A Phase IIb, Nonrandomized, Open-Label Trial With Mouse Renal Adenocarcinoma (RENCA) Cell Containing Agarose-Agarose Macrobeads Compared With Best Supportive Care in Patients With Treatment-Resistant, Metastatic Colorectal Carcinoma
Phase: PHASE2
Conditions: Colorectal Cancers
Sponsor: The Rogosin Institute

The Rogosin Institute 
Protocol No.  RI-MB-203 
 
 
CONFIDENTIAL 
 
 
 
®®            ® 
                
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
 
Protocol Title: 
A Phase IIb, Nonrandomized, Open-Label Trial 
with Mouse Renal Adenocarcinoma (RENCA) 
Cell-Containing Agarose-Agarose Macrobeads 
Compared with Best Supportive Care in Patients 
with Treatment-Resistant, Metastatic Colorectal 
Carcinoma 
 
 
Protocol Number: 
RI-MB-203 
 
 
Investigational Phase: 
IIb 
 
 
IND Number: 
IND 10091 
 
 
Date of Original Protocol: 
23 October 2013 
 
Date of Amendment 1 
Protocol: 
 
23 December 2013 
 
Sponsor: 
 
The Rogosin Institute 
505 East 70th Street 
New York, NY 10021 
USA 
 
 
Sponsor’s Responsible 
Medical Officer: 
Barry H. Smith, MD, PhD 
President/CEO 
The Rogosin Institute 
Telephone: 212-746-1551  
 
 
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.  RI-MB-203 
 
Version: 23 December 2013 
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ADMINISTRATIVE STRUCTURE OF THE STUDY 
Clinical Operations 
See the Study Procedures Manual. 
Medical Monitor 
See the Study Procedures Manual. 
Central Laboratory  
See the Laboratory Manual. 
Clinical Supplies 
The Rogosin Institute, Xenia Division 
740 Birch Road 
Xenia, OH 
USA 
Data Management and Statistics 
Vital Systems, Inc. 
3701 Algonquin Road 
Suite 310 
Rolling Meadows, IL 60008 
USA 
 

The Rogosin Institute 
Protocol No.  RI-MB-203 
 
Version: 23 December 2013 
CONFIDENTIAL 
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SYNOPSIS  
Sponsor: 
The Rogosin Institute 
Protocol Number:  RI-MB-203 
Name of Study Drug:   
Not applicable 
Protocol Title:  A Phase IIb, Nonrandomized, Open-Label 
Trial with Mouse Renal Adenocarcinoma (RENCA) 
Cell-Containing Agarose-Agarose Macrobeads Compared 
with Best Supportive Care in Patients with 
Treatment-Resistant, Metastatic Colorectal Carcinoma 
Name of Active Ingredient:   
Mouse renal adenocarcinoma 
(RENCA) cell-containing 
agarose-agarose macrobeads 
Phase of Development:  IIb 
Objectives: The primary objective of this study is to evaluate the efficacy of renal 
adenocarcinoma (RENCA) macrobead implantation compared with best supportive care, as 
assessed by overall survival, in patients with treatment-resistant, metastatic colorectal carcinoma. 
Secondary objectives, defined only for patients with treatment-resistant, metastatic colorectal 
carcinoma who undergo RENCA macrobead implantation (i.e., Group A), are to determine or 
evaluate the effect of RENCA macrobead implantation on the following variables: 
 
change from baseline over the period after the first RENCA macrobead implantation in 
clinical status, as measured by Eastern Cooperative Oncology Group (ECOG) 
performance status score and global clinical assessment  
 
change from baseline over the period after the first RENCA macrobead implantation in 
quality of life, as measured by the European Organisation for Research and Treatment of 
Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and Karnofsky Performance 
Status Scale 
 
change from baseline over the period after the first RENCA macrobead implantation in 
erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and CA 125 levels 
 
change from baseline over the period after the first RENCA macrobead implantation in 
levels of tumor markers (including carcinoembryonic antigen [CEA] and carbohydrate 
antigen 19-9 [CA19-9], with carbohydrate antigen 125 [CA125]) being used as a marker 
of inflammation (see immediately above).  
 
tumor marker response rate, defined as the proportion of patients who have a decrease 
from baseline of 20% or more in CEA or CA 19-9 values 
 
safety and tolerability of RENCA macrobeads, as measured by the following: 
o adverse events 
o clinical laboratory tests, including chemistry, hematology, coagulation, 
urinalysis, and test for presence of ecotropic murine leukemia virus (eMuLV)  
o murine allergen skin test  
Methodology: This is a Phase IIb, multicenter, nonrandomized, open-label study with RENCA 
macrobeads in patients with treatment-resistant, metastatic colorectal carcinoma to determine the 
effect of RENCA macrobead implantation on overall survival compared with that achieved by 
best supportive care alone.   
Two treatment groups will be enrolled in this study, as follows: 
 
Group A (n=40) – patients who will undergo up to 4 implantations of RENCA 
macrobeads, at an amount of 8 RENCA macrobeads /kg body weight 

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 
Group B (n=80) – patients who will receive, or are receiving, best supportive care, 
defined as management of symptoms aimed at maintaining or improving quality of life, 
but not including approved therapies targeting the patient’s malignancy  
For patients in Group A, the study will consist of a screening period lasting up to 30 days; up to 
4 RENCA macrobead implantation procedures at least 90 days apart: and a 90-day follow-up 
period after the final implantation procedure.  Patients will be expected to participate in a 
long-term follow-up period until death.  RENCA macrobead implantation procedures may be 
delayed at the investigator’s discretion/medical judgment, by patient decision, or due to initiation 
of a medically necessary or palliative therapy or procedure that is not specifically directed at 
more effectively treating the cancer itself.  No maximum period between implantation procedures 
will be defined, and patients having treatment delays will not be removed from the study.  
However, if more than 30 days pass between a Day 90 visit and Day 0 of a subsequent 
implantation, patients will have re-screening assessments performed to ensure continued 
eligibility.  Re-screening assessments will not include re-administration of informed consent or a 
new review of medical history. Inclusion/exclusion criteria applied to determine eligibility for the 
first implant, do not have to be re-applied at this time. However, patients must continue to be 
acceptable surgical candidates, as per the investigator’s and surgeon’s medical judgment and the 
standards of optimal patient care. Discontinuation of the macrobead protocol for a given patient 
may be the result of the investigator’s and/or surgeons decision based on the patient’s best 
medical interest, significant disease progression despite macrobead implantation, an unexpected 
serious adverse event related or unrelated to the macrobead implantation, or the patient’s decision 
to withdraw for any reason. 
After informed consent has been obtained, patients in Group A will undergo screening/baseline 
assessments.  For eligible patients, the first procedure to implant RENCA macrobeads into the 
peritoneal cavity will be scheduled for Day 0.  Patients will be expected to return to the clinic on 
Days 14, 30, 60, and 90 after each RENCA macrobead implantation procedure for efficacy, 
exploratory, and safety assessments.  Up to 3 additional (for a total of 4) RENCA macrobead 
implantation procedures will be performed at the investigator’s discretion.   
Patients will be considered for enrollment in Group B only if they have already decided 
independently of this study not to pursue further therapeutic treatment of their cancer.  For these 
patients, the study will consist of administration of informed consent, which will include 
permission to review medical records and record relevant medical information, agreement to be 
followed for survival, and review of entry criteria to ensure that they are comparable to the 
patients in Group A.  Patients in Group B will not have any assessments performed as part of this 
study. 
It is expected that study centers will enroll patients in either Group A or Group B, and not 
necessarily both, treatment groups. 
Number of patients to be enrolled: A total of 120 patients with treatment-resistant, metastatic 
colorectal cancer will be entered in the study -- 40 patients who will undergo RENCA macrobead 
implantation and 80 patients who will receive or are receiving best supportive care.  
Criteria for inclusion:  Patients in both treatment groups must meet all of the following criteria 
to be considered eligible to participate in the study: 
1. Patients are adult men or women, aged 18 years or older, with histologically-confirmed, 
metastatic adenocarcinoma of the colon or rectum that is resistant to available treatment 
options, including at least two such options from available chemotherapy, targeted, and 
other regimens. 
2. Patients have radiographically documented evidence of disease progression. 
3. Patients have a life expectancy of at least 6 weeks, in the investigator’s opinion, at the 
time disease progression is documented. 

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4. Patients are considered surgical candidates on the basis of co-morbidity risks, number 
and sites of metastases, and ability to withstand general anesthesia. 
5. Patients are able to provide written informed consent. 
Patients in Group A must also meet all of the following additional criteria: 
6. Patients have an ECOG performance status score of 0, 1, or 2. 
7. Patients have adequate hematologic function, defined as follows: 
a. absolute neutrophil count (ANC) ≥1500 /mL 
b. hemoglobin ≥9 g/dL 
c. platelets ≥75,000 /mL 
8. Patients have adequate hepatic function, defined as follows: 
a. bilirubin ≤1.5 times the upper limit of normal (x ULN) 
b. aspartate transaminase (AST) ≤3 x ULN, or ≤5 x ULN if liver metastases are 
present 
c. alanine transaminase (ALT) ≤3, x ULN, or ≤5 x ULN if liver metastases are 
present 
9. Patients have adequate renal function, defined as creatinine ≤2.0 mg/dL. 
10. Patients have adequate coagulation function, defined as follows: 
a. International Normalized Ratio (INR) ≤1.5 or between 2 and 3 if the patient is 
receiving anticoagulation 
b. partial thromboplastin time (PTT) ≤5 seconds above the ULN 
Note: Patients receiving full-dose anticoagulation therapy must be receiving a stable dose 
of oral anticoagulant therapy or low-molecular-weight heparin. 
11. Clinically significant toxic effects of chemotherapy (excluding alopecia), radiotherapy, 
hormonal therapy, or prior surgery must have resolved to Grade 1 or better, with the 
exception of peripheral neuropathy, which must have resolved to Grade 2 or better. 
12. Female patients of childbearing potential must have a negative serum pregnancy test at 
screening (and a negative urine pregnancy test 2 days prior to the first and each 
subsequent macrobead implantation if the screening serum pregnancy test result was 
obtained more than 2 weeks before surgery); patients must agree to use a medically 
appropriate form of birth control (i.e., barrier method or abstinence) from screening 
throughout their participation in the study.  Male patients and partners must agree to use 
condoms.  
Patients in either treatment group who meet any of the following criteria will be excluded from 
participating in the study:   
1. Patient has hepatic blood flow abnormalities, i.e., portal vein hypertension and 
thrombosis, and/or a large volume of ascites. 
2. Patient has concurrent cancer of any other type, except skin cancers other than 
melanoma. 
3. Patient has a positive test result for human immunodeficiency virus (HIV) or any 
hepatitis other than A at screening. 
4. Patient is considered by the investigator to be unsuitable for participation in the study 
upon review of medical history, physical examination, or clinical laboratory test results. 
Patients in Group A who meet any of the following criteria will be excluded from participating in 
the study:   

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5. Patient received FDA-approved chemotherapy within 3 weeks of Day 0, or bevacizumab 
(or similar drugs) within 4 weeks of Day 0, or radiation therapy at any site within 4 
weeks of Day 0. 
6. Patient received investigational anticancer therapy within 4 weeks of Day 0. 
7. Patient has a positive reaction to the skin test for allergy to mouse antigen (Greer 
Laboratories, Inc. product #E2 [mouse epithelia], Lenoir, NC). 
8. Patient has a history of hypersensitivity reaction that, in the opinion of the investigator, 
poses an increased risk of an allergic reaction to the RENCA macrobeads, particularly 
any known allergy to murine antigens or body tissues. 
9. The patient has an ongoing or active infection, symptomatic congestive heart failure, 
unstable angina pectoris, serious cardiac arrhythmias (with the exception of well 
controlled atrial fibrillation), active bleeding, or psychiatric illness, or social situations 
that could interfere with the patient's ability to participate in the study.  
Duration of treatment: The treatment period consists of up to 4 RENCA macrobead 
implantation procedures no less than 90 days apart, each followed by a 90-day follow-up period. 
Criteria for evaluation:   
Efficacy Assessments 
For patients in Group A and Group B, the primary efficacy measurement is overall survival, 
defined as the time interval from the date of radiographically documented disease progression 
(and therefore failure of the latest available therapy) to the date of death due to any cause.  
Secondary efficacy measurements include assessment of clinical status (ECOG performance 
status score and global clinical assessment) and quality of life assessments (EORTC QLQ-30 and 
Karnofsky Performance Status Scale). 
Exploratory Assessments 
For patients in Group A, exploratory assessments include assessment of ESR, CRP, and CA 125 
levels, tumor marker levels (CEA and CA19-9), CTC levels, tumor changes in size or metabolic 
activity , analysis of biopsy samples (if obtained), and autopsy (for consenting patients only). 
Safety Assessments 
For patients in Group A, safety assessments will include monitoring of adverse events, clinical 
laboratory tests (chemistry, hematology, coagulation, urinalysis, and eMuLV testing), vital signs 
measurements (blood pressure, pulse, respiration rate, and temperature), physical examinations, 
12-lead ECGs, chest x-rays, and murine allergen skin testing. 
Investigational product: The investigational product to be used in this study is mouse RENCA 
cell-containing agarose-agarose macrobeads.  Each RENCA macrobead is 6 to 8 mm and contains 
RENCA cells embedded in 1.0% Lonza HSB-LV agarose, surrounded by a second concentric 
layer made of 5.0% Lonza HSB-LV agarose layer. It should be noted that 150,000 RENCA are 
placed initially in each agarose-agarose macrobead and that an estimated 99% of these cells die 
off with one to two weeks, with the subsequent formation of colonies of tumor cells consisting of 
RENCA cells with stem cell properties and their daughter cells.  It is when these colonies have 
formed that the macrobead produces the factor or factors that inhibit the growth of tumor cells 
outside the macrobead, both in vitro and in vivo. 
The number of RENCA macrobeads to be surgically implanted in each patient in Group A is 
based on body weight and will be calculated to provide a dosage of 8 macrobeads /kg body 
weight.   
Reference therapy: For patients in Group B, best supportive care is defined as management of 
symptoms aimed at maintaining or improving quality of life and does not include approved 
therapies specifically targeting the patient’s malignancy.  

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Statistical methods:  All available data will be listed and summarized by treatment group (if 
applicable) and study visit.  Categorical variables will be summarized using frequencies and 
percentages for each category.  Continuous variables will be summarized using number of 
patients, mean, standard deviation, median, and range.  All programs for data output and analyses 
will be written in Statistical Analysis System® (SAS) version 9.1.3 or higher (SAS Institute, Inc., 
Cary, NC).   
Efficacy Variables and Analyses 
The primary efficacy variable, overall survival, will be defined as the time interval between the 
date of radiographically documented disease progression and the date of death due to any cause.   
Because treatment group assignment in this study is not randomized, balance of baseline 
covariates potentially related to both treatment and survival between Group A and Group B will 
be achieved through the use of propensity scores.  A propensity score for each patient will be 
defined as the probability of being in Group A given a vector of observed baseline covariates xi 
and will be derived using logistic regression.  The final propensity score model will be selected 
based on univariable relationships between covariates derived from the baseline characteristics 
and group membership, collinearity among the candidate covariates, and number of patients 
enrolled (with the standard target of 10 patients per covariate). 
Estimated survival functions will be presented graphically.  A proportional hazards model will be 
used to estimate and compare functions for overall survival for Groups A and B.  Patients who are 
lost to follow-up before the time of the analysis endpoint (te) will be considered censored as of the 
day the patient was last known to be alive.  Patients who are still alive as of te will be considered 
censored at te. 
The proportion of patients having improvement in ECOG performance status score at any time 
point will be summarized.  The proportion of patients having improvement in the global clinical 
assessment score at any time point will be summarized.  Observed values for responses to the 
EORTC QLQ-C30 will be used to calculate the derived scales for physical functioning, emotional 
functioning, cognitive functioning, social functioning, role functioning, individual symptoms, and 
financial difficulties (Fayers et al. 2001).  The proportion of patients having improvement in any 
of the derived scales of the EORTC QLQ-C30 at any time point will be summarized.  The 
proportion of patients having improvement at any time point in scores for the Karnofsky 
Performance Status Scale will be summarized.  
Exploratory Variables and Analyses 
Observed values and changes from baseline to each time point after each RENCA macrobead 
implantation in levels of tumor markers (CEA and CA19-9) will be summarized using descriptive 
statistics.  The proportion of patients who have a tumor marker response (i.e., at least 
20% decrease from baseline in CEA or CA19-9) will also be summarized. 
Observed values and changes from baseline to each time point after each RENCA macrobead 
implantation in levels of CTCs, immunoglobulin levels (IgA, IgE, IgG, and IgM) and markers of 
cellular immune function (T cells, B cells, and NK cells [i.e., CD16 count]) will be summarized 
using descriptive statistics. 
Characterization of changes from baseline to 90 days after each RENCA macrobead implantation 
in tumors will be listed.  Depending on available results, these data may be summarized. 
Results for analysis of any tumor biopsy samples obtained will be listed. Any autopsy results will 
be listed. 
Safety Variables and Analyses 
Exposure to study treatment, i.e., number of implantations and amount of macrobeads implanted, 
will be summarized using descriptive statistics. 

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Adverse events will be coded using MedDRA (Medical Dictionary for Regulatory Activities) 
version 10.1.  A treatment-emergent adverse event will be defined as an adverse event that began 
or worsened after the first implantation and within 90 days after the last implantation.  Summaries 
of treatment-emergent adverse events will be provided separately by implantation and for all 
implantations.   
Treatment-emergent adverse events will be summarized by overall incidence, by severity, and by 
relationship.  Summaries will also be provided for deaths, serious adverse events, and adverse 
events leading to discontinuation of study treatment.  Listings will be provided for all adverse 
events, deaths, serious adverse events, and adverse events leading to discontinuation of study 
treatment. 
For clinical laboratory parameters (chemistry (including metabolic, liver and renal function), 
hematology (including markers of inflammation), coagulation, and urinalysis), absolute values 
and changes from baseline to each time point after each RENCA macrobead implantation will be 
summarized.  The proportion of patients with abnormal results will be summarized.  Shifts from 
normal at baseline to abnormal after RENCA macrobead implantation will also be provided.  
Abnormal clinical laboratory results and NCI CTCAE v4.0 toxicity grade (if applicable) will be 
noted in the listings, and a separate listing for Grade 3 or higher laboratory values will be 
provided.  Results from eMuLV testing will be listed. 
Vital signs measurements (blood pressure, pulse, respiration rate, and temperature) will be listed. 
Weight changes, along with calculated Body Mass Index (BMI) based on height measurement, 
will be listed.   
Physical examination findings will be listed. 
For 12-lead ECGs, results (normal, abnormal but not clinically significant, or abnormal and 
clinically significant) will be summarized by time point as frequencies and percentages of 
patients. 
For chest x-rays, results (normal, abnormal but not clinically significant, or abnormal and 
clinically significant) will be summarized by time point as frequencies and percentages of 
patients. 
Results from murine allergen skin testing will be listed. 
 

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TABLE OF CONTENTS 
DOCUMENT APPROVAL PAGE .................................................................................... 2 
INVESTIGATOR SIGNATURE PAGE ............................................................................ 3 
ADMINISTRATIVE STRUCTURE OF THE STUDY ..................................................... 4 
SYNOPSIS .......................................................................................................................... 5 
LIST OF TABLES ............................................................................................................ 14 
LIST OF ABBREVIATIONS ........................................................................................... 15 
1. BACKGROUND INFORMATION .......................................................................... 17 
1.1. Introduction ......................................................................................................... 17 
1.2. Name and Description of Investigational Product .............................................. 19 
1.3. Findings from Nonclinical and Clinical Studies ................................................. 19 
1.3.1. Summary of Nonclinical Studies ................................................................. 19 
1.3.2. Summary of Clinical Studies ....................................................................... 20 
1.3.2.1. Study RI-MB-101 (Formerly Known as Study 0407007343 and 
Including Study 0610008795) .............................................................. 20 
1.3.2.2. Study RI-MB-201 (Formerly Known as Study 0911010739) .............. 21 
1.4. Known Benefits and Risks .................................................................................. 21 
1.5. Justification for Dose Selection .......................................................................... 22 
1.6. Compliance Statement ........................................................................................ 22 
1.7. Population to be Studied ..................................................................................... 23 
2. STUDY OBJECTIVES AND ENDPOINTS ............................................................. 24 
2.1. Primary Objective ............................................................................................... 24 
2.2. Secondary Objectives.......................................................................................... 24 
3. INVESTIGATIONAL PLAN .................................................................................... 25 
3.1. Overall Study Design .......................................................................................... 25 
3.2. Measures and Endpoints ..................................................................................... 26 
3.2.1. Efficacy Measures and Endpoints (All Patients) ......................................... 26 
3.2.2. Exploratory Measures and Endpoints (Group A) ........................................ 26 
3.2.3. Safety Measures and Endpoints (Group A) ................................................. 26 
3.3. Measures Taken to Avoid Bias ........................................................................... 27 
3.4. Study Treatment and Dosage .............................................................................. 27 
3.5. Duration of Patient Participation ........................................................................ 28 
3.6. Stopping Rules and Discontinuation Criteria ..................................................... 28 
3.6.1. Stopping Rules ............................................................................................. 28 
3.6.2. Discontinuation Criteria ............................................................................... 29 
3.7. Clinical Supplies and Accountability.................................................................. 29 
3.8. Study Procedures ................................................................................................ 29 
3.8.1. Screening/Re-Screening/Baseline Visit ....................................................... 32 
3.8.2. Day 0 (Day of Each Implantation Procedure).............................................. 32 
3.8.3. Days 14, 30, and 60 After Implantation Procedure ..................................... 33 
3.8.4. Day 90 After Implantation Procedure .......................................................... 33 
3.8.5. Long-Term Follow-Up (Every 6 Months for 2 Years, Then Annually 
Thereafter)................................................................................................. 34 
4. SELECTION AND WITHDRAWAL OF PATIENTS ............................................. 35 
4.1. Inclusion Criteria ................................................................................................ 35 
4.1.1. Inclusion Criteria for All Patients ................................................................ 35 

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4.1.2. Additional Inclusion Criteria for Patients Who Will Undergo RENCA 
Macrobead Implantation (Group A) ......................................................... 35 
4.2. Exclusion Criteria ............................................................................................... 36 
4.2.1. Exclusion Criteria for All Patients ............................................................... 36 
4.2.2. Additional Exclusion Criteria for Patients Who Will Undergo RENCA 
Macrobead Implantation (Group A) ......................................................... 36 
4.3. Withdrawal Criteria and Procedures ................................................................... 37 
5. TREATMENTS ......................................................................................................... 38 
5.1. Implantation of RENCA Macrobeads ................................................................. 38 
5.2. Best Supportive Care .......................................................................................... 38 
5.3. Treatment Compliance ........................................................................................ 38 
5.4. Concomitant Medications or Therapies .............................................................. 39 
5.4.1. Prior and Concomitant Medications or Therapies ....................................... 39 
5.4.2. Other Therapy During Implantation vs. Alternative Therapy ..................... 39 
6. ASSESSMENT OF EFFICACY ............................................................................... 40 
6.1. Primary Efficacy Measurement .......................................................................... 40 
6.2. Secondary Efficacy Measurements ..................................................................... 40 
6.2.1. Clinician-Rated Assessments of Clinical Status .......................................... 40 
6.2.1.1. Eastern Conference Oncology Group Performance Status ................... 40 
6.2.1.2. Global Clinical Assessment .................................................................. 40 
6.2.2. Quality of Life (Patient-Rated Assessments) ............................................... 40 
6.2.2.1. European Organisation for Research and Treatment of Cancer Quality 
of Life Questionnaire ............................................................................ 40 
6.2.2.2. Karnofsky Performance Status Scale .................................................... 41 
6.3. Exploratory Assessments .................................................................................... 41 
6.3.1. Erythrocyte Sedimentation Rate and C-Reactive Protein ............................ 41 
6.3.2. Tumor Markers ............................................................................................ 41 
6.3.3. Circulating Tumor Cells .............................................................................. 41 
6.3.4. Immunoglobulins ......................................................................................... 42 
6.3.5. Cellular Immune Function ........................................................................... 42 
6.3.6. Assessment of Tumor Changes .................................................................... 42 
6.3.7. Tumor biopsies............................................................................................. 42 
6.3.8. Autopsy ........................................................................................................ 42 
7. ASSESSMENT OF SAFETY .................................................................................... 43 
7.1. Adverse Events ................................................................................................... 43 
7.1.1. Definition of an Adverse Event ................................................................... 43 
7.1.2. Recording and Reporting of Adverse Events............................................... 43 
7.1.3. Severity of an Adverse Event ...................................................................... 44 
7.1.4. Relationship of an Adverse Event to the Study Treatment .......................... 45 
7.1.5. Serious Adverse Events ............................................................................... 45 
7.1.5.1. Definition of a Serious Adverse Event ................................................. 45 
7.1.5.2. Reporting a Serious Adverse Event ...................................................... 46 
7.2. Clinical Laboratory Parameters .......................................................................... 47 
7.2.1. Chemistry, Hematology, Coagulation, and Urinalysis ................................ 47 
7.2.2. Ecotropic Murine Leukemia Virus .............................................................. 48 
7.3. Vital Sign Measurements .................................................................................... 48 

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7.4. Physical Examinations ........................................................................................ 48 
7.5. Electrocardiograms ............................................................................................. 48 
7.6. Chest X-Rays ...................................................................................................... 48 
7.7. Other Safety Assessments ................................................................................... 48 
8. STATISTICAL METHODOLOGY .......................................................................... 49 
8.1. Determination of Sample Size ............................................................................ 49 
8.2. Criteria for Termination of the Study ................................................................. 49 
8.3. Analysis Populations ........................................................................................... 49 
8.4. Statistical Analysis Methods ............................................................................... 49 
8.4.1. Study Population .......................................................................................... 50 
8.4.2. Efficacy Analyses ........................................................................................ 50 
8.4.2.1. Primary Efficacy Analysis .................................................................... 50 
8.4.2.2. Secondary Efficacy Analyses ............................................................... 51 
8.4.2.3. Exploratory Analyses ............................................................................ 51 
8.4.3. Safety Analyses ............................................................................................ 53 
8.4.3.1. Exposure to Study Treatment................................................................ 53 
8.4.3.2. Adverse Events ..................................................................................... 53 
8.4.3.3. Clinical Laboratory Parameters ............................................................ 53 
8.4.3.4. Vital Sign Measurements ...................................................................... 53 
8.4.3.5. Physical Examinations .......................................................................... 53 
8.4.3.6. Electrocardiograms ............................................................................... 53 
8.4.3.7. Chest X-Rays ........................................................................................ 54 
8.4.3.8. Other Safety Assessments ..................................................................... 54 
8.5. Interim Analyses ................................................................................................. 54 
8.6. Deviations from the Planned Statistical Analyses .............................................. 54 
9. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ........................................ 55 
10. QUALITY CONTROL AND QUALITY ASSURANCE ....................................... 56 
10.1. Amendments ..................................................................................................... 56 
10.2. Monitoring ........................................................................................................ 56 
10.3. Audits and Inspections ...................................................................................... 56 
10.4. Data Quality Assurance .................................................................................... 56 
11. ETHICS.................................................................................................................... 58 
11.1. Informed Consent.............................................................................................. 58 
11.2. Health Insurance Portability and Accountability Act of 1996 .......................... 58 
11.3. Confidentiality Regarding Study Patients ......................................................... 58 
12. DATA HANDLING AND RECORD KEEPING ................................................... 59 
13. FINANCING AND INSURANCE .......................................................................... 60 
14. REPORTING AND PUBLICATION OF RESULTS ............................................. 61 
15. REFERENCES ........................................................................................................ 62 

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LIST OF TABLES 
Table 1: 
Schedule of Study Procedures .................................................................. 30 
Table 2: 
Chemistry, Hematology, Coagulation, and Urinalysis Parameters........... 47 
 

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LIST OF ABBREVIATIONS  
Abbreviation 
Definition 
ALT 
alanine transaminase 
AST 
aspartate transaminase 
BMI 
Body Mass Index 
BUN 
blood urea nitrogen 
CA19-9 
carbohydrate antigen 19-9, marker for certain 
gastrointestinal tumors 
CA125 
carbohydrate antigen 125, marker for ovarian cancer 
but, in this case, for intraperitoneal inflammation  
CEA 
carcinoembryonic antigen, marker for colorectal 
cancer 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
COPD 
chronic obstructive pulmonary disease 
CRF 
case report form 
CRP 
C-reactive protein 
CTC 
circulating tumor cell assay 
DNA 
deoxyribonucleic acid 
DSMB 
Data Safety Monitoring Board 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eMuLV 
ecotropic murine leukemia virus 
EORTC QLQ-C30 
European Organisation for Research and Treatment of 
Cancer Quality of Life Questionnaire 
ESR 
erythrocyte sedimentation rate 
FDA 
Food and Drug Administration 
FOLFIRI 
leucovorin/5-fluorouracil/irinotecan 
FOLFOX 
leucovorin/5-fluorouracil/oxaliplatin 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyltransferase 
HIV 
human immunodeficiency virus 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Community 
IgA 
immunoglobulin A 
IgE 
immunoglobulin E 
IgG 
immunoglobulin G 
IgM 
immunoglobulin M 
IL-6 
interleukin 6 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IPTW 
inverse probability treatment weight 
IRB 
Institutional Review Board 
LDH 
lactate dehydrogenase 
HIV 
human immunodeficiency virus 
HSB-LV 
HSB low-viscosity agarose (Lonza Group Ltd.) 

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Abbreviation 
Definition 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
NCI CTCAE 
National Cancer Institute Common Terminology 
Criteria for Adverse Events 
NK 
natural killer cell 
PET-CT 
positron emission tomography-computed tomography 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QTcB 
QT interval corrected using Bazett’s formula 
RBC 
red blood cell 
RDW 
red blood cell distribution width 
RENCA 
renal adenocarcinoma 
RT-PCR 
reverse transcriptase polymerase chain reaction 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SOC 
system organ class 
SUV 
standardized uptake value 
TNF 
tumor necrosis factor 
ULN 
upper limit of normal 
US(A) 
United States (of America) 
WBC 
white blood cell 

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1. BACKGROUND INFORMATION 
1.1. 
Introduction 
Treatment for cancer has traditionally consisted of surgery, radiation therapy, and 
chemotherapy.  The advent of targeted, 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, and immune cell activation has changed the 
face of anti-cancer therapy.  Although advances have produced encouraging prognoses in 
certain types of cancer, much remains to be accomplished 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. 
Cancer of the colon is a highly treatable and often curable disease when localized to the 
bowel (Wolpin and Mayer 2008).  Surgery is the primary form of treatment and results in 
cure in approximately 50% of 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 leucovorin/5-fluorouracil/oxaliplatin (FOLFOX) and 
leucovorin/5-fluorouracil/irinotecan (FOLFIRI), with or without the addition of 
bevacizumab and cetuximab (the latter for patients without the KRAS mutation), many 
patients become resistant to available chemotherapies and targeted biological therapies.  
In addition, other surgical and ablative techniques may no longer be an option.  With 
liver and lung metastases being common problems, and brain metastases being less 
common, but potentially devastating, there is clearly a need for new, more effective 
therapeutic measures, especially for those patients who have metastatic spread of their 
tumors (Gleisner et al. 2008, Onaitis et al. 2009). 
Among the therapeutic possibilities currently being explored for colorectal cancer, as 
well as other solid tumors, those that involve cellular biological control mechanisms are 
both appealing and promising. 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, seem to be feasible with significant potential for clinical use (Littlepage et al 
2007).  Furthermore, studies have suggested 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 (Clark and Fuller 2006, Moore and Lemischka 2006).  These cell populations 
may represent a novel and fundamental target for anti-neoplastic therapy.  

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The development of new and more effective therapeutic approaches to the treatment of 
neoplastic disease requires exploration into the nature of cancer and tumor cell growth.  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 complex and multivariate biological system, in a sense a kind of (undesirable) 
organ or organ system.  Adding to this complexity is the fact that the genomic patterns of 
the primary tumors may differ from among themselves within the same organ type and 
their metastases, but also the metastases may differ among themselves in this regard.  
Furthermore, cancer is not an 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.  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 the 
frankly neoplastic cells.   
The fact that cancer can be considered 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 subject to such 
regulation. Not surprisingly, an important signal in the growth-regulatory process for 
tumor cells is the mass of tumor present (Prehn 1991). Tumor growth slows as the mass 
of both primary and metastatic tumors increase (Keir CH, Ocean AJ, Fahey TJ, Berman 
N, Wadke A, Kelly-Rossini L, Goldstein MJ, Leeser DB, Michelassi F, Smith BH. 
Treatment of advanced, epithelial-derived cancer (AEC) with intraperitoneal implantation 
of agarose-agarose macrobeads (MB) containing mouse renal adenocarcinoma cells 
(RENCA). American Society of Clinical Oncology (ASCO) Annual 2011 Meeting; J Clin 
Oncol 29: 2011 (suppl; abstr e13594). 
Laird 1965; Norton et al, 1976; Speer et al., 1984; Norton, 1988; Norton, 2008; Weedon-
Fekjaer et al, 2008). 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 
distant metastases.  The same phenomenon has been demonstrated in animal models of 
tumors (De Wys 1972, Fisher et al. 1989).  In these studies, removal of the primary tumor 
at an early stage of development of the malignancy resulted in the appearance of 
dramatically greater numbers of distal metastases. Other work in breast cancer has 
confirmed and extended the understanding of growth control in tumors (Norton L, Simon 
R, Bereton HD, Bogden AE. Predicting the course of Gompertzian growth. Nature 
1976:264:542-5. 
Norton L. Gompertzian model of human breast cancer growth. Cancer Res 
1988:48:7067-71. 

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Norton et al 2008).  Taking these various findings into account, it is not unreasonable to 
argue 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 (Prehn, 1991). 
The proposed cancer treatment to be evaluated in this study is based, at least in part, on 
the concept that tumor growth can be controlled by tumor mass or signals that indicate 
that such mass is present.  In this case, the induction of inhibitory signals is brought about 
not by true tumor mass, but rather by placing cancer cells in a proliferation-restrictive 
hydrophilic matrix composed of agarose (Smith et al. 2011a, b).  The release of such 
inhibitory signals from cancer cells in a proliferation-restrictive environment has been 
shown to inhibit the proliferation of freely growing cancer cells without specificity of 
species or target tumor cell type in both nonclinical and clinical studies.  
Beyond the specifics of tumor growth inhibition by mass, it is important to add that the 
RENCA macrobead represents a complex biological system in and of itself.  In its 
interactions with tumor cells outside the macrobead, whether in vitro or in vivo, this 
complex system interacts with the target neoplastic cells and tumors to produce a variety 
of inhibitory and stimulating actions that cause gene expression changes in the target 
cells.  These changes range from the down-regulation of genes involved in DNA 
replication and angiogenesis to striking up-regulation of genes concerned with 
programmed cell death (apoptosis) so that tumor cell proliferation is inhibited and cell 
survival is shortened (Smith et al, 2011b). Thus, the RENCA macrobeads represent one 
cancer cell system trapped in an agarose matrix regulating the “behavior” of tumor cells 
outside the bead, suggesting a potentially new and important approach to biologically-
based anti-cancer therapy.  
  
1.2. 
Name and Description of Investigational Product 
The investigational product to be used in this study is mouse RENCA cell-containing agarose-
agarose macrobeads.  Each RENCA macrobead is 6 to 8 mm and contains RENCA cells 
embedded in 1.0% Lonza HSB-LV agarose, surrounded by a second concentric layer made of 
5.0% Lonza HSB-LV agarose layer. It should be noted that 150,000 RENCA are placed initially 
in each agarose-agarose macrobead and that an estimated 99% of these cells die off with one to 
two weeks, with the subsequent formation of colonies of tumor cells consisting of RENCA cells 
with stem cell properties and their daughter cells.  It is when these colonies have formed that the 
macrobead produces the factor or factors that inhibit the growth of tumor cells outside the 
macrobead, both in vitro and in vivo. 
 
1.3. 
Findings from Nonclinical and Clinical Studies 
1.3.1. Summary of Nonclinical Studies 
Nonclinical studies in mouse tumor models, both in vivo and in vitro, have indicated 
statistically significant activity of the RENCA macrobeads with respect to suppression of 
tumor growth.   

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RENCA macrobead-conditioned medium demonstrated growth inhibition of human 
epithelial cell lines including prostate cancer cells (36% to 40%), bladder cancer cells 
(17% to 43%), and colorectal cancer cells (43 to 58%), demonstrating that the inhibitory 
effect of RENCA macrobeads operates across species lines and is not specific to tumor 
cell type (Smith et al. 2011a).  
In mice injected with RENCA tumor cells under the renal capsule, animals which were 
implanted with 4 RENCA macrobeads had significantly smaller tumors (30% to -60%) 
compared with those implanted with empty macrobeads or sham surgery (Smith et al. 
2011a).  When implanted in the peritoneal cavity of 11 dogs with prostate 
adenocarcinoma, RENCA macrobeads significantly extended survival compared with no 
treatment (177 days vs 21 to 30 days).  Improvements in appetite and/or weight and 
activity level were observed in 39 of 51 cats and dogs after RENCA macrobead 
implantation. Long-term survivals without further macrobead treatment were also 
observed in these veterinary patients. 
1.3.2. Summary of Clinical Studies 
Two clinical studies with RENCA macrobeads have been initiated, one Phase I study and 
two Phase II studies.   
1.3.2.1.Study RI-MB-101 (Formerly Known as Study 0407007343 and 
Including Study 0610008795) 
Study RI-MB-101 (formerly known as Study 0407007343) was an investigator-
sponsored, exploratory, Phase I, open-label study to evaluate the safety of RENCA 
macrobead implantation patients with a stage IV, treatment-resistant, epithelial-derived 
tumors.  An exception protocol (Study 0610008795) was initiated to allow patients with 
non-epithelial-derived tumors to be included in Study RI-MB-101.  Tumor types for 
patients enrolled in this study included colorectal carcinoma, gall bladder cancer, gastric 
carcinoma, pancreatic carcinoma, ovarian carcinoma, and non-small cell lung carcinoma.  
Each patient was scheduled for 1 implantation procedure; however, a maximum of 
4 implants, no less than 120 days apart, was allowed on a case-by-case basis.  Thirty-one 
patients underwent RENCA macrobead implantation (28 subjects with epithelial-derived 
tumors and 3 subjects with non-epithelial-derived tumors).   
The mean (standard deviation [SD]) age of all patients was 59 (8.6) years.  Similar 
numbers of men and women were enrolled (15 and 16, respectively). The number of 
RENCA macrobeads implanted was 8 or 16 macrobeads /kg body weight; the mean (SD) 
number of RENCA macrobeads implanted during the first implantation procedure was 
661 (296.9) macrobeads /kg body weight.  Twenty-three (74%) patients had a single 
implantation, and 8 (26%) patients had multiple implantations.  
All 31 patients died.  Median overall survival, measured as date of first implantation to 
date of death due to any cause, was 5.4 months (95% confidence interval [CI]: 2.2, 
7.0 months) for all patients and 7.0 months (95% CI: 1.1, 9.7 months) for patients with 
colorectal cancer (n=12).  

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Most patients had increases in erythrocyte sedimentation rate (ESR), C-reactive protein 
(CRP), CA 125, and IL-6, levels after the implantation procedure, indicating a systemic 
inflammatory response.  These values remained elevated for up to several weeks after the 
implantation procedure, but returned to baseline or near-baseline values by 90 days after 
implantation.   
The RENCA macrobeads were generally well tolerated.  No deaths or serious adverse 
events were considered related to the RENCA macrobead implantations.  The most 
common adverse events that were considered related to study treatment involved 
systemic inflammation as the underlying problem (Keir et al, 2011).   
1.3.2.2.Study RI-MB-201 (Formerly Known as Study 0911010739) 
Study RI-MB-201 (formerly known as Study 0911010739) is an ongoing, Phase II, 
open label study to evaluate the efficacy and safety of RENCA macrobead implantation 
in patients with advanced pancreatic or colorectal cancer.  Patients could have had a 
maximum of 4 implants, with a minimum of 90 days between each implant.   
As of the data cutoff date of 9 April 2013, 46 patients had undergone RENCA macrobead 
implantation, 30 patients with colorectal and 16 patients with pancreatic cancer.   
The mean (SD) age of all patients was 59 (8.9) years.  The number of RENCA 
macrobeads implanted was 8 macrobeads /kg body weight; the mean (SD) number of 
macrobeads implanted during the first implantation procedure was 
617 (136.1) macrobeads.  Thirty-three (72%) patients had a single implantation, and 
13 (28%) patients had multiple implantations. 
Overall survival was defined as the date of first implantation to date of death due to any 
cause. Overall, 36 (78%) patients died.  Median overall survival was 5.6 months 
(95% CI: 4.2, 8.7) for the combined analysis of the colorectal and pancreatic patients.  
Twenty-two (76%) patients with colorectal cancer died, and median overall survival of 
patients with colorectal cancer was 7.2 months (95% CI: 5.0, 12.3). Among patients with 
colorectal cancer, product-limit median survival was 10.1 months (95% CI: 4.3, 13.5) for 
patients who had a tumor marker response* compared with 5.6 months (95% CI: 2.4, 
6.0 months) for patients who did not have a tumor marker response (p=0.51, log-rank 
test). 
 
No new safety or tolerability concerns were discovered during this study (Ocean et al, 
2013). 
* Tumor marker response was defined as a 20% or greater decrease in either or both CEA 
and CA 19-9 levels within the first thirty days after implantation. 
 
1.4. 
Known Benefits and Risks 
Treatment with RENCA macrobeads has been shown to increase survival in patients who 
have an increase in ESR, CRP, and interleukin 6 (IL-6) levels and a concurrent decrease 
in tumor markers (Ocean et al. 2013).  Implantation with RENCA macrobeads has also 

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been associated with tumor necrosis in patients with longer overall survival after 1 
implantation.  RENCA macrobeads have been generally well tolerated with no 
treatment-related adverse events of Grade 3 or higher being reported in clinical studies. 
The surgical procedure required for implantation of RENCA macrobeads in the 
peritoneal cavity is simple and minimally invasive as it is performed by laparoscopy.  
There are risks associated with any surgical procedure, including those related to 
anesthesia, infection, and bleeding, and with laparoscopic surgery, in particular, 
accidental damage to the bowel or blood vessels within the abdomen.  The screening 
process will take into account individual patient risk factors, and patients with any 
condition that makes them an unsuitable surgical candidate will not be enrolled.   
As with any xenograft procedure, allergic reaction to foreign antigens (in this case, 
mouse antigens) is a potential risk (Chapman et al 1995).  Patients who undergo RENCA 
macrobead implantation will have skin testing performed during their participation in the 
study to detect an allergy to mouse antigens. 
Theoretically, there is a potential for transmission of a murine virus to a patient implanted 
with RENCA macrobeads.  However, the only virus identified to date in the RENCA cell 
line is the ecotropic (non-xenotropic) variant of the murine leukemia virus (eMuLV), an 
endogenous retrovirus that is not known to infect human cells (National Research 
Council, 1991).  Precautions taken to avoid transmission of a murine virus include 
screening for known murine viruses, including those that present a possible risk of 
infection for humans and routine testing for microbiological contaminants, during their 
maintenance in culture as well as after their incorporation into the RENCA macrobeads.  
It is important to note that no evidence of viral or other infection related to RENCA 
macrobead implantation has been observed in any of the animals or clinical study patients 
who have undergone RENCA macrobead implantation over the past 8 years.   
1.5. 
Justification for Dose Selection 
In the Phase I, open-label study of RENCA macrobead implantation in 31 patients with 
end-stage, treatment-resistant tumors, single implantations of 8 macrobeads /kg body 
weight were determined to be well tolerated when implanted in the abdominal cavity.  
RENCA macrobeads in the amount of 16 macrobeads/kg body weight were also 
determined to be well tolerated, but did not appear to offer any additional treatment 
effect.  Therefore, the amount of RENCA macrobeads to be implanted in patients in this 
study will be 8 macrobeads /kg body weight.  Both dose levels were derived from the 
animal studies summarized above (see Section 1.3.1 above). 
RENCA macrobeads have been shown to produce an inhibitory effect for at least 3 years 
in vitro and up to 6 months in vivo animal studies.  Data from the Phase I clinical trial 
indicate that RENCA macrobeads have a functional longevity of 3 to 4 months in the 
human peritoneal cavity, Therefore, the minimum time between successive RENCA 
macrobead implantations in this study will be no less than 90 days. 
A maximum of 4 RENCA macrobead implantations has its basis in results from the 
veterinary patient studies and previous human clinical studies in which the majority of 

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patients had 1 or 2 implantations.  This number is also considered sufficient to provide 
potential benefit to patients with advanced disease and lack of other treatment options. 
1.6. 
Compliance Statement 
This study will be conducted in compliance with the United States IND regulations 
(21 Code of Federal Regulations [CFR] Parts 50, 54, 56, 312, and 314), International 
Conference on Harmonization (ICH) Guidance for Industry, E6 Good Clinical Practice 
(GCP), the Nuremberg Code, and the most recent guidelines of the Declaration of 
Helsinki.   
1.7. 
Population to be Studied 
A total of 120 patients with treatment-resistant, metastatic colorectal cancer will be 
entered in the study. Forty patients will undergo RENCA macrobead implantation and 80 
patients will receive, or are receiving, best supportive care. 

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2. STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Primary Objective 
The primary objective of this study is to evaluate the efficacy of RENCA macrobead 
implantation compared with that seen with best supportive care, as assessed by overall 
survival, in patients with treatment-resistant, metastatic colorectal carcinoma. 
2.2. 
Secondary Objectives 
Secondary objectives, defined only for patients with treatment-resistant, metastatic 
colorectal carcinoma who undergo RENCA macrobead implantation (i.e., Group A), are 
to determine or evaluate the effect of RENCA macrobead implantation on the following 
variables: 
 change from baseline over the period after the first RENCA macrobead 
implantation in clinical status, as measured by Eastern Cooperative Oncology 
Group (ECOG) performance status score and global clinical assessment  
 change from baseline over the period after the first RENCA macrobead 
implantation in quality of life, as measured by the European Organisation for 
Research and Treatment of Cancer Quality of Life Questionnaire 
(EORTC QLQ-C30) and Karnofsky Performance Status Scale 
 change from baseline over the period after the first RENCA macrobead 
implantation in erythrocyte sedimentation rate (ESR) and C-reactive protein 
(CRP) levels.  CA-125 will also be used as a marker of inflammation, especially 
that localized in the peritoneal cavity. 
 change from baseline over the period after the first RENCA macrobead 
implantation in levels of tumor markers (including carcinoembryonic antigen 
[CEA] and carbohydrate antigen 19-9 [CA19-9])  
 tumor marker response rate, defined as the proportion of patients who have a 
decrease from baseline of 20% or more in CEA or CA 19-9 values 
 change from baseline over the period after the first RENCA macrobead 
implantation in circulating tumor cells (CTCs)  
 safety and tolerability of RENCA macrobeads, as measured by the following: 
o adverse events 
o clinical laboratory tests, including chemistry, hematology, coagulation, 
urinalysis, and PCR-based testing for presence of ecotropic murine 
leukemia virus (eMuLV) in serum  
o murine allergen skin test  

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3. INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design 
This is a Phase IIb, multicenter, nonrandomized, open-label study with RENCA 
macrobeads in patients with treatment-resistant, metastatic colorectal carcinoma to 
determine the effect of RENCA macrobead implantation on overall survival compared 
with best supportive care.   
Two treatment groups will be enrolled in this study, as follows: 
 Group A (n=40) – patients who will undergo up to 4 implantations of RENCA 
macrobeads, at an amount of 8 RENCA macrobeads /kg body weight 
 Group B (n=80) – patients who will receive or are receiving best supportive care, 
defined as management of symptoms aimed at maintaining or improving quality 
of life, but not including approved therapies targeting the patient’s malignancy  
For patients in Group A, the study will consist of a screening period lasting up to 30 days, 
up to 4 RENCA macrobead implantation procedures at least 90 days apart, and a 90-day 
follow-up period after the final implantation procedure.  Patients will be expected to 
participate in a long-term follow-up period until death.  RENCA macrobead implantation 
procedures may be delayed at the investigator’s discretion, by patient decision, or due to 
initiation of another approved or experimental therapy other than localized radiation for 
symptom relief or therapeutic or palliative surgery (see Section 5.4.2).  No maximum 
period between implantation procedures will be defined, and patients having treatment 
delays will not be discontinued from the study.  However, if more than 30 days pass 
between a Day 90 visit and Day 0 of a subsequent implantation, patients will have re-
screening assessments performed to ensure continued eligibility.  Re-screening 
assessments will not include administration of informed consent, review of medical 
history, or murine allergen skin test.  Inclusion/exclusion criteria do not have to be 
applied at this time. However, patients must continue to be surgical candidates, as per the 
medical judgment of the investigator and surgeon and consistent with the standards of 
optimal patient care. 
After informed consent has been obtained, patients in Group A will undergo 
screening/baseline assessments.  For eligible patients, the first procedure to implant 
RENCA macrobeads into the peritoneal cavity will be scheduled for Day 0.  Patients will 
be expected to return to the clinic on Days 14, 30, 60, and 90 after each RENCA 
macrobead implantation procedure for efficacy, exploratory, and safety assessments.  Up 
to 3 additional (for a total of 4) RENCA macrobead implantation procedures will be 
performed dependent on the patient’s disease state and at the investigator’s discretion.   
Patients will be considered for enrollment in Group B only if they have already decided 
independently of this study not to pursue therapeutic treatment of their cancer.  For 
patients in Group B, the study will consist of administration of informed consent, which 
will include permission to review medical records and record relevant medical 
information, agreement to be followed for survival, and evaluation of the appropriate 

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inclusion/exclusion entry criteria.  Patients in Group B will not have any subsequent 
assessments performed as part of this study. 
It is expected that study centers will enroll patients in either Group A or Group B, but not 
necessarily both treatment groups. 
3.2. 
Measures and Endpoints 
3.2.1. Efficacy Measures and Endpoints (All Patients) 
For all patients, the primary efficacy variable is overall survival, defined as the time 
interval from the date of radiographically documented disease progression to the date of 
death due to any cause.  Secondary efficacy measurements include assessment of clinical 
status (ECOG performance status score and global clinical assessment) and quality of life 
assessments (EORTC QLQ-30 and Karnofsky Performance Status Scale). 
3.2.2. Exploratory Measures and Endpoints (Group A) 
For patients in Group A, exploratory measures and endpoints are as follows: 
 ESR, CRP, and CA 125 levels at Days 14, 30, 60, and 90 after each RENCA 
macrobead implantation 
 Tumor marker (including CEA and CA19-9) levels at Days 14, 30, 60, and 90 
after each RENCA macrobead implantation  
 CTCs at Day 90 after each RENCA macrobead implantation 
 Immunoglobulin (IgA, IgE, IgG, and IgM) levels at Day 90 after each RENCA 
macrobead implantation  
 Cellular immune function, as measured by T cell count; B cell count, NK cell 
counts (e.g., CD16 count), at Day 90 after each RENCA macrobead implantation 
 Characterization of tumor changes at Day 90 after each RENCA macrobead 
implantation using PET-CT scans 
 Appropriate histopathological analysis of tumor biopsy samples, when medically 
indicated and at the investigator’s discretion  
 Examination of tumor state and any inflammatory or connective tissue reaction to 
the RENCA macrobeads after autopsy, if applicable 
3.2.3. Safety Measures and Endpoints (Group A) 
For patients in Group A, the safety of treatment with RENCA macrobeads will be 
assessed as follows:  
 Monitoring of adverse events throughout the study 
 Clinical laboratory tests (including chemistry, hematology, coagulation, 
urinalysis) at Days 14, 30, 60, and 90 after RENCA macrobead implantation 
 eMuLV test at Days 30 and 90 after RENCA macrobead implantation 
 Vital signs measurements at Days 14, 30, 60, and 90 after RENCA macrobead 
implantation 

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 Physical examinations at Days 14, 30, 60, and 90 after RENCA macrobead 
implantation 
 12-lead ECG at Day 90 after RENCA macrobead implantation 
 Chest x-ray at Day 90 after RENCA macrobead implantation 
 Murine allergen skin test at Day 90 after RENCA macrobead implantation 
3.3. 
Measures Taken to Avoid Bias 
This study has a nonrandomized, open-label design.  Previous clinical studies with 
RENCA macrobead implantation have not included a control group, primarily because a 
blinded placebo control is not feasible with the surgical procedure required for treatment 
with RENCA macrobeads.  In this study, RENCA macrobead implantation will be 
compared to best supportive care with regard to overall survival as the primary endpoint.  
Secondary efficacy parameters will also be evaluated as specified in section 2.2. 
In addition, the advanced disease state that characterizes the patient population selected 
for this study precludes the use of an active control since no alternative therapies exist 
currently.  Patients considered for RENCA macrobead implantation will be those patients 
who are seeking alternative treatment for their disease.  Patients in the best supportive 
care treatment group will have already decided independently of this study that they are 
not seeking additional treatment for their disease.  Randomization of patients into 1 of the 
2 treatment groups would take away the patient’s decision to seek or not to seek further 
treatment and would have unacceptable ethical implications.  The survival of the best 
supportive care group (Group B) will be compared to Group A using the 
inclusion/exclusion criteria of the protocol and propensity score matching statistical 
techniques in accord with best statistical practice and draft FDA guidance and 
consultation.  
Comparison of RENCA macrobead implantation and best supportive care, where 
applicable and using appropriate statistical methods referred to above, will allow for an 
informative statistical analysis of the efficacy data collected during this study and will 
provide a context for data collected in previous studies. 
3.4. 
Study Treatment and Dosage 
The investigational product to be used in this study is mouse RENCA cell-containing 
agarose-agarose macrobeads.  Each RENCA macrobead is 6 to 8 mm and contains 
RENCA cells embedded in 1.0% Lonza HSB-LV agarose, surrounded by a second 
concentric layer made of 5.0% Lonza HSB-LV agarose layer. It should be noted that 
150,000 RENCA are placed initially in each agarose-agarose macrobead and that an 
estimated 99% of these cells die off with one to two weeks, with the subsequent 
formation of colonies of tumor cells consisting of RENCA cells with stem cell properties 
and their daughter cells.  It is when these colonies have formed that the macrobead 
produces the factor or factors that inhibit the growth of tumor cells outside the 
macrobead, both in vitro and in vivo.  
 

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The amount of RENCA macrobeads to be surgically implanted in each patient will be 
8 macrobeads /kg body weight. Only patients in Group A will undergo implantation with 
RENCA macrobeads. 
The RENCA macrobeads are prepared, counted, and packaged in vials at The Rogosin 
Institute, Xenia Division (Xenia, Ohio) for each individual patient scheduled for an 
implantation procedure.  An extra vial containing 10 RENCA macrobeads will be 
included with each shipment.  The label on each package of RENCA macrobeads 
contains the following information: patient number, lot number, date of production, date 
of shipment, and intended implant date.  The RENCA macrobeads are then sent by 
courier to the study center to be available the night before the scheduled day of 
implantation. After the RENCA macrobeads arrive, they are stored at room temperature 
until implanted, which should occur within 24 hours after receipt.  If the RENCA 
macrobeads are not used within the designated 24-hour period, they are to be returned to 
The Rogosin Institute, Xenia Division. 
More information regarding the implantation procedure is provided in Section 5.1. 
3.5. 
Duration of Patient Participation 
Patients in Group A are expected to participate in a screening period lasting a maximum 
of 30 days, a treatment period including up to 4 RENCA macrobead implantation 
procedures no less than 90 days apart (and no maximum period between implantations 
defined), a follow-up period after the last implantation procedure lasting 90 days and a 
long-term follow-up period lasting the duration of their lives.  Not including the 
long-term follow-up period, the total expected duration is a minimum of 120 days (for 
1 implantation procedure) or 390 days (for 4 implantation procedures).   
Patients in Group B are expected to participate in this study for the duration of their lives, 
though no active participation is required. 
3.6. 
Stopping Rules and Discontinuation Criteria 
3.6.1. Stopping Rules 
If the sponsor, investigator, study monitor, Data Safety Monitoring Board (DSMB) (see 
also Section 7), 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 
Conditions that may result in termination of participation by a particular study center may 
include, but are not limited to, the following:  

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 Failure of the investigator to enroll patients into the study at an acceptable rate 
 Failure of the investigator to comply with pertinent FDA regulations 
 Submission of information known to be false from the research facility to the 
sponsor, study monitor, or the FDA 
 Insufficient adherence to protocol requirements  
3.6.2. Discontinuation Criteria 
Study termination and follow-up would be performed in accordance with 21 CFR 312.50 
and 21 CFR 312.56. 
For individual patients in Group A, it is planned that the RENCA macrobeads will remain 
in the peritoneal cavity for the life of the patient unless it is considered in the best interest 
of the patient to consider removal of the macrobeads. Removal of RENCA macrobeads 
may be considered for reasons including, but not limited to, the following: 
 Evidence of active infection by eMuLV, as evidenced by a viral load detected 
through RT-PCR 
 Occurrence of a Grade 4 or Grade 5 adverse event that is considered unexpected 
and related to the RENCA macrobeads 
 Occurrence of a Grade 3 or higher chronic peritonitis reaction, as described in the 
National Cancer Institute Common Terminology Criteria for Adverse Events, 
version 4.0 (NCI CTCAE v4.0): 
o Grade 3 – symptomatic and severely altered gastrointestinal function (e.g., 
inadequate oral caloric or fluid intake); intravenous fluids, tube feedings, 
or total parenteral nutrition indicated for more than 24 hours 
o Grade 4 – life-threatening consequences 
3.7. 
Clinical Supplies and Accountability 
The investigator must maintain accurate records of receipt of the RENCA macrobeads, 
inventory at the site, use by each patient, and the prompt return of unused supplies.  
These records must include dates, quantities, and batch numbers. 
3.8. 
Study Procedures 
A schedule of study procedures for patients in Group A is provided in Table 1. 
Participation in the study by patients in Group B will consist of administration of 
informed consent, which will include permission to review medical records and record 
relevant medical information, agreement to be followed for survival, and review of entry 
criteria.  Patients in Group B will not have any assessments performed as part of this 
study. 

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Table 1: 
Schedule of Study Procedures 
 
Screening/Re-screeninga/
Baseline 
Active Treatment  (Implants 1, 2, 3, and 4) 
 
Long-Term 
 
Days –30 to –1 
Day 0 
Day 14±3 
Day 30±5 
Day 60±5 
Day 90±5 
Follow-Upb 
Visit number 
 
1, 6, 11, 16 
2, 7, 12, 17 
3, 8, 13, 18 
4, 9, 14, 19 
5, 10, 15, 20 
 
Procedure 
 
 
 
 
 
 
 
Informed consent 
Xa 
 
 
 
 
 
 
Inclusion/exclusion criteria 
Xa 
 
 
 
 
 
 
Medical history, including prior anticancer treatments 
Xa 
 
 
 
 
 
 
Physical exam, including weight, and height (height 
at screening/baseline only) 
X 
 
X 
X 
X 
X 
 
Vital signsc 
X 
X 
X 
X 
X 
X 
 
12-Lead ECG 
X 
 
 
 
 
X 
 
Chest x-ray 
X 
 
 
 
 
X 
 
Viral screening (HIV, hepatitis B, C, E) 
X 
 
 
 
 
 
 
Pregnancy test (females of childbearing potential 
only) 
Xd,e 
 
 
 
 
 
 
Chemistryf 
X 
 
X 
X 
X 
X 
 
Hematologyg 
X 
 
X 
X 
X 
X 
 
Coagulation (PT, PTT, INR) 
X 
 
X 
X 
X 
X 
 
Urinalysish 
X 
 
 
 
 
X 
 
eMuLV 
X 
 
 
X 
 
X 
X 
Murine allergen skin test  
Xa 
 
 
 
 
X 
 
CRP, ESR, CA 125 
X 
 
X 
X 
X 
X 
 
Tumor markers (CEA, CA19-9) 
X 
 
X 
X 
X 
X 
 
Circulating Tumor Cells (CTCs) 
X 
 
 
 
 
X 
 
Immunoglobulins (IgA, IgE, IgG, IgM) 
X 
 
 
 
 
X 
 
Cellular immune functioni 
X 
 
 
 
 
X 
 
PET-CT for assessment of tumor changesj 
X 
 
 
 
 
X 
 
ECOG Performance Scale 
X 
 
X 
X 
X 
X 
 
Global clinical assessment  
X 
 
X 
X 
X 
X 
 
EORTC QLQ-C30 
X 
 
X 
X 
X 
X 
 
Karnofsky Performance Status Scale 
X 
 
X 
X 
X 
X 
 
Macrobead implantationk 
 
X 
 
 
 
 
 
Tumor mass biopsyl 
 
X 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
 
Adverse events 
X 
X 
X 
X 
X 
X 
 
 

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a If more than 30 days pass between a Day 90 visit and Day 0 of a subsequent implantation, patients will have re-screening assessments performed to ensure 
continued eligibility. Re-screening assessments will not include administration of informed consent, review of medical history, or murine allergen skin test.  
Inclusion/exclusion criteria do not have to be verified in their entirety; however, patients must continue to be surgical candidates, as deemed by the investigator. 
b Additional procedures may be performed at long-term follow-up visits, as clinically indicated. Long-term follow-up visits will occur every 6 months (±14 days) 
for 2 years, then every year (±1 month) thereafter until death to determine overall survival status, to test for the presence of eMuLV, and to determine whether 
any adverse events that would be considered related to the RENCA macrobeads occurred. 
c Vital signs measurements include blood pressure, pulse, respiration rate, and temperature.  
d A serum pregnancy test will be performed at baseline screening/re-screening baseline visits.  
e If the screening serum pregnancy test result was obtained more than 2 weeks before Day 0 of each implant, then a urine pregnancy test must be done 2 days 
prior to the planned laparoscopic procedure.  If this has not been (or cannot be done) done, the procedure should be postponed until the result is available and the 
patient can be cleared for surgery based on a negative result. 
f Chemistry parameters include AST, ALT, GGT, lactate dehydrogenase, alkaline phosphatase, total bilirubin, direct bilirubin, albumin, creatinine, BUN, total 
protein, glucose, carbon dioxide, sodium, potassium, chloride, and calcium. Amylase and lipase will be done at baseline.  If within normal limits, they need not 
be repeated.  
g Hematology parameters include WBC count, RBC count, hemoglobin, hematocrit, MCV, MCH, MCHC, RDW, platelets, and automated differential WBC. 
h Urinalysis parameters include color, appearance, glucose, bilirubin, ketones, specific gravity, pH, blood, protein, urobilinogen, nitrite, leukocyte esterase, and 
urine sediments. 
i Cellular immune function will be assessed by measuring the following: T cells; B cells, and NK cells (i.e., CD16 count). 
j Additional imaging techniques (i.e., MRI, CT, sonography, bone scans, or x rays) may be performed for further assessment of tumor changes, as clinically 
indicated. 
k All patients will receive antibiotic prophylaxis prior to the implantation procedure. 
l At the investigator’s discretion during the implantation procedure, tumor biopsy samples may be collected for appropriate, medically-indicated histopathological 
analysis. 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; CA19-9=carbohydrate antigen 19-9; CA125=carbohydrate 
antigen 125; CEA=carcinoembryonic antigen; CRP=C-reactive protein; CTCs=circulating tumor cells; ECG=electrocardiogram; ECOG=Eastern Cooperative 
Oncology Group; eMuLV=ecotropic murine leukemia virus; EORTC QLQ-C30=European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire; ESR=erythrocyte sedimentation rate; HIV=human immunodeficiency virus; Ig=immunoglobulin; IL-6=interleukin 6; INR=International 
Normalized Ratio; MCH=mean corpuscular hemoglobin; MCHC=mean corpuscular hemoglobin concentration; MCV=mean corpuscular volume; NK=natural 
killer; PET-CT=positron emission tomography-computed tomography; PT=prothrombin time; PTT=partial thromboplastin time; RBC=red blood cell; RDW=red 
blood cell distribution width; TNF=tumor necrosis factor; WBC=white blood cell. 
 

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3.8.1. Screening/Re-Screening/Baseline Visit 
For patients in Group A, the screening/re-screening/baseline visit will occur within 30 
days of Day 0 (day of implantation procedure).  All of the following procedures or 
assessments will be performed at the screening/re-screening/baseline visit: 
 Informed consent (not to be performed at the re-screening visit) 
 Inclusion/exclusion criteria (not to be performed in entirety at the re-screening 
visit; patients must continue to be surgical candidates, as deemed by the 
investigator) 
 Medical history (at the screening visit only) 
 Physical examination, including height (baseline only) and weight 
 Vital signs (blood pressure, pulse, respiration rate, and temperature) 
 12-lead ECG 
 Chest x-ray 
 Collection of blood samples 
o Viral screening for HIV and hepatitis B, C, and E  
o eMuLV test 
o Serum pregnancy test for women of childbearing potential only 
o Clinical laboratory tests (chemistry, hematology, coagulation) 
o CRP, ESR, CA 125 
o Tumor markers (CEA, CA19-9) 
o CTCs 
o IgA, IgE, IgG, and IgM 
o Cellular immune function (T cells; B cells, and NK cells [i.e., CD16]) 
 Collection of urine sample for urinalysis 
 Murine allergen skin test (not to be performed at a re-screening visit) 
 Assessment of tumor changes, using PET-CT scans (and additional imaging 
techniques [i.e., MRI, CT, sonography, bone scans, or x-rays], as clinically 
indicated) 
 ECOG performance status 
 Global clinical assessment 
 EORTC QLQ-C30 
 Karnofsky Performance Status Scale 
 Concomitant medications 
 Adverse events (re-screening only) 
3.8.2. Day 0 (Day of Each Implantation Procedure) 
Unless a serum pregnancy test result for females of childbearing potential in Group A 
only was obtained within the 2 weeks before Day 0, female patients of childbearing 
potential must have a urine pregnancy test performed 2 days prior to the RENCA 
macrobead implantation procedure or otherwise the procedure should be postponed until 
the result is available and negative for pregnancy.  RENCA macrobeads implanted in the 
amount of 8 macrobeads per kilogram, based on the body weight obtained during the 
pretreatment evaluations. See also Section 5.1. 

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A review of concomitant medications and adverse events should be performed at this 
visit.  Vital signs (blood pressure, pulse, respiration rate, and temperature) will also be 
measured. 
At the investigator’s discretion during the implantation procedure, tumor biopsy samples 
may be collected for appropriate, medically-indicated histopathological analysis. 
3.8.3. Days 14, 30, and 60 After Implantation Procedure 
For patients in Group A, the following assessments will be performed on Days 14 (±3), 
30 (±5), and 60 (±5), unless otherwise noted: 
 Physical examination, including weight 
 Vital signs (blood pressure, pulse, respiration rate, and temperature) 
 Collection of blood samples 
o Clinical laboratory tests (chemistry, hematology, coagulation) 
o eMuLV test (Day 30 only) 
o CRP, ESR, CA 125 
o Tumor markers (CEA, CA19-9) 
 ECOG performance status 
 Global clinical assessment 
 EORTC QLQ-C30 
 Karnofsky Performance Status Scale 
 Concomitant medications 
 Adverse events 
 
3.8.4. Day 90 After Implantation Procedure 
For patients in Group A, the following procedures or assessments will be performed at 
the Day 90 (±5) visit: 
 Physical examination, including weight 
 Vital signs (blood pressure, pulse, respiration rate, and temperature) 
 12-lead ECG 
 Chest x-ray 
 Collection of blood samples 
o Clinical laboratory tests (chemistry, hematology, coagulation) 
o eMuLV test 
o CRP, ESR, and CA 125 
o Tumor markers (CEA, CA19-9) 
o CTCs 
o IgA, IgE, IgG, and IgM 
o Cellular immune function (T cells; B cells, and NK cells (i.e., CD16]) 
 Collection of urine sample for urinalysis 
 Murine allergen skin test  

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 Assessment of tumor changes using PET-CT scans (and additional imaging 
techniques [i.e., MRI, CT, PET-CT, sonography, bone scans, or x-rays], as 
clinically indicated) 
 ECOG performance status 
 Global clinical assessment 
 EORTC QLQ-C30 
 Karnofsky Performance Status Scale 
 Concomitant medications 
 Adverse events 
 
3.8.5. Long-Term Follow-Up (Every 6 Months for 2 Years, Then Annually 
Thereafter) 
For patients in Group A, long-term follow-up visits will occur every 6 months (±14 days) 
after the Day 90 visit following the last implantation procedure for 2 years and annually 
(±1 month) thereafter until death to test for presence of eMuLV, to determine overall 
survival status, and to determine whether any adverse events considered related to the 
RENCA macrobeads occurred. 
Attempts to contact patients by telephone should be made on a regular basis as 
determined by the investigator to document survival. 

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4. SELECTION AND WITHDRAWAL OF PATIENTS 
A total of 120 patients with treatment-resistant, metastatic colorectal carcinoma will be 
entered in the study at a maximum of 6 study centers in the US.  Forty patients will 
undergo RENCA macrobead implantation, and 80 patients will receive or are receiving 
best supportive care.  It is expected that study centers will enroll patients in either Group 
A or Group B and not necessarily both treatment groups. 
4.1. 
Inclusion Criteria  
4.1.1. Inclusion Criteria for All Patients 
Patients in both treatment groups must meet all of the following criteria to be considered 
eligible to participate in the study: 
1. Patients are adult men or women, aged 18 years or older, with histologically-
confirmed, metastatic adenocarcinoma of the colon or rectum that is resistant to 
available treatment options, including at least two such options from available 
chemotherapy, targeted, and other regimens. 
2. Patients have radiographically documented evidence of disease progression. 
3. Patients have a life expectancy of at least 6 weeks, in the investigator’s opinion, at 
the time disease progression is documented. 
4. Patients are considered surgical candidates on the basis of co-morbidity risks, 
number and sites of metastases, and ability to withstand general anesthesia. 
5. Patients are able to provide written informed consent. 
 
4.1.2. Additional Inclusion Criteria for Patients Who Will Undergo RENCA 
Macrobead Implantation (Group A) 
Patients in Group A must also meet all of the following additional criteria: 
6. Patients have an ECOG performance status score of 0, 1, or 2. 
7. Patients have adequate hematologic function, defined as follows: 
a. absolute neutrophil count (ANC) ≥1500 /mL 
b. hemoglobin ≥9 g/dL 
c. platelets ≥75,000 /mL 
8. Patients have adequate hepatic function, defined as follows: 
d. bilirubin ≤1.5 times the upper limit of normal (x ULN) 
e. aspartate transaminase (AST) ≤3 x ULN, or ≤5 x ULN if liver metastases 
are present 
f. alanine transaminase (ALT) ≤3 x ULN, or ≤5 x ULN if liver metastases are 
present 
9. Patients have adequate renal function, defined as creatinine ≤2.0 mg/dL. 
10. Patients have adequate coagulation function, defined as follows: 

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g. International Normalized Ratio (INR) ≤1.5 or between 2 and 3 if the patient is 
receiving anticoagulation 
h. partial thromboplastin time (PTT) ≤5 seconds above the ULN 
Note: Patients receiving full-dose anticoagulation therapy must be receiving a 
stable dose of oral anticoagulant therapy or low-molecular-weight heparin. 
11. Clinically significant toxic effects of chemotherapy (excluding alopecia), 
radiotherapy, hormonal therapy, or prior surgery must have resolved to Grade 1 or 
better, with the exception of peripheral neuropathy, which must have resolved to 
Grade 2 or better. 
12. Female patients of childbearing potential must have a negative serum pregnancy 
test at screening (and a negative urine pregnancy test 2 days prior to the first and 
each subsequent macrobead implantation if the screening serum pregnancy test 
result was obtained more than 2 weeks before surgery); patients must agree to use 
a medically appropriate form of birth control (i.e., barrier method or abstinence) 
from screening throughout their participation in the study.  Male patients and 
partners must agree to use condoms. 
 
4.2. 
Exclusion Criteria  
4.2.1. Exclusion Criteria for All Patients 
Patients in both treatment groups who meet any of the following criteria will be excluded 
from participating in the study:   
1. Patient has hepatic blood flow abnormalities, i.e., portal vein hypertension and 
thrombosis, and/or a large volume of ascites. 
2. Patient has concurrent cancer of any other type, except skin cancers other than 
melanoma. 
3. Patient has a positive test result for human immunodeficiency virus (HIV) or any 
hepatitis other than A at screening. 
4. Patient is considered by the investigator to be unsuitable upon review of medical 
history, physical examination, or clinical laboratory test results. 
4.2.2. Additional Exclusion Criteria for Patients Who Will Undergo 
RENCA Macrobead Implantation (Group A) 
Patients in Group A who meet any of the following additional criteria will be excluded 
from participating in the study:   
5. Patient received FDA-approved chemotherapy within 3 weeks of Day 0, or 
bevacizumab (or similar drugs) within 4 weeks of Day 0, or radiation therapy at 
any site within 4 weeks of Day 0. 
 
6. Patient received investigational anticancer therapy within 4 weeks of Day 0. 

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7. Patient has a positive reaction to the skin test for allergy to mouse antigen (Greer 
Laboratories, Inc. product #E2 [mouse epithelia], Lenoir, NC). 
8. Patient has a history of hypersensitivity reaction that, in the opinion of the 
investigator, poses an increased risk of an allergic reaction to the RENCA 
macrobeads, particularly any known allergy to murine antigens or body tissues. 
9. The patient has an ongoing or active infection, symptomatic congestive heart 
failure, unstable angina pectoris, serious cardiac arrhythmias (with the exception 
of well controlled atrial fibrillation), active bleeding, or psychiatric illness, or 
social situations that could interfere with the patient's ability to participate in the 
study.  
4.3. 
Withdrawal Criteria and Procedures 
Patients can withdraw their consent to participate in the study without risk to their 
individual health care at any time.  Patients in Group A may also be removed from 
consideration for RENCA macrobead implantation by the investigator or the sponsor at 
any time, if either determines that it is in the best interest of the patient.   
If patients in Group A will no longer consider or be considered for RENCA macrobead 
implantation, they will be encouraged to continue in the 90-day follow-up period, which 
includes reporting of serious adverse events (see Section 7.1.5) and/or the long-term 
follow-up period.  The primary reason for discontinuation of treatment with RENCA 
macrobeads will be recorded on the case report form (CRF).   
Patients who do not complete the study will not be replaced. 

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5. TREATMENTS 
5.1. 
Implantation of RENCA Macrobeads  
The number of RENCA macrobeads to be surgically implanted in each patient in Group 
A is based on body weight and will be calculated as 8 RENCA macrobeads /kg body 
weight.  Each patient will have up to 4 macrobead implantations, with at least 90 days 
between each implantation.   
A patient’s body weight as measured within 30 days of Day 0 (i.e., at the 
screening/baseline visit, a Day 90 visit following a previous implantation procedure, or a 
re-screening visit) will be used to calculate the amount of RENCA macrobeads to be 
implanted.  The investigator will contact The Rogosin Institute, Xenia Division to request 
shipment of the RENCA macrobeads (see the Study Procedures Manual for details). 
Patients will have a small abdominal incision(s) using laparoscopy under general 
anesthesia, as indicated.  The location of the incision(s) will be at the investigator’s 
discretion. Antibiotic prophylaxis should be administered before surgery, as consistent 
with standard of care. 
The RENCA macrobeads will be placed into the peritoneal cavity.  Once implanted, the 
beads should remain in a free-floating state in the intraperitoneal space.  The macrobeads 
do not become vascularized, and thus remain as implants rather than true grafts. 
Assuming a patient’s post-surgical condition is stable, the patient will be discharged from 
the surgical recovery room to either home care or hospital admission, as medically 
indicated, which may be as soon as the same day as the procedure. Hospital admission 
postoperatively has not been necessary in any of the patients in the RI-MB-201 study. 
5.2. 
Best Supportive Care 
For patients in Group B, best supportive care is defined as management of symptoms 
aimed at maintaining or improving quality of life, but not including approved therapies 
targeting the patient’s malignancies. 
5.3. 
Treatment Compliance 
For patients in Group A, compliance with the schedule of RENCA macrobead 
implantations will be dictated by a patient’s ability to meet the clinical requirements for 
continued treatment and a patient’s willingness to continue participation in the study. 
The number of implantations and amount of macrobeads implanted will be recorded for 
each patient. 

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5.4. 
Concomitant Medications or Therapies 
5.4.1. Prior and Concomitant Medications or Therapies  
Medications taken within 30 days before Day 0 will be recorded in the CRF.  In addition, 
patients’ prior anticancer treatment will also be recorded.   
Antibiotic prophylaxis will be administered prior to RENCA macrobead implantation. 
All medications and other treatments taken by patients during the study will be recorded 
on the CRF.   
5.4.2. Other Therapy During Implantation vs. Alternative Therapy 
During their participation in this study, patients in Group A will be allowed to have local 
radiation for symptom relief and/or surgery for therapeutic or palliative purposes.   Use of 
alternative therapy, including chemotherapy or a different investigational product of 
whatever nature may be indicated for disease progression.  In that case, the subject will 
be removed from the active protocol and will not be eligible for further implantation.* 
Where procedures to provide palliation or symptom relief have been performed, any 
subsequent implantations, if indicated, will need to be scheduled at the discretion of the 
investigator and surgeon.  Re-screening procedures to confirm continued eligibility of the 
subject may be required. 
* Removal from the “active” protocol, i.e., that protocol involving continuing eligibility 
for macrobead implantation, for reasons of disease progression, medical decision, or 
voluntary patient withdrawal, does not mean complete “termination” since the protocol 
requires subsequent follow-up to determine the presence or absence of the RT-PCR of the 
presence of eMuLV DNA.  Patients in this category have been released from the active 
protocol and should be considered “inactive,” but subject to lifetime follow-up for viral; 
detection.  “Inactive status” in this case does not require the recording of adverse events 
associated with other treatments or therapeutic procedures beyond 90 days from the last 
macrobead implant covered by this protocol.  

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6. ASSESSMENT OF EFFICACY 
6.1. 
Primary Efficacy Measurement 
For patients in Group A and Group B, the primary efficacy measurement is overall 
survival, defined as the time interval from the date of radiographically documented 
disease progression to the date of death due to any cause. 
6.2. 
Secondary Efficacy Measurements 
For patients in Group A, secondary efficacy measurements include clinician-rated 
assessments to evaluate clinical status (ECOG and global clinical assessment) and 
patient-rated assessments to evaluate quality of life (EORTC QLQ-C30 and Karnofsky 
Performance Status Scale). 
6.2.1. Clinician-Rated Assessments of Clinical Status 
6.2.1.1.Eastern Conference Oncology Group Performance Status 
For patients in Group A, the ECOG performance score is determined by the investigator 
and ranges from 0 to 5, as follows (Oken et al. 1982): 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
 
6.2.1.2.Global Clinical Assessment 
For patients in Group A, the global clinical assessment is performed by the investigator 
and measures clinical status using a visual analog scale.   
6.2.2. Quality of Life (Patient-Rated Assessments) 
6.2.2.1.European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire 
For patients in Group A, the EORTC QLQ-C30, version 3.0 is a validated questionnaire 
completed by the patient and developed to assess quality of life in patients with cancer.  It 
includes subscales measuring physical functioning, social functioning, emotional 
functioning, cognitive functioning, and role performance as well as subscales and single 
items assessing symptoms (e.g., fatigue, pain, nausea/vomiting), and financial impact of 
the disease. 

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6.2.2.2.Karnofsky Performance Status Scale 
For patients in Group A, the Karnofsky Performance Status Scale ranges from 0 to 100, 
where 0 is death and 100 is perfect health, as follows (Karnofsky and Burchenal 1949). 
100% 
Normal, no complaints, no signs of disease 
90% 
Capable of normal activity, few symptoms or signs of disease 
80% 
Normal activity with some difficulty, some symptoms or signs 
70% 
Caring for self, not capable of normal activity or work 
60% 
Requiring some help, can take care of most personal requirements 
50% 
Requires help often, requires frequent medical care 
40% 
Disabled, requires special care and help 
30% 
Severely disabled, hospital admission indicated, but no risk of death 
20% 
Very ill, urgently requiring admission, requires supportive measures of treatment 
10% 
Moribund, rapidly progressive fatal disease processes 
0 
Death 
 
6.3. 
Exploratory Assessments 
For patients in Group A, exploratory assessments include measurement of ESR and CRP 
levels, tumor marker levels, CTCs, immunoglobulins, cellular immune function, 
examination of tumor changes, at the investigator’s discretion during the implantation 
procedure, tumor biopsy samples may be collected for appropriate, medically-indicated 
histopathological analysis, and autopsy (for consenting patients only). 
6.3.1. Erythrocyte Sedimentation Rate and C-Reactive Protein  
For patients in Group A, erythrocyte sedimentation rate and CRP levels are nonspecific 
markers of inflammation and will be considered both safety and efficacy assessments.  A 
rise in ESR and CRP levels that is temporally associated with an implantation procedure 
could be considered an indication of an inflammatory reaction to placement of the 
macrobeads in the intraperitoneal cavity. 
6.3.2. Tumor Markers  
For patients in Group A, blood samples will be collected for measurement of tumor 
markers CEA, CA19-9, and CA125.  A decrease in tumor marker levels may be 
associated with a decrease in tumor activity and biological response. Although CA125 is 
often used as a tumor marker, for the purposes of this study, its levels will be used as an 
indication of an inflammatory reaction to placement of the macrobeads. 
6.3.3. Circulating Tumor Cells  
For patients in Group A, circulating tumor cells (CTCs) in blood will be measured 
throughout the study and allow for a noninvasive measure of disease status.  They may 
also give some indication of prognosis. 

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6.3.4. Immunoglobulins  
For patients in Group A, immunoglobulin levels will be used to measure the body’s 
immune reaction to RENCA macrobead implantation.  Immunoglobulins A, E, G, and M 
(IgA, IgE, IgG, and IgM) will be measured.  A rise in specific immunoglobulin levels 
reflective of inflammation may be considered part of an inflammatory reaction to 
placement of the macrobeads in the intraperitoneal cavity. The immunoglobulin 
measurements are also important in evaluating the humoral immune status of the patient 
so that they are not only indicative of response to the macrobeads, but also the functional 
integrity of the humoral immune system after macrobead implantation. 
6.3.5. Cellular Immune Function 
For patients in Group A, the effect of implantation with RENCA macrobeads on cellular 
immune function will be assessed by measuring T cells, B cells, and NK cells (i.e., 
CD16) in blood.  This evaluation is to determine both the functional level of this system 
and any possible stimulation or inhibition by the macrobeads. 
6.3.6. Assessment of Tumor Changes 
For patients in Group A, tumors will be assessed approximately every 90 days using 
PET-CT scans with fluorine deoxglucose.  Tumor locations (primary and metastatic) 
volumes, and metabolic assessments (SUVs) will be assessed. Additional imaging 
techniques (i.e., MRI, CT, sonography, bone scans, and x-rays), may be performed for 
further assessment, as clinically indicated.   
6.3.7. Tumor biopsies 
For patients in Group A, at the investigator’s discretion during the implantation 
procedure, tumor biopsy samples may be collected for appropriate, medically-indicated 
histopathological analysis.  It should be emphasized that the performance of the tumor 
biopsies is not a requirement of the protocol. 
6.3.8. Autopsy 
Autopsies may be performed on patients in Group A who provide separate consent.  
However, consent to autopsy is not a condition for participation in the study.  Patients 
may withdraw consent to have an autopsy performed at any time without risk to their 
participation in the study or medical care.  A patient’s decision to consent to have an 
autopsy performed will not be binding on family members, if they do not also agree to 
the autopsy.  
Samples of tumor tissue (primary and metastatic sites), peritoneum, internal organ serosa, 
and underlying tissue may be taken during an autopsy to evaluate tumor state and any 
inflammatory or connective tissue reaction to the RENCA macrobeads.  Standard 
histopathological and immunohistochemical analyses may be performed on the tissue 
obtained. 

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7. ASSESSMENT OF SAFETY 
For patients in Group A, safety assessments will include monitoring of adverse events, 
clinical laboratory tests including eMuLV testing, vital signs measurements, physical 
examinations, 12-lead ECGs, chest x-rays, and murine allergen skin testing. 
A DSMB will be established to ensure the safety of patients participating in this study.  
Details regarding the structure, function, and decision-making guidelines for the DSMB 
are provided in a separate DSMB charter. 
7.1. 
Adverse Events 
It is the responsibility of the investigator to document all adverse events that occur during 
the study. 
7.1.1. Definition of an Adverse Event 
For the purposes of this study, an adverse event is defined as the appearance of (or 
worsening of any pre-existing) undesirable sign(s), symptom(s), or medical condition(s) 
that occur after a patient’s signed informed consent has been obtained.  Abnormal 
laboratory values or test results occurring after informed consent constitute AEs only if 
they induce clinical signs or symptoms, are considered clinically meaningful, require 
therapy (e.g., hematologic abnormality that requires transfusion), or require changes in 
study drug treatment.  Adverse events (including laboratory abnormalities that constitute 
adverse events) should be described using diagnosis whenever possible, rather than 
individual underlying signs and symptoms.  When an abnormal laboratory or test result 
corresponds to a sign or symptom of a previously reported adverse event, it is not 
necessary to separately record the laboratory/test result as an additional event.  Disease 
progression will not be captured as an adverse event. 
An adverse event is any untoward medical occurrence in a patient administered an 
investigational product and that does not necessarily have a causal relationship with this 
treatment. An adverse event can therefore be any unfavorable and unintended (including 
an abnormal laboratory finding) symptom, or disease temporally associated with the use 
of a medicinal (investigational) product, whether or not considered related to the product. 
7.1.2. Recording and Reporting of Adverse Events  
Adverse events will be recorded and reported from the time of the patient’s signed 
informed consent through 90 days after the last RENCA macrobead implantation 
procedure.  The occurrence of adverse events should be sought by non-directive 
questioning of the subject.  Adverse events may also be detected when they are 
volunteered by the subject.  Treatment-emergent adverse events are defined as any 
adverse events that are reported after the first RENCA macrobead implantation procedure 
through 90 days after the last implantation procedure.  An adverse event that occurs 
outside the reporting period, but in the opinion of the investigator, is related to the study 
treatment should be reported as described for a treatment-emergent adverse event.   

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All adverse events should be followed until the event has resolved, the condition has 
stabilized, or etiology of the event is determined to be not related to study treatment, or 
the patient is lost to follow-up.  For each patient for whom an adverse event was reported 
that did not resolve before the end of the reporting period, follow-up information on the 
subsequent course of events must be submitted to the medical monitor.  This requirement 
indicates that follow-up may be required for some adverse events after the patient has 
completed his/her participation in the study.   
7.1.3. Severity of an Adverse Event 
The severity of adverse events will be assessed by the investigator according to the 
NCI CTCAE v4.0.  CTCAE Grade 5 (death) will be reported as per DSMB, IRB, and 
FDA guidelines and, of course, will be used to define the time interval from baseline to 
provide the survival period.  It is to be reported as an outcome and not as an adverse 
event per se.  It is, however, maintained as part of the CTCAE Grades for purposes of 
completeness and accuracy of reporting.  Of specific safety concern would be any death 
thought to be related directly to the implantation of the macrobeads themselves. If the 
severity of an adverse event is not described in the NCI CTCAE v4.0, the investigator 
will use the following scale to determine the severity. 
Grade 1/mild: 
transient or mild discomfort, no limitation in 
activity, and no medical intervention/therapy is 
required 
Grade 2/moderate: 
mild to moderate limitation in activity, some 
assistance may be needed, no or minimal medical 
intervention/therapy required 
Grade 3/severe: 
marked limitation in activity, some assistance 
usually required, medical intervention/therapy 
required, hospitalizations possible 
Grade 4/life-threatening or disabling: extreme limitation in activity, significant assistance 
required, significant medical intervention/therapy 
required, hospitalization or hospice care probable 
Grade 5/death 
When the intensity of an adverse event changes over time for a reporting period (e.g., 
between visits), each change in intensity will be reported as an adverse event until the 
adverse event resolves. For example, 2 separate adverse events will be reported if a 
subject experiences Grade 1 diarrhea for 3 days, meeting the definition of an adverse 
event, and then after 3 days the adverse event increases to a Grade 3 intensity that lasts 
for 2 days and then resolves. The Grade 1 event will be reported as an adverse event with 
a start date equal to the day the event met the adverse event definition and a stop date 
equal to the day that the event increased in intensity from Grade 1 to Grade 3. The 
Grade 3 event will also be reported as an adverse event with the start date equal to the 
day the event changed in intensity from Grade 1 to Grade 3 and a stop date on the day 

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that the event changed intensity again or resolved. For analysis purposes, this will be 
considered one AE for this subject and the maximum intensity will be recorded. 
7.1.4. Relationship of an Adverse Event to the Study Treatment 
The investigator will assess the relationship of each adverse event to treatment with 
RENCA macrobeads as unrelated or related. 
An adverse event will be considered “not related” to the use of the investigational product 
if there is not a possibility that the event has been caused by the investigational product.  
Factors pointing toward this assessment include, but are not limited to, the lack of 
reasonable temporal relationship between administration of the investigational product 
and the event, the presence of a biologically implausible relationship between the 
investigational product and the adverse event (e.g., the event occurred before 
administration of the product), or the presence of a more likely alternative explanation for 
the adverse event (e.g., the underlying disease). 
An adverse event will be considered “related” to the use of the investigational product if 
there is a possibility that the event may have been caused by the product under 
investigation.  Factors that point toward this assessment include, but are not limited to, a 
reasonable temporal sequence between administration of the investigational product and 
the event, a known response pattern of the investigational product, a biologically 
plausible relationship between the product and the adverse event, or a lack of an 
alternative explanation for the adverse event (e.g., the underlying disease). 
7.1.5. Serious Adverse Events 
7.1.5.1.Definition of a Serious Adverse Event 
A serious adverse event (experience) or reaction is any untoward medical occurrence 
that, at any dose, meets any of the following criteria: 
 is fatal or life-threatening (i.e., immediate risk of dying) 
 results in persistent or significant disability/incapacity 
 constitutes a congenital anomaly or birth defect 
 is clinically meaningful, (i.e., defined as an event that jeopardizes the subject or 
requires potential medical or surgical intervention to prevent 1 of the outcomes 
listed above), or is considered meaningful by the investigator as an important 
medical event that may not result in death, be life-threatening, or require 
hospitalization, but may be considered a serious adverse event when, based upon 
appropriate medical judgment, it may jeopardize the subject or may require 
medical or surgical intervention to prevent 1 of the outcomes listed in this 
definition 
 requires in-patient hospitalization or prolongation of existing hospitalization, 
unless hospitalization is due to one of the following reasons: 
o routine treatment or monitoring of the studied indication, not associated 
with any deterioration in condition, or elective or pre-planned treatment 

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for a pre-existing condition that is unrelated to the indication under 
study and has not worsened since signing the informed consent form 
o treatment on an emergency outpatient basis for an event not fulfilling 
any of the definitions of a serious adverse event given above and not 
resulting in hospital admission 
o social reasons and respite care, in the absence of any deterioration in the 
subject’s general condition 
o any serious adverse events that are expected because of the condition 
being treated, including if the serious adverse event is a primary 
outcome measure, and whether there has been a clear agreement with 
regulators not to consider these as serious adverse events, provided the 
information is collected elsewhere 
 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize 
the patient or may require intervention to prevent one of the other outcomes listed in the 
definition above. These events should also usually be considered serious. 
7.1.5.2.Reporting a Serious Adverse Event 
Every serious adverse event, regardless of suspected causality, occurring after the subject 
has signed informed consent and up to 90 days after the last RENCA macrobead 
implantation, must be reported to the sponsor or designee within 24 hours of learning of 
its occurrence. Any serious adverse events experienced after this period should be 
reported to the Sponsor, or designee, only if the investigator suspects a causal 
relationship to the study mediation.  Recurrent episodes, complications, or progression of 
the initial SAE must be reported as follow-up to the original episode within 24 hours of 
the investigator receiving the follow-up information.  A serious adverse event occurring 
at a different time interval or otherwise considered completely unrelated to a previously 
reported one should be reported separately as a new event.  Previously planned surgeries 
should not be reported as serious adverse events unless the underlying medical condition 
worsens over the course of the study.  All patients (including discontinued patients) with 
a serious adverse event must be followed until the event resolves or reaches a new 
baseline, but for a minimum of 90 days after the last implantation procedure.  A serious 
adverse event that occurs outside the reporting period after completion of the study, but 
in the opinion of the investigator, is related to the study treatment should be reported as 
described for a serious adverse event.   
Investigators should not wait to receive additional information to fully document the 
event before notifying the sponsor of a serious adverse event.  The telephone report 
should be followed by full written summary detailing relevant aspects of the serious 
adverse event in question.  Where applicable, information from relevant hospital case 
records and autopsy reports should be obtained.  The serious adverse event should also be 
recorded on the adverse event page of the patient’s CRF.  If additional information 
becomes available, follow-up reports must be submitted no more than 7 days after 
receipt.   

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Contact telephone and facsimile numbers for serious adverse event reporting will be 
provided separately.  
If the serious adverse event is not previously documented in the Investigator’s Brochure 
for the study drug (new occurrence) and is thought to be related to study treatment, the 
sponsor may urgently require further information from the investigator for reporting to 
local regulatory authorities.  
Serious adverse events that are considered to be unexpected and related to study 
treatment will be reported by the sponsor to the FDA, and all participating investigators 
shall be notified no later than 15 calendar days from the “date learned” of the event.  
Investigators are responsible for reporting all serious adverse events to their IRB in 
accordance with local regulations. 
7.2. 
Clinical Laboratory Parameters 
For patients in Group A, clinical laboratory tests will include chemistry, hematology, 
coagulation, urinalysis, and eMuLV. Details of processing, storage, and shipping of 
samples are provided in a separate Laboratory Manual. 
7.2.1. Chemistry, Hematology, Coagulation, and Urinalysis 
Chemistry, hematology, coagulation, and urinalysis parameters are listed in Table 2. 
Table 2: 
Chemistry, Hematology, Coagulation, and Urinalysis Parameters 
Chemistry 
Hematology 
Urinalysis 
Metabolic 
glucose 
carbon dioxide 
sodium 
potassium 
chloride 
calcium  
Hepatic Function 
aspartate aminotransferase (AST) 
alanine aminotransferase (ALT) 
gamma glutamyltransferase (GGT) 
lactate dehydrogenase 
alkaline phosphatase 
total bilirubin 
direct bilirubin 
total protein  
albumin 
Renal Function 
creatinine 
blood urea nitrogen (BUN) 
 
Complete Blood Count 
(CBC) with differential 
platelets 
 
Inflammation: 
CRP 
ESR 
CA 125 
 
Tumor Markers: 
CEA 
CA 19-9 
 
Color 
appearance 
glucose 
bilirubin 
ketones 
specific gravity 
pH 
blood 
protein 
urobilinogen 
nitrite 
leukocyte esterase 
urine sediments 
Coagulation 
Partial thromboplastin time 
(PTT) 
Prothrombin time (PT) 
International Normalized 
Ratio (INR) 

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amylase (if clinically indicated) 
lipase (if clinically indicated) 
 
 
7.2.2. Ecotropic Murine Leukemia Virus 
For patients in Group A, blood samples will be collected for analysis by a validated 
reverse transcriptase polymerase chain reaction (RT-PCR)-based assay o detect the 
presence of eMuLV gene sequences. Over the past eight years of human implantation, the 
presence of eMuLV sequences has not been documented in any patient, and there have 
been no clinical symptoms, signs or other evidence of transmission of, or infection with, 
the eMuLV in any patient. 
eMuLV is not known to infect human cells (National Research Council, 1991).   
7.3. 
Vital Sign Measurements 
For patients in Group A, vital signs measurements include blood pressure, pulse, 
respiration rate, and temperature.   
7.4. 
Physical Examinations 
For patients in Group A, complete physical examinations will be performed and will 
include a neurological examination, weight, and height (height to be measured at the 
screening/baseline visit only).  Any abnormalities noted at a post-baseline visit that were 
not present at screening/baseline should be recorded as adverse events.  Weight and 
height (the latter at baseline only) should be recorded as part of the physical examination. 
7.5. 
Electrocardiograms 
For patients in Group A, 12-lead ECGs will be performed, and rhythm results will be 
recorded as normal, abnormal but not clinically significant, or abnormal and clinically 
significant. 
7.6. 
Chest X-Rays 
For patients in Group A, chest x-rays will be performed, and results will be reported as 
normal, abnormal but not clinically significant, or abnormal and clinically significant. 
7.7. 
Other Safety Assessments  
For patients in Group A, a standard skin test for hypersensitivity response to murine 
allergens will be performed to ensure that patients do not have an allergy to murine 
antigens, cells or tissues. 
 

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8. STATISTICAL METHODOLOGY 
This is a Phase IIb, multicenter, nonrandomized, open-label study to evaluate the safety 
and efficacy of RENCA macrobead implantation in patients with metastatic, 
treatment-resistant colorectal carcinoma.  The primary efficacy variable is overall 
survival at 12 months after the last RENCA macrobead implantation, which will be 
compared between patients who undergo RENCA macrobead implantation (Group A) 
and patients who receive best supportive care (Group B).  For patients in Group A, safety 
variables include monitoring of adverse events, clinical laboratory tests including testing 
for eMuLV, vital signs measurements, physical examinations, 12-lead ECGs, chest x-rays 
and murine allergen skin testing.   
8.1. 
Determination of Sample Size 
A total of 120 patients will be entered in this study, 40 patients who will undergo 
RENCA macrobead implantation (Group A) and 80 patients who will receive or are 
receiving best supportive care (Group B). For the primary outcome of overall survival, 
this sample size will provide at least 80% power to detect a hazard ratio of 0.505.  For 
example, assuming a mortality rate of 60% in Group A at 12 months, the mortality rate in 
Group B would have to be no less than 74% at 12 months.  This assumes balance 
between groups on factors that may be associated with mortality.   
8.2. 
Criteria for Termination of the Study 
Stopping rules are described in Section 3.6.1.  No statistical criteria for termination of the 
study are defined. 
8.3. 
Analysis Populations 
The full analysis population will include all patients who were implanted with RENCA 
macrobeads (Group A) and all patients enrolled to receive best supportive care 
(Group B). 
The all treated population will include all patients in Group A who were implanted with 
RENCA macrobeads. 
8.4. 
Statistical Analysis Methods 
All available data will be listed and summarized by treatment group (if applicable) and 
study visit.  Data from unscheduled visits will be listed but may not be summarized or 
analyzed.  Baseline will be defined as the most recent visit or observation before the first 
implantation.  Secondary baselines may be similarly defined for each subsequent 
implantation. Categorical variables will be summarized using frequencies and 
percentages for each category.  Continuous variables will be summarized using number 
of patients, mean, standard deviation, median, and range. All programs for data output 
and analyses will be written in Statistical Analysis System® (SAS) version SAS 9.1.3 or 
higher, or other specialized analysis software as appropriate (SAS Institute, Inc., Cary, 
NC). Additional analysis details will be described in the Statistical Analysis Plan (SAP).   

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For purposes of reporting results, the study will be considered complete 12 months after 
the last implantation procedure or when all patients have reached the primary endpoint 
(i.e., death) or have been lost to follow-up, whichever occurs first.  If the last patient 
undergoes less than 4 implantation procedures, then the first, second, or third 
implantation procedure may be considered to be “the last implantation procedure” if more 
than 120 days pass before the subsequent procedure.  This last patient would not be 
prohibited from undergoing a subsequent protocol-specified implantation procedure. 
8.4.1. Study Population 
In general, the full analysis population will be used for study population analyses.  The 
all treated population will be used for those variables that were collected only for 
Group A. 
Disposition of patients will include the numbers of patients in each analysis population, 
numbers and percentages of patients who discontinued treatment prior to receiving 
4 implantations with RENCA macrobeads, and the reasons for discontinuing the study or 
study treatment (e.g., disease progression, adverse event, investigator decision, patient 
decision).   
Demographics and baseline characteristics, medical history, and concomitant medications 
will be summarized using descriptive statistics or listed, as appropriate. 
8.4.2. Efficacy Analyses 
8.4.2.1.Primary Efficacy Analysis 
The primary efficacy analysis will be performed using the all treated population. 
For all patients, the primary efficacy variable, overall survival, is defined as the date of 
radiographically documented disease progression to date of death due to any cause 
assessed at 12 months after the last RENCA macrobead implantation.   
Because treatment group assignment in this study is not randomized, balance of baseline 
covariates potentially related to both treatment and survival between Group A and 
Group B will be achieved through the use of propensity scores.  
A propensity score for each patient will be defined as the probability of being in Group A 
given a vector of observed baseline covariates xi and will be derived using logistic 
regression.  Specifically, for a given patient i, 
probabilityi (Group A | xi) = [1 + exp(–c + bxi)]-1, 
where c and b are the logistic regression parameter estimates.  
The final propensity score model will be selected based on univariable relationships 
between covariates derived from the baseline characteristics (to be defined in the SAP) 
and group membership, collinearity among the candidate covariates, and number of 
patients enrolled (with the standard target of 10 patients per covariate) (Smith BH, Gazda 

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LS, Conn BL, et al. Three-dimensional culture of mouse renal carcinoma cells in agarose 
macrobeads selects for a subpopulation of cells with cancer stem cell or cancer progenitor 
properties. Cancer Res. 2011;71(3):716-724. (b) 
Speer JF, Petrosky VE, Retsky MW, Wardwell RH. A stochastic numerical model of 
breast cancer growth that simulates clinical data. Cancer Res 1984: 44:4124-30. 
Weeden-Fekjaer H, Lindqvist BH, Vatten LJ,Aalen OO, Tretli S. Breast cancer tumor 
growth estimated through mammography screening data. Breast Cancer Res 2008: 
10:R41. 
Weitzen et al. 2004). Additional details regarding choice of candidate covariates and 
specific use of propensity score in the survival analysis will be described in the SAP. 
Estimated survival functions will be presented graphically.  A proportional hazards model 
will be used to estimate and compare functions for overall survival for Groups A and B.  
Patients who are lost to follow-up before the time of the analysis endpoint (te) will be 
considered censored as of the day the patient was last known to be alive.  Patients who 
are still alive as of te will be considered censored at te.   
8.4.2.2.Secondary Efficacy Analyses 
Secondary efficacy analyses will be performed using the full analysis population. 
Secondary efficacy variables include the following: 
 proportion of patients who show improvement in ECOG performance status score 
at any post-baseline time point 
 proportion of patients who show improvement in the global clinical assessment at 
any post-baseline time point 
 proportion of patients who show improvement in any subscale of the EORTC 
QLQ-30 at any post-baseline time point 
 proportion of patients who show improvement in Karnofsky Performance Status 
Scale score at any post-baseline time point 
The proportion of patients having improvement in ECOG performance status score at any 
time point will be summarized.   
Global clinical assessment will be reported as the distance from the left endpoint to the 
clinician’s mark divided by the total length of the horizontal line being marked.  The 
proportion of patients having improvement in the global clinical assessment score will be 
summarized. 
Observed values for responses to the EORTC QLQ-C30 will be used to calculate the 
derived scales for physical functioning, emotional functioning, cognitive functioning, 

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social functioning, role functioning, individual symptoms, and financial difficulties 
(Fayers et al. 2001).  The proportion of patients having improvement in any of the 
derived scales of the EORTC QLQ-C30 at any time point will be summarized. 
The proportion of patients having improvement at any time point in scores for the 
Karnofsky Performance Status Scale will be summarized.  
8.4.2.3.Exploratory Analyses 
For patients in Group A, exploratory variables include  
 Change from baseline in ESR, CRP, and CA 125 levels at Days 14, 30, 60, and 90 
after each RENCA macrobead implantation 
 Change from baseline in tumor marker (including CEA and CA19-9) levels at 
Days 14, 30, 60, and 90 after each RENCA macrobead implantation  
 Change from baseline in CTCs to Day 90 after each RENCA macrobead 
implantation 
 Change from baseline in immunoglobulin (IgA, IgE, IgG, and IgM) levels at 
Day 90 after each RENCA macrobead implantation  
 Change from baseline in cellular immune function, as measured by T cell count; 
B cell count, NK cell counts (e.g., CD16 count), at Day 90 after each RENCA 
macrobead implantation 
 Characterization of tumor changes at Day 90 after each RENCA macrobead 
implantation using PET-CT scans 
 At the investigator’s discretion during the implantation procedure, tumor biopsy 
samples may be collected for appropriate histopathological analysis  
 Examination of tumor state and any inflammatory or connective tissue reaction to 
the RENCA macrobeads after autopsy, if applicable 
Exploratory analyses will be performed using the all treated population. 
Observed values and changes from baseline in relation to the first implant and the most 
recent implant in ESR, CRP, CA 125 levels and immunoglobulin levels (IgA, IgE, IgG, 
and IgM) will be summarized using descriptive statistics.   
Observed values and changes from baseline to each time point after each RENCA 
macrobead implantation in levels of tumor markers (CEA and CA19-9) will be 
summarized using descriptive statistics.  The proportion of patients who have a tumor 
marker response (i.e., at least 20% decrease from baseline in CEA or CA19-9) will also 
be summarized.   
Observed values and changes from baseline to each time point after each RENCA 
macrobead implantation in levels of CTCs, immunoglobulin levels (IgA, IgE, IgG, and 
IgM) and markers of cellular immune function (T cells, B cells, and NK cells [i.e., CD16 
count]) will be summarized using descriptive statistics. 

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Characterization of tumor changes from baseline to 90 days after each RENCA 
macrobead implantation will be listed.  Depending on available results, these data may be 
summarized. 
Results of any histopathological analysis will be made part of the patient’s permanent 
medical and protocol records. 
Any autopsy results will also be made part of the patient’s permanent medical and 
protocol records. 
8.4.3. Safety Analyses 
The entire treated population will be used for the analysis of all safety variables.  Safety 
data will be summarized using descriptive statistics; no formal statistical analyses are 
planned. 
8.4.3.1.Exposure to Study Treatment 
Exposure to study treatment, i.e., number of implantations and numbers of macrobeads 
implanted, will be summarized using descriptive statistics. 
8.4.3.2.Adverse Events 
Adverse events will be coded using MedDRA (Medical Dictionary for Regulatory 
Activities) version 10.1 or later.  A treatment-emergent adverse event will be defined as 
an adverse event that began or worsened after the first implantation and within 90 days 
after the last implantation.  Summaries of treatment-emergent adverse events will be 
provided separately by implantation and for all implantations.   
Treatment-emergent adverse events will be summarized by overall incidence, by severity, 
and by relationship.  Summaries will also be provided for deaths, serious adverse events, 
and adverse events leading to discontinuation of study treatment.  Listings will be 
provided for all adverse events, deaths, serious adverse events, and adverse events 
leading to discontinuation of study treatment. 
8.4.3.3.Clinical Laboratory Parameters 
For clinical laboratory parameters (chemistry, hematology, coagulation, and urinalysis), 
absolute values and changes from baseline to each time point after each RENCA 
macrobead implantation will be summarized.  The proportion of patients with abnormal 
results will be summarized.  Shifts from normal at baseline to abnormal after RENCA 
macrobead implantation will also be provided.  Abnormal clinical laboratory results and 
NCI CTCAE v4.0 toxicity grade (if applicable) will be noted in the listings, and a 
separate listing for Grade 3 or higher laboratory values will be provided.   
Results from eMuLV testing will be listed. 

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8.4.3.4.Vital Sign Measurements 
Vital signs (blood pressure, pulse, respiration rate, and temperature) results will be listed.   
8.4.3.5.Physical Examinations 
Physical examination findings will be listed. 
8.4.3.6.Electrocardiograms 
For 12-lead ECGs, results (normal, abnormal but not clinically significant, or abnormal 
and clinically significant) will be summarized by time point as frequencies and 
percentages of patients. 
8.4.3.7.Chest X-Rays 
For chest x-rays, results (normal, abnormal but not clinically significant, or abnormal and 
clinically significant) will be summarized by time point as frequencies and percentages of 
patients. 
8.4.3.8.Other Safety Assessments 
Results from the murine allergen skin tests performed will be listed. 
8.5. 
Interim Analyses 
No interim analyses are planned. 
8.6. 
Deviations from the Planned Statistical Analyses 
Any changes to the planned statistical analyses will be described and justified in the 
clinical study report. 

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9. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
It is an expectation of regulatory authorities that monitors, auditors, and representatives 
of national and international government regulatory agency bodies have access to original 
source documentation (see examples in Section 10.4) to ensure data integrity.  “Original” 
in this context is defined as the first documentation of an observation and does not 
differentiate between hard copy and electronic records.   
The Investigator must make study data accessible to the clinical monitor, to other 
authorized representatives of the sponsor, and to FDA inspectors.   

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10. QUALITY CONTROL AND QUALITY ASSURANCE 
10.1. Amendments 
Any amendments to the protocol will be written and approved by the sponsor.  All 
amendments must be submitted to the IRB for approval prior to implementing the 
changes.  In some instances, an amendment requires changes to the informed consent 
form, which also must be submitted for IRB approval prior to administration to patients.   
10.2. Monitoring 
The sponsor is responsible for ensuring the proper conduct of the study with regard to 
ethics, protocol adherence, site procedures, integrity of the data, and applicable laws 
and/or regulations.  At regular intervals during the study and following completion of the 
study, the sponsor’s study monitors will contact the study site via visits to the site, 
telephone calls, and letters in order to review study progress, CRF completion, and 
address any concerns or questions regarding the study conduct.  During monitoring visits, 
the following aspects of study conduct will be carefully reviewed:  informed consent of 
patients, patient recruitment, patient compliance with the study procedures, source data 
verification, drug accountability, use of concomitant therapy by patients, adverse event 
and serious adverse event documentation and reporting, and quality of data.  Records 
pertaining to these aspects are expected to be kept current. 
10.3. Audits and Inspections 
The sponsor, a regulatory authority, or an IRB may visit the study site at any time during 
the study or after completion of the study to perform audits or inspections.  The purpose 
of a sponsor audit or regulatory inspection is to systematically and independently 
examine all study-related activities and documents to determine whether these activities 
were conducted according to the protocol, GCP, ICH guidelines, and any other applicable 
regulatory requirements.  Investigators should contact the sponsor immediately if 
contacted by a regulatory agency about an inspection at their site. 
10.4. Data Quality Assurance 
The investigator is responsible for completing and maintaining adequate and accurate 
CRFs and source documentation.  Source documentation constitutes original records, 
which may include: progress notes, medication administration records, laboratory reports, 
ECG tracings, chest x-ray images, discharge summaries, etc.   
The investigator must sign the investigator’s statement in each patient’s CRF indicating 
that the data reported are accurate. 
At the study sites, clinical research associates will manually review CRFs against source 
documentation.  Computer-programmed edit checks will be run against the database to 
check for discrepancies and reasonableness of the data, and the safety database will be 
reconciled with the clinical database.  All issues resulting from the computer-generated 
checks and the safety database reconciliation will be resolved according to standard data 

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management practices in conjunction with the medical monitor, clinical study personnel, 
and the study investigators. 

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11. ETHICS 
11.1. Informed Consent 
Written informed consent must be obtained from each patient prior to any protocol-
related activities.  As part of this procedure, the investigator or appropriate personnel at 
each site will explain orally and in writing the nature, duration, and purpose of the study, 
and the action of the study treatment in such a manner that the patient is aware of the 
potential risks, inconveniences, or adverse effects that may occur.  Patients should be 
informed that they can withdraw from the study at any time.  If the patient decides to 
withdraw from the study, he or she will be asked if they would agree to continue to be 
monitored (including the long-term screening for the presence of eMuLV viral DNA as 
requested by the FDA).   
One copy of the signed informed consent document will be given to the patient, and the 
original will be retained by the investigator.  Additionally, the participant must be 
allowed adequate time to consider the potential risks and benefits associated with his/her 
participation in the study.   
The informed consent document must have been reviewed and approved by the sponsor 
and by the investigator’s IRB prior to the initiation of the study.   
11.2. Health Insurance Portability and Accountability Act of 1996 
The investigator agrees to comply with all applicable federal, state, and local laws and 
regulations relating to the privacy of patient health information, including, but not limited 
to, the Standards for Individually Identifiable Health Information, 45 CFR. Parts 160 and 
164 (the Health Insurance Portability and Accountability Act of 1996 [HIPAA] Privacy 
Regulation).  The investigator shall ensure that study patients authorize the use and 
disclosure of protected health information in accordance with HIPAA Privacy Regulation 
and in a form satisfactory to the sponsor.   
11.3. Confidentiality Regarding Study Patients 
The privacy of participating patients must be maintained.  Patients will be identified by 
their initials and an assigned patient number on CRFs and other documents submitted to 
the clinical monitor.  Any documents that identify the patient (e.g., the signed informed 
consent document) must be maintained in strict confidence by the investigator, except to 
the extent necessary to allow auditing by the FDA, the clinical monitor, or sponsor 
personnel. 
All information regarding the nature of the proposed investigation provided by the 
sponsor to the investigator (with the exception of information required by law or 
regulations to be disclosed to the IRB, the patient, or the FDA) must be kept in 
confidence by the investigator. 

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12. DATA HANDLING AND RECORD KEEPING 
According to 21 CFR Part 312.62 and ICH E6, study-related records must be retained for 
at least 2 years after the last approval of a marketing application in an ICH region and 
until there are no pending or contemplated marketing applications in an ICH region, or at 
least 2 years have elapsed since the formal discontinuation of clinical development of the 
investigational product.  These documents should be retained for a longer period, 
however, if required by applicable regulatory requirements or by an agreement with the 
sponsor. 
The investigator must not destroy any study-related records without receiving approval 
from the sponsor.  The investigator must notify the sponsor in the event of accidental loss 
or destruction of any study records.  If the investigator leaves the institution where the 
study was conducted, the sponsor must be contacted to arrange alternative record storage 
options. 

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13. FINANCING AND INSURANCE 
The investigator shall provide to the sponsor sufficient accurate financial information to 
allow the sponsor to submit complete and accurate financial certification or disclosure 
statements to the FDA.  The investigator shall promptly update this information if any 
relevant changes occur in the course of the study and for one year following completion 
of the study. 

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14. REPORTING AND PUBLICATION OF RESULTS 
The sponsor is responsible for preparing a clinical study report of the result from this 
study. 
All unpublished information given to investigators by the sponsor shall not be published 
or disclosed to a third party without written authorization by the sponsor.   
 

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15. REFERENCES 
Chapman LE, Folks TM, Salomon DR, Patterson AP, Eggerman, TE, Noguchi PD et al. 
Xenotransplantation xenogenic infections. N Eng J Med 1995;333:1498-500. 
Clark MF and Fuller M. Stem cells and cancer: two faces of Eve. Cell 2006;124:1111-5. 
De Wys WD. Studies correlating the growth rate of a tumor and its metastases and 
providing evidence for tumor-related systemic growth-retarding factors. Cancer Res 
1972; 32(2):374-9. 
Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A, on behalf 
of the EORTC Quality of Life Group.  The EORTC QLQ-C30 Scoring Manual (3rd 
Edition). Published by: European Organisation for Research and Treatment of Cancer, 
Brussels 2001. 
Fisher B, Gunduz N, Coyle J, Rudock C, Saffer E. Presence of a growth-stimulating 
factor in serum following primary tumor removal in mice. Cancer Res 1989;49(8):1996-
2001. 
Gleisner AL, Choti MA, Assumpcao L, Nathan H, Schulick RD, Pawlik TM. Colorectal 
liver metastases: recurrence and survival following hepatic resection, radiofrequency 
ablation, and combined resection-radiofrequency ablation. Arch Surg 
2008;143(12):1204-12. 
Jain K, Yang H, Cai BR, Hauque B, Hurvitz AI, Diehl C, et al. Retrievable, replaceable, 
macroencapsulated pancreatic islet xenografts. Long-term engraftment without 
immunosuppression. Transplantation 1995;59:319-24. 
Jain K, Asina S, Yang H, Blount ED, Smith BH, Diehl CH, et al. Glucose control and 
long-term survival in biobreeding/Worcester rats after intraperitoneal implantation of 
hydrophilic macrobeads containing porcine islets without immunosuppression. 
Transplantation 1999;68:1693-700. 
Karnofsky DA, Burchenal JH. The Clinical Evaluation of Chemotherapeutic Agents in 
Cancer. In: MacLeod CM (Ed), Evaluation of Chemotherapeutic Agents. Columbia Univ 
Press 1949. page 196. 
Keir CH, Ocean AJ, Fahey TJ, Berman N, Wadke A, Kelly-Rossini L, Goldstein MJ, 
Leeser DB, Michelassi F, Smith BH. Treatment of advanced, epithelial-derived cancer 
(AEC) with intraperitoneal implantation of agarose-agarose macrobeads (MB) containing 
mouse renal adenocarcinoma cells (RENCA). American Society of Clinical Oncology 
(ASCO) Annual 2011 Meeting; J Clin Oncol 29: 2011 (suppl; abstr e13594). 
Laird AK. Dynamics of tumor growth: comparison of growth rates and extrapolation of 
growth curve to one cell. Brit J Cancer 1965;29:278-91. 

The Rogosin Institute 
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Version: 23 December 2013 
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Page 63 of 66 
 
 
 
Littlepage LE, Egeblad M, Werb Z. Coevolution of cancer and stromal cellular responses. 
Cancer Cell 2007;7:499-500. 
Moore KA and Lemischka IR. Stem cells and their niches. Science 2006;311:1880-5. 
National Research Council. Companion Guide to Infectious Diseases of Mice and Rats. 
Washington, DC: National Academy Press; 1991. 
Norton L, Simon R, Bereton HD, Bogden AE. Predicting the course of Gompertzian 
growth. Nature 1976:264:542-5. 
Norton L. Gompertzian model of human breast cancer growth. Cancer Res 
1988:48:7067-71. 
Norton L. Cancer stem cells, self-seeding, and decremented exponential growth: 
theoretical and clinical implications. Breast Dis 2008;29:27-36. 
Ocean AJ, Parikh T, Berman N, Escalon J, Shah MA, Andrada Z.  Phase I/II trial of 
intraperitoneal implantation of agarose-agarose macrobeads (MB) containing mouse renal 
adenocarcinoma cells (RENCA) in patients (pts) with advanced colorectal cancer (CRC). 
American Society of Clinical Oncology (ASCO) Annual 2013 Meeting, Chicago IL 
(Abstract). 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity 
and response criteria of the Eastern Cooperative Oncology Group. Am. J Clin Oncol 
1982;5 6):649–55.  
Onaitis MW, Peterson RP, Haney JC, Saltz L, Park B, Flores R et al. Prognostic factors 
after pulmonary resection of colorectal cancer metastases. Ann Thorac Surg 
2009;87(6):1684-8. 
Prehn RT. The inhibition of tumor growth by tumor mass. Cancer Res 1991;51(1):2-4. 
Smith BH, Gazda LS, Conn BL, Jain K, Asina S, Levine DM, et al. Hydrophilic agarose 
macrobead cultures select outgrowth of carcinoma cell populations that can restrict 
cancer growth. Cancer Res 2011;71(3):725-35. (a) 
Smith BH, Gazda LS, Conn BL, et al. Three-dimensional culture of mouse renal 
carcinoma cells in agarose macrobeads selects for a subpopulation of cells with cancer 
stem cell or cancer progenitor properties. Cancer Res. 2011;71(3):716-724. (b) 
Speer JF, Petrosky VE, Retsky MW, Wardwell RH. A stochastic numerical model of 
breast cancer growth that simulates clinical data. Cancer Res 1984: 44:4124-30. 
Weeden-Fekjaer H, Lindqvist BH, Vatten LJ,Aalen OO, Tretli S. Breast cancer tumor 
growth estimated through mammography screening data. Breast Cancer Res 2008: 
10:R41. 

The Rogosin Institute 
Protocol No.  RI-MB-203 
 
Version: 23 December 2013 
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Page 64 of 66 
 
 
 
Weitzen S, Lapane KL, Toledano AY, Hume AL, Mor V. Principles for modeling 
propensity scores in medical research: a systematic literature review. Pharmacoepidemol 
Drug Saf 2004;13:841-53. 
Wolpin BM and Mayer RJ. Systemic treatment of colorectal cancer. Gastroenterology 
2008;34(5):1296-310. 
 
Additional references not cited in the protocol: 
Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective 
identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 
2003;100(7):3983-8. 
Bach FH.  Xenotransplantation: problems and prospects. Ann Rev Med 1998;49:301-10. 
Boneva RS, Folks TM, Chapman LE. Infectious disease issues in xenotransplantation. 
Clinical Microbiol Rev 2001;14:1-14.  
Charles River Laboratories. Testing for Xenotropic and Non-Xenotropic Murine 
Leukemia Virus. Protocols GP-600 and GP-V601.1 in accordance with GLP regulations, 
Title 21 CFR Section 58. 
Fan X, Matsui W, Khaki L, Stearns D, Chun J, Li YM, et al. Notch pathway inhibition 
depletes stem-like cells and blocks engraftment in embryonal brain tumors. Cancer Res 
2007;66:7445-52. 
Fishman J, Sachs D, Shaikh R, eds. Xenotransplantation: Scientific Frontiers and Public 
Policy. New York: New York Academy of Sciences, 1998. 
Gazda LS, Martis PC, Laramore MA, Bautista MA, Dudley A, Vinerean HV, Smith BH. 
Treatment of agarose-agarose RENCA macrobeads with docetaxel selects for OCT4+ 
cells with tumor-initiating capability. Cancer Biology & Therapy December 2013; 14:12, 
1-11. 
Ganguly K, Kalyanaraman VS, Sarngadharan MG. Cell surface receptors for ecotropic 
murine viruses are different from those for xenotropic and amphotropic viruses. 
Intervirology 1983;19:224-9. 
Gilbertson RJ and Rich JN. Making a tumour’s bed: glioblastoma stem cells and the 
vascular niche. Nat Rev Cancer 2007;7:733-6. 
Hanahan D and Weinberg RA. The hallmarks of cancer. Cell 2000;100:57-70. 
Institute of Medicine (US) Committee on Xenograft Transplantation: Ethical Issues and 
Public Policy. Xenotransplantation: Science, Ethics and Public Policy. Washington 
(DC): National Academies Press (US), 1996. 

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Kobielak K, Stokes N, de la Cruz J, Polak L, Fuchs E. Loss of a quiescent niche but not 
follicle stem cells in the absence of bone morphogenic protein signaling. Proc Nat Acad 
Sci USA 2007;104:10062-8. 
Laird AK, Tyler SA, Barton AD. Dynamics of normal growth. Growth 1965;29: 233-48. 
Lower R, Lower J, Kurth R. The viruses in all of us: characteristics and biological 
significance of human endogenous retrovirus sequences. Proc Nat Acad Sci 
1996;93:5177-84.  
Matsushansky I, Hernando E, Socci N, Mills JE, Matos TA, Edgar MA, et al. Derivation 
of sarcomas from mesenchymal stem cells via inactivation of the Wnt pathway. J Clin 
Invest 2007;117:3248-57. 
Mattiuzzo G, Scobie L, Takeuchi Y. Strategies to enhance the safety profile of 
xenotransplantation: minimizing the risk of viral zoonoses. Curr Opin Organ Transplant 
2008;13:184-8. 
Moore KA and Lemischka IR. Stem cells and their niches. Science 2006;311:1880-5.  
Norton L, Simon R, Bereton HD, Bogden AE. Predicting the course of Gompertzian 
growth. Nature 1976;264:542-5. 
Platt JL and Nagayasu T. Current status of xenotransplantation. Clin Exp Pharm Physiol 
1999;26:1026-32. 
Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem 
cells. Nature 2001;414(6859):105-11. 
Sanai N, Alvarez-Buylla A, Berger MS. Neural stem cells and the origins of gliomas. 
N Engl J Med 2005;353:811-22. 
Sneddon JB and Werb Z. Location, location, location: the cancer stem cell niche. Cell 
Stem Cell 2007;1:607-11. 
Soin B, Vial CM, Friend PJ. Xenotransplantation. British J Surg 2000;87:138-48. 
Speer JF, Petrosky VE, Retsky MW, Wardwell RH. A stochastic numerical model of 
breast cancer growth that simulates clinical data. Cancer Res 1984;44:4124-30. 
Timmerman RD, Bizekis CS, Pass HI, Fong Y, Dupuy DE, Dawson LA, et al. Local 
surgical, ablative, and radiation treatment of metastases.  CA Cancer J Clin 
2009;59(3):145-70 (Epub, April 2009). 
Tu SM, Lin SH, Logothetis CJ. Stem-cell origin of metastasis and heterogeneity in solid 
tumors. Lancet Oncol 2002;3(8):508-13. 
Weiss, RA. Xenografts and retroviruses. Science 1999;285:1221. 

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Weiss, RA. Xenotransplantation: pausing to reflect. Hospital Practice 2000(Oct 15);71-8. 
Yamane B and Weber S. Liver-directed treatment modalities for primary and secondary 
hepatic tumors. Surg Clin N Amer 2009;89(1):97-113.