 
to death is defined as the time from the first scan showing disease progression 
after completion of prior treatment (time of origin, T0) to death from any cause. 
 
Secondary efficacy outcomes are (if feasible): 
• Time from first implantation to death. 
• Time from disease Stage IV diagnosis to death. 
• Changes from baseline based on Magnetic Resonance Imaging (MRI), 
computerized tomography (CT) or positron emission tomography (PET)-CT 
scan, and other appropriate imaging techniques (e.g., sonography, bone 
scans, other x-rays) as indicated, if feasible. 
o In primary and/or secondary tumor size (volume, area) and  
o In state (necrosis, vascularization) on MRI, CT or PET-CT scan, and other 
appropriate imaging techniques (e.g., sonography, bone scans, other x-
rays) as indicated. 
• Change from baseline in tumor markers (CEA, CA19-9) 
• Changes from baseline in CA125 (as a marker of inflammation) 
• Changes from baseline in  
o Clinician Global Clinical Assessment 
o Activities of daily living 
o Symptom rating 
o Quality of life (QCQ-C30) 

 
 
 
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o Pain scale 
o ECOG 
• Additional exploratory efficacy outcomes may be analyzed if feasible and will 
be defined in the CSR. 
3.1.2 Safety 
Safety outcomes will include: 
• Reason for study discontinuation (coming off protocol). 
• Incidence of adverse events (AEs). 
• Changes from baseline in physical examination parameters, including weight, 
vital signs, and electrocardiogram (ECG). 
• Changes from baseline in laboratory parameters (see section 5.6 of the 
protocol). 
• Changes from baseline in murine antigens skin test. 
• Changes from baseline in status of murine leukemia virus as detected by 
polymerase chain reaction (PCR). 
3.1.3 Exploratory 
 
Exploratory outcomes will include presence or absence of circulating tumor 
cells. An addition to the endpoints for assessing efficacy will be, where 
possible, when a biopsy is indicated, a careful search for, and identification of, 
the niches of cancer stem and other cells within the niche bodies of the tumors 
the macrobeads are being used to treat.  Markers of the niche used to identify 
these cells and study their properties (numbers, integrity of surrounding blood 
vessels, degree of stress) will include HLA, CD44+, CD133+. 
 
3.2 
Objectives for the advanced pancreatic cancer  
3.2.1 Primary Objective 
To determine the Response Rate (RR), at 2 weeks, 4 weeks, 8 weeks, 3 months, 
6 months, 9 months, 12 months or longer as possible, of subjects treated with 
macrobeads after they have failed standard chemotherapeutic regimens or have 
decided not to pursue standard or experimental chemotherapy for treatment-
resistant, metastatic pancreatic adenocarcinoma, where RR is defined as: 
 

 
 
 
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o Evidence of change in primary or secondary tumor size (volume, area) 
as well as state (necrosis, vascularization, metabolic rate) on PET-CT, 
as well as MRI and/or CT as appropriate 
o Decrease in tumor markers (including CEA and CA 19-9) and specific 
biochemical parameter levels in plasma/serum 
o Stable or improved quality of life as measured by EORTC QLQ-C30, 
weight, and pain control 
o Stable or improved global clinical rating of subject by physician and/or 
nurse 
o Increase in LDH consistent with tumor necrosis (significance of LDH 
changes will be determined in relation to imaging changes indicative of 
necrosis) 
3.2.2 Secondary Objectives 
 
1. To determine the safety and tolerability of the implantation of the RENCA 
cancer-cell-containing macrobeads in advanced pancreatic cancer subjects 
with respect to: 
 
• The peritoneum: irritation, inflammation, mechanical effects (over a period 
of at least 3 months); 
• Other intraperitoneal organs (liver, spleen, large and small intestines, 
kidney, bladder, omentum, etc.); 
• Local and systemic immune response (T and B cell/cellular, antibody 
responses); 
• Bacterial, viral zoonotic infection (clinical and hematological examination; 
PCR DNA analysis for viral DNA; specific viral antibodies); 
• Hypersensitivity reactions to murine antigens. 
 
2. To determine progression, defined as the time from the first implantation 
until the first occurrence of any of the following events 
a. Death due to any cause, or 
b. Progression as defined by the presence of the occurrence of any 
three of the five following events: 
i. An increase in the levels of tumor markers (e.g., CEA, CA19-
9) of 50% from baseline determinations  
ii. Radiographic progression including increase in primary or 
metastatic tumor size/volume; increasing metabolic activity of 
the presenting tumor or of new metastatic lesions on a 
PET/CT scan after the administration of radio-labeled 
fluorodeoxyglucose (FDG); and evidence of new metastatic 
lesions. 

 
 
 
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iii. A decrease in the EORTC QLQ-C30 quality of life scale as 
compared to baseline of more than 25%; 
 (Above data will also be analyzed with censorship of deaths to 
further evaluate progression) 
 
3. Determine overall survival (OS) 
 
4. Circulating tumor cells will also be measured 
 
3.2.3 Exploratory objectives 
 
An addition to the endpoints for assessing efficacy will be, where possible, 
when a biopsy is indicated, a careful search for, and identification of, the niches 
of cancer stem and other cells within the niche bodies of the tumors the 
macrobeads are being used to treat.  Markers of the niche used to identify 
these cells and study their properties (numbers, integrity of surrounding blood 
vessels, degree of stress) will include HLA, CD44+, CD133+. 
 
3.3 Rationale for Study Dosages 
 
Based on the animal studies conducted to date, as well as the Phase I 
human trial that has been completed to date, a reasonable dosage range (number 
of beads to be implanted) is 8 macrobeads per kilogram of body weight.  We know 
that 16 macrobeads per kilogram were also well-tolerated in the Phase I human 
trial, but, at least with a single dose, this number was not seen to be any more 
effective than 8 macrobeads per kilogram.  As it is planned to carry out up to four 
implants (over 12 months) in this Phase II trial, each implantation will be carried 
out with the 8 macrobeads per kilogram dosage. 
 
 
 
 

 
 
 
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4 
INVESTIGATIONAL PLAN 
4.1 Description of Overall Study Design and Plan 
 
 
This is an open-label clinical trial.  The clinical trial will have duration of 
approximately 12 months and involve a potential total of four macrobead implants, 
each no less than three months apart.  
 
 
Each subject will serve as his own control. This means that changes from 
baseline to various post-treatment time points will be analyzed for some variables (such 
as tumor markers, for example). The confidence intervals for these changes will be 
calculated. Of course, it is not planned for the survival analysis.  
 
 Seventy-four (74) male and female subjects with advanced pancreatic 
cancer or metastatic, treatment-resistant colorectal cancer meeting all the above 
inclusion criteria will be recruited and treated for the study.  Baseline 
measurements will include tumor burden and size, tumor history and pathological 
diagnosis and grade, global clinical state, activities of daily living, symptom 
checklist including tumor-related symptoms, a sense-of-well-being scale, routine 
clinical biochemistry and any appropriate tumor markers as available, and an 
assessment of cellular and humoral immune status.  
 
The primary tumor histopathology will be reviewed and will be evaluated 
with special staining to identify, if possible, the presence or absence of cancer 
stem cells and niche bodies. 
 
The response of each subject to the intraperitoneal implantation of the 
RENCA agarose-agarose macrobeads will then be measured over the ensuing 3 
months (and a 6, 9, and 12 months, if possible) with respect to changes in:  
 
• Primary tumor size 
• Size or number of secondary/metastatic tumors 
• Tumor marker or relevant biochemical parameters such as liver 
enzymes, alkaline phosphatase, lactic dehydrogenase 
• Cellular or humoral immune status 
• Global clinical status or rating 
• Performance status (Karnofsky PS and ECOG PS) 
• Activities of daily living (ADL) rating 
• Symptom rating/severity (including use of pain medications) 
• Quality of life scale 
• Circulating tumor cells (when possible) 
 

 
 
 
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After each successive implant, follow-up will be at Days 14, 30, 60, and 90. 
Because much of the testing will be objective in terms of quantifiable clinical 
laboratory and imaging testing, bias on the part of subjects, investigator, and 
analysts should be minimized. 
 
Each implant will be considered as Day 0. Post implant follow-up visits will be 
done in reference to the corresponding implantations i.e. Days 14, 30, 60 and 90 
for each implantation.   
4.2 Study Device/Biological Product 
 
In this study, the study device/drug is the RENCA macrobead.  The cancer 
cell-containing agarose-agarose macrobeads that are to be used for the Phase II 
clinical trial are composed of two concentric spherical agarose layers.  The inner 
layer, which is also the layer in which the neoplastic cells (in this case, mouse 
renal adenocarcinoma cells) are embedded, is made up of 1.0% agarose.  The 
outer layer is composed of 5% agarose.  150,000 mouse renal adenocarcinoma 
(RENCA) cells are placed in each bead.  The diameter of the macrobead is 6,000-
8,000 μM or 6-8 mm.  Its structure is such that molecules above 80,000 kD are 
largely excluded from either entering or leaving the bead.  Importantly, the cancer 
cells, although they proliferate in the inner layer of agarose, do not invade the 
outer layer or escape from an intact bead.  In addition, peritoneal or immune 
system cells from the host cannot enter into the macrobead as well.  The 
macrobeads produce the inhibitory effect for at least 3 years in vitro and up to 6 
months in vivo in animal studies.  Data from the Phase I human clinical trial 
indicate the macrobeads have a functional longevity of from 3 to 4 months. 
 
The cancer-cell containing macrobead is derived from previous and 
currently ongoing work with a porcine-islet containing agarose-agarose 
macrobead, an IND for the human Phase I testing of which has been submitted to 
the FDA (IND # 9672, originally submitted April 9, 2001 and now continuing with 
further submissions to address the outstanding “clinical hold” issues).  This islet 
macrobead is described in detail in that IND and also in publications from our 
laboratory (Jain et al, 1995, 1999; Gazda, 2003, Gazda et al, 2005, Vinerean et al, 
2008 contained in that IND).     
 
 
The overall process of preparing the RENCA-cell-containing macrobead is 
described in the IND documents.  As for the islet macrobeads, the cancer 
macrobeads are placed in the peritoneal cavity in humans.  In the peritoneal cavity 
the beads should remain free (floating) in the intraperitoneal space.  They do not 
become vascularized and thus will remain as implants rather than true grafts. 
 

 
 
 
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It is important to emphasize that the macrobeads must be allowed to 
“mature” in vitro prior to their implantation into animals or humans willing to 
participate in the Phase II trial.  Although there is an early proliferation-inhibitory 
effect related to the apoptotic death of cancer cells in the macrobead, the effect of 
interest and therapeutic effectiveness is seen after approximately three weeks 
increasing to a maximum by approximately 8-10 weeks.  The appearance of the 
inhibitory effect coincides with dramatic changes in the tumors cells in the 1% 
agarose matrix.  
 
The use of immunohistological and gene chip microarray techniques 
indicates that the cancer cells in the macrobeads undergo dramatic changes over 
the first several weeks of their encapsulation.  After 14-21 days, the cells begin to 
form ovoid colonies, which are characterized by proliferation (as indicated by a 
proliferation marker, Ki67) and growth inhibition (as indicated by the appearance of 
p27, a cyclin-dependent kinase inhibitor, which acts to inhibit cell proliferation at 
the G1-S checkpoint of the cell cycle).  Changes in the expression of genes 
involved in signal transduction and stem cell pathways are confirmatory of these 
dramatic changes in the cell populations within the bead. For example, they show 
decreased expression of genes related to DNA synthesis and angiogenesis 
(VEGF). 
 
In sum, the colonies formed by the RENCA cells thus emerge following a 
process marked by both proliferation and apoptotic cell death.  The appearance of 
the cell-proliferation inhibitory effect coincides with the formation of the colonies. It 
should be emphasized again that RENCA cells removed from the colonies in the 
macrobeads after periods of up to 3 years return quickly to their prior malignant 
cell growth patterns both in vitro and in vivo.    
 
The cellular products of the cancer-cell-containing macrobeads are 
beginning to be resolved by a variety of techniques including most importantly, the 
gene arrays already described, as well as Western blot analysis.  The products 
indicating the greatest changes include osteocalcin, bone morphogenic protein-4, 
GADD45, connexin 43, and aldehyde dehydrogenase.  It would appear from the 
data we have that there are likely to be multiple signals.  Based on the physical 
constraints of the 5% outer layer of agarose, the active product(s) must be less 
than 80 kD in molecular weight, but may include proteins, peptides, and lipids of 
many different types.  It is possible that small tumor antigens are also released, 
but it does not appear that these are one and the same with the signaling 
molecules.  A recent advance has been the ability to maintain the macrobeads in 
serum-free medium.  Analyses of the serum-free conditioned media by gel 
electrophoresis indicate that there are approximately 20 bands.  These are being 
analyzed now to determine which are the signals producing the inhibitory effect on 
the growth of non-constrained tumor cells. 
 

 
 
 
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4.3 Selection of Study Population  
4.3.1 Inclusion Criteria:  
1. Histologically-confirmed adenocarcinoma of the pancreas, colon, or rectum. 
2. Radiographic evidence of metastatic cancer of the colon or rectum 
3. The subject has pancreatic cancer that is unresectable or already metastatic or 
colorectal cancer that has failed available treatment modalities.  
4. For the pancreas subjects, he/she may be accepted without prior 
chemotherapy or with multiple therapies that have failed. The colon and rectal 
cancer subjects must have failed available chemotherapy/targeted regimens.  
There is no limit to the number of prior chemotherapeutic regimens.  
5. The subject must have evidence of progressive disease defined as at least one 
of the following: 
        a.  Progressive measurable disease: using conventional solid tumor criteria 
        b.  Increasing tumor markers and/or activity on PET-CT SUV measurement 
6. All clinically significant toxic effects (excluding alopecia) of prior surgery, 
radiotherapy, or hormonal therapy have resolved to ≤ Grade 1 based on the 
NCI-CTCAE v 3.0, with the exception of peripheral neuropathy, which must 
have resolved to Grade ≤ 2. 
7. The subject has an Eastern Cooperative Oncology Group performance status 
(ECOG PS) of 0-2. 
8. The subject has adequate hematologic function (minimum requirements: 
absolute neutrophil count [ANC] ≥ 1500/mL, hemoglobin ≥ 9 g/dL, and platelets 
≥ 100,000/mL). 
9. The subject has adequate hepatic function (bilirubin ≤ 1.5 times the upper limit 
of normal (ULN)], aspartate transaminase [AST] and alanine transaminase 
[ALT] ≤ 3 times the ULN, or ≤ 5 times the ULN, if liver metastases are present). 
10. The subject has adequate renal function (creatinine ≤ 2.0 mg/dL) 
11. The subject has adequate coagulation function (an international normalized 
ratio [INR] ≤ 1.5 and a partial thromboplastin time [PTT] ≤ 5 seconds above the 
ULN [unless on oral anticoagulant therapy]). Subjects receiving full-dose 
anticoagulation therapy are eligible provided they meet all other criteria, are on 
a stable dose of oral anticoagulant or low molecular weight heparin (and if on 
warfarin have a therapeutic INR between 2 and 3). 
12. The subject has a life expectancy of 6 weeks. 
13. The subject is male or female and at least 18 years of age.  For females of 
childbearing potential, a negative pregnancy test is required. 
14. The subject agrees to use contraceptives (barrier method) while on study, if 
sexually active. 
15. The subject has provided signed informed consent. 
 

 
 
 
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4.3.2 Exclusion Criteria: 
 
1. Any condition (cardiovascular or other), making subject an unacceptably high 
anesthetic or surgical risk based on current anesthesia/general surgery 
standards. 
2. Positive testing for HIV. 
3. Cognitive impairment sufficient to render the subject incapable of giving 
informed consent.  
4. Hypersensitivity reaction that, in the opinion of the investigators, poses an 
increased risk of an allergy to the macrobeads, particularly any known allergy 
to murine antigens or body tissues. 
5. Surgical treatment or chemotherapy within three weeks of scheduled 
macrobead implantation or within four weeks of bevacizumab (or similar 
drugs), or radiation therapy within four weeks of scheduled macrobead 
implantation. 
6. Investigational medications for their respective tumors within one month of 
baseline evaluation. 
7. The subject has inadequate hematologic function (absolute neutrophil count 
[ANC] <1500/mL, hemoglobin <9 g/dL, and platelets  <100,000/mL). 
8. The subject has inadequate hepatic function [bilirubin >1.5 times the upper limit 
of normal (ULN)], aspartate transaminase [AST] and alanine transaminase 
[ALT] > 3 times the ULN, or > 5 times the ULN, if liver metastases are present). 
9. The subject has inadequate renal function (serum creatinine > 2.0 mg/dL). 
10. The subject has inadequate coagulation function (an international normalized 
ratio [INR] > 1.5 and a partial thromboplastin time [PTT] > 5 seconds above the 
ULN [unless on oral anticoagulant therapy]). Subjects receiving full-dose 
anticoagulation therapy are eligible provided they meet all other criteria, are on 
a stable dose of oral anticoagulant or low molecular weight heparin (and if on 
warfarin have a therapeutic INR between 2 and 3). 
11. Hepatic blood flow abnormalities: portal vein hypertension and thrombosis; 
and/or large volume of ascites. 
12. Concurrent cancer of any other type except skin cancer (excluding melanoma). 
13. History of allergic reactions to mouse antigen. 
14. The subject has an ongoing or active infection, symptomatic congestive heart 
failure, unstable angina pectoris, serious cardiac arrhythmias, (well-controlled 
atrial fibrillation, is permitted,) psychiatric illness/social situations that could 
interfere with the subject’s ability to participate in the protocol, active bleeding.  
15. As a result of the medical history, examination or blood testing, the investigator 
considers the subject unfit for the study. 
 
 

 
 
 
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4.4  Screening to Exclude Subjects with Allergic Reactions to Mouse 
Antigens 
All subjects eligible for this protocol will be screened by history of allergy to 
mouse antigens and with an available mouse allergen extract using skin testing 
initially to determine if a wheal and flare reaction is present.  This will be carried 
out with Greer Laboratories, Inc. product # E2 (mouse epithelia).  A positive 
reaction in the skin test will exclude the subject from this protocol.  Positive control 
with histamine, and negative control with saline or glycerin will be done along with 
each murine skin test. 
 
Baseline and follow-up Human Anti-Mouse Antibody (HAMA) levels will not 
be followed in this Phase 2 trial in as much as the experience in the Phase I trial 
indicated that HAMA is not a reliable indicator of reaction to mouse antigens.  
False positives are a major problem. 
 
4.5  Treatments 
4.5.1 Dosage Determination 
 
 
Based on the animal studies conducted to date, as well as the Phase I 
human trial, a reasonable dosage range (number of beads implanted) is 8 
macrobeads per kilogram of body weight.  We know that 16 macrobeads per 
kilogram was also well tolerated in the Phase I human trial, but, at least with a 
single dose, this number was not seen to be any more effective than 8 
macrobeads per kilogram. Given the fact, it is planned to carry out up to four 
implants (over approximately 12 months) in this Phase II trial, each implantation 
will be carried out at the 8 macrobeads per kilogram dosage.    
 
4.5.2 Drug Labeling 
 
Labeling will be defined as in BB-IND 10092. 
 
4.6  Assessments 
 
 
The objective of the proposed Phase II study of the RENCA macrobeads is, 
as stated above, to determine the human clinical efficacy of the cancer 
macrobeads in advanced pancreatic and colorectal cancer.  Responses will be 

 
 
 
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assessed according to the usual categories of complete or partial response (with 
specification of percentage), and none/progression (with specification of 
percentage).  Response assessment will be measured in terms of changes in 
volume of primary tumor and number of metastases as assessed by CT or MRI; 
tumor marker PSA, as well as the physician global clinical assessment; 
performance rating scale (Karnofsky or similar); quality of subject life as measured 
by the EORTC Quality of Life Scale. Alkaline phosphatase and lactic 
dehydrogenase will also be followed. 
 
Other laboratory determinations to monitor subject response to the 
implantation of the macrobeads will include detection of inflammatory responses 
(CBC with differential WBC and platelet count, erythrocyte sedimentation rate, C-
reactive protein, amylase, immunological changes, and cytokine production), RT-
PCR (polymerase chain reaction) specific to e-MuLV DNA, plasma viremia, and 
antibodies to normal murine antigens.  
 
 
A critical and unique addition to the endpoints for assessing efficacy will be, 
where possible, a careful search for and identification of the niches of cancer stem 
and other cells within the niche bodies of the tumors the macrobeads are being 
used to treat.  Markers of the niche bodies used to identify them and study their 
state (numbers, integrity of surround blood vessels, degree of stress) will include 
HLA, CD44+, CD133+, p27, Ki67, and the Tunel assay for apoptosis, 
Determination of the presence or absence of circulating tumor cells will also be 
made.  When possible/available, pathology specimens will be examined for cancer 
stem cell niches. 

 
 
 
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5 STUDY CONDUCT 
 
5.1  Schedule of Assessments 
 
Clinical procedures, laboratory tests, and other measures to be utilized (and 
their order and flow) in the trial are indicated in Appendix 2 (section 9.2), and 
below:  
5.1.1 Study Days -28 to -1: 
 
1. Pretreatment evaluations used to determine the subject’s study eligibility must 
be completed within 28 days prior to implantation unless otherwise specified for 
particular individuals and circumstances 
2. Written informed consent must be obtained prior to performing to any study-
specific evaluations. Results of all pretreatment evaluations must be reviewed by 
the Principal Investigator or his/her designee to ensure that all eligibility criteria 
have been satisfied prior to subject implantation. There will be a complete review 
of the subject’s cancer history and reports of tumor biopsies obtained. A series of 
clinical tests and procedures are to be performed at different intervals throughout 
the study.  
3. All subjects must undergo the following pretreatment evaluations: 
• Medical history (including an assessment of baseline conditions, global 
clinical assessment, symptoms rating/severity assessment, quality of life 
scale [EORTC], pain scale assessment and activity of daily living rating) 
• Physical examination (including neurological examination, height and 
weight measurements) 
• Recording ECOG Performance Status and Karnofsky Performance Status  
• Vital signs (including temperature, pulse rate, respiration rate and blood 
pressure) 
• Concomitant medication assessment (including those medications taken 
within 30-days prior to implantation) 
• Hematology profile (CBC with differential WBC and platelet count) 
• Coagulation profile (PT, PTT and INR) 
• Erythrocyte sedimentation rate 
• Comprehensive chemistry profile (CO2, sodium, potassium, chloride, 
creatinine, BUN, glucose, calcium, total protein, albumin, total bilirubin, 
alkaline phosphatase, AST and ALT), glucose, GGT, LD 
• Urinalysis, and if clinically indicated, a 24-hour urine collection 
• Amylase, lipase 
• Serum direct bilirubin 

 
 
 
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• Immunoglobulin levels 
• Tumor markers: CEA, CA 19-9, CA 125. 
• Circulating Tumor Cell levels (if possible) 
• Baseline ECG within 28 days of implantation 
• PA/lateral chest x-ray (within 28 days of implantation). If chest x-ray results 
indicate potential thoracic cancer-related abnormalities, then perform a non-
contrast chest CT (within 21 days of implantation). 
• PET-CT of whole body or MRI of the abdomen and pelvis (within 21 days 
prior to receiving first implant) 
• Radionuclide bone scan (only if medically indicated) 
• Disease assessment (baseline tumor assessment from x-rays, CT/MRI, and 
bone scans) 
• C-reactive protein 
• Hepatitis B, C, E  
• HIV 
• Cellular immune function 
o T cells 
o Cytokine production 
o B cells 
o Antibodies to common bacteria and viruses (diphtheria, tetanus, 
mumps, rubella) 
o Quantitative IgG subclass determinations 
o NK cells count (CD16) 
• Ecotropic murine leukemia virus (e-MuLV) (PCR-based assay) 
• Murine allergen skin test, including positive and negative controls 
• Pregnancy test for females of childbearing potential 
 
5.1.2 Decision to Proceed with First Implantation 
 
The medical/surgical decision to proceed to the first implantation will be 
made based on the overall clinical assessment (physical examination, vital signs, 
EKG, routine blood work, status of the subject’s cancer, availability of alternate 
treatment modalities, and the absence of evidence of allergic reaction to mouse 
antigens).  Much of the above testing, such as that for immunological function, will 
not be available by Day -1, but the samples for testing will be obtained prior to 
therapy and the results of the testing is intended to establish a reliable baseline for 
research purposes and would not have an impact on the clinical decision-making 
process. 
 
 
 

 
 
 
The Rogosin Institute 
 
Protocol No.  0911010739 
 
 
Version: Amendment 11 
 
 
CONFIDENTIAL 
 
 
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5.1.3 Study Day -28 to Study Day -1: 
 
 
From Study Day -28 to Study Day -1, all test results that are available will 
be collected and reviewed.  If the data indicate that there are no contraindications 
to proceeding, on Day 0 (Day of Implantation), RENCA macrobeads (8 per kg 
body weight) will be implanted intraperitoneally.  
5.1.4 Visit 1 / Study Day 0: 
 
The day of implantation will be protocol Implant 1 / Study Day 0.  RENCA 
macrobeads (8 per kg body weight) will be implanted intraperitoneally. The subject 
will receive a small abdominal incision(s) utilizing laparoscopy, when possible, 
under general or local anesthesia, as indicated, and under sterile conditions in the 
operating rooms of New York Presbyterian Hospital.  The location of the incision(s) 
will be at the surgeon’s discretion. Standard procedures call for the administration 
of 1 gm of cefazolin just prior to surgery as antibiotic prophylaxis, unless otherwise 
indicated by the subject’s medical history (allergies or other condition). 
 
Standard surgical procedures and three-layer closure of the abdominal 
wound, if possible, will be carried out.  Vital signs will be monitored as per routine 
for a post-laparoscopy subject and according to any special needs individual 
subjects may have. Assuming that the subject’s post-surgical condition is stable 
(as defined by standard post-operative criteria) and that the subject is taking oral 
fluids and soft foods at a minimum, the subject will be discharged from surgical 
recovery room to either home care or hospital confinement as soon as medically 
indicated which may be same day as implantation. Any other blood drawing or 
procedures will be those dictated by optimal clinical care.   
 
If deemed medically and surgically safe by the operating surgeon, one or 
more biopsies of tumor mass will be taken during this procedure. Fresh frozen 
tissue 
and 
fixative-treated 
tissue 
will 
be 
sent 
to 
the 
laboratory 
for 
immunohistochemical and gene array analysis to determine baseline tumor 
histopathology and gene expression patterns. 
 
5.1.5 Home Care: 
 
 
Post-surgical home care requirements are expected to be minimal. Medical 
and wound care regimens will be carried out as individually prescribed by the 
investigators and appropriate physicians directly involved in the subject’s care.  
The subject will complete a daily log of activity (ADL) and a general symptom 
checklist (defined subjectively), but with special emphasis on appetite, abdominal 
symptoms such as pain or cramping, bowel movements, urination (frequency, 

 
 
 
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dysuria), and pain medication requirements.  Both the subject and her/his family 
members will be trained in the simple vital sign measurements and the filling in of 
the activity log/assessment and symptom checklist.  Vital signs will be measured 
twice daily at 8am and 8pm for the first month after implantation, then once a day 
for the next two months. The investigators may modify this schedule, if the clinical 
circumstances demand such modification.  Subject and family training will take 
place prior to macrobead implantation, with a review prior to discharge after 
implantation.  
 
A critical safety parameter will be the determination of the presence or 
absence of antibody to murine viruses, including mouse leukemia virus (MuLV), as 
well as viral titers for murine viruses known to be infective for humans.  The 
published literature and the co-culture experiments carried out in our laboratory do 
not indicate that MuLV can infect human cells.  Furthermore, the RENCA cells 
used to prepare the cancer macrobead have tested negative for other known 
murine viruses (Charles River panel of 18 murine viruses).  In addition, none of the 
thirty-one (31) subjects treated to date in the Phase I study have shown any 
evidence of viral infection associated with the macrobeads. Nonetheless, this 
protocol includes laboratory and clinical monitoring for any such viral transmission.  
If there is any laboratory or clinical evidence indicating or suggesting a viral 
infection with MuLV, all family members having direct physical contact with that 
subject will also be assessed for the identified murine virus or for any clinical or 
laboratory evidence of a known or unknown viral infection.  Virological monitoring 
of all staff in contact with the subject will be carried out at that time as well.  It 
should be emphasized again that there has been no evidence of such 
transmission or infection in the Phase I trial. 
 
5.1.6 Visit 2, Study Day 14 ± 3 days: 
 
A brief examination including the parameters listed below will be performed. 
Assuming that the wound examination is satisfactory, all sutures/staples will be 
removed by the surgeon who performed the laparoscopy or appropriate surrogate.  
In addition, the Investigator will also examine the subject.   
 
The following data will be obtained: 
 
• Vital signs with weight 
• Physical examination with brief neurological exam 
• CBC with differential WBC, platelet count 
• Coagulation profile (PT, PTT and INR) 
• Erythrocyte sedimentation rate 
• Comprehensive Metabolic Panel with LD, GGT, CRP, direct bilirubin 

 
 
 
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• Cytokine panel  
• CEA, CA 19-9, CA 125 
• Circulating Tumor Cell Levels 
• Monitoring of adverse events and concomitant medications 
• Global clinical assessment 
• Quality of life scale 
• ECOG and Karnofsky Performance status rating 
• Pain scale, if appropriate 
 
5.1.7 Visit 3, Study Day 30 ± 5 days: 
The following data will be obtained: 
 
• Vital signs with weight 
• Physical examination with brief neurological exam 
• CBC with differential WBC, platelet count 
• Coagulation profile (PT, PTT and INR) 
• Erythrocyte sedimentation rate 
• Comprehensive Metabolic Panel with LD, GGT, CRP, direct bilirubin 
• Cytokine panel  
• CEA, CA 19-9, CA 125 
• Circulating Tumor Cell Levels 
• Ecotropic murine leukemia virus tests 
• Monitoring of adverse events and concomitant medications 
• Global clinical assessment 
• Quality of life scale 
• ECOG and Karnofsky Performance status rating 
• Pain scale, if appropriate 
 
 
5.1.8 Visit 4, Study Day 60 ± 5 days: 
The following data will be obtained: 
 
• Vital signs with weight 
• Physical examination with brief neurological exam 
• CBC with differential WBC, platelet count 
• Coagulation profile (PT, PTT and INR) 
• Erythrocyte sedimentation rate 
• Comprehensive Metabolic Panel with LD, GGT, CRP, direct bilirubin 
• Cytokine panel  
• CEA, CA 19-9, CA 125 

 
 
 
The Rogosin Institute 
 
Protocol No.  0911010739 
 
 
Version: Amendment 11 
 
 
CONFIDENTIAL 
 
 
Page 34 of 77 
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• Circulating Tumor Cell Levels 
• Monitoring of adverse events and concomitant medications 
• Global clinical assessment 
• Quality of life scale 
• ECOG and Karnofsky Performance status rating 
• Pain scale, if appropriate 
 
5.1.9 Visit 5, Study Day 90 ± 5 days: 
 
The following data will be obtained: 
 
• Vital signs with weight 
• Physical examination with brief neurological exam 
• CBC with differential WBC, platelet count 
• Coagulation profile (PT, PTT and INR) 
• Erythrocyte sedimentation rate 
• Comprehensive Metabolic Panel with LD, GGT, CRP, direct bilirubin 
• Cytokine panel  
• CEA, CA 19-9, CA 125 
• Circulating Tumor Cell Levels 
• Ecotropic murine leukemia virus (immunology, PCR) tests 
• Monitoring of adverse events and concomitant medications 
• Global clinical assessment 
• Quality of life scale 
• ECOG and Karnofsky Performance status rating 
• Pain scale, if appropriate 
• MRI if needed  
• PET-CT scan of whole body 
• Pregnancy test, females of childbearing potential only  
• Urinalysis 
• EKG 
• CXR 
• Cellular immune function [T cells, B cells, Antibodies to common bacteria 
and viruses (diphtheria, tetanus, mumps, rubella), Quantitative IgG 
subclass determinations, NK cells count (CD16)] 
• Immunoglobulin Levels (IgA, IgG, IgE, IgM) 
• Murine allergen skin test, including positive and negative controls 

 
 
 
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Protocol No.  0911010739 
 
 
Version: Amendment 11 
 
 
CONFIDENTIAL 
 
 
Page 35 of 77 
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Decision to Proceed with Second Implantation 
All available information from the imaging studies, tumor marker and other 
laboratory findings, as well as physical examination findings and quality of life 
measurements from Visit 5 will be reviewed to determine if a subject is cleared for 
the proposed anesthesia and second implantation of macrobeads.  Assuming the 
subject is cleared, the second implantation will proceed as soon as possible.  
 
5.1.10  
Visit 6, Implant 2 / Study Day 0: 
 
Beginning 3 months after the first implant, the subject will be scheduled for 
a second implant of the cancer macrobeads at a dosage of 8 macrobeads per 
kilogram body weight.  Assuming that the subject’s post-surgical condition is stable 
(as defined by standard post-operative criteria) and that the subject is taking oral 
fluids and soft foods at a minimum, the subject will be discharged to home care as 
soon as medically indicated which may be the same day as implantation. 
 
If deemed medically and surgically safe by the operating surgeon, one or 
more biopsies of tumor mass will be taken during this procedure.  Fresh frozen 
tissue and fixative-treated tissue will be sent to the laboratory for 
immunohistochemical and gene array analysis to determine any changes in tumor 
state that may have been the result of exposure to the cancer macrobeads. 
 
5.1.11  
Visit 7, Implant 2 / Study Day 14 ± 3 days: 
 
A brief examination including the parameters listed below will be performed. 
Assuming that the wound examination is satisfactory, all sutures/staples will be 
removed by the surgeon who performed the laparoscopy or appropriate surrogate.  
In addition, the Investigator will also examine the subject.   
 
The following data will be obtained: 
 
• Vital signs with weight 
• Physical examination with brief neurological exam 
• CBC with differential WBC, platelet count 
• Coagulation profile (PT, PTT and INR) 
• Erythrocyte sedimentation rate 
• Comprehensive Metabolic Panel with LD, GGT, CRP, direct bilirubin 

 
 
 
The Rogosin Institute 
 
Protocol No.  0911010739 
 
 
Version: Amendment 11 
 
 
CONFIDENTIAL 
 
 
Page 36 of 77 
November 12th 2014 
  
 
 
 
 
 
 
 
 
• Cytokine panel  
• CEA, CA 19-9, CA 125 
• Circulating Tumor Cell Levels 
• Monitoring of adverse events and concomitant medications 
• Global clinical assessment 
• Quality of life scale 
• ECOG and Karnofsky Performance status rating 
• Pain scale, if appropriate 
 
5.1.12  
Visit 8, Implant 2 / Study Day 30 ± 5 days: 
The following data will be obtained: 
 
• Vital signs with weight 
• Physical examination with brief neurological exam 
• CBC with differential WBC, platelet count 
• Coagulation profile (PT, PTT and INR) 
• Erythrocyte sedimentation rate 
• Comprehensive Metabolic Panel with LD, GGT, CRP, direct bilirubin 
• Cytokine panel  
• CEA, CA 19-9, CA 125 
• Circulating Tumor Cell Levels 
• Ecotropic murine leukemia virus tests 
• Monitoring of adverse events and concomitant medications 
• Global clinical assessment 
• Quality of life scale 
• ECOG and Karnofsky Performance status rating 
• Pain scale, if appropriate 
 
 
5.1.13  
Visit 9, Implant 2 / Study Day 60 ± 5 days: 
The following data will be obtained: 
 
• Vital signs with weight 
• Physical examination with brief neurological exam 
• CBC with differential WBC, platelet count 
• Coagulation profile (PT, PTT and INR) 
• Erythrocyte sedimentation rate 
• Comprehensive Metabolic Panel with LD, GGT, CRP, direct bilirubin 
• Cytokine panel  
• CEA, CA 19-9, CA 125 

 
 
 
The Rogosin Institute 
 
Protocol No.  0911010739 
 
 
Version: Amendment 11 
 
 
CONFIDENTIAL 
 
 
Page 37 of 77 
November 12th 2014 
  
 
 
 
 
 
 
 
 
• Circulating Tumor Cell Levels 
• Monitoring of adverse events and concomitant medications 
• Global clinical assessment 
• Quality of life scale 
• ECOG and Karnofsky Performance status rating 
• Pain scale, if appropriate 
 
5.1.14  
Visit 10, Implant 2 / Study Day 90 ± 5 days: 
The following data will be obtained: 
 
• Vital signs with weight 
• Physical examination with brief neurological exam 
• CBC with differential WBC, platelet count 
• Coagulation profile (PT, PTT and INR) 
• Erythrocyte sedimentation rate 
• Comprehensive Metabolic Panel with LD, GGT, CRP, direct bilirubin 
• Cytokine panel  
• CEA, CA 19-9, CA 125 
• Circulating Tumor Cell Levels 
• Ecotropic murine leukemia virus (immunology, PCR) tests 
• Monitoring of adverse events and concomitant medications 
• Global clinical assessment 
• Symptoms rating/severity assessment 
• Quality of life scale 
• ECOG and Karnofsky Performance status rating 
• Pain scale, if appropriate 
• MRI if needed  
• PET-CT scan of whole body 
• Pregnancy test, females of childbearing potential only  
• Urinalysis 
• EKG 
• CXR 
• Cellular immune function [T cells, B cells, Antibodies to common bacteria 
and viruses (diphtheria, tetanus, mumps, rubella), Quantitative IgG 
subclass determinations, NK cells count (CD16)] 
• Immunoglobulin Levels (IgA, IgG, IgE, IgM) 
• Murine allergen skin test, including positive and negative controls 
 

 
 
 
The Rogosin Institute 
 
Protocol No.  0911010739 
 
 
Version: Amendment 11 
 
 
CONFIDENTIAL 
 
 
Page 38 of 77 
November 12th 2014 
  
 
 
 
 
 
 
 
 
Decision to Proceed with Third Implantation 
All available information from the imaging studies, tumor marker and other 
laboratory findings, as well as physical examination findings and quality of life 
measurements from Visit 10 will be reviewed to determine if a subject is cleared 
for the proposed anesthesia and third implantation of macrobeads.  Assuming the 
subject is cleared, the third implantation will proceed as soon as possible.  
 
5.1.15  
Visit 11, Implant 3 / Study Day 0: 
 
Beginning 3 months after the second implant, the subject will be scheduled 
for a third implant of the cancer macrobeads at a dosage of 8 macrobeads per 
kilogram body weight.  Assuming that the subject’s post-surgical condition is stable 
(as defined by standard post-operative criteria) and that the subject is taking oral 
fluids and soft foods at a minimum, the subject will be discharged to home care as 
soon as medically indicated which may be same day as implantation. 
 
If deemed medically and surgically safe by the operating surgeon, one or 
more biopsies of tumor mass will be taken during this procedure.  Fresh frozen 
tissue and fixative-treated tissue will be sent to the laboratory for 
immunohistochemical and gene array analysis to determine any changes in tumor 
state that may have been the result of exposure to the cancer macrobeads. 
 
5.1.16  
Visit 12, Implant 3 / Study Day 14 ± 3 days: 
 
A brief examination including the parameters listed below will be performed. 
Assuming that the wound examination is satisfactory, all sutures/staples will be 
removed by the surgeon who performed the laparoscopy or appropriate surrogate.  
In addition, the Investigator will also examine the subject.   
 
The following data will be obtained: 
 
• Vital signs with weight 
• Physical examination with brief neurological exam 
• CBC with differential WBC, platelet count 
• Coagulation profile (PT, PTT and INR) 
• Erythrocyte sedimentation rate 
• Comprehensive Metabolic Panel with LD, GGT, CRP, direct bilirubin 
• Cytokine panel  
• CEA, CA 19-9, CA 125 

 
 
 
The Rogosin Institute 
 
Protocol No.  0911010739 
 
 
Version: Amendment 11 
 
 
CONFIDENTIAL 
 
 
Page 39 of 77 
November 12th 2014 
  
 
 
 
 
 
 
 
 
• Circulating Tumor Cell Levels 
• Monitoring of adverse events and concomitant medications 
• Global clinical assessment 
• Quality of life scale 
• ECOG and Karnofsky Performance status rating 
• Pain scale, if appropriate 
 
5.1.17  
Visit 13, Implant 3 / Study Day 30 ± 5 days: 
The following data will be obtained: 
 
• Vital signs with weight 
• Physical examination with brief neurological exam 
• CBC with differential WBC, platelet count 
• Coagulation profile (PT, PTT and INR) 
• Erythrocyte sedimentation rate 
• Comprehensive Metabolic Panel with LD, GGT, CRP, direct bilirubin 
• Cytokine panel  
• CEA, CA 19-9, CA 125 
• Circulating Tumor Cell Levels 
• Ecotropic murine leukemia virus tests 
• Monitoring of adverse events and concomitant medications 
• Global clinical assessment 
• Quality of life scale 
• ECOG and Karnofsky Performance status rating 
• Pain scale, if appropriate 
 
 
5.1.18  
Visit 14, Implant 3 / Study Day 60 ± 5 days: 
The following data will be obtained: 
 
• Vital signs with weight 
• Physical examination with brief neurological exam 
• CBC with differential WBC, platelet count 
• Coagulation profile (PT, PTT and INR) 
• Erythrocyte sedimentation rate 
• Comprehensive Metabolic Panel with LD, GGT, CRP, direct bilirubin 
• Cytokine panel  
• CEA, CA 19-9, CA 125 
• Circulating Tumor Cell Levels 
• Monitoring of adverse events and concomitant medications 

 
 
 
The Rogosin Institute 
 
Protocol No.  0911010739 
 
 
Version: Amendment 11 
 
 
CONFIDENTIAL 
 
 
Page 40 of 77 
November 12th 2014 
  
 
 
 
 
 
 
 
 
• Global clinical assessment 
• Quality of life scale 
• ECOG and Karnofsky Performance status rating 
• Pain scale, if appropriate 
 
5.1.19  
Visit 15, Implant 3 / Study Day 90 ± 5 days: 
The following data will be obtained: 
 
• Vital signs with weight 
• Physical examination with brief neurological exam 
• CBC with differential WBC, platelet count 
• Coagulation profile (PT, PTT and INR) 
• Erythrocyte sedimentation rate 
• Comprehensive Metabolic Panel with LD, GGT, CRP, direct bilirubin 
• Cytokine panel  
• CEA, CA 19-9, CA 125 
• Circulating Tumor Cell Levels 
• Ecotropic murine leukemia virus (immunology, PCR) tests 
• Monitoring of adverse events and concomitant medications 
• Global clinical assessment 
• Quality of life scale 
• ECOG and Karnofsky Performance status rating 
• Pain scale, if appropriate 
• MRI if needed  
• PET-CT scan of whole body 
• Pregnancy test, females of childbearing potential only  
• Urinalysis 
• CXR 
• EKG 
• Cellular immune function [T cells, B cells, Antibodies to common bacteria 
and viruses (diphtheria, tetanus, mumps, rubella), Quantitative IgG 
subclass determinations, NK cells count (CD16)] 
• Murine allergen skin test, including positive and negative controls 
• Immunoglobulin Levels (IgA, IgG, IgE, IgM) 
 
Decision to Proceed with Fourth Implantation 
All available information from the imaging studies, tumor marker and other 
laboratory findings, as well as physical examination findings and quality of life 
measurements from Visit 15 will be reviewed to determine if a subject is cleared 

 
 
 
The Rogosin Institute 
 
Protocol No.  0911010739 
 
 
Version: Amendment 11 
 
 
CONFIDENTIAL 
 
 
Page 41 of 77 
November 12th 2014 
  
 
 
 
 
 
 
 
 
for the proposed anesthesia and fourth implantation of macrobeads.  Assuming 
the subject is cleared, the fourth implantation will proceed as soon as possible.  
 
5.1.20  
Visit 16, Implant 4 / Study Day 0: 
 
Beginning 3 months after the third implant, the subject will be scheduled for 
a fourth implant of the cancer macrobeads at a dosage of 8 macrobeads per 
kilogram body weight.  Assuming that the subject’s post-surgical condition is stable 
(as defined by standard post-operative criteria) and that the subject is taking oral 
fluids and soft foods at a minimum, the subject will be discharged to home care as 
soon as medically indicated which may be same day as implantation. 
 
If deemed medically and surgically safe by the operating surgeon, one or 
more biopsies of tumor mass will be taken during this procedure.  Fresh frozen 
tissue and fixative-treated tissue will be sent to the laboratory for 
immunohistochemical and gene array analysis to determine any changes in tumor 
state that may have been the result of exposure to the cancer macrobeads. 
 
5.1.21  
Visit 17, Implant 4 / Study Day 14 ± 3 days: 
 
A brief examination including the parameters listed below will be performed. 
Assuming that the wound examination is satisfactory, all sutures/staples will be 
removed by the surgeon who performed the laparoscopy or appropriate surrogate.  
In addition, the Investigator will also examine the subject.   
 
The following data will be obtained: 
 
• Vital signs with weight 
• Physical examination with brief neurological exam 
• CBC with differential WBC, platelet count 
• Coagulation profile (PT, PTT and INR) 
• Erythrocyte sedimentation rate 
• Comprehensive Metabolic Panel with LD, GGT, CRP, direct bilirubin 
• Cytokine panel  
• CEA, CA 19-9, CA 125 
• Circulating Tumor Cell Levels 
• Ecotropic murine leukemia virus tests 
• Monitoring of adverse events and concomitant medications 
• Global clinical assessment 

 
 
 
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Protocol No.  0911010739 
 
 
Version: Amendment 11 
 
 
CONFIDENTIAL 
 
 
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November 12th 2014 
  
 
 
 
 
 
 
 
 
• Quality of life scale 
• ECOG and Karnofsky Performance status rating 
• Pain scale, if appropriate 
 
5.1.22  
Visit 18, Implant 4 / Study Day 30 ± 5 days: 
The following data will be obtained: 
 
• Vital signs with weight 
• Physical examination with brief neurological exam 
• CBC with differential WBC, platelet count 
• Coagulation profile (PT, PTT and INR) 
• Erythrocyte sedimentation rate 
• Comprehensive Metabolic Panel with LD, GGT, CRP, direct bilirubin 
• Cytokine panel  
• CEA, CA 19-9, CA 125 
• Circulating Tumor Cell Levels 
• Ecotropic murine leukemia virus tests 
• Monitoring of adverse events and concomitant medications 
• Global clinical assessment 
• Quality of life scale 
• ECOG and Karnofsky Performance status rating 
• Pain scale, if appropriate 
 
5.1.23  
Visit 19, Implant 4 / Study Day 60 ± 5 days: 
The following data will be obtained: 
 
• Vital signs with weight 
• Physical examination with brief neurological exam 
• CBC with differential WBC, platelet count 
• Coagulation profile (PT, PTT and INR) 
• Erythrocyte sedimentation rate 
• Comprehensive Metabolic Panel with LD, GGT, CRP, direct bilirubin 
• Cytokine panel  
• CEA, CA 19-9, CA 125 
• Circulating Tumor Cell Levels 
• Monitoring of adverse events and concomitant medications 
• Global clinical assessment 
• Quality of life scale 
• ECOG and Karnofsky Performance status rating 
• Pain scale, if appropriate 

 
 
 
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5.1.24  
Visit 20, Implant 4 / Study Day 90 ± 5 days: 
The following data will be obtained: 
 
• Vital signs with weight 
• Physical examination with brief neurological exam 
• CBC with differential WBC, platelet count 
• Coagulation profile (PT, PTT and INR) 
• Erythrocyte sedimentation rate 
• Comprehensive Metabolic Panel with LD, GGT, CRP, direct bilirubin 
• Cytokine panel  
• CEA, CA 19-9, CA 125 
• Circulating Tumor Cell Levels 
• Ecotropic murine leukemia virus (immunology, PCR) tests 
• Monitoring of adverse events and concomitant medications 
• Global clinical assessment 
• Quality of life scale 
• ECOG and Karnofsky Performance status rating 
• Pain scale, if appropriate 
• Urinalysis 
 
5.1.25  
Visit 21, Implant 4 / Study Day 120 ± 5 days: 
 
This will be the last formal protocol visit.  The following data will be 
obtained: 
 
• Physical examination with brief neurological exam 
• Vital signs with weight 
• CBC with differential WBC and platelet count 
• Coagulation profile (PT, PTT and INR) 
• Erythrocyte sedimentation rate 
• Comprehensive Metabolic Panel with LD, GGT, CRP, direct bilirubin 
• Cytokine levels 
• Ecotropic murine leukemia virus tests 
• CEA, CA 19-9, CA 125 
• Circulating tumor cells 
• Monitoring of adverse events and concomitant medications 
• Global clinical assessment 
• ECOG and Karnofsky Performance status rating 
• Quality of life scale 

 
 
 
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• ECOG performance scale rating 
• MRI as needed, PET-CT scan of whole body 
• Pain scale, if appropriate 
 
After Day 120 of the fourth implantation, all examinations and further 
treatment will be guided by optimal patient care principles and the decisions of the 
physicians providing overall health care to the subject.  It should be noted that all 
subjects entered into this trial will be followed at appropriate intervals (not less 
than yearly) for the rest of their lives in accord with USPHS regulations and 
guidelines for any procedures or treatments involving xenotransplantation. 
 
With regard to the question of whether the macrobeads can or should 
remain implanted or be removed, the safety data in the laboratory animals and the 
veterinary patients (cats and dogs) have indicated that the beads are well tolerated 
for at least one year, four years being the longest that any of the RENCA 
macrobeads have been followed in vivo to date. Some chronic peritoneal 
inflammation has been seen with RENCA macrobeads in those animals where the 
RENCA macrobeads have been in place for more than 3 months, although no 
clinical evidence of functional problems or signs or symptoms resulting from this 
reaction has been documented.  
 
In human subjects in the Phase I trial, there has been no evidence that the 
macrobeads have caused any adverse clinical effects and thus far have been well-
tolerated for up to 24 months. This has been true for subjects receiving the 8 
macrobeads per kg or 16 macrobeads per kg doses.  Four subjects also received 
a second implant at the 8 macrobeads per kg dose and tolerated that well.  Post-
mortem results in those subjects consenting to such examination have revealed 
some fibrinous collections around some of the beads, but no clinically significant 
peritonitis and no alterations in organ structure or function, specifically bowel 
function.  There have been no requests for or attempts at macrobead removal. 
 
Unfortunately, macrobeads removed at post-mortem examination are not 
suitable for any testing other than formalin fixation and possibly histology because 
of the time from death to actual performance of the autopsy.  Should any beads be 
removed in the course of one of the subsequent implantations, they will be sent for 
histology, MTT testing, inhibition testing, and routine microbiology screening. 
 
The study will continue to follow the subject regardless of macrobead 
function.  Further examinations will be at approximately 6-month intervals for 2 
years and then yearly thereafter for the life of the subject.  Per PI’s discretion, 
these long-term examinations may include: 
 
• General Physical Examination with Brief neurological Exam; 

 
 
 
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• Vital signs with weight; 
• PET-CT of whole body; 
• MRI scans as needed; 
• CBC with differential WBC and platelet count; 
• Coagulation Panel; 
• Erythrocyte sedimentation rate; 
• Comprehensive Metabolic Panel with LD, GGT, CRP, direct bilirubin 
• CEA, CA 19-9, CA 125; 
• Cytokine panel; 
• Ecotropic murine leukemia virus tests 
• All subjects will be monitored for adverse events and concomitant 
medications; 
• Global clinical assessment; 
• Activities of daily living rating; 
• Symptoms rating/severity assessment; 
• Quality of life scale; 
• ECOG and Karnofsky Performance status rating; 
• Pain scale, if appropriate; 
 
Should the subject die, and the subject and/or his/her family have 
consented to it, a postmortem examination will be carried out.  Permission for such 
an examination is requested in the consent form, although the subject’s decision 
cannot be binding on his/her family in the event of the subject’s death.  The 
subject is also free to change his/her own decision at any time during or after the 
study. Samples of tumor tissue (primary and metastatic sites), peritoneum, internal 
organ serosa and underlying tissue may be taken at any postmortem examination 
to evaluate tumor state and any inflammatory or connective tissue reaction to the 
RENCA macrobeads.  
5.2  Number of Clinical Sites 
 
One clinical site will be utilized. 
 
5.3  Safety and Tolerability Assessments 
 
All subjects will be monitored for safety at every visit and with telephone 
follow-ups at regular intervals between visits.  At every scheduled study visits, this 
monitoring will include routine checks of the subject’s clinical status, measuring of 
vital signs, physical examination including a neurological examination, clinical 
laboratory evaluations including clinical chemistries, hematology, urinalysis, liver 
functions tests, monitoring of tumor markers, CT/MRI scans as appropriate, and 

 
 
 
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the monitoring of adverse events, as well as global clinical assessments, quality of 
life, performance and pain, if any. At unscheduled visits, evaluations will be done 
at the PI’s discretion.  
 
5.4  Medical History 
 
A complete medical history will be collected from each subject.  This will 
include an evaluation of the subject’s malignancy, a recording of the results of 
previous diagnostic tests and therapies.  This evaluation will include an 
assessment of possible therapies that can be used for the management of the 
malignant condition.  The medical/surgical decision to proceed to the first 
implantation will be made based on the overall clinical assessment.  This overall 
clinical assessment will include an evaluation of the medical history, physical 
examination, vital signs, EKG, routine blood work, and the absence of evidence of 
allergic reaction to mouse antigens. 
 
5.5  Physical Examination 
 
All subjects will undergo a complete physical examination including vital 
signs, with measurement of height and weight.   
 
• Complete physical examination with all vital signs 
• Weight 
• Global Clinical Assessment 
 
5.6  Clinical Laboratory Parameters 
 
The following clinical laboratory parameters will be tested in all subjects (the 
schedule is summary in Appendix 2 – Section 9.2): 
 
• EKG 
• Biochemical/immune system profile including  
• Complete blood count (CBC) with differential WBC and platelet count 
• Erythrocyte sedimentation rate 
• C-reactive protein 
• Biochemical profile as outlined above with amylase, lipase at screening, 
and thereafter as medically necessary 
• Liver function (AST, ALT, LD, alkaline phosphatase, GGT)  
• Urinalysis 
• Coagulation profile (PT, INR, PTT) 

 
 
 
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• Hepatitis B, C, E 
• HIV 
• CEA, CA 19-9, CA 125   
• Immunoglobulin levels (IgA, IgG, IgE, IgM) 
• Skin testing with murine epithelial antigen preparation, along with positive 
and negative controls 
• Cellular immune function 
o T cells 
o Cytokine production 
o B cells 
o Antibodies to common bacteria and viruses (diphtheria, pertussis, 
tetanus, mumps, rubella) 
o Quantitative IgG subclass determinations 
o NK cells count (CD16) 
• Ecotropic murine leukemia virus (e-MuLV) (PCR-based assay) 
• Abdominal/whole body MRI/CT scan with other imaging studies as 
appropriate for the subject’s tumor (primary and metastatic) and condition. 
Ultrasound examination, if medically indicated, will include views of the 
hepatic veins and inferior vena cava to be certain that they are free of clots 
and that there is free peritoneal drainage. 
 
5.7  Appropriateness of Measurements and Assessments 
 
In the evaluation of a therapeutic entity for the treatment of a malignant 
condition such as advanced pancreatic or colon cancer, the following 
measurements are appropriate. The response of each subject to the 
intraperitoneal implantation of RENCA agarose-agarose macrobeads will be 
measured with respect to: 
• primary tumor size 
• response: complete, partial, stable disease, progression 
• progression as defined in Section 3 of the protocol 
• size or number of secondary/metastatic tumors; tumor markers or relevant 
biochemical parameters such as liver enzymes 
• tumor metabolic activity as measured by 19F-fluorodeoxyglucose uptake (if 
applicable) 
• cellular or humoral immune status 
• cytokines 
• inflammatory response 
• global clinical assessment 
• activities of daily living (ADL) rating/performance status 
• symptom rating/ severity (including use of pain medications) 

 
 
 
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• quality of life 
• neuropsychological status/cognitive function 
• pain rating scale, if appropriate 
 
5.8  Progression of Disease During the Study 
 
In addition to the subject’s overall response to the implantation of the 
RENCA agarose-agrose macrobeads, subjects will be monitored for evidence of 
progression during the study.  Evidence of local or metastatic disease progression 
will be based on clinical signs and symptoms, imaging studies and biochemical 
parameters as appropriate after a minimum period of eight weeks after each 
RENCA macrobead implantation will initiate a formal, documented discussion of 
the Principal Investigator, subject’s attending or primary physician, if any, other 
consultants if appropriate, and the subject and his/her family regarding 
consideration of the use of other available standard or experimental therapies.  
The decision to employ another therapy may be made jointly or by the subject 
himself/herself.  
 
Where the evidence of such progression is questionable or unclear, review 
of the subject’s condition and laboratory or imaging data (after the minimum period 
of nine weeks) as defined by the protocol and discussion with the subject and 
his/her primary physician/consultant(s) will be carried out with careful 
documentation of the discussions and any decisions or uncertainties.  New bone 
lesions detected on bone scans at the end of the initial 90 days after implantation) 
may reflect pretreatment disease activity, and may not necessarily constitute 
disease progression unless confirmed by additional lesions developing 
subsequently.  Hence, subjects will be evaluated for progression based on the 
following criteria: 1. Tumor progression with PET-CT/MRI assessments after every 
cycle). 2. Evidence of progression demonstrating the appearance of ≥ 2 new 
lesions. New lesions detected at the end of the initial implantation period and 
confirmed confirmation ≥ 6 weeks later. 3. Symptomatic progression (for subjects 
without measurable disease). Deterioration in ECOG PS of ≥ 2 units compared to 
baseline attributable to cancer in the opinion of the investigator. 4. Weight loss ≥ 
20% (NCI-CTCAE v 3.0, Grade 3) of the initial body weight attributable to cancer 
in the opinion of the investigator.  5. Other clinical events attributable to the cancer 
that in the opinion of the investigator require major interventions, such as surgical 
intervention for pain control.  6. Death from any cause. If in the opinion of the 
investigator, the subject has symptomatic improvement as measured by 
improvement in pain scales or narcotic analgesic consumption and there is 
evidence of bone scan or biochemical progression, he may be continued on 
treatment at the investigators discretion. 

 
 
 
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5.9  Rescue Program 
 
During the time period that a subject is participating in this clinical study, the 
need may arise for additional oncologic therapy.  If an alternative or additional 
therapy other than the macrobeads becomes indicated, because of disease 
progression, this type of therapy would be considered Rescue Therapy.  This 
would include, for example, chemotherapy, radiation, surgery, or a different 
experimental protocol.  This rescue program would be instituted and would not 
require the suject to be discontinued from the RENCA macrobead protocol.  While 
undergoing these treatments, the subject will continue to be closely monitored for 
disease status as well as toxicity, as specified in this protocol.  Should the clinical 
situation develop, the principal investigator and subject, with appropriate 
consultant input, could restart treatment with the macrobeads.  A treatment 
“holiday” of at least three weeks (for chemotherapy) and four weeks (for radiation) 
would be required before commencing with this phase II protocol. 
 
6 SAFETY EVALUATIONS 
 
6.1 
Adverse Events 
 
Adverse events mean any sign, symptom, syndrome or illness that occurs 
or worsens during the use of the study device/drug, regardless of causality.  
Symptoms of abnormal laboratory values and clinically significant asymptomatic 
laboratory values will constitute adverse events.  A medical condition that is 
present when the subject enters the study is not defined as an adverse event, 
unless this medical condition worsens after the study drug has been administered.  
The Investigator, the safety physician of The Rogosin Institute, and the 
Safety Data Monitoring Board will be responsible for monitoring the safety 
parameters that are collected in the study.  As of their review of the safety/toxicity 
date from Phase I in June 2009, they found no adverse events attributable to the 
macrobeads.  The Safety Data Monitoring Board will independently review all 
safety parameters and safety results in the study.   
 
The description of the adverse events will use the CTCAE v3.0 definitions 
(issued on December 12, 2003) to define the severity or intensity of the adverse 
events and clinical laboratory abnormalities.  The coding of the adverse events will 
use the most current version of the Medical Dictionary for Regulatory Agencies 
(MedDRA).  The coding will include reported term, preferred term, and 
classification of the System, Organ, Class (SOC).  The coding of concomitant 
medications will use the latest version of the WHO Drug Dictionary (WHODD). 
 

 
 
 
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6.2 Classification of Adverse Events by Intensity 
 
If the intensity of the adverse event is not described in the CTCAE v3.0, the 
Investigator will rate the intensity of the adverse event according to the following 
scale. 
 
Grade 1 
Mild AE. The adverse event is transient and easily tolerated 
by the subject. 
 
Grade 2: 
Moderate AE. The adverse event causes the subject 
discomfort and interrupts the subject’s normal activities. 
 
Grade 3: 
Severe AE.   The adverse event causes considerable 
interference with the subject’s normal activities. 
 
Grade 4: 
Life-threatening or Disabling AE. 
 
Grade 5: 
Death 
 
6.3 Classification of Adverse Events by Relationship to Study Drug 
The Investigator will also assess the relationship of the adverse event to the 
RENCA macrobead according to the following definitions: 
 
Not related:  
The adverse event does not follow a reasonable temporal sequence from 
administration of the study drug, or that can be reasonably explained by 
other factors, including underlying disease, complications, concomitant 
drugs or concurrent treatment.  Even if the investigator feels there is no 
relationship to the study drug, the adverse event must be reported.   
 
Remote: 
The adverse event follows an improbable temporal sequence to study drug 
administration and in which underlying disease, complications, concomitant 
drugs or concurrent treatment offers a plausible explanation.   
 
Possibly related: 
The adverse event follows a reasonable temporal sequence from 
administration of the study drug (including the course after withdrawal of the 
study drug), that can not exclude the possibility of the study drug 
involvement, although other factors such as underlying disease, 
complications, concomitant drugs or concurrent treatment are presumable. 
 

 
 
 
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Probably related: 
The adverse event follows a reasonable temporal sequence from 
administration of the drug (including the course after withdrawal of the 
drug), and that can exclude the possibilities of other factors, such as 
underlying disease, complications, concomitant drugs or concurrent 
treatment, other than the study drug. 
 
These events will be reported to the IRB and FDA according to their requirements. 
 
6.4  
Serious Adverse Events 
 
A serious adverse event is any untoward medical occurrence, regardless of 
relationship to the study drug and intensity, at any dose that: 
 
• Results in death 
• Is life-threatening – (which is defined as an event in which the patient or 
subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it were more severe) 
• Requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in a persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Is an important medical event – (which is defined as a medical event(s) that 
may not be immediately life-threatening or results in death or hospitalization 
but, based upon appropriate medical and scientific judgment, may 
jeopardize the subject or may require intervention (e.g., medical, surgical) 
to prevent any of the other serious outcome listed in the definition above.   
Examples of such event include, but are not limited to, intensive treatment 
in an emergency room or at home or allergic bronchospasm; blood 
dyscrasias, or convulsions that do not result in hospitalization 
 
Adverse events classified as “serious” require expeditious handling and 
reporting to the product’s sponsor to comply with regulatory requirements.  Any 
SAE must be reported as quickly as possible after learning of the event by 
telephone or by a facsimile transmission of a Serious Adverse Event Form.  The 
reporting requirements are outlined in The Rogosin Institute Clinical Research 
Program Operating Procedure. 
 
Serious adverse events (i.e., any adverse event that meets the FDA 
definition and has a CTCAE Grade of 3-5) in subjects receiving the RENCA 
macrobeads will be reported as soon as possible to: 
 
 

 
 
 
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Stuart Saal, MD 
Attending Physician 
The Rogosin Institute 
505 East 70th Street 
New York, NY  10021 
 
Office:   
(212) 746-6117 
 
Service:  
(212) 535-1120 
Fax:       
(212) 288-8370 
 
If only limited information is initially available, follow-up reports will be 
required, and must be submitted to the study contact named above no greater 
than fifteen (15) days of receipt of additional information.  Copies of SAE reports 
are to be forwarded to the DSMB as per Weill Cornell Medical College DSMB/IRB 
procedures and to the IND as per FDA current reporting procedures. 
 
All adverse events will also be evaluated for intensity using the CTCAE v3.0.  
 
Any serious adverse events 120 days after the last implantation, not related to the 
RENCA macrobeads will not need to be reported to the sponsor. 
6.5  
Stopping Rule for an Individual Subject 
 
If the sponsor, investigator, study monitor, Data Safety Monitoring Board (DSMB) 
or officials from the Food and Drug Administration (FDA) discover conditions 
arising during the study that indicate that the study should be halted or that the 
study center should be terminated, this action may be taken after appropriate 
consultation between the sponsor and investigator. Conditions that may warrant 
termination of the study include, but are not limited to, the following: 
• The discovery of an unexpected, serious, or unacceptable risk to the 
patients enrolled in the study 
• A decision on the part of the sponsor to suspend or discontinue testing, 
evaluation, or development of the product 
6.5.1 Maximum Tolerated Dose/Dose Limiting Toxicity 
 
In this protocol, there will be four implantations of macrobeads.  The single 
dose (i.e., 8 macrobeads per kilogram) was previously shown to be well tolerated. 
In this study, the dose limiting toxicity (DLT) is most likely to be related to the 
number of implantations rather than the number of macrobeads implanted at each 
implantation.  
 
Dose limiting toxicity (DLT) will be defined as  

 
 
 
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1. Any Grade 2 allergic reaction of generalized urticaria or any other 
grade > 3 allergic reaction; 
2. Any Grade > 3 infection; 
3. Any grade > 3 local (intraperitoneal) reaction including peritoneal 
irritation or interference with intraperitoneal organ function; and 
4. Any grade > 3 hematologic or non-hematologic reaction. 
 
 
This definition of DLT is in accord with the NCI Common Terminology 
Criteria for Adverse Events v3.0 (CTCAE). 
 
6.6  
Premature Termination of the Study 
 
This protocol provides for four doses of the RENCA macrobeads.  The 
dosage to be used at each implantation will be 8 RENCA macrobeads per kg of 
subject body weight.  The Safety Committee, as well as the investigators, will 
review each instance of Grade 5 adverse event.  In order to protect subjects from 
excessive toxicities possibly associated with the study treatment, the following 
stopping rule will be utilized: if 3 or more subjects experience a grade 5 adverse 
event deemed possibly related to treatment, accrual will be halted and a thorough 
investigation will take place before the re-opening of accrual may be considered.  
 
6.7  
Potential Risks 
 
Animal and human subjects studies to date have defined the parameters of 
the safety of the RENCA cancer macrobeads. In summary, the RENCA 
macrobeads have been well tolerated in murine tumor models, in cats and dogs 
with naturally occurring tumors of various types, where the RENCA macrobeads 
have now been implanted for periods of up to four years.  Furthermore, in 13 
humans with end-stage cancer implanted with the macrobeads (up to 17 months), 
no serious adverse events have been recorded which can be attributed to the 
marcobeads. Typically, the animals undergoing implantation have exhibited 
improved appetite, weight gain, and increased activity levels (the latter have been 
remarkable in at least one half of the animals treated).  Adverse reactions 
observed to date have been 1) mild-to-moderate intraperitoneal chronic 
inflammatory reaction evident after 3 months in cats and dogs, but not mice; and 
2) entrapment of some macrobeads in the feline and canine omentum.  In the 
humans the reactions have been mild as well.  Some subjects have experienced 
mild, intermittent fevers after implantation (generally resolved by four to six weeks 
after implant).  
 

 
 
 
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A mild-to-moderate inflammatory reaction to the intraperitoneal placement 
of the macrobeads has been noted in humans and veterinary patients, but not 
mice.  In the cats and dogs, where the RENCA macrobeads have been implanted 
for periods of up to four years, this reaction becomes apparent beyond three 
months.  It consists of a minimal to moderate increase in inflammatory markers, 
with no disruption of normal physiological functions, such as those of intestinal 
peristalsis or biliary or pancreatic drainage/secretion.  Neither has it interfered with 
subsequent re-implantations of the RENCA macrobeads when indicated.  In 
humans, implantation has led to an increase in inflammatory markers, with 
intermittent, self- limiting, low grade fevers in some cases.  However, as observed 
in animals, the reactions were mild and not accompanied by clinical limitations. 
 
Comparison of the reaction to the RENCA macrobeads with that seen with 
the porcine islet agarose-agarose macrobeads implanted in mice, cats and dogs 
described in IND BB-IND 9762 submitted April 9, 2001, is useful. In these 
experiments porcine islet-containing macrobeads were implanted in mice, Wistar-
Furth rats, cats, and dogs with both streptozotocin-induced and naturally occurring 
insulin-dependent diabetes and in a large series of normal (non-diabetic) Sprague-
Dawley rats.  Beads have remained in some of the animals for long periods of time 
(in rats, 1 year; in cats for up to 6 years; and in dogs, over 3 years.)  One subject 
in the Phase I clinical trial had the macrobeads in place for 24 months without any 
evidence of adverse effects. No significant toxicity, other than the chronic 
inflammatory reaction, has occurred as documented by clinical veterinary 
observations, laboratory blood chemistry results, or histopathological analysis of 
recipient organs and tissues after sacrifice by euthanasia.  
 
Beyond macrobead removal (likely to be only partial (50-70%), but also not 
needed in any of the subjects treated with the macrobeads to date), whatever 
medical or surgical treatments are in the best interests of the subject and 
consistent with optimal medical care will be carried out with subject and/or family 
consent at any stage of the formal sixteen month protocol period and for the 
lifetime of the subject as the protocol indicates  
 
A second potential adverse effect of the implantation of the RENCA 
macrobeads is the transmission of a murine virus to a human host. Theoretically, 
this could involve transmission of the virus to the subject without infection; 
clinically significant infection; and infection of a third party via exposure to the 
beads or to the potentially infected subject.  Such risks are greatly reduced by the 
fact that the RENCA cell line has been maintained in our laboratory over many 
years and has been screened for known murine viruses, including those that 
present a possible risk of infection for humans.  Although the RENCA cell line 
does require passing through Balb/c mice approximately three times a year to 
maintain its tumorigenicity, the mice used for this passing are from Charles River 
Laboratories, are pathogen-free to the most stringent possible standards, and are 

 
 
 
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maintained under strictly controlled animal care conditions.  Furthermore, the 
passing process itself is carried out in the Rogosin laboratories under sterile 
conditions.  The RENCA cells are routinely tested for microbiological contaminants 
during their maintenance in culture as well as after their incorporation into the 
agarose-agarose macrobeads so that the risk of their carrying any known 
infectious agent is eliminated.  Clinical monitoring of the approximately 500 mice, 
cats and dogs treated to date, furthermore, has given no indication of any viral or 
other infection related to the implantation of the macrobeads.  
 
The only virus identified to date in the RENCA cell line is the ecotropic (non-
xenotropic) variant of the murine leukemia virus (MLV), an endogenous retrovirus 
that is not known to infect human cells.  Literature reports (National Research 
Council, 1991) of its lack of ability to infect human cells have been confirmed in 
our laboratory using a standard co-culture protocol (for up to 30 days) with human 
293, an embryonic kidney cell line.  Thus, there is no evidence that this murine 
retrovirus variant poses any threat to humans.  In the 30 subjects in the Phase I 
clinical trial there has been no evidence to date of the transmission of or infection 
with the MuLV. 
 
Risks associated with the surgical procedure (including anesthesia) 
required for the implantation of the RENCA macrobeads will be those normally 
expected for such a procedure involving a simple abdominal incision.  They will be 
dependent, of course, on individual subject risk factors, but no subjects with 
unacceptable risks for such a procedure will be admitted to this study.  The 
performance of the abdominal incision and the placement of the macrobeads in 
the peritoneal cavity are both simple and minimally invasive. 
 
Allergic reaction to mouse antigens is a potential risk.  With respect to this 
risk the following procedures will be in place: 
 
All subjects eligible for this protocol will be screened with available mouse 
allergen extracts using intradermal skin testing (Greer Diagnostics) initially to 
determine if a wheal and flare reaction is present, indicating the presence of 
human anti-mouse antibody.  Positive and negative skin test controls will be done 
at the same time. 
 
Data from repeated implantations of mouse RENCA macrobeads in dogs 
and cats with spontaneously occurring tumors of various types have not provided 
any clinical or laboratory evidence of sensitization to mouse proteins over periods 
of up to four years.  It should also be noted that, over the period of 4 to 6 months 
after a given implant, the RENCA cells in the macrobeads die so that there is not 
an ongoing production of antigenic substances by the mouse cells after this time.  
The agarose itself has been well tolerated (except for local foreign body reaction) 
for periods of up to several years in studies with porcine islet macrobeads and for 

 
 
 
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up four years (the longest the veterinary patients have been followed to date) with 
the RENCA cancer macrobeads implanted up to five times.  The beads have been 
tolerated without evidence of adverse reaction in humans now for up to 24 months.  
There has also been no evidence of recreation to mouse antigen skin testing in 
any of the subjects in the Phase I clinical trial. 
 
Should a subject in the protocol develop evidence of sensitization to mouse 
proteins, appropriate local and systemic therapy (antihistamines, steroids) will be 
given.  If the reaction is medically manageable, it should not be necessary to 
remove the RENCA macrobeads, given the gradual loss of cells within these 
beads.  Should the reaction not be amenable to medical treatment removal of the 
beads will be performed via an open procedure, although complete retrieval may 
not be surgically possible (see below). 
 
The total amount of blood drawn over the first 180 days of the study will be 
approximately 300 cc.  This amount will hold constant for the subsequent study 
periods of the same length. The risk of mild anemia secondary to this blood 
withdrawal is low, but will be appropriately treated if present.  The exact amount of 
blood to be drawn, as the study progresses past 6 months will depend on the 
subject’s clinical status and the need for tests to monitor the patient’s clinical 
status. As noted, the protocol blood drawing amounts will be constant in each of 
the 180-day study periods. In addition, the placement of an intravenous catheter 
involves the risk of bleeding around the needle site, local inflammation, pain or 
infection. 
6.7.1  Procedures to minimize risks 
 
 
In all cases, the Investigators will minimize risks by carefully screening 
subjects prior to admission to the study and by carefully monitoring their clinical 
status during the course of the study.  The RENCA macrobeads themselves will 
be monitored carefully with rigorous GMP and GLP standards as defined in the 
IND application.  The lack of adverse events attributable to the macrobeads 
evident in the Phase I trial is reassuring, especially with regard to the potential 
problems of peritonitis, viral transmission (eMuLV) problems interference with 
abdominal organ function, seeding of mouse tumor cells in the human peritoneal 
cavity and sensitivity to mouse antigens.   
 
 
For phlebotomies and intravenous line placements, the usual sterile 
technique will be used and adequate pressure applied when the indwelling 
catheters are removed.  Confidentiality will be observed for all data obtained from 
clinical or laboratory evaluations.  
 

 
 
 
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6.8  
Escape Arm (Withdrawal with/without Bead Removal) 
 
The RENCA macrobeads will be left in place in the peritoneal cavity for the 
life of the subject unless consideration of the removal of the macrobeads is 
occasioned by: 
• Subject request; 
• Principal Investigator, attending or consulting physician decision, and/or 
Safety Board/IRB/FDA decision that such removal is in the best medical 
interests of the subject. 
 
The events or findings that would initiate such considerations/discussion include, 
but are not limited to: 
 
• Any finding of Dose Limiting Toxicity (DLT) as defined above; 
 
• Evidence of active e-MuLV viral infection in subject’s cells/serum/plasma 
(i.e., transmission of MuLV from the mouse cells to the subject with active 
infection productive of a viral load in the subject); 
 
• Chronic peritonitis reaction > grade 3.  Although not specifically defined per 
se in the NCI Common Terminology Criteria for Adverse Events v3.0, 
several of the subcategories under the Gastrointestinal section are 
applicable.  The GI-Other sub-category will be used: Peritonitis/Chronic 
Inflammatory Reaction. 
 
Grade 1: Asymptomatic; radiographic (flat plate, CT, or MRI) or 
ultrasound imaging of peritoneal reaction. 
 
Grade 2: Symptomatic: abdominal pain or tenderness or pain on 
palpation (direct, rebound); altered dietary habits (i.e., appetite, fluid 
intake); requirement or IV fluids <24 hours indicated; altered bowel 
function (mild constipation or diarrhea). 
 
Grade 3: Symptomatic and severely altered GI function (e.g., 
inadequate oral caloric or fluid intake); IV fluids, tube feedings, or 
TPN indicated > 24hours. 
 
Grade 4: Life-threatening consequences. 
 
Any toxicity of Grade 2 or above as defined above in relation to the NCI 
CTCAE v3.0 or DLT, as defined immediately above, will initiate discussion of the 
possibility/ desirability/ necessity of the removal of the RENCA macrobeads.  Any 
such discussion will necessarily involve multiple considerations including the 

 
 
 
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advisability of a surgical procedure in the subject and the best interests of that 
subject from a medical point of view.  As such, all discussions will involve, at a 
minimum, the Principal Investigator, the subject’s primary or attending physician, 
relevant consultants, and the Safety Board as appropriate, with notification of the 
IRB and the FDA. It should be noted and emphasized that it will not be possible to 
remove all of the macrobeads. 50 to 80% removal is likely to be possible, but the 
exact level of removal of macrobeads that is achievable will depend on many 
factors, most importantly the subject’s overall health status and best medical 
interests.  Again, the removal of any macrobeads has not been warranted in any of 
the humans implanted with them thus far. 
 
6.9  
Treatment of Adverse Effects 
 
Should any subject in this Phase II trial of the RENCA experience an 
adverse event directly related to the Macrobeads or study-related procedures, all 
appropriate medical care will be provided at no cost to the subject. 
 

 
 
 
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7 DATA MANAGEMENT AND STATISTICAL ANALYSIS  
 
The critical parameters of this Phase II trial are those related to efficacy.  
Various markers, such as C-reactive protein, amylase, liver function tests, cell 
counts, and cytokine levels, will be sampled and analyzed.  Given the study 
design, we will undertake simple population comparisons designed for small 
samples (non-normal distribution) as well as simple trend analysis for selected 
parameters.  The data from all subjects, including those who withdraw or are 
withdrawn from the study will be analyzed.  All data will be analyzed using SAS 
software. 
 
7.1  Determination of Sample Size 
 
Seventy-four (74) male and female subjects with advanced pancreatic or 
metastatic, treatment-resistant colorectal cancer meeting the protocol inclusion 
criteria will be sought for this study.  Each subject will serve as his/her own control 
with measurements obtained and evaluated in an unbiased manner. This means 
that changes from baseline to various post-treatment time points will be analyzed 
for some variables (such as tumor markers, for example). The confidence intervals 
for these changes will be calculated. Of course, it is not planned for the survival 
analysis which will use a retrospective patient population comparison as defined in 
the Statiscal Analysis Plan (a copy of which is attached). The colorectal patient 
data from this study has already been used to plan a controlled Phase IIb protocol 
for colorectal cancer. Data from the pancreatic patients, when completed, will be 
utilized to plan a phase IIb controlled protocol for the pancreatic patients. 
 
7.2  Determination of  Response 
 
All subjects will be evaluated for response.  The Evaluation Team will be 
composed of the Investigators, and one outside physician.  All of the clinical tests 
will be evaluated independently by each member of the Team for changes against 
the baseline findings.  This evaluation will take place prior to each implantation or 
when the subject leaves the study.  The individual subject’s baseline established 
prior to the first implantation will be used for the entire study.  A table will be 
constructed using the changes from baseline.   
 
 

 
 
 
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Outline of Response Rate  
TESTS 
Baseline Prior 
to First 
Implantation 
Results Prior 
to Second 
Implantation 
Results Prior 
to Third 
Implantation 
Results Prior to 
Fourth 
Implantation 
Clinical Findings 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Symptoms 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Global Clinical 
Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Quality of Life 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Laboratory 
Tests (Abnormalities ) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Markers 
(Decrease) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Imaging Studies 
(Evidence of Change, 
e.g., volume or area) 
 
 
 
 
CT 
 
 
 
 
PET 
 
 
 
 
MRI 
 
 
 
 
 
 
 
 
 
Rating Scale 
 
 
 
 
Major Improvement: 3 
 
 
 
 
Improvement: 2 
 
 
 
 
No Change: 1 
 
 
 
 
 
 
 
 
 

 
 
 
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8 STUDY MANAGEMENT  
 
8.1  Recruitment and Consent Procedures 
 
Subjects will be recruited by physician referral.  Full informed consent will be 
obtained prior to admission by one of the physician investigators.  The hospital 
and state guidelines for obtaining consent prior to HIV testing will be followed. 
 
8.2  Regulatory Guidelines 
 
The study will be performed in accordance with United States IND 
regulations (21 CFR Part 312), the guidelines of the International Conference on 
Harmonization (ICH), Good Clinical Practice (GCP) Guidelines, and the most 
recent guidelines of the Declaration of Helsinki.  These Guidelines will be on file in 
the Investigator’s office and in The Rogosin Institute Clinical Research Program 
Operating Procedure Manual and, in addition, are available on the FDA’s Web 
Site. 
 
8.3  Institutional Review Board  
 
Conduct of the study must be approved by an appropriately constituted 
Institutional Review Board (IRB).  Approval is required for the study protocol, 
protocol amendments, informed consent forms, subject information sheets, and 
advertising materials (if any).  No study drug will be shipped to the study center 
until written IRB authorization has been received by the Investigator or his or her 
representative. 
 
8.4  Informed Consent 
 
For each subject enrolled into the study, written informed consent will be 
obtained prior to any protocol-related activities.  As part of this procedure, the 
principal investigator or appropriate personnel must explain orally and in writing 
the nature, duration, and purpose of the study, and the action of the study drug in 
such a manner that the subject is aware of the potential risks, inconveniences, or 
adverse effects that may occur.  Subjects should be informed that they could 
withdraw from the study at any time.  If the subject decides to withdraw from the 

 
 
 
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study, he or she will be asked if they would agree to continue to be monitored.  
They will receive all information that is required by federal regulations and ICH 
guidelines.  The Principal Investigator will have on file a copy of the IRB-approved 
Informed Consent form prior to the start of the study. 
 
8.5  Data Monitoring and Safety Board 
 
The Data Safety and Monitoring Board will be provided with detailed safety 
information from the trial.  This information will include information on adverse 
events, clinical laboratory results, and the results of all imaging studies.  They are 
responsible along with the Investigator and The Rogosin Institute’s’ Medical 
Monitor for providing oversight and monitoring of the safety of the participants in 
the study.   
 
8.6  Study Documentation 
 
By signing a copy of Form FDA 1572, the Principal Investigator 
acknowledges that he or she has a copy of the Investigator’s Brochure and has 
reviewed the latest version.  In addition, he or she will comply with the protocol 
and the provisions stated in Form FDA 1572.  No changes in this protocol can be 
made without the written approval of the IRB and the FDA, unless the change is to 
protect the immediate safety of a subject.  If changes are made to protect the 
safety of a subject, approval of the IRB and the FDA will be obtained as soon as 
possible.   
 
The investigator will have the following forms and documents on file:  
 
• 
Original, signed Form FDA 1572 
• 
Curricula vitae for all investigators listed on Form FDA 1572 
• 
Copy of principal investigator’s state medical license 
• 
Signed protocol signature page 
• 
List of IRB members and their occupations/affiliations or multiple assurance 
number 
• 
Letter indicating IRB approval to conduct the protocol 
• 
Copy of IRB-approved informed consent form 
• 
Laboratory certification records and reference ranges  
• 
A statement of financial disclosure 
 
A Case Report Form will be used to collect the data from the ongoing 
clinical study.  This Case Report Form will be compiled in relationship to the 
protocol. In addition, to the pages for the collection of the results of all evaluations, 

 
 
 
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there will be sections for the entry of text to describe the progress of the subject 
and any significant events. 
 
8.7  Study Monitoring and Auditing 
 
This study will be monitored as outlined in 21CFR§312.50 and 
21CFR§312.56, the Guidelines of Good Clinical Practice (ICH-E6), and The 
Rogosin Institute Clinical Research Program Operating Procedures.  Monitoring 
will include personal visits and telephone communication to assure that the 
investigation is conducted according to the protocol and Guidelines of Good 
Clinical Practice (ICH-E6).  Review of Case Report Forms (CRF) at the study 
center will include a review of printed or electronic forms for completeness and 
clarity, and consistency with source documents available for each subject.  Note 
that a variety of original documents, data, and records will be considered as 
source documents in this trial.  The CRF itself is not to be used as a source 
document under any circumstances, although some of the original source 
documents, such as those reporting laboratory values/data will themselves be 
electronic. Physician and nursing records will also be only electronic and so will 
form original source documents.  The electronic records will be recorded in MIQS, 
a clinical data collection system that is compliant with all FDA-mandated regulatory 
requirements.   
 
8.8  HIPAA  
 
This study will be conducted in compliance with the protocol, FDA 
regulations, ICH, and GCP guidelines, and all other applicable federal, state, and 
local laws, rules, regulations, ordinances and guidelines, all other relevant 
professional standards, all requirements of the host institution or facility, and the 
Statement of Investigation, FDA Form 1572, as described in 21CFR§312.53, 
which the investigator has completed and signed, in the performance and 
documentation of the study.  Without in any way limiting the foregoing, the 
investigator shall obtain valid advance written informed consent and advance 
written authorization for use and disclosure of protected health information from 
each of the subjects participating in the study and shall retain such documentation 
after completion of the study. 
 
8.9  Retention of Records 
 
In accordance with 21CFR§312.62, the investigator must arrange for 
retention of study records at the study center for 2 years after the study drug’s 

 
 
 
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New Drug Application is approved or the IND is withdrawn, as required by FDA 
regulations.  The investigator should take measures to prevent accidental or 
premature destruction of these documents. 
 

 
 
 
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APPENDICES 
 
Appendix 1 
 
Name, Address, and Qualifications of Each Investigator 
 
Principal Investigator:  
 
Thomas J. Fahey III, M.D. 
Professor of Surgery 
Section Chief of Endocrine Surgery 
Weill Cornell Medical Center / New York Presbyterian Hospital 
520 East 70th Street, Starr 8 
New York, NY 10021 
Phone: 212 746-5130 
Fax: 212 746-8771 
 
 
Sub-Investigators 
 
Nathaniel Berman, MD 
Assistant Attending Physician 
Assistant Professor of Medicine 
The Rogosin Institute 
505 E. 70th Street 
New York, NY 10021 
Phone: 212-746-1551 
Fax: 212-288-8370 
 
Barry H. Smith MD, PhD 
Director/President/CEO 
The Rogosin Institute 
505 E. 70th Street 
New York, NY 10021 
Phone: 212-746-1551 or 212-750-5075 
Fax:   212-371-2776  
 
 
 

 
 
 
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Allyson Ocean, M.D.  
Medical Oncologist and Attending Physician 
Gastrointestional Oncology 
Weill Cornell Medical Center / New York Presbyterian Hospital 
1305 York Avenue 
New York, NY 10021 
Phone: 212 746-2844 
Fax: 212 746-0416 
 
Zoe P. Andrada, NP 
The Rogosin Institute 
505 E. 70th Street 
New York, NY 10021 
Phone: 212-746-9233 
 
Cytokines/Genomics 
 
Daniel Levine, PhD 
Thomas Parker, PhD 
 
The Rogosin Institute 
505 E. 70th Street 
New York, NY 10021 
Tel: 212-570-3252 
       212-570-3044 
Fax: 212-570-3083 
 
 
Appendix 2 
Schedule of assessments (see pages 67-68) 
 
 
 
 
 

 
 
 
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Screening 
Visit 1 / Day 0 
Visit 2 / Day 14 
Visit 3 / Day 30 
Visit 4 / Day 60 
Visit 5 / Day 90 
Visit 6 / Implant 2  
Visit  7 / Day 14 
Visit 8 / Day 30 
Visit 9 / Day 60 
Visit 10 / Day 90 
Visit 11 / Implant 3 
Visit  12 / Day 14 
Visit 13 / Day 30 
Visit 14 / Day 60 
Visit 15 / Day 90 
Visit 16 / Implant 4 
Visit  17 / Day 14 
Visit 18 / Day 30 
Visit 19 / Day 60 
Visit 20 / Day 90 
Visit 21 / Day 120 
Follow-Up12 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PE / VS / Medical History 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
ConMed / AE Review 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Global Clinical Assessment 
Questionnaire 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Karnofsky Performance Status 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Quality of Life Scale 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Pain Scale Assessment 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
ECOG Performance Scale 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Neurological Examination 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
12-Lead ECG 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
Tumors Markers (CEA, CA19-9, CA125) 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Hematology Profile1 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Coagulation Panel2 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Erythrocyte sedimentation rate 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Comprehensive Metabolic Panel3 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
GGT4 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Amylase5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipase5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lactate Dehydrogenase 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
C-Reactive Protein 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Bilirubin, Direct 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Hepatitis Panel6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy (Qualitative)7 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
Immunoglobulin Levels8 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
Cytokine Panel9 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Cellular Immune Function10 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
Ecotropic Murine Leukemia Virus 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
X 

 
 
 
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Screening 
Visit 1 / Day 0 
Visit 2 / Day 14 
Visit 3 / Day 30 
Visit 4 / Day 60 
Visit 5 / Day 90 
Visit 6 / Implant 2  
Visit  7 / Day 14 
Visit 8 / Day 30 
Visit 9 / Day 60 
Visit 10 / Day 90 
Visit 11 / Implant 3 
Visit  12 / Day 14 
Visit 13 / Day 30 
Visit 14 / Day 60 
Visit 15 / Day 90 
Visit 16 / Implant 4 
Visit  17 / Day 14 
Visit 18 / Day 30 
Visit 19 / Day 60 
Visit 20 / Day 90 
Visit 21 / Day 120 
Follow-Up12 
Immunohistochemical & Gene Array 
Analysis (when indicated) 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
Murine Allergen Skin Test with positive 
and negative controls 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
Circulating Tumor Cells 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
Macrobeads Implantation (8 per kg body 
wt) 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
Cefazolin (Prophylaxis – 1 gm) 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
Chest X-Ray (PA/lateral) 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
CT Scan Chest (Non-Contrast)11 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRI of Abdomen11 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
MRI of Pelvis11 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Tumor Mass Biopsy (where indicated) 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
PET-CT Scan Whole Body 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X11 
Radionuclide Bone Scan11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
1 Hematology Profile: WBC, RBC, hemoglobin, hematocrit, MCV, MCH, MCHC, RDW, platelets, automated differential WBC 
2 Coagulation Panel: PT, PTT, INR 
3 Comprehensive Metabolic Panel: CO2, sodium, potassium, chloride, creatinine, BUN, calcium, total protein, albumin, total bilirubin, alkaline phosphatase, AST, ALT, glucose 
4 GGT: gamma glutamyl-transpeptidase 
5 Amylase and lipase are done at baseline, then as medically necessary for individual subjects 
6 Hepatitis Panel: Hepatitis B, C and E 
7 Serum pregnancy only for females of childbearing potential 
8 Immunoglobulin Levels: IgA, IgG, IgE and IgM 
9 Cytokine Panel: IL-6, TNF-α, TNF receptors p55, TNF receptors p75 
10 Cellular Immune Function: T cells; B cells; antibodies to diphtheria, tetanus, mumps, rubella; quantitative IgG subclasses, NK cells count (CD16) 
11 Only if clinically indicated 
12 Long-term follow-up visits will consist of a telephone contact every 6 months for 2 years, then every year thereafter until death to determine overall survival

 
 
 
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Appendix 3 
 
Statistical considerations 
 
1. 
Study design 
 
Study 0911010739 is an open-label, non-randomized, single-center Phase II trial 
of RENCA agarose-agarose macrobeads.  The study is designed to assess the 
efficacy and safety of this new treatment for subjects with treatment-resistant 
pancreatic adenocarcinoma or colorectal cancer.  The study will enroll a total of 
116 evaluable subjects with advanced pancreatic cancer and colorectal cancer, 
and implant 74 eligible patients. An evaluable subject is defined as a subject who 
completes the first implantation of the RENCA agarose-agarose macrobeads.  If a 
subject signs an Informed Consent and is not implanted, the subjects will not be 
classified as evaluable and will be replaced.   These subjects will be classified as 
screen failures.  All efficacy and safety analyses will be by cancer-type, that is, 
pancreatic and colorectal subjects will be evaluated separately with no formal 
between group comparisons.  Analyses will be performed with a focus on an 
estimation of specific clinically important parameters for use in the planning of 
larger subsequent Phase IIb and/or Phase III trials designed to fully assess 
efficacy and safety. 
 
There will be no formal interim statistical analysis.  The amount and nature of 
missing data will be characterized and no method of imputation will be used for 
missing data.  All statistical analyses will be carried out using SAS version 9.2 (or 
higher) statistical software. 
 
 
2. 
Study objectives 
 
 
All study objectives, as detailed in Section 3 of the protocol, will be assessed in 
each of the two study groups to be enrolled in this clinical trial: subjects with 
advanced pancreatic cancer and subjects with advanced colorectal cancer.  
 
 
3. 
Accrual 
 
The projected accrual is approximately 3 subjects per month and therefore 
recruitment is expected to be completed at about 12 months following the study 
starting point.  
 
 

 
 
 
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4. 
Analysis populations 
 
Efficacy/Safety Population 
The efficacy/safety population is defined as all evaluable subjects regardless of 
subject compliance with protocol procedures.  This population will be used in the 
primary analysis for assessment of efficacy.  Efficacy sub-analyses may be 
performed on various subsets of subjects, such as those with no major protocol 
deviations or those who continued in the study for the entire treatment period (i.e., 
did not withdraw prematurely).  One of the sub-analyses will include efficacy 
response after one, two, three, and/or four implantations.   
 
All evaluable subjects enrolled in the study who complete at least one implantation 
procedure will be included in the safety population and considered evaluable for 
toxicity and safety.  The efficacy and safety populations do not differ.  All treatment 
related toxicities will be recorded and then tabulated at the end of the study.  All 
treatment related toxicities will be recorded and then tabulated at the end of the 
study.   
 
Screen Failures 
All subjects who sign an Informed Consent but for any reason are not implanted 
will be considered screen failures.  These subjects will be listed and the reasons 
for not being implanted listed and described. 
 
 
 
5. 
Descriptive analyses 
 
Measured outcome variables will be summarized overall and by relevant 
demographic and baseline variables.  Descriptive statistics such as frequencies 
and relative frequencies will be computed for all categorical variables. Numeric 
variables will be summarized using simple descriptive statistics such as the mean, 
standard deviation and range.  A variety of graphical techniques will also be used 
to display data, for example, histograms, boxplots, scatterplots, etc.   
 
 
6. 
Primary statistical analyses 
 
The primary objectives are outlined in Section 3 of this protocol. The analysis will 
be performed as detailed in Statistical Analysis Plan (SAP). 
 
 
7. 
Secondary statistical analyses 
 

 
 
 
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The secondary objectives are outlined in Section 3 of this protocol. The analysis 
will be performed as detailed in Statistical Analysis Plan (SAP). 
 
8. 
Stopping rules 
 
In order to protect subjects from excessive toxicities possibly associated with the 
study treatment the following stopping rule will be utilized: if 3 or more subjects 
experience a grade 5 adverse event deemed possibly related to treatment, accrual 
will be halted and a thorough investigation will take place before the re-opening of 
accrual may be considered.  The probability of excising the stopping rule within 
this study is a function of the true unknown probability of a grade 5 adverse event 
possibly related to the treatment corresponding to the study population.  The table 
below contains the probability of observing at least 3 such toxicities in the 30 
subjects for a variety of values of the true probability within the population. 
 
True probability 
of treatment 
related toxicity 
5% 
10% 
20% 
30% 
Probability of 
stopping the 
study based on 
30 subjects 
19% 
59% 
96% 
99.8
% 
 
The calculations above are based on the assumption that our study sample may 
be treated as a random sample from the population of interest.  As can be seen 
there does exist acceptable properties associated with the stopping rule. 
 
 
9. 
Sample size justification 
 
Since the primary objectives are addressed through estimation and not formal 
hypothesis testing, the original sample size of 20 colorectal subjects and 10 
pancreatic subjects was based on the expected precision corresponding to the 
estimates of the progression at appropriate intervals and toxicity rates.  We believe 
that these statistical goals will be fulfilled with the current intended sample size of 
74 patients, of which, 40 patients will be pancreatic cancer type. The precision 
associated with these estimates is a function of the true unknown parameter value 
and the sample size used in the calculation.  Note that a true rate of 50% 
represents the worst case scenario with in regards to precision and therefore we 
may take precision at that point to be an upper bound of expected accuracy in the 
estimation of study parameters.  Calculations reveal that the precision associated 
with estimates based on the colorectal subjects will be at most 22 percentage 
points.  In the case of pancreatic subjects, the corresponding quantity is 31 
percentage points.  

 
 
 
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10. 
References 
 
Brookmeyer, R. and Crowley, J.J. (1982).  A confidence interval for the median 
survival time. Biometrics; 38:29-41. 
 
Clopper, C.J. and Pearson, E.S. (1934).  The use of confidence or fiducial limits 
illustrated in the case of the binomial.  Biometrika; 26:404-413. 
 
Hosmer, D.W. and Lemeshow, S. (2000).  Applied Logistic Regression.  Wiley and 
Sons, New York. 
 
Kaplan, E.L. and Meier, P.J. (1958).  Nonparametric estimation from incomplete 
observations.  Journal of the American Statistical Association; 53:457-481. 
 
 
REFERENCES 
 
References in Introduction: 
 
Pancreatic cancer: 
 
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Cancer Society, 2009.   
Greenlee RT, Murray T, Bolden S, et al.: Cancer statistics, 2000. CA Cancer J Clin 
50 (1): 7-33, 2000 Jan-Feb 
Yeo CJ, Abrams RA, Grochow LB, et al.: Pancreaticoduodenectomy for pancreatic 
adenocarcinoma: postoperative adjuvant chemoradiation improves survival. A 
prospective, single-institution experience. Ann Surg 225 (5): 621-33; discussion 
633-6, 1997.   
Lillemoe KD: Current management of pancreatic carcinoma. Ann Surg 221 (2): 
133-48, 1995.  
Yeo CJ: Pancreatic cancer: 1998 update. J Am Coll Surg 187 (4): 429-42, 1998.   
Nitecki SS, Sarr MG, Colby TV, et al.: Long-term survival after resection for ductal 
adenocarcinoma of the pancreas. Is it really improving? Ann Surg 221 (1): 59-66, 

 
 
 
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1995.  [•  Conlon KC, Klimstra DS, Brennan MF: Long-term survival after curative 
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Willett CG, Daly WJ, Warshaw AL: CA 19-9 is an index of response to 
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Norton, L, Simon, R., Bereton, H.D., Bogden, A.E.  Predicting the course of 
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Norton, L.  A Gompertzian model of human breast cancer growth. Cancer Res 48; 
7067-71. 1988. 
 
Norton, L.  Cancer stem cells, self-seeding, and decremented exponential growth: 
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Speer, J.F., Petrosky, V.E., Retsky, M.W., Wardwell, R.H.  A stochastic numerical 
model of breast cancer growth that simulates clinical data. Cancer Res 44:4124-
30. 1984. 
 
Laird, A.K. Dynamics of tumor growth: Comparison of growth rates and 
extrapolation of growth curve to one cell.  Brit J Cancer 29:278-291. 1965. 
 
Laird, A.K., Tyler, S.A., Barton, A.D. Dynamics of normal growth. Growth 29: 233-
248. 1965. 
 
De Wys, WD. Studies correlating the growth rate of a tumor and its metastases 
and providing evidence for tumor-related systemic growth-retarding factors. 
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Fisher, B. et al. Presence of a growth-stimulating factor in serum following primary 
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Colorectal cancer: 
 
Gleisner, A.L., Choti, M.A., Assumpcao, L., Nathan, H. Schulick, RD, Pawlik, T.M. 
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Ocean AJ, Parikh T, Berman N, Escalon J, Shah MA, Andrada Z.  Phase I/II trial of 
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mouse renal adenocarcinoma cells (RENCA) in patients (pts) with advanced 

 
 
 
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colorectal cancer (CRC). American Society of Clinical Oncology (ASCO) Annual 
2013 Meeting, Chicago IL (Abstract). 
 
Onaitis, M.W., Peterson, RP, Haney, J.C., Saltz, L. Park, B. Flores, R., Bains, M.S. 
Dycoco J., D’Amico, T.A., Harpole, D.H., Kemeny, N., Rusch, V.W., Downey, R. 
Prognostic factors after pulmonary resection of colorectal cancer metastases. Ann 
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Timmerman, R.D., Bizekis, C.S., Pass, H.I., Fong, Y., Dupuy, D.E., Dawson, L.A., 
Lu, D. Local surgical, ablative, and radiation treatment of metastases.  CA Cancer 
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Wolpin, B.M., Mayer, R.J. Systemic treatment of colorectal cancer. 
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Yamane, B., Weber, S. Liver-directed treatment modalities for primary and 
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Hanahan, D, Weinberg, RA. The hallmarks of cancer. Cell 100: 57-70, 2000. 
 
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Smith BH, Gazda LS, Conn BL, et al. Three-dimensional culture of mouse renal 
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