Conditions: Colorectal Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 109
Healthy volunteers: no

Brief summary:
The purpose of this study is to find out if giving reolysin in combination with FOLFOX6/ bevacizumab can offer better results than standard therapy with FOLFOX6/ bevacizumab.

Detailed description:
Researchers doing this study also want to evaluate the side effects of reolysin when given together with FOLFOX6/ bevacizumab.

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Folfox plus Bevacizumab and reolysin intervention 2: Folfox plus Bevacizumab
Intervention descriptions: intervention 1: FOLFOX6/bevacizumab given every 14 days plus reolysin days 1-5 on cycles 1, 2, 4, 6, 8 and alternate cycles thereafter intervention 2: FOLFOX6/bevacizumab given every 14 days.

Protocol document:
Prot_000.pdf: 
 
PROTOCOL DATE: 2012-MAY-03 
 
NCIC CTG TRIAL: IND.210 
 
 
CONFIDENTIAL 
CONFIDENTIAL 
HEALTH CANADA SUBMISSION 
AMENDMENT #1: 2013-APR-25 
AMENDMENT #2: 2013-JUN-26 
ADMINISTRATIVE UPDATE #1: 2014-MAY-23 (withdrawn) 
AMENDMENT #3: 2014-JUN-16 
AMENDMENT #4: 2014-NOV-17 
 
AMENDMENT #5: 2015-DEC-07 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NCIC CLINICAL TRIALS GROUP (NCIC CTG) 
 
A RANDOMIZED PHASE II STUDY OF REOLYSIN IN COMBINATION WITH 
FOLFOX6/BEVACIZUMAB OR FOLFOX6/BEVACIZUMAB ALONE IN PATIENTS WITH 
METASTATIC COLORECTAL CANCER 
 
NCIC CTG Protocol Number: IND.210 
 
 
 
STUDY CHAIRS: 
PATRICIA TANG 
 
 
DEREK JONKER 
 
 
SENIOR INVESTIGATOR: 
LESLEY SEYMOUR 
 
 
SENIOR BIOSTATISTICIAN: 
DONGSHENG TU 
 
 
STUDY COORDINATOR: 
ASHLEY THEIS 
 
 
SUPPORTED BY: 
ONCOLYTICS BIOTECH INC. 
 
 
 (For contact information of study personnel see Final Page.) 
 


 
PROTOCOL DATE: 2012-MAY-03 
 
NCIC CTG TRIAL: IND.210 
 
 
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TABLE OF CONTENTS 
 
STUDY ACKNOWLEDGMENT/DISCLOSURE ............................................................................................... 1 
 
TREATMENT SCHEMA ..................................................................................................................................... 2 
 
1.0 
OBJECTIVES ......................................................................................................................................... 5 
1.1 
Primary Objective ................................................................................................................................... 5 
1.2 
Secondary Objectives .............................................................................................................................. 5 
 
2.0 
BACKGROUND INFORMATION AND RATIONALE ...................................................................... 6 
2.1 
Colorectal Cancer .................................................................................................................................... 6 
2.2 
Chemotherapy in Metastatic Colorectal Cancer ...................................................................................... 6 
2.3 
Antiangiogenic Therapy in Metastatic Colorectal Cancer ...................................................................... 6 
2.4 
Reolysin .................................................................................................................................................. 7 
2.5 
Rationale ................................................................................................................................................. 8 
 
3.0 
BACKGROUND THERAPEUTIC INFORMATION............................................................................ 9 
3.1 
Reolysin .................................................................................................................................................. 9 
3.2 
FOLFOX6/Bevacizumab ...................................................................................................................... 14 
 
4.0 
TRIAL DESIGN ................................................................................................................................... 15 
 
5.0 
STUDY POPULATION ....................................................................................................................... 16 
5.1 
Eligibility Criteria ................................................................................................................................. 16 
5.2 
Ineligibility Criteria ............................................................................................................................... 18 
 
6.0 
PRE-TREATMENT EVALUATION ................................................................................................... 19 
 
7.0 
ENTRY/RANDOMIZATION PROCEDURES .................................................................................... 20 
7.1 
Entry Procedures ................................................................................................................................... 20 
7.2 
BSA Calculation .................................................................................................................................... 20 
7.3 
Stratification .......................................................................................................................................... 20 
 
8.0 
TREATMENT PLAN ........................................................................................................................... 21 
8.1 
Chemotherapy Treatment Plan .............................................................................................................. 21 
8.2 
Duration of Therapy .............................................................................................................................. 27 
8.3 
Concomitant Therapy ............................................................................................................................ 27 
 
9.0 
EVALUATION DURING AND AFTER PROTOCOL TREATMENT .............................................. 29 
9.1 
Evaluation During Protocol Treatment ................................................................................................. 29 
9.2 
Evaluation After Protocol Treatment .................................................................................................... 30 
 
10.0 
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS ......................................................... 31 
10.1 
Definitions ............................................................................................................................................. 31 
10.2 
Objective Response and Evaluation Endpoints ..................................................................................... 31 
 
11.0 
SERIOUS ADVERSE EVENT REPORTING ..................................................................................... 35 
11.1 
Definition of a Reportable Serious Adverse Event ............................................................................... 35 
11.2 
Serious Adverse Event Reporting Instructions ..................................................................................... 35 
11.3 
NCIC CTG Responsibility for Reporting Serious Adverse Events to Health Canada .......................... 36 
11.4 
NCIC CTG Reporting Responsibility to Oncolytics Biotech Inc. ......................................................... 36 
11.5 
NCIC CTG and Oncolytics Biotech Inc. Reporting Responsibilities ................................................... 36 
11.6 
Reporting Safety Reports to Investigators ............................................................................................. 37 


 
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NCIC CTG TRIAL: IND.210 
 
 
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12.0 
PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING ............ 38 
12.1 
Criteria for Discontinuing Protocol Treatment ..................................................................................... 38 
12.2 
Duration of Protocol Treatment ............................................................................................................ 38 
12.3 
Therapy After Protocol Treatment is Stopped ...................................................................................... 38 
12.4 
Follow-up Off Protocol Treatment ........................................................................................................ 38 
 
13.0 
CENTRAL REVIEW PROCEDURES AND TISSUE COLLECTION ............................................... 39 
13.1 
Central Radiology Review .................................................................................................................... 39 
13.2 
Central Pathology Review ..................................................................................................................... 39 
13.3 
Tissue Collection ................................................................................................................................... 39 
 
14.0 
STATISTICAL CONSIDERATIONS .................................................................................................. 40 
14.1 
Objectives and Design ........................................................................................................................... 40 
14.2 
Primary Endpoints and Analysis ........................................................................................................... 40 
14.3 
Sample Size and Duration of Study ...................................................................................................... 40 
14.4 
Safety Monitoring ................................................................................................................................. 41 
14.5 
Quality of Life ....................................................................................................................................... 41 
 
15.0 
PUBLICATION POLICY ..................................................................................................................... 42 
15.1 
Authorship of Papers, Meeting Abstracts, Etc ...................................................................................... 42 
15.2 
Responsibility for Publication ............................................................................................................... 42 
15.3 
Submission of Material for Presentation or Publication ........................................................................ 42 
 
16.0 
ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES ...................................................... 43 
16.1 
Regulatory Considerations .................................................................................................................... 43 
16.2 
Inclusivity in Research .......................................................................................................................... 43 
16.3 
Obtaining Informed Consent ................................................................................................................. 44 
16.4 
Discontinuation of the Trial .................................................................................................................. 44 
16.5 
Retention of Patient Records and Study Files ....................................................................................... 44 
16.6 
Centre Performance Monitoring ............................................................................................................ 45 
16.7 
On-Site Monitoring/Auditing ................................................................................................................ 45 
16.8 
Case Report Forms ................................................................................................................................ 45 
 
17.0 
TRANSLATIONAL RESEARCH STUDIES ...................................................................................... 46 
17.1 
Correlative Studies of Archival Paraffin Embedded Tumour Samples– All patients ........................... 46 
17.2 
Correlative Studies of  Serum and Plasma Samples – All patients ....................................................... 48 
 
18.0 
REFERENCES ...................................................................................................................................... 50 
 
APPENDIX I -  
PATIENT EVALUATION FLOW SHEET......................................................................... 53 
APPENDIX II -  PERFORMANCE STATUS SCALES/SCORES ................................................................ 54 
APPENDIX III - DRUG DISTRIBUTION, SUPPLY AND CONTROL ....................................................... 55 
APPENDIX IV -  DOCUMENTATION FOR STUDY .................................................................................... 56 
APPENDIX V -  NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS ...................... 57 
APPENDIX VI -  MANAGEMENT OF ANGIOGENESIS INHIBITOR (AI)-INDUCED  
HYPERTENSION................................................................................................................ 58 
APPENDIX VII -  QUALITY OF LIFE ASSESSMENT .................................................................................. 60 
 
LIST OF CONTACTS ........................................................................................................................... Final Page 
 


 
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NCIC CTG TRIAL: IND.210 
 
 
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STUDY ACKNOWLEDGMENT/DISCLOSURE 
 
I understand that this protocol contains information that is confidential and proprietary to Oncolytics 
Biotech Inc.  
 
I have read the protocol and agree that it contains all necessary details for carrying out the study as 
described. I will conduct this protocol as outlined therein, and according to Good Clinical Practice and 
any applicable local regulations. I will make a reasonable effort to complete the study within the time 
designated. I confirm that I and study personnel participating under my supervision have adequate 
resources to fulfill their responsibilities as outlined in this protocol. I will maintain documentation of any 
investigator responsibilities assigned to participating study personnel. I confirm that all data will be 
submitted in a timely manner and will be accurate, complete and supported by source documents. 
 
I will provide copies of the protocol and access to all information furnished by NCIC CTG and 
Oncolytics Biotech Inc. to study personnel under my supervision. I will discuss this material with them to 
ensure that they are fully informed about the investigational product and the study.  
 
I will provide protocol information to my Research Ethics Board (REB), subject to the following 
condition: The contents of this protocol may not be used in any other clinical trial and may not be 
disclosed to any other person or entity without the prior written permission of Oncolytics Biotech Inc. and 
NCIC CTG. The foregoing shall not apply to disclosure required by governmental regulations or laws; 
however, I will give prompt notice to Oncolytics Biotech Inc. and NCIC CTG of any such disclosure. 
 
I understand that any inventions or discoveries made by any Principal Investigator during the course of 
this Study which directly relate to the study drug shall be disclosed to CTG and Oncolytics Biotech Inc. 
and shall become the property of Oncolytics Biotech Inc. However, the Principal Investigator shall retain 
the right to use any such inventions or discoveries for their own internal research and education. 
 
I understand that I may terminate or suspend enrolment of the study at any time if it becomes necessary to 
protect the best interests of the study subjects, however I will give prompt notice to NCIC CTG. The 
study may be terminated at any time by NCIC CTG or Oncolytics Biotech Inc. with or without cause. 
 
Any supplemental information that may be added to this document is also confidential and proprietary to 
Oncolytics Biotech Inc. and NCIC CTG and must be kept in confidence in the same manner as the 
contents of this protocol. 
 
 
___________________________________________________ 
_________________________ 
Investigator 
Date 
(printed name and signature) 
 
 
Protocol Number: NCIC CTG IND.210 
 
CENTRE: ___________________________________________ 


 
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AMENDMENT #1: 2013-APR-25; ADMIN UPDATE #1: 2014-MAY-23 (withdrawn); AMEND #3: 2014-JUN-16: 
 
AMEND #4: 2014-NOV-17 
TREATMENT SCHEMA 
 
This is an open-label, randomized, non-blinded, phase II clinical study of reolysin day 1-5 (cycles 1, 2, 4, 
6, 8 and alternate cycles thereafter) plus q2 weekly FOLFOX6/bevacizumab versus q2 weekly 
FOLFOX6/bevacizumab as first line palliative treatment for patients with advanced or metastatic 
colorectal cancer. Prior to the randomized component, 6-9 patients will first be accrued to ensure safety 
and tolerability of the combination. 
 
SAMPLE SIZE 
 
Up to 100 evaluable patients (50 per arm) will be randomized. The estimated accrual for this study is 8 
patients per month. Thus, patient accrual is expected to be completed within 13-15 months.  
 
ELIGIBILITY 
 
All patients: 
• 
Histologically diagnosed colorectal adenocarcinoma 
• 
Paraffin embedded primary (or metastatic) tumour sample available for assessment; patient must have 
provided informed consent for release of the sample 
• 
Metastatic or advanced disease for which systemic treatment with FOLFOX6/bevacizumab is 
indicated 
• 
Patients must have measureable disease as per RECIST 1.1 
• 
ECOG performance status 0, 1, 2 
• 
Age > 18 years 
• 
No prior chemotherapy regimens for advanced or metastatic disease 
• 
No prior oxaliplatin based or bevacizumab based therapy, but may have had adjuvant 
fluoropyrimidine-based therapy provided completed at least one year prior to enrolment. Exceptions 
may be given for low dose chemotherapy given as a radiosensitizer  
• 
No contraindications to treatment with 5FU (for e.g. known DPD deficiency or severe cardiac 
disease), and no neuropathy > grade 1 
• 
Prior radiation permitted > 4 weeks since last dose  
• 
No major surgery within 21 days prior to randomization 
 
Absolute granulocyte count (AGC)  > 1.5 x109/L 
 
Platelet count  > 100 x109/L 
 
Total bilirubin < 1 x ULN 
 
Serum creatinine < 1.5 x ULN 
 
ALT and AST < 3 x ULN (If documented liver metastasis, ≤ 5xULN) 
• 
Proteinuria < 2 g/24 hrs 
• 
No significant cardiac (including uncontrolled hypertension) or pulmonary disease, active CNS 
disease or infection 
• 
No immunosuppressive treatment of known hepatitis or HIV positive patients 
• 
Patients with active or uncontrolled infections, or with serious illnesses or medical conditions, which 
would not permit the patient to be managed according to the protocol. 
• 
No history of other malignancies, except adequately treated non-melanoma skin cancer or solid 
tumours with no evidence of disease > 3 years. 
• 
No history of central nervous system metastases or untreated spinal cord compression. 
• 
All patients (unless sterile) must use an adequate method of birth control. 


 
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AMEND #1: 2013-APR-25 
PRE-TREATMENT EVALUATIONS 
 
• 
History, physical exam, hematology, biochemistry, urinalysis and adverse events/baseline symptoms, 
within 7 days prior to randomization 
• 
Quality of life questionnaire within 14 days prior to randomization 
• 
Blood samples for correlative studies after randomization but prior to first dose of chemotherapy 
• 
Radiology: chest CT; abdominal/pelvic CT; other scans as necessary, within 28 days prior to 
randomization (within 35 days if negative) 
 
TREATMENT 
 
Arm A and safety run in patients:  
FOLFOX6/bevacizumab given every 14 days plus reolysin days 1-5 on cycles 1, 2, 4, 6, 8 and alternate 
cycles thereafter. 
 
Arm B: 
FOLFOX6/bevacizumab given every 14 days. 
 
Patients in the randomized component of the study will be randomly assigned to Arm A or Arm B. 
 
DRUG ADMINISTRATION SCHEDULE 
 
Arm A and safety run in: 
Cycle 
1 
 
 
 
2 
 
 
 
3 
 
 
 
4 
 
 
 
Day 
1 
2 
3-5 
8 
15/1 
2 
3-5 
8 
15/1 
2 
3-5 
8 
15/1 
2 
3-5 
8 
Bevacizumab (5mg/kg) 
Oxaliplatin (85mg/m2) 
Leucovorin (400mg/m2) 
Fluorouracil (400mg/m2 bolus) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fluorouracil (2400 mg/m² inf x 
46hrs) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reolysin (3 x 1010 TCID50)*:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Arm B: 
Cycle 
1 
 
 
 
2 
 
 
 
3 
 
 
 
4 
 
 
 
Day 
1 
2 
3-5 
8 
15/1 
2 
3-5 
8 
15/1 
2 
3-5 
8 
15/1 
2 
3-5 
8 
Bevacizumab (5mg/kg) 
Oxaliplatin (85mg/m2) 
Leucovorin (400mg/m2) 
Fluorouracil (400mg/m2 bolus) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fluorouracil (2400 mg/m² inf x 
46hrs) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* dose may be modified dependent on results of safety run component 


 
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AMEND #1: 2013-APR-25; AMEND #2: 2013-JUN-26; ADMIN UPDATE #1: 2014-MAY-23 (withdrawn);  
 
AMEND #3: 2014-JUN-16 
ON TREATMENT EVALUATIONS 
 
• 
Hematology and Biochemistry: weekly for cycles 1 and 2 then day 1 for subsequent cycles 
• 
Urinalysis: each cycle (day 1) 
• 
CEA: end of every 2nd cycle (every 4 weeks) 
• 
Physical exam (weight, blood pressure, heart rate, ECOG PS): Baseline and every cycle (day 1) 
• 
Blood samples for correlative studies: end of cycle 2 and at off treatment 
• 
Radiology:  every 8 weeks to assess all sites of disease 
• 
Quality of life: day 1 cycle 5 and at off treatment 
• 
Adverse events: evaluated continuously 
 
DURATION OF TREATMENT 
 
Treatment will continue until: 
• 
Patient experiences progression as defined in section 10.0  
• 
Unacceptable toxicity 
• 
Patient chooses to withdraw 
 


 
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1.0 
OBJECTIVES 
 
Six to nine patients will be enrolled initially to confirm the safety and tolerability of the 
combination (FOLFOX6/bevacizumab/reolysin). 
 
1.1 
Primary Objective  
 
To evaluate the effect of reolysin in combination with standard FOLFOX6 chemotherapy on the 
progression free survival of patients with advanced or metastatic colorectal cancer.  
 
1.2 
Secondary Objectives 
 
1.2.1 
To determine the tolerability and toxicity of reolysin and FOLFOX6/bevacizumab when given in 
combination. 
 
1.2.2 
To investigate additional potential measures of efficacy including: 
• 
change in CEA levels 
• 
objective response rate  
• 
to evaluate the effect of both treatments on overall survival (OS) 
 
1.2.3 
To explore potential molecular factors which may be prognostic, or predictive of response, by 
assessment of archival tumour tissue and serial blood samples.  
 
1.2.4 
To explore the Quality of Life (as measured by the EORTC QLQC30). 


 
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2.0 
BACKGROUND INFORMATION AND RATIONALE 
 
2.1 
Colorectal Cancer 
 
Colorectal cancer (CRC) is the second-leading cause of cancer death in Canada [Statistics CCS 2011] 
and has historically been refractory to most chemotherapeutics. Over the past five years, the 
introduction of irinotecan and oxaliplatin have enabled patients with advanced colorectal cancer 
to live longer than before, with a median survival for these patients of over 20 months [Tournigand 
2004]. Although a number of new effective therapies have been developed for patients with 
metastatic colorectal cancer, all patients treated in the palliative setting will ultimately succumb to 
their disease. New treatments are needed. 
 
2.2 
Chemotherapy in Metastatic Colorectal Cancer 
 
Oxaliplatin, a third generation cisplatin analogue, is a pivotal component of systemic therapy for 
metastatic CRC. Two multicenter randomized studies compared 5 fluorouracil/folinic acid 
(5FUFA) with and without oxaliplatin as first-line treatment for metastatic CRC [de Gramont 2000; 
Giacchetti 2000]. The combination of oxaliplatin to 5FU FA (FOLFOX) demonstrated superior 
response rates (51% vs 22%, p<0.0001; 53% vs 16%, p< 0.001) and longer progression-free 
survival (PFS) (9.0 vs 6.2 months, p = 0.0003; 8.7 vs 6.1 months, p < 0.05). In a North American 
Intergroup trial (N9741), FOLFOX4 was superior to irinotecan and bolus 5FUFA (IFL) with 
respect to response rate, PFS, and overall survival (OS) [Goldberg 2004]. In Europe, FOLFOX6 and 
FOLFIRI have been compared to each other, used sequentially, in the management of patients 
with advanced colorectal cancer, and there does not appear to be a significant difference in 
outcome based on the sequence of administration, although the toxicity profiles are dissimilar. 
Both FOLFIRI and FOLFOX are standard first line chemotherapy options. In some instances, 
clinical response may permit post-chemotherapy surgical resection with curative intent. 
 
There are numerous published regimens that combine varying doses and schedules of oxaliplatin 
and 5-FUFA. These combinations have been named FOLFOX 1-7. There is no clear evidence that 
any one FOLFOX regimen is superior to another. The role of FOLFOX as front-line therapy for 
patients with advanced or metastatic colorectal cancer is supported by the findings of the N9741 
intergroup study. This trial will use the modified FOLFOX6 regimen that has been evaluated in 
prior clinical trials [Hochster 2008]. 
 
2.3 
Antiangiogenic Therapy in Metastatic Colorectal Cancer 
 
Inhibition of VEGF with antiangiogenic drugs is thought to improve delivery of chemotherapy 
via vascular normalization and disruption of tumour vasculature [Jain 2009]. Bevacizumab, a 
monoclonal antibody that binds to VEGF, significantly improves outcomes when added to 
standard chemotherapy for metastatic colorectal cancer (MCRC) [Giantonio 2007; Hurwitz 2004; 
Hurwitz 2005; Kabbinavar 205; Saltz 2008]. It has been approved for use in untreated patients with 
advanced colorectal cancer in combination with 5FU-based chemotherapy. In the pivotal first line 
trial, bevacizumab in combination with IFL compared to IFL alone led to superior response rates, 
PFS, and OS (20.3 months in the bevacizumab group versus 15.6 months, HR 0.66, p<0.001). A 
meta-analysis of randomized trials comparing chemotherapy plus bevacizumab with 
chemotherapy alone as first or second line therapy for metastatic CRC detected a significant 
advantage in favor of the addition of bevacizumab to chemotherapy in terms of OS [HR 0.79; 
95% CI 0.69-0.90; p = 0.0005], PFS (HR 0.63; 95% CI 0.49-0.81, p=0.0004), and response rate 
(RR 1.50; 95% CI 1.06-2.10, p=0.02) [Welch 2010]. Bevacizumab does not appear to alter the 
toxicity profile of chemotherapy, although hypertension and proteinuria are commonly seen. 
Approximately 3-4% of patients receiving bevacizumab suffer arterial thrombotic events. 
Bevacizumab in combination with modified FOLFOX6 is a standard chemotherapy option in the 
first line treatment of metastatic CRC. 


 
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2.4 
Reolysin 
 
Reolysin is a Dearing strain of reovirus serotype 3, with demonstrated in vitro and in vivo activity 
in many cancers including colorectal cancer [Hirasawa 2002]. Reovirus has an inherent propensity 
to preferentially infect and destroy cancer cells through exploitation of activated Ras pathway and 
downstream elements. It causes virus-mediated cell death due to inhibition of double-stranded 
RNA-activated protein kinase [Marcanto 2007; Strong 1998]. It appears to have minimal human 
toxicity and its human safety and potential efficacy have been demonstrated with > 360 patients 
treated on clinical trials to date. In phase I trials, reolysin was well tolerated and dose limiting 
toxicities were not observed [Vidal 2008]. The most common side effect is a flu-like illness. An 
international randomized phase III trial of reolysin with paclitaxel and carboplatin in head and 
neck cancers is presently under way. 
 
In preclinical studies, reolysin has cytopathic effect in tumours driven by KRAS mutations or 
upstream activation of the Ras pathway, both of which are important in colorectal cancer. The 
Ras oncogene plays an important role in colorectal cancer tumourigenesis [Shirasawa 1993]. 
Activating mutations in the KRAS oncogene are present in 40 to 50% of colorectal cancers 
[Vogelstein 1988]. Ligand binding of the epidermal growth factor receptor (EGFR) leads to a 
cascade of intracellular events which include activation of the Ras pathway. Expression or up-
regulation of EGFR occurs in 60 to 80% of colorectal cancer [Porebska 2000]. 
 
Reolysin has preclinical activity against colorectal cancer. In cell proliferation studies in HCT116 
colon cancer cells, Reolysin was highly cytopathic against HCT116. HCT116 variants in which 
Ras was disrupted by homologous recombination demonstrated equivalent sensitivity to reolysin. 
Reovirus enhanced the cytopathic effects of fluorouracil at every concentration tested [Wadler 
2004]. Hirasaw et al. evaluated the antitumour activity of Reolysin in preclinical models of 
colorectal cancer [Hirasawa 2002]. Reolysin infected five human colon cancer cell lines (Caco-2, 
DLD-1, HCT-116, HT-29, and SW48) but not a normal colon cell line (CCD-18-Co). After over 
72 hours post infection, > 95% of cancer cell lines were destroyed. Ras activity in the human 
colon cancer cell lines was elevated compared to normal colon cancer cell lines. Intravenous 
treatment with reolysin in three different colon tumour xenografts models resulted in significant 
inhibition of tumour growth. Histological examination of tumours revealed necrosis and fibrosis 
in reolysin treated mice compared to controls and active viral replication in the tumours.  
 
Transient inhibition of continuous VEGF signaling to tumour-associated endothelium, followed 
by a recovery period induces a proviral state. B16-VEGF tumours treated in vivo with either 
sunitinib or bevacizumab became highly susceptible to systemic treatment with reolysin. 
Combined treatment with Reolysin and antiangiogenic therapy was superior to single agent 
treatment when reolysin [Kottke 2011] was administered after antiangiogenic therapy. 
 
In a window-of-opportunity clinical study, a single cycle of intravenous reolysin was given to 
patients at a dose of 1 x 1010 TCID50 from days 1 to 5, between 6 and 28 days prior to a planned 
resection of colorectal cancer metastatic to the liver (Adair et al, unpublished data). There were 
no surgical complications and treatment was well tolerated with no grade 3 or 4 toxicities. There 
was greater selective expression of reovirus protein in malignant cells compared to either tumour 
stroma or surrounding normal liver tissue. Tubulin is an indirect marker of replication in viral 
factories. In four out of six assessable cases, co-localization of reolysin was seen with tubulin in 
tumour tissue but not in adjacent stroma. Recovery of replicating virus from tumour (but not 
liver) was achieved in all 4 patients from whom fresh tissue was available. A phase I study of 
FOLFIRI and reolysin is ongoing (ClinicalTrials.gov identifier NCT01274624).  


 
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2.5 
Rationale 
 
Reolysin has single agent activity in colorectal non clinical models, and appears to have 
additive/synergistic effects when combined with 5-FU and bevacizumab in preclinical models. 
We hypothesize that reolysin added to standard modified FOLFOX6 plus bevacizumab in the first 
line metastatic setting will demonstrate improved progression-free survival compared to 
FOLFOX6 plus bevacizumab. As FOLFOX6 is administered every 14 days, and the standard 
dose of reolysin in other studies is administered every 3 to 4 weeks, reolysin will be given on 
alternate cycles after cycles 1 and 2 (i.e. cycles 1, 2, 4, 6, 8 etc.) 
 
Formal phase I studies of reolysin in combination with FOLFOX6/bevacizumab have not been 
conducted. No clinically relevant interactions have been reported with other combinations in the 
clinical program, and none are expected with the combination being tested in this protocol. To 
ensure patient safety, a safety run-in of 6 to 9 patients will be conducted; with a provision for 
dose de-escalation should this be required.  
 
Quality of life (QoL) in this study will be assessed using the EORTC QLQ-C30 questionnaire. 
This self-administered questionnaire consists of 30 items in which are embedded five functional 
domains (physical, role, emotional, cognitive and social), three symptom domains and a global 
assessment. The validity and reliability of this questionnaire have been studied by the EORTC 
Study Group on Quality of Life [Aaronson 1993]. This tool has also been used extensively in 
previous NCIC CTG trials. It has been demonstrated to be sensitive to detecting clinically and 
statistically important changes in this patient population [Jonker 2007]. 
 


 
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3.0 
BACKGROUND THERAPEUTIC INFORMATION 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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NCIC CTG TRIAL: IND.210 
 
 
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4.0 
TRIAL DESIGN 
 
This is an open-label, randomized, non-blinded, phase II clinical study of reolysin day 1-5 (cycles 
1, 2, 4, 6, 8 and alternate cycles thereafter) plus q2 weekly FOLFOX6/bevacizumab versus q2 
weekly FOLFOX6/bevacizumab as first line palliative treatment for patients with advanced or 
metastatic colorectal cancer. Prior to the randomized component 6-9 additional patients will be 
accrued to ensure safety and tolerability of the combination (see protocol section 8.1.1). The 
study is being conducted by the NCIC Clinical Trials Group, with support of Oncolytics Biotech 
Inc. 
 


 
PROTOCOL DATE: 2012-MAY-03 
 
NCIC CTG TRIAL: IND.210 
 
 
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AMEND #2: 2013-JUN-26 
5.0 
STUDY POPULATION 
 
Patients will have documented evidence of advanced metastatic colorectal cancer. This study is 
designed to include minorities as appropriate, but is not designed to measure differences in 
intervention effects.  
 
5.1 
Eligibility Criteria 
 
There will be NO EXCEPTIONS to eligibility requirements at the time of randomization. 
Questions about eligibility criteria should be addressed PRIOR to randomization. 
 
The eligibility criteria for this study have been carefully considered. Eligibility criteria are 
standards used to ensure that patients who enter this study are medically appropriate candidates 
for this therapy. For the safety of the patients, as well as to ensure that the results of this study can 
be useful for making treatment decisions regarding other patients with similar diseases, it is 
important that no exceptions be made to these criteria for admission to the study. 
 
Patients must fulfill all of the following criteria to be eligible for admission to the study: 
 
5.1.1 
Patients must have a histological diagnosis of colorectal adenocarcinoma.  
 
5.1.2 
All patients must have a formalin fixed paraffin embedded tissue block (from their primary or 
metastatic tumour) available for translational studies and must have provided informed consent 
for the release of the block. 
 
5.1.3 
Presence of clinically and/or radiologically documented disease. All radiology studies must be 
performed within 28 days prior to randomization (within 35 days if negative). 
 
All patients must have measurable disease as defined by RECIST 1.1. 
 
The criteria for defining measurable disease are as follows: 
 
Chest X-ray  
> 20 mm  
CT/MRI scan (with slice thickness of < 5 mm)  > 10 mm   longest diameter  
Physical exam (using calipers)  
> 10 mm  
Lymph nodes by CT scan  
> 15 mm   measured in short axis  
 
5.1.4 
Patients must have advanced and or metastatic disease, for which no curative therapy exists and 
for which systemic therapy is indicated. 
 
5.1.5 
ECOG performance of 0, 1 or 2. 
 
5.1.6 
Age > 18 years of age. 
 
5.1.7 
Previous Therapy 
 
Surgery:  
Previous major surgery is permitted provided that it has been at least 21days prior to patient 
randomization and that wound healing has occurred.  


 
PROTOCOL DATE: 2012-MAY-03 
 
NCIC CTG TRIAL: IND.210 
 
 
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AMEND #1: 2013-APR-25; AMEND #2: 2013-JUN-26; ADMIN UPDATE #1: 2014-MAY-23 (withdrawn);  
 
AMEND #3: 2014-JUN-16; AMEND #4: 2014-NOV-17 
Chemotherapy:  
Patients may NOT have received any prior cytotoxic chemotherapy for advanced or metastatic 
disease. Prior adjuvant fluoropyrimidine-based therapy is permitted provided completed at least 
one year prior to enrolment and the regimen did not include oxaliplatin or bevacizumab. 
Exceptions may be made for low dose chemotherapy given as a radiosensitizing agent. 
 
Other Therapy:  
Patients may have received other therapies including immunotherapy, or with signal transduction 
inhibitors, providing that the patient has recovered from all reversible drug related toxicity (with 
the exception of alopecia) and adequate washout period has been met. 
 
Radiation:  
Prior external beam radiation is permitted provided a minimum of 4 weeks has elapsed between 
the last dose and enrollment to the trial. Exceptions may be made for low dose, non-
myelosuppressive radiotherapy after consultation with NCIC CTG.  
 
5.1.8 
Laboratory Requirements (must be done within 7 days prior to randomization) 
 
Hematology:  
Granulocytes (AGC) 
> 1.5 x 109/L  
Platelets 
> 100 x 109/L 
 
Biochemistry:  
Serum creatinine 
< 1.5 x ULN  
Total bilirubin 
< 1.0 x ULN 
(unless elevated secondary to conditions such as Gilbert’s 
disease)  
ALT and AST 
< 3 x ULN  
(Note: ≤ 5 x ULN if documented liver metastasis) 
Proteinuria  
< 2 g/24 hrs 
(screen using spot testing; if > grade 2 repeat with mid-stream 
urine - if still > grade 2 then urine collection for 24 hours to 
confirm< 2 g/24 hrs) 
 
5.1.9 
Patient consent must be appropriately obtained in accordance with applicable local and regulatory 
requirements. Each patient must sign a consent form prior to enrollment in the trial to document 
their willingness to participate.  
 
Patients who cannot give informed consent (i.e. mentally incompetent patients, or those 
physically incapacitated such as comatose patients) are not to be recruited into the study. Patients 
competent but physically unable to sign the consent form may have the document signed by their 
nearest relative or legal guardian. Each patient will be provided with a full explanation of the 
study before consent is requested. 
 
5.1.10 Patients must be accessible for treatment and follow-up. Patients registered on this trial must be 
treated and followed at the participating centre. This implies there must be reasonable 
geographical limits (for example: 2 hour's driving distance) placed on patients being considered 
for this trial. (Call the NCIC CTG office (613-533-6430) if questions arise regarding the 
interpretation of this criterion.) Investigators must assure themselves that the patients registered 
on this trial will be available for complete documentation of the treatment, adverse events, 
response assessment and follow-up. 


 
PROTOCOL DATE: 2012-MAY-03 
 
NCIC CTG TRIAL: IND.210 
 
 
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AMEND #2: 2013-JUN-26; ADMIN UPDATE #1: 2014-MAY-23 (withdrawn); AMEND #3: 2014-JUN-16 
5.1.11 Patient is able (i.e. sufficiently fluent) and willing to complete the quality of life (EORTC QLQ-
C30) in either English or French. The baseline assessment must already have been completed. 
Inability (illiteracy in English or French, loss of sight, or other equivalent reason) to complete the 
questionnaires will not make the patient ineligible for the study. However, ability but 
unwillingness to complete the questionnaires will make the patient ineligible. The baseline 
assessment must be completed within 14 days prior to randomization. 
 
5.1.12 In accordance with NCIC CTG policy, protocol treatment is to begin within 5 working days of 
patient randomization. 
 
 
5.2 
Ineligibility Criteria 
 
Patients who fulfill any of the following criteria are not eligible for admission to the study: 
 
5.2.1 
Patients with a history of other malignancies, except for adequately treated non-melanoma skin 
cancer or solid tumours curatively treated with no evidence of disease for > 3 years. (Please call 
NCIC CTG if any questions about the interpretation of this criterion). 
 
5.2.2 
Patients who are on immunosuppressive therapy or have known HIV infection or active hepatitis 
B or C.  
 
5.2.3 
Patients with active or uncontrolled infections or with serious illnesses or medical conditions 
which would not permit the patient to be managed according to the protocol.  
 
5.2.4 
Patients with significant cardiac (including uncontrolled hypertension) or pulmonary disease, or 
active CNS disease or infection. 
 
5.2.5 
Patients are not eligible if they have a known hypersensitivity to the study drug(s) or their 
components. 
 
5.2.6 
Patients with history of central nervous system metastases or untreated spinal cord compression. 
 
5.2.7 
Patients who have had prior treatment with oxaliplatin or bevacizumab, who have 
contraindications to treatment with 5FU (for e.g. known DPD deficiency or severe cardiac 
disease), and or neuropathy > grade 1. 
 
5.2.8 
Patients who are not sterile unless they use an adequate method of birth control. 
 


 
PROTOCOL DATE: 2012-MAY-03 
 
NCIC CTG TRIAL: IND.210 
 
 
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AMEND #1: 2013-APR-25; ADMIN UPDATE #1: 2014-MAY-23 (withdrawn); AMEND #3: 2014-JUN-16 
6.0 
PRE-TREATMENT EVALUATION 
(See Appendix I) 
 
Investigations 
Timing 
History and 
Physical Exam 
including: 
History including:  
• 
diagnosis  
• 
prior therapy  
• 
concurrent illness  
• 
concomitant medication  
Physical Exam including:  
• 
height, weight  
• 
blood pressure, pulse  
• 
performance status  
• 
tumour assessment documentation of all 
measurable and non-measurable disease 
Within 7 days prior to randomization 
Hematology 
• 
CBC, differential, platelets 
Biochemistry 
• 
serum creatinine 
• 
bilirubin  
• 
alkaline phosphatase 
• 
AST, ALT  
• 
LDH  
• 
total protein 
• 
CEA  
Other Investigations 
• 
Urinalysis (see section 5.1.8) 
• 
Pregnancy test*  
• 
Quality of life (EORTC QLQC30)** 
Radiology*** 
• 
chest CT scan 
• 
abdominal/pelvic CT scan  
• 
other scans/x-rays as necessary to document 
disease 
Within 28 days prior to 
randomization (within 35 days if 
negative) 
Correlative Studies 
• 
Archival tissue block (all patients)  
Must be confirmed available prior to 
randomization 
• 
Blood samples for correlative studies  
AFTER randomization but BEFORE 
first dose of study treatment 
Adverse Events 
• 
Baseline toxicity evaluation (to document 
residual toxicity from previous therapy and 
baseline symptoms) 
Within 7 days prior to randomization 
*  
For women of childbearing potential only. Required within 7 days prior to randomization. 
** Within 14 days of randomization. 
*** To ensure comparability, the baseline scans and subsequent scans to assess response must be performed using identical 
techniques (i.e. scans performed immediately following bolus contrast administration using a standard volume of contrast, 
the identical contrast agent, and preferably the same scanner). 
  
 Samples for correlative studies (archival tissue block, blood, serum, plasma) required for ALL patients. See Section 17.0 
and IND.210 Lab Manual for details. 
 Adverse events will be recorded and graded according to the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) (Appendix V). 


 
PROTOCOL DATE: 2012-MAY-03 
 
NCIC CTG TRIAL: IND.210 
 
 
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AMEND #1: 2013-APR-25 
7.0 
ENTRY/RANDOMIZATION PROCEDURES 
 
7.1 
Entry Procedures 
 
All randomizations will be done through the NCIC CTG web-based, password-operated 
Electronic Data Capture (EDC) system. Complete details regarding obtaining a password, 
accessing the system and registering/randomizing patients will be provided at the time of study 
activation and will also be included in the “EDC Data Management Guidebook”, posted on the 
IND.210 trial specific web-site. If sites experience difficulties accessing the system and/or 
registering/randomizing patients please contact the help desk (link in EDC) or the IND.210 Study 
Coordinator. 
 
All eligible patients enrolled on the study by the participating treatment centre will be assigned a 
serial number which must be used on all documentation and correspondence with NCIC CTG. 
 
The following information will be required: 
• trial code (NCIC CTG IND.210) 
• investigator NCIC CTG user ID 
• patient's initials (may be coded), hospital number (if permitted by the local REB)  
• informed consent version date, date signed by patient, name of person conducting consent 
discussion and date signed 
• confirmation of the requirements listed in Section 5.0, including dates of essential tests and 
actual laboratory values 
 
7.2 
BSA Calculation 
 
In calculating surface areas, actual heights and weights should be used, that is, there will be no 
downward adjustment to "ideal" weight.  
 
Note: All eligible patients admitted to the trial will be followed by the coordinating centre. It is the 
responsibility of the physician in charge to satisfy himself or herself that the patient is indeed 
eligible before requesting randomization. 
 
7.3 
Stratification 
 
Patients will be stratified for the following factors 
• 
KRAS mutation status (if known) 
• 
prior adjuvant chemotherapy 


 
PROTOCOL DATE: 2012-MAY-03 
 
NCIC CTG TRIAL: IND.210 
 
 
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8.0 
TREATMENT PLAN 
 
Although the NCIC Clinical Trials Group acts as the coordinating agency for the trial, the 
responsibility for treatment of patients rests with the individual investigator. In accordance with 
NCIC CTG policy, protocol treatment is to begin within 5 working days of patient randomization. 
 
8.1 
Chemotherapy Treatment Plan 
 
8.1.1 
Drug Administration 
 
Safety run-in: 
Prior to the randomized component of this study, six to nine patients will be enrolled in three 
participating sites. Initially, one patient will be enrolled at the doses indicated below and observed 
for 2 weeks. Two additional patients will be enrolled providing no safety concerns (i.e. 
unexpected severe toxicity) are identified in the initial patient, and observed for 2 weeks. If no 
safety concerns, 3-6 additional patients will be enrolled prior to the initiation of the randomized 
component of the trial. If safety concerns are identified, the dose of reolysin will be de-escalated 
by one dose level (see 8.1.3), an additional 3 patients enrolled, and that chosen as the dose for the 
randomized component. 
 
Randomized trial: 
Agent(s) 
Dose 
Route 
Duration  
Schedule 
Bevacizumab 
5mg/kg 
IV 
1 hour 
Day 1 every 2 weeks 
oxaliplatin 
85 mg/m² 
IV 
2 hours 
Day 1 every 2 weeks 
leucovorin 
400 mg/m² 
IV 
2 hours (concurrently 
with oxaliplatin) 
Day 1 every 2 weeks 
fluorouracil 
400 mg/m² 
IV 
bolus, after leucovorin 
Day 1 every 2 weeks 
fluorouracil 
2400 mg/m² 
IV 
continuous infusion over 
46 hours  
Day 1 every 2 weeks 
Reolysin 
3x1010 TCID50 
IV 
1 hour 
Days 1–5 (every 2 weeks 
cycles 1,2,4,6,8 etc) 
1 cycle = 2 weeks on study 
 


 
PROTOCOL DATE: 2012-MAY-03 
 
NCIC CTG TRIAL: IND.210 
 
 
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AMEND #1: 2013-APR-25; AMEND #2: 2013-JUN-26; ADMIN UPDATE #1: 2014-MAY-23 (withdrawn);  
 
AMEND #3: 2014-JUN-16 
Arm A and safety run in: 
Cycle 
1 
 
 
 
2 
 
 
 
3 
 
 
 
4 
 
 
 
Day 
1 
2 
3-5 
8 
15/1 
2 
3-5 
8 
15/1 
2 
3-5 
8 
15/1 
2 
3-5 
8 
Bevacizumab (5mg/kg) 
Oxaliplatin (85mg/m2) 
Leucovorin (400mg/m2) 
Fluorouracil (400mg/m2 bolus) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fluorouracil (2400 mg/m² inf x 
46hrs) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reolysin (3 x 1010 TCID50)*:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Arm B: 
Cycle 
1 
 
 
 
2 
 
 
 
3 
 
 
 
4 
 
 
 
Day 
1 
2 
3-5 
8 
15/1 
2 
3-5 
8 
15/1 
2 
3-5 
8 
15/1 
2 
3-5 
8 
Bevacizumab (5mg/kg) 
Oxaliplatin (85mg/m2) 
Leucovorin (400mg/m2) 
Fluorouracil (400mg/m2 bolus) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fluorouracil (2400 mg/m² inf x 
46hrs) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* dose may be modified dependent on results of safety run component 
 
Protocol treatment is to begin within 5 working days of patient randomization. Patients on the 
FOLFOX-6/bevacizumab-reolysin arm who discontinue one of the protocol therapies for toxicity 
related to that therapy may continue with the other, at the discretion of the investigator. Cross 
over is not permitted. Patients who continue treatment with either FOLFOX/bevacizumab or 
reolysin are considered on study and all evaluations and data submission are required as outlined 
in sections 9.1 and Appendix IV unless otherwise discussed with the Senior Investigator. 
Components of the FOLFOX/bevacizumab regimen may be held or discontinued for toxicity but 
must be discussed with the Senior Investigator. 
 
Reolysin should be administered after chemotherapy on days 1 (i.e. before fluorouracil infusion 
starts) and 3, and in a separate line on day 2 (during fluorouracil infusion). Centres may use 
different sequencing of bevacizumab and FOLFOX where the local formulary dictates (e.g. 
bevacizumab given after cytotoxic chemotherapy but before reolysin). 
 
In the case of short weeks (e.g. a public holiday), the duration of the reolysin schedule may be 
shortened for that week (i.e. given day 1-4 on Tuesday to Friday). 
 
8.1.2 
Premedication 
 
All patients will receive antiemetics as per standard centre practice prior to each infusion of 
chemotherapy. 


 
PROTOCOL DATE: 2012-MAY-03 
 
NCIC CTG TRIAL: IND.210 
 
 
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AMEND #1: 2013-APR-25; AMEND #2: 2013-JUN-26; ADMIN UPDATE #1: 2014-MAY-23 (withdrawn);  
 
AMEND #3: 2014-JUN-16; AMEND #4: 2014-NOV-17 
APAP (acetaminophen) may be used for the prophylaxis or treatment of the flu-like signs and 
symptoms, especially fever, that are commonly associated with REOLYSIN. The decision about 
using APAP should be considered for each individual patient, with particular attention to the 
patient's hepatic status at the time of entry into the trial. Extra caution should be used if there is a 
history of viral (HBV or HCV) hepatitis and/or a preentry elevation of bilirubin above normal.  
 
If the patient has metastatic cancer in the liver, the impact of the metastases on overall liver 
function should be considered. If the values for AST and ALT are less than twice the upper limit 
of normal, APAP may still be used, but careful monitoring of hepatic function should be done.  
 
Given the usual timing of fever and other "flu-like" adverse events associated with REOLYSIN, 
treatment with APAP should be limited to the days on which REOLYSIN is administered and the 
day following the last dose of each cycle. When REOLYSIN is administered in combination with 
bone marrow suppressing chemotherapies, it is recommended not to continue APAP longer in 
order to prevent the possible "masking" of fever due to infection---especially in the presence of 
neutropenia.  
 
Dosing of APAP: The recommended dose is 500 or 1000 mg every 6 to 8 hours. The 
MAXIMUM daily (24-hour) dose must NOT exceed 3000 mg. (NB: Given that there are more 
than 600 products that contain APAP, it is also essential that patients be warned NOT to use other 
products containing APAP at the same time)  
 
If used for prophylaxis, it is recommended that the first dose be given 1 to 3 hours following the 
completion of reolysin infusion on day 1 of the cycle. 
 
NSAID usage should be avoided in patients with known renal dysfunction especially when they 
are planned for contrast enhanced imaging. Patients should be encouraged to ensure good 
hydration especially when febrile. 
 
Management of symptoms should take place as necessary (see Section 8.1.3 below). Details of 
any premedication or concomitant medication given to manage or prevent adverse events should 
be recorded on case report forms (CRFs).  
 
Diarrhea: 
Upon FIRST occurrence of diarrhea, loperamide (Imodium) is recommended at an initial dose of 
4 mg (two capsules) followed by 2 mg (one capsule) after each unformed stool. The total daily 
dose should not exceed 16 mg (eight capsules). For patients who experience either persistent 
diarrhea(> 24 hours), diarrhea that is still severe (6+ episodes per day) after 12 hours of Imodium, 
or who exceed the recommended dose of Imodium, treatment with dyphenoxylate and atropine 
(Lomotil) every 6-8 hours until diarrhea is controlled is recommended.  
 
The addition of Lomotil typically reduces the need for Imodium. The recommended initial dosage 
of Lomotil is two tablets four times daily or 10 ml (two regular teaspoonfuls) of Lomotil liquid 
four times daily (20 mg per day). Most patients will require this dosage until initial control has 
been achieved, after which the dosage may be reduced to meet individual requirements. In 
patients who required both Imodium and Lomotil for diarrhea control, it is recommended that 
reduction of Imodium be implemented first. 


 
PROTOCOL DATE: 2012-MAY-03 
 
NCIC CTG TRIAL: IND.210 
 
 
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ADMIN UPDATE #1: 2014-MAY-23 (withdrawn); AMEND #3: 2014-JUN-16; AMEND #4: 2014-NOV-17 
Once diarrhea is controlled with either Imodium and/or Lomotil, it is generally recommended that 
patients continue to use at least one drug as a prophylactic regimen. For patients whose diarrhea 
was well-controlled with Imodium alone, the recommended treatment regimen is 1 capsule after 
each regular (non-diarrheal) bowel movement. For patients who required both Imodium and 
Lomotil to achieve diarrhea control, the recommended regimen is Lomotil 1 tablet every 12 
hours, or 2 tablets every 24 hours, with Imodium added as needed. Treatment with Imodium or 
Lomotil should be avoided in the presence of fever or if the stool is bloody. 
 
8.1.3 
Dose Adjustments 
 
Doses of each drug/agent used as protocol therapy will be modified for hematologic and other 
adverse events considered related to that drug/agent; doses of other drugs/agents do not require 
modification. Dose adjustments are to be made according to the system showing the greatest 
degree of toxicity. Adverse events will be graded using the NCI Common Terminology Criteria 
for Adverse Events (CTCAE). Doses reduced for toxicity will not be re-escalated.  
 
In general when treatment is held because of drug related adverse effects for > 3 weeks without 
recovery to the degree required for restarting treatment, the patient should go off protocol 
therapy. Specific details are found in the sections below.  
 
The use of an institution’s written standard procedures for dose modification of bevacizumab / 
FOLFOX6 is permissible. Dose reductions or treatment interruption for reasons other than those 
described below may be made by the clinical investigator if it is deemed in the best interest of 
patient safety. Whenever possible, these decisions should first be discussed with the senior 
investigator. Note: response evaluation must be performed every 8 weeks even if cycles are 
delayed. 
 
The next cycle should not be given until platelets >  75 x 109/L and ANC > 1.5 x 109/L, all other 
laboratory requirements defined in protocol Section 5.1.8 have been met (including creatinine), 
and all other toxicity is < grade 2.  
 
Suggested dose levels. 
 
Doses of leucovorin do not need reductions after toxicity.  It is not anticipated that the dose of 
reolysin will need to be reduced. 
 
 
FOLFOX doses (mg/m2) 
Bevacizumab 
(mg/kg) 
Reolysin 
(TCID50)* 
Oxaliplatin 
5FU bolus 
5FU infusion 
Starting dose 
85 
400 
2400 
5 
3x1010 
1st dose reduction 
65 mg/m2 
320 
2000 
Not 
applicable** 
1x1010 
2nd dose reduction 
50 mg/m2 
200 
1600 
Discontinue 
3rd dose reduction  
Discontinue 
Discontinue 
* It is not anticipated that the dose of reolysin will require reduction. 
** No dose modification is required. Doses will be held for bevacizumab related toxicities. If toxicity does not 
resolve, bevacizumab will be discontinued.  
 


 
PROTOCOL DATE: 2012-MAY-03 
 
NCIC CTG TRIAL: IND.210 
 
 
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ADMIN UPDATE #1: 2014-MAY-23 (withdrawn); AMEND #3: 2014-JUN-16 
Hypertension (Bevacizumab only) 
Patients who develop hypertension should have their blood pressure monitored daily until ≤ grade 
1. Consult Appendix VI for tables and flow diagrams regarding management. 
 
Grade of Event 
Management/Next Dose* 
Grade 1 
Consider increased BP monitoring 
Grade 2 
• 
Persistent mild 
hypertension 
(140-149/90-99) 
Consider starting or adding a long acting DHP CCB (Table 1 of 
Appendix VI). Gradually increase dose up to maximum dose until BP 
control.  
• 
Persistent moderate 
hypertension 
(150-179/100-109) 
Start/ add long acting DHP CCB (Table 1 of Appendix VI). Gradually 
increase dose up to maximum dose to control BP.  
If partial or no control and still in the moderate hypertension range, 
add an additional drug and increase dose up to maximum dose until 
BP control.  
If partial or no control thereafter, and still in the moderate range, hold 
bevacizumab and add an additional drug at increasing dose up to 
maximum dose until BP control to mild hypertension. Restart 
bevacizumab only when controlled 
Grade 3 
• 
Severe 
(>180/>110) 
If asymptomatic: Hold bevacizumab and start immediate 
antihypertensive therapy with 2 drug combination including at least a 
DHP CCB (table 1 of Appendix VI).  
- 
Increase dose up to maximum dose of both agents until BP 
control. If control to mild hypertension range, restart 
bevacizumab.  
- 
If partial or no BP control, add another drug and increase dose up 
to maximum dose until BP control (see Appendix VI). Restart 
bevacizumab only when controlled 
If symptomatic: stop bevacizumab, hospitalize with aggressive I.V. 
therapy as per hypertensive crisis management (see Appendix VI) 
Grade 4 
• 
Hypertensive crisis 
Discontinue permanently 
* Discontinue permanently if hold > 3 weeks  
 


 
PROTOCOL DATE: 2012-MAY-03 
 
NCIC CTG TRIAL: IND.210 
 
 
CONFIDENTIAL 
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AMEND #4: 2014-NOV-17 
Proteinuria (Bevacizumab and Reolysin) 
Initial screening may be done with urinalysis of spot samples. If protein > grade 2, 24-hour urine 
collection and urine microscopy is mandatory. A urine specimen should be taken and frozen for 
virus shedding studies (contact NCIC CTG for instructions). 
 
Degree of 
proteinuria 
Bevacizumab dosing 
Reolysin dosing 
Grade 1 
Administer bevacizumab dose as 
scheduled 
Administer reolysin dose as scheduled 
Grade 2 
Administer bevacizumab dose as 
scheduled.  
- 
Collect 24 hour urine for 
total protein* within 3 days 
prior to the next scheduled 
bevacizumab administration.  
Hold dose until results of urine microscopy are 
available. 
• 
If no evidence of glomerulonephritis on 
microscopy,  
- Administer reolysin doses as scheduled** 
- Collect 24 hour urine for total protein* 
within 3 days prior to start of the next cycle  
• 
If active sediment (suggestive of 
glomerulonephritis), 
- Hold dose 
- Collect 24-hour urine for protein 
immediately. 
- Investigate further (nephrology consult)  
May restart** when protein <2.0 g/24 hrs AND no 
evidence of glomerulonephritis 
Grade 3 
Discontinue therapy 
* 24 hr urine for protein 
• If < 2g/24hours, administer as scheduled 
• If 2-3.4g/24hrs, hold dose and recheck 24 hour urine prior to each cycle, resume therapy when < 2g/24 h 
** If initial reolysin dose(s) are held due to urine screening, remaining reolysin doses that cycle may be given if 
protein result is <2g/24h. 
 
Dose reductions for Neurotoxicity (Oxaliplatin only) 
Only the dose of oxaliplatin should be modified for neurotoxicity. There is evidence that 
infusions of calcium gluconate and magnesium sulphate prior to and following oxaliplatin may 
reduce the incidence and severity of oxaliplatin induced peripheral neuropathy. Concomitant 
therapy with calcium gluconate and magnesium sulphate is permitted at the discretion of the 
investigator. Caution is warranted in patients with known hypercalcemia or those receiving 
therapy with digitalis or thiazide diuretics.  
 
Adverse Event 
Grade 
Duration of Toxicity 
Persistent (present at  
start of next cycle) 
1 – 7 days 
> 7 days 
Grade 1 
No Change 
No Change 
Maintain dose level 
Grade 2 
No Change 
No Change 
Reduce 65mg/m2 
Grade 3 
No Change 
Reduce 65mg/m2 
Discontinue oxaliplatin 
Grade 4 
Discontinue oxaliplatin 
Discontinue oxaliplatin 
Pharyngolaryngeal 
dysesthesia 
Hold infusion and observe the patient. Check oxygen saturation; if normal, an 
anxiolytic agent may be given. May restart at a slower. Increase duration of 
infusion to 6 hours for subsequent cycles. 


 
PROTOCOL DATE: 2012-MAY-03 
 
NCIC CTG TRIAL: IND.210 
 
 
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AMEND #1: 2013-APR-25; AMEND #2: 2013-JUN-26;ADMIN UPDATE #1: 2014-MAY-23 (withdrawn);  
 
AMEND #3: 2014-JUN-16; AMEND #4: 2014-NOV-17 
Dose Reductions for Other Hematological and Non-Hematological Toxicity (All Agents) 
Worst toxicity with previous cycle or 
during therapy 
FOLFOX6 * 
Bevacizumab 
Reolysin 
Grade 4 ANC ≥ 7 days  
or > G3 platelets 
Hold until recovery * 
and reduce by 1 DL 
** 
** 
Febrile neutropenia or  
thrombocytopenic bleeding 
Hold until recovery * 
and reduce by 1 DL 
** 
** 
Delay in next cycle by 2-3 weeks ***  
or 2 x 1 week delays 
Hold until recovery * 
and reduce by 1 DL 
** 
** 
Other grade 3 non-hematologic or 
intolerable grade 2 toxicity related to 
FOLFOX6 
Hold until recovery * 
reduce by one DL 
** 
** 
Gastrointestinal perforation or wound 
dehiscence requiring medical 
intervention, arterial or venous 
thromboemboli 
Hold until recovery*. 
Consider discontinuing 
if grade 4. 
Discontinue 
Hold until 
recovery 
Grade 3 or 4 skin toxicity 
Hold until recovery  
and reduce fluorouracil 
by 1 DL * 
** 
** 
Grade 3 or 4 Hypersensitivity 
Discontinue causal agent 
** 
** 
Pneumonitis, RPLS 
Discontinue 
Discontinue 
** 
Other grade 4 non-hematologic 
Discontinue 
Discontinue 
Discontinue 
*  
Do not retreat until the ANC is > 1.5 x 109/L, the platelet count is > 75 x 109/L, creatinine has 
returned to ≤ 1.5 x ULN and other non-hematologic toxicity < grade 2.  
** Hold start of next cycle until able to receive FOLFOX; no dose modification required 
*** Discontinue if delay > 3 weeks 
 
8.2 
Duration of Therapy 
 
Treatment will continue until the criteria for removal from protocol treatment have been met (see 
Section 12.0). 
 
8.3 
Concomitant Therapy 
 
8.3.1 
Permitted 
• 
Other supportive and palliative care (e.g. pain control) as required throughout the study.  
• 
Growth factors may be used according to centre policy but cannot be used in place of 
protocol defined dose adjustments or delays. Please consult NCIC CTG in the case of patients 
experiencing multiple delays as exceptions may be made for patients who are benefiting from 
protocol therapy.. 
• 
Anti-emetics or anti-diarrheal agents as required (see section 8.1.2). 
• 
APAP (acetaminophen) may be used for the prophylaxis or treatment of the flu-like signs and 
symptoms especially fever, that are commonly associated with reolysin as described in 
section 8.1.2. Given that there are more than 600 products that contain APAP, it is also 
essential that patients be warned NOT to use other products containing APAP. 


 
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AMEND #4: 2014-NOV-17  
8.3.2 
Not permitted 
• 
Other anti-cancer therapy or investigational therapy. 
• 
The use of NSAIDs should be avoided by patients with symptoms or risk factors for renal 
dysfunction and those with fever, dehydration, or prior to administration of contrast agents 
used in imaging. 


 
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AMEND #1: 2013-APR-25; AMEND #2: 2013-JUN-26; ADMIN UPDATE #1: 2014-MAY-23 (withdrawn);  
 
AMEND #3: 2014-JUN-16; AMEND #4: 2014-NOV-17 
9.0 
EVALUATION DURING AND AFTER PROTOCOL TREATMENT 
 
All patients entered on study must be evaluated according to the schedule outlined in Appendix I 
with documentation submitted according to the schedule in Appendix IV. 
 
9.1 
Evaluation During Protocol Treatment 
 
Investigations 
Timing 
Physical Exam** 
including: 
• 
history 
• 
weight 
• 
ECOG performance status  
• 
clinical tumour measurements 
• 
blood pressure 
• 
heart rate (pulse) 
Day 1 each cycle* 
Hematology** 
• 
CBC, differential, platelets 
Weekly for cycle 1 and 2 and then day 1 
each cycle and as clinically indicated 
Biochemistry** 
• 
serum creatinine 
• 
bilirubin  
• 
alkaline phosphatase 
• 
AST, ALT  
• 
LDH  
• 
total protein 
Weekly for cycle 1 and 2, then day 1 
each cycle and as clinically indicated 
• 
CEA 
End of every second cycle (every 4 weeks) 
Radiology*** 
• 
chest CT 
• 
abdominal/pelvic CT 
• 
other scans as necessary to follow 
known disease  
Every 8 weeks**** 
Other 
Investigations** 
• 
urinalysis  
Day 1 each cycle and as clinically indicated 
Correlative 
Studies 
• 
Blood samples for correlative 
studies 
End of cycle 2 and at  
end of last cycle 
Quality of Life** 
• 
EORTC QLQ-C30 
Day 1 cycle 5 and at off treatment 
Adverse Events Patients must be evaluated continuously for adverse events 
* 
Physical exam must be conducted by physician on participant list prior to reolysin contained cycles. For 
FOLFOX/bevacizumab cycles only, physical exam may be delegated according to centre policy. Person evaluating 
patients  per protocol must be delegated that responsibility by PI and be on the participants list. 
** 
Timing of Day 1 Assessments: Pre-treatment blood draws, physical exams, urinalysis and QoL may be done one 
working day prior to treatment if necessary (e.g. Friday for treatment on Monday, or to accommodate holidays). 
NOTE: labs do NOT need to be repeated on day 1 cycle 1. 
*** 
To ensure comparability, baseline X-rays/CT/MRI/bone scans and subsequent X-rays/CT/MRI bone scans to assess 
response must be performed using identical technique (i.e. scans performed immediately following bolus contrast 
administration using a standard volume of contrast, the identical contrast agent, and preferably the same scanner).  
**** Maintain schedule even if cycles are delayed. 
 
Initial screening may be done by dipstick. If protein ≥ grade 2, 24 hour urine collection and urine microscopy is 
mandatory. A urine specimen should be taken and frozen for virus shedding studies (contact NCIC CTG for 
instructions) 
 
Samples for correlative studies (blood, serum, plasma) required for ALL patients. See Section 17.0 and the Lab 
Manual for details. 
 
Adverse events will be recorded and graded according to the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) (Appendix V). 
 Day 8 Cycle 1 and 2 only: bilirubin, ALP, AST, ALT, LDH. 


 
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AMEND #1: 2013-APR-25; ADMIN UPDATE #1: 2014-MAY-23 (withdrawn); AMEND #3: 2014-JUN-16; 
 
AMEND #4: 2014-NOV-17 
9.2 
Evaluation After Protocol Treatment 
 
All patients will be seen at 4 weeks after the end of last cycle date. Thereafter, continued follow-
up is not required for patients who go off protocol treatment with progressive disease, except to 
document ongoing toxicities (until resolved to < grade 2) and late toxicities (including second 
malignancies) and death. For patients who go off protocol treatment before progression is 
documented OR have objective CR, PR, or SD ongoing, follow-up and a Follow-Up Report will 
be required every 3 months until relapse/progression (see Appendix I for investigations to be 
performed). Death Report will be required for all patients. Due within 2 weeks of knowledge of 
death (see Appendix IV - Documentation for Study). 
 
Investigations 
Timing 
History and 
Physical Exam: 
• 
Blood pressure 
• 
ECOG performance status 
• 
tumour assessment 
(including clinical tumour 
measurement if applicable) 
Four weeks after completion of protocol treatment 
Laboratory 
Investigations 
• 
CBC, differential, platelets 
• 
serum creatinine 
• 
bilirubin  
• 
alkaline phosphatase 
• 
AST and ALT 
• 
LDH 
• 
total protein  
• 
urinalysis* 
Four weeks after completion of protocol treatment 
Every three months thereafter only if ongoing protocol 
related toxicity until resolved to < grade 2 
• 
CEA 
Four weeks after completion of protocol therapy  
Every three months thereafter until relapse/PD; ONLY 
for patients with CR, PR, or SD ongoing   
Correlative 
Studies 
• Blood sample 
Four weeks after completion of protocol therapy if 
not done at off treatment 
Radiology** 
• 
as required to follow 
measureable disease, and 
as clinically indicated  
Every three months thereafter until relapse/PD;. ONLY 
for patients with CR, PR, or SD ongoing 
Quality of Life 
• 
EORTC QLQ-C30 
At four week evaluation if not completed at off 
treatment 
Adverse Events 
AEs graded according to the 
CTCAE (Appendix V) 
Four weeks after completion of protocol treatment (See 
Appendix IV) 
Every three months thereafter only if ongoing protocol 
related toxicity until resolved to < grade 2 
* 
Initial screening may be done by dipstick. If protein ≥ grade 2, 24 hour urine collection and urine microscopy is 
mandatory. A urine specimen should be taken and frozen for virus shedding studies (contact NCIC CTG for 
instructions). 
** To ensure comparability, baseline X-ray/CT/MRI bone scan and subsequent X-ray/CT/MRI/bone scan to assess 
response must be performed using identical technique (i.e. scans performed immediately following bolus contrast 
administration using a standard volume of contrast, the identical contrast agent, and preferably the same scanner). 
Either CT or MRI may be used for baseline and subsequent imaging, but the same imaging modality must be used 
for baseline and subsequent scans for each individual patient. 


 
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AMEND #1: 2013-APR-25 
10.0 
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS 
 
10.1 
Definitions 
 
10.1.1 Evaluable for Toxicity 
 
All patients will be evaluable for toxicity from the time of their first treatment with reolysin or 
FOLFOX6/bevacizumab. 
 
10.1.2 Evaluable for RECIST Response 
 
All patients with measurable disease at baseline who have had their disease re-evaluated will be 
considered evaluable for response. Patients on therapy for at least this period and who meet the 
other listed criteria will have their response classified according to the definitions set out below 
[Eisenhauer 2009]. Patients should have response evaluations performed at least once while on study 
or within 4 weeks of last dose. 
 
In some trials, late responses (i.e. after 6-8 cycles) have been observed. 
 
10.1.3 Evaluable for Quality of Life Response 
 
All patients who have completed the baseline questionnaire and at least one subsequent time point 
will be evaluable. 
 
10.2 
Objective Response and Evaluation Endpoints 
 
Response and progression will be evaluated in this study using the revised international criteria 
(1.1) proposed by the RECIST (Response Evaluation Criteria in Solid Tumours) committee.  
 
10.2.1 Measurable Disease 
 
Measurable tumour lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as > 20 mm with chest x-ray and as > 10 mm with 
CT scan or clinical examination. Bone lesions are considered measurable only if assessed by CT 
scan and have an identifiable soft tissue component that meets these requirements (soft tissue 
component > 10 mm by CT scan). Malignant lymph nodes must be > 15 mm in the short axis to 
be considered measurable; only the short axis will be measured and followed. All tumour 
measurements must be recorded in millimetres (or decimal fractions of centimetres). Previously 
irradiated lesions are not considered measurable unless progression has been documented in the 
lesion.  
 
10.2.2 Non-measurable Disease 
 
All other lesions (or sites of disease), including small lesions are considered non-measurable 
disease. Bone lesions without a measurable soft tissue component, leptomeningeal disease, 
ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, 
lymphangitic involvement of lung or skin and abdominal masses followed by clinical 
examination are all non-measurable. Lesions in previously irradiated areas are non-measurable, 
unless progression has been demonstrated.  


 
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AMEND #1: 2013-APR-25 
10.2.3 Target Lesions 
 
When more than one measurable tumour lesion is present at baseline all lesions up to a maximum 
of 5 lesions total (and a maximum of 2 lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. Note that pathological nodes must meet the criterion of a 
short axis of ≥ 15 mm by CT scan and only the short axis of these nodes will contribute to the 
baseline sum. All other pathological nodes (those with short axis ≥ 10 mm but <15 mm) should 
be considered non-target lesions. Nodes that have a short axis < 10 mm are considered non-
pathological and should not be recorded or followed (see 10.2.4). At baseline, the sum of the 
target lesions (longest diameter of tumour lesions plus short axis of lymph nodes: overall 
maximum of 5) is to be recorded.  
 
After baseline, a value should be provided on the CRF for all identified target lesions for each 
assessment, even if very small. If extremely small and faint lesions cannot be accurately 
measured but are deemed to be present, a default value of 5 mm may be used. If lesions are too 
small to measure and indeed are believed to be absent, a default value of 0 mm may be used.  
 
10.2.4 Non-target Lesions 
 
All non-measurable lesions (or sites of disease) plus any measurable lesions over and above those 
listed as target lesions are considered non-target lesions. Measurements are not required but these 
lesions should be noted at baseline and should be followed as “present” or “absent”.  
 
10.2.5 Objective (RECIST 1.1) Response Definition 
 
All patients will have their BEST RESPONSE from the start of study treatment until the end of 
treatment classified as outlined below:  
 
Complete Response (CR): disappearance of target and non-target lesions and normalization of 
tumour markers. Pathological lymph nodes must have short axis measures < 10mm (Note: 
continue to record the measurement even if < 10mm and considered CR). Residual lesions (other 
than nodes < 10mm) thought to be non-malignant should be further investigated (by cytology or 
imaging) before CR can be accepted. Confirmation of response is not required.  
 
Partial Response (PR): at least a 30% decrease in the sum of measures (longest diameter for 
tumour lesions and short axis measure for nodes) of target lesions, taking as reference the 
baseline sum of diameters. Non target lesions must be non-PD. Confirmation of response is not 
required.  
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD taking as reference the smallest sum of diameters on study. Minimum duration of 
stable disease is 4 weeks.  
 


 
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AMEND #1: 2013-APR-25 
Progressive Disease (PD): at least a 20% increase in the sum of diameters of measured lesions 
taking as reference the smallest sum of diameters recorded on study (including baseline) AND an 
absolute increase of ≥ 5mm. Appearance of new lesions will also constitute progressive disease 
(including lesions in previously unassessed areas). In exceptional circumstances, unequivocal 
progression of non-target disease may be accepted as evidence of disease progression, where the 
overall tumour burden has increased sufficiently to merit discontinuation of treatment or where 
the tumour burden appears to have increased by at least 73% in volume. Modest increases in the 
size of one or more non-target lesions are NOT considered unequivocal progression. If the 
evidence of PD is equivocal (target or non-target), treatment may continue until the next 
assessment, but if confirmed, the earlier date must be used.  
 
Table:  Time Point response: Integration of Target, Non-Target and New lesions into response 
assessment:  
 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
at this time point 
Target lesions ± non target lesions  
 
 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not all evaluated 
No 
PR 
PR 
Non-PD/ not all evaluated 
No 
PR 
SD 
Non-PD/ not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Any 
PD 
Any 
PD 
Any 
PD 
Any 
Any 
Yes 
PD 
Non target lesions ONLY 
 
 
 
No Target 
CR 
No 
CR 
No Target 
Non-CR/non-PD 
No 
Non-CR/non-PD 
No Target 
Not all evaluated 
No 
NE 
No Target 
Unequivocal PD 
Any 
PD 
No Target 
Any 
Yes 
PD 
Note:  Patients with a global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be reported as “symptomatic deterioration”. This is a 
reason for stopping therapy, but is NOT objective PD. Every effort should be made to document the objective 
progression even after discontinuation of treatment.  
 
Best Response:  
In this trial confirmation of response is NOT required.  
 


 
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10.2.6 Response Duration 
 
Response duration will be measured from the time measurement criteria for CR/PR (whichever is 
first recorded) are first met until the first date that recurrent or progressive disease is objectively 
documented, taking as reference the smallest measurements recorded on study (including 
baseline).  
 
10.2.7 Stable Disease Duration 
 
Stable disease duration will be measured from the time of start of treatment until the criteria for 
progression are met, taking as reference the smallest sum on study (including baseline).  


 
PROTOCOL DATE: 2012-MAY-03 
 
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AMEND #1: 2013-APR-25 
11.0 
SERIOUS ADVERSE EVENT REPORTING 
 
The descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) will be utilized for Adverse Event (AE) reporting (version can be found in 
Appendix V). All appropriate treatment areas should have access to a copy of the CTCAE. A 
copy of the CTCAE can be downloaded from the CTEP web site: 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
 
All serious adverse events (SAE) defined as per ICH guidelines (see below) and other adverse 
events must be recorded on case report forms. In addition, all “reportable” serious adverse events 
are subject to expedited reporting using the NCIC CTG SAE form. The term ‘reportable SAE’ is 
used in the definitions which follow to describe those SAEs which are subject to expedited 
reporting to NCIC CTG.  
 
11.1 
Definition of a Reportable Serious Adverse Event 
 
• 
All serious adverse events related to protocol treatment (reolysin and/or folfox/bevacizumab) 
regardless of whether they are unexpected or not, occurring during the treatment period and 
within 30 days after the last protocol treatment administration, must be reported in an 
expedited manner. Any late serious adverse event occurring after this 30-day period which is 
unexpected and related to protocol treatment must also be reported in an expedited manner 
(see Section 11.2 for reporting instructions). 
• 
A serious adverse event (SAE) is any adverse event that at any dose: 
− 
results in death 
− 
is life-threatening 
− 
requires inpatient hospitalization or prolongation of existing hospitalization (excluding 
hospital admissions for study drug administration, transfusional support, scheduled 
elective surgery and admissions for palliative or terminal care) 
− 
results in persistent or significant disability or incapacity 
− 
is a congenital anomaly/birth defect 
 
Medical and scientific judgement 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 events listed above. 
 
11.2 
Serious Adverse Event Reporting Instructions 
 
All reportable serious adverse events must be reported using a web-based Electronic Data 
Capture (EDC) system being used for this trial. For details about accessing the EDC system and 
completing the on-line SAE report form, please refer to the NCIC CTG Generic Data 
Management Guidebook for SAE Reporting posted on the IND. 210 section of the NCIC CTG 
website (www.ctg.queensu.ca). 
 
Within 24 hours: 
Complete preliminary Serious Adverse Event Report and submit to 
NCIC CTG via EDC system. 
 
Within 7 days: 
Update Serious Adverse Event Report as much as possible and submit 
report to NCIC CTG via EDC system. 


 
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AMEND #1: 2013-APR-25; ADMIN UPDATE #1: 2014-MAY-23 (withdrawn); AMEND #3: 2014-JUN-16 
EDC SAE web application interruption: 
In the rare event that internet connectivity to the EDC SAE system is disrupted, please print and 
complete a paper copy of the SAE Report, available from the trial specific website. 
 
FAX paper SAE Report to: 
 
Ashley Theis, Study Coordinator 
NCIC Clinical Trials Group 
Fax No.: 613-533-2411 
 
Please use the same timelines for submission as for direct EDC reporting. 
 
Once internet connectivity is restored, the information that was FAXED to NCIC CTG on the 
paper SAE Report must also be entered by the site into the EDC SAE web application.  
 
Local internet interruption: 
If you are unable to access the EDC SAE system, and cannot access a paper copy of the SAE 
Report from the trial website, please phone the IND trial team (613-533-6430) to obtain a copy of 
the SAE Report by FAX. Once completed, the report must be FAXED back to NCIC CTG as 
indicated above. Once internet connectivity is restored, the information that was FAXED to 
NCIC CTG on the paper SAE Report must also be entered by the site into the EDC SAE web 
application.  
 
In cases of prolonged internet interruptions, please contact the NCIC CTG Safety Desk for further 
instructions (613-533-6430).  
 
11.3 
NCIC CTG Responsibility for Reporting Serious Adverse Events to Health Canada 
 
The NCIC CTG will provide expedited reports of SAEs to Health Canada (Office of Clinical 
Trials and the Biologics and Genetics Therapies Directorate) for those events which meet 
regulatory requirements for expedited reporting, i.e. events which are BOTH serious AND 
unexpected, AND which are thought to be related to protocol treatment (or for which a causal 
relationship with protocol treatment cannot be ruled out). 
 
11.4 
NCIC CTG Reporting Responsibility to Oncolytics Biotech Inc. 
 
Oncolytics Biotech Inc. will be notified of all serious adverse events reported to Health Canada. 
NCIC CTG as sponsor will determine regulatory reportability in Canada.  
 
11.5 
NCIC CTG and Oncolytics Biotech Inc. Reporting Responsibilities 
 
Oncolytics Biotech Inc. will report all reolysin regulatory reportable serious adverse events from 
non-NCIC CTG trials (Safety Updates) to Health Canada and also provide to NCIC CTG within 
the timelines outlined in the contract. NCIC CTG will review these events to determine which 
meet the criteria (serious, unexpected, drug related) for IND.210 investigator distribution.  
 


 
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11.6 
Reporting Safety Reports to Investigators 
 
NCIC CTG will notify Investigators of all Safety Reports (Serious Adverse Events (SAEs) from 
this trial and Safety Updates (SUs) from other clinical trials) that are reportable to regulatory 
authorities in Canada as reported to the NCIC CTG. This includes all serious events that are 
unexpected and related (i.e. possibly, probably, or definitely) to protocol treatment. The reports 
will be posted to the NCIC CTG trial IND.210 web-based safety monitoring utility. 
 
Investigators must notify their Research Ethics Boards (REBs) of events which involve corrective 
action(s) to be taken as a result of the event(s) such as protocol and/or informed consent changes. 
The date of REB Submission for these SAEs and SUs will need to be entered into the NCIC CTG 
trial IND.210 web based safety monitoring utility and documentation of REB submission must be 
retained in the study binder on site. The REB submission template provided by NCIC CTG can 
be used to assist with tracking, submission, filing and monitoring. 
 
The submission of events to your ethics board should be done as soon as possible (we suggest 
within 30 days). REB submissions greater than 90 days from the date of notification will be 
regarded as delinquent and a major deficiency will be assigned. These safety reports are to be 
filed in the trial files on site. 


 
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AMEND #1: 2013-APR-25; ADMIN UPDATE #1: 2014-MAY-23 (withdrawn); AMEND #3: 2014-JUN-16 
12.0 
PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING 
 
12.1 
Criteria for Discontinuing Protocol Treatment 
 
Patients may stop protocol treatment in the following instances: 
• 
Intercurrent illness, which would, in the judgement of the investigator, affect assessments of 
clinical status to a significant degree, and require discontinuation of protocol therapy. 
• 
Unacceptable toxicity as defined in Section 8.0. 
• 
Objective tumour progression or disease recurrence as defined in section 10. 
• 
Request by the patient. 
• 
Completion of therapy as outlined below. Efforts should be made to maintain the 
investigations schedule and continue follow-up, even if patients discontinue protocol 
treatment prematurely and/or no longer attend the participating institution. 
 
12.2 
Duration of Protocol Treatment  
(see Section 10.0 for response definition) 
• 
In the absence of serious or unmanageable toxicity or disease progression, patients may 
continue on therapy. 
• 
Patients randomized to the FOLFOX6/bevacizumab/reolysin arm may continue on 
FOLFOX6/ bevacizumab or reolysin, if the other component of protocol treatment was 
discontinued due to unacceptable toxicity, at the discretion of the investigator; cross over is 
not permitted. Patients who continue treatment with either FOLFOX/Bevacizumab or 
reolysin are considered on study and all evaluations and data submission are required as 
outlined in sections 9.1 and Appendix IV unless otherwise discussed with the Senior 
Investigator. 
 
12.3 
Therapy After Protocol Treatment is Stopped 
 
Further treatment, if any, is at the discretion of the investigator.  
 
12.4 
Follow-up Off Protocol Treatment 
 
All patients will be seen at 4 weeks after completion of protocol therapy. Thereafter, continued 
follow-up is not required for patients who go off protocol treatment with progressive disease, 
except to document ongoing toxicities (until resolved to < grade 2) and late toxicities (including 
second malignancies) and death. For patients who go off protocol treatment before progression is 
documented OR have objective CR, PR, or SD ongoing, follow-up and a Follow-Up Report will 
be required every 3 months until relapse/progression (see Appendix I for investigations to be 
performed). If the patient starts new anticancer therapy, contact the study coordinator to discuss 
whether further follow-up is required. Death Report will be required for all patients. Due within 2 
weeks of knowledge of death (see Appendix IV - Documentation for Study). 


 
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13.0 
CENTRAL REVIEW PROCEDURES AND TISSUE COLLECTION 
 
13.1 
Central Radiology Review 
 
At the conclusion of the trial, a central review of scans may be carried out if any responses have 
been claimed. For purposes of reporting, the results of both local and central radiology reviews 
will be included. 
 
13.2 
Central Pathology Review 
 
There will be no central pathology review for this study. 
 
13.3 
Tissue Collection 
 
Archival tissue samples will be collected on all patients for correlative studies. See Section 17.0 
for complete details. 


 
PROTOCOL DATE: 2012-MAY-03 
 
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AMEND #1: 2013-APR-25; AMEND #5: 2015-DEC-07 
14.0 
STATISTICAL CONSIDERATIONS 
 
14.1 
Objectives and Design 
 
This is an open label multicentre randomized phase II trial to determine the anti-tumour activity 
of reolysin in patients with colorectal cancer. 
 
The expected progression free survival for FOLFOX6/bevacizumab is 8.5 months. The clinical 
trial will accrue up to 100 evaluable patients (50 per arm). Patients will have an equal probability 
of receiving reolysin plus FOLFOX6/bevacizumab or FOLFOX6/bevacizumab alone. Six to 9 
additional patients will be accrued in a safety run in to evaluate the safety and tolerability of the 
combination. 
 
Patients will be stratified for the following factors 
• 
KRAS mutation status (if known at the time of randomization – if unknown will be corrected 
for at the time of the primary analysis) 
• 
prior adjuvant chemotherapy 
 
14.2 
Primary Endpoints and Analysis 
 
The primary objective of the study is progression free survival (progression is defined in Section 
10). Secondary endpoints include evaluation of:  
• 
Changes in CEA levels 
• 
Objective response rate  
• 
The effect of both treatments on overall survival (OS)  
• 
Potential prognostic or predictive molecular factors by assessment of archival tumour tissue 
or blood samples. 
• 
Quality of Life 
 
14.3 
Sample Size and Duration of Study 
 
Accrual and Analysis:  
The clinical trial will accrue up to 100 evaluable patients (50 per arm) in around 13 months. Final 
analysis will be performed when 50 PFS events are observed, which is projected at the time after 
all patients are followed for at least 6 months. One-sided log-rank test adjusting for stratification 
factors at randomization will be used the compare the PFS between two treatment groups.  
 
Since the survival data was immature at the time of the primary analysis, an additional analysis 
with a focus on overall survival will be performed when 80 deaths are observed. 
 
Significance Level and Power:  
The expected progression free survival for FOLFOX6/bevacizumab is 8.5 months. With a total 
sample size of 100 accrued in around 13 months and followed for 6 months, we will have 80% 
power to detect a difference between two treatment groups in PFS from 8.5 to 15.5 months (i.e. 
hazard ratio of 0.55) with a one-sided alpha 0.1.  
 
The number of deaths (80) required for the final analysis of OS will enable us to detect a hazard 
ratio of 0.62 with 80% power and a one-sided 0.1 alpha level which is corresponding to an 
increase of median survival from 15 months for patients on FOLFOX6/bevacizumab to 24.2 
months for patients on reolysin plus FOLFOX6/bevacizumab. 


 
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AMEND #5: 2015-DEC-07 
Accrual and Duration of Study:  
The estimated monthly accrual for this study is 8 patients a month. Thus, patient accrual is 
expected to be completed within 13 months. Additional 6 months is required to allow the PFS 
data to mature. 
 
The estimated event rate of survival is around 3 per month and therefore, 6 to 8 more months of 
follow-up would be required to observe number of events required for final analysis of survival. 
 
14.4 
Safety Monitoring 
 
Adverse events will be monitored on an ongoing basis by the central office and their frequencies 
reported annually at investigators' meetings. 
 
14.5 
Quality of Life 
 
The quality of life of patients will be assessed using EORTC QLQ-C30. The EORTC QLQ-C30 
is a self-administered cancer specific questionnaire with multi-dimensional scales. It consists of 
both multi-item scales and single item measures, including five functional domains, a global 
quality of life domain, three symptom domains, and six single items. Questionnaire compliance 
rates will be ascertained for each group at each measurement time point. Scoring of the EORTC 
QLQ-C30 data will be completed following the procedures recommended by the EORTC Study 
Group on Quality of Life. For each domain or single item measure a linear transformation will be 
applied to standardize the raw score to range between 0 and 100 and the mean and standard 
deviation of the baseline scores and changes from baseline at each of post-baseline assessments 
will be calculated. The Wilcoxon test will be used to compare the differences in change scores 
from baseline between the two groups.  Time to definitive quality of life deterioration, defined a 
priori as a 10 unit or greater deterioration from baseline scores, for EORTC QLQ-C30 physical 
function and global QoL scores will be the primary analyses for quality of life and analysed by 
log-rank test and Kaplan-Meier methodology. The Hockberg procedure will be used to adjust for 
multiple testing [Hochberg 1988]. It has been shown that 10 unit change is a degree of change that is 
perceptible and meaningful to patients [Osoba 1998]. The standard NCIC CTG QOL Response 
Analysis categorizing patients as either having improved, stable, or worsened QOL will also be 
performed [Osoba 2005].  In this analysis, a change score of 10 points from baseline is defined a 
priori as clinically relevant. For functional scales and global health status, patients will be 
considered to have QOL improvement if reporting a score 10- points or better than baseline at any 
time of QOL assessment. Conversely, patients will be considered worsened if reporting a score 
minus 10-points or worse than baseline at any time of QOL assessment without any 
improvement. Patients whose scores fall between 10-point changes from baseline at every QOL 
assessment will be considered as stable. In contrast to functional scales, for the determination of 
patient’s QOL response, classification of patients into improved and worsened categories will be 
reversed for symptom scales. Other exploratory QoL evaluations will be completed as 
appropriate.  
 


 
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ADMIN UPDATE #1: 2014-MAY-23 (withdrawn); AMEND #3: 2014-JUN-16 
15.0 
PUBLICATION POLICY 
 
15.1 
Authorship of Papers, Meeting Abstracts, Etc 
 
15.1.1 The results of this study will be published. Prior to trial activation, the chair will decide whether 
to publish the trial under a group title, or with naming of individual authors. If the latter approach 
is taken, the following rules will apply: 
• 
The first author will generally be the chair of the study. 
• 
A limited number of the members of the NCIC Clinical Trials Group and Oncolytics Biotech 
Inc., may be credited as authors depending upon their level of involvement in the study. 
• 
Additional authors, up to a maximum of 15, will be those who have made the most significant 
contribution to the overall success of the study. This contribution will be assessed, in part but 
not entirely, in terms of patients enrolled and will be reviewed at the end of the trial by the 
study chair. 
 
15.1.2 In an appropriate footnote, or at the end of the article, the following statement will be made: 
 
"A study coordinated by the NCIC Clinical Trials Group. Participating 
investigators included: (a list of the individuals who have contributed 
patients and their institutions)." 
 
15.2 
Responsibility for Publication 
 
It will be the responsibility of the Study Chair to write up the results of the study within a 
reasonable time of its completion. If after a period of six months following study closure the 
manuscript has not been submitted, the central office reserves the right to make other 
arrangements to ensure timely publication. 
 
Dissemination of Trial Results 
NCIC CTG will inform participating investigators of the primary publication of this trial. The 
complete journal reference and, if where publicly available, the direct link to the article will be 
posted on the Clinical Trial Results public site of the NCIC CTG web site 
(http://www.ctg.queensu.ca). 
 
15.3 
Submission of Material for Presentation or Publication 
 
Material may not be submitted for presentation or publication without prior review by Oncolytics 
Biotech Inc., the NCIC CTG Senior Investigator, Senior Biostatistician, Study Coordinator, and 
approval of the Study Chair. Individual participating centres may not present outcome results 
from their own centres separately. Supporting groups and agencies will be acknowledged. 
 


 
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16.0 
ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES 
 
16.1 
Regulatory Considerations 
 
All institutions in Canada must conduct this trial in accordance with International Conference on 
Harmonization-Good Clinical Practice (ICH-GCP) Guidelines. 
 
This trial is being conducted under a Clinical Trial Application (CTA) with Health Canada. As a 
result, the conduct of this trial must comply with Division 5 of the Canadian Regulations 
Respecting Food and Drugs (Food and Drugs Act). 
 
16.2 
Inclusivity in Research 
 
NCIC CTG does not exclude individuals from participation in clinical trials on the basis of 
attributes such as culture, religion, race, national or ethnic origin, colour, mental or physical 
disability (except incapacity), sexual orientation, sex/gender, occupation, ethnicity, income, or 
criminal record, unless there is a valid reason (i.e. safety) for the exclusion.  
 
In accordance with the Declaration of Helsinki and the Tri-Council Policy Statement (TCPS), it is 
the policy of NCIC CTG that vulnerable persons or groups will not be automatically excluded 
from a clinical trial (except for incompetent persons) if participation in the trial may benefit the 
patient or a group to which the person belongs.  
 
However, extra protections may be necessary for vulnerable persons or groups. It is the 
responsibility of the local investigator and research ethics board (REB) to ensure that appropriate 
mechanisms are in place to protect vulnerable persons/groups. In accordance with TCPS, 
researchers and REBs should provide special protections for those who are vulnerable to abuse, 
exploitation or discrimination. As vulnerable populations may be susceptible to coercion or undue 
influence, it is especially important that informed consent be obtained appropriately.  
 
Centres are expected to ensure compliance with local REB or institutional policy regarding 
participation of vulnerable persons/groups. For example, if a vulnerable person/group would be 
eligible for participation in a NCIC CTG clinical trial under this policy but excluded by local 
policy, it is expected that they would not be enrolled in the trial. It is the centre’s responsibility to 
ensure compliance with all local SOPs.  
 
It is NCIC CTG’s policy that persons who cannot give informed consent (i.e. mentally 
incompetent persons, or those physically incapacitated such as comatose persons) are not to be 
recruited into NCIC CTG studies. It is the responsibility of the local investigator to determine the 
subject’s competency, in accordance with applicable local policies and in conjunction with the 
local REB (if applicable).  
 
Subjects who were competent at the time of enrolment in the clinical trial but become 
incompetent during their participation do not automatically have to be removed from the study. 
When re-consent of the patient is required, investigators must follow applicable local policies 
when determining if it is acceptable for a substitute decision maker to be used. NCIC CTG will 
accept re-consent from a substitute decision maker. If this patient subsequently regains capacity, 
the patient should be re-consented as a condition of continuing participation.  
 


 
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16.3 
Obtaining Informed Consent 
 
It is expected that consent will be appropriately obtained for each participant/potential participant 
in an NCIC CTG trial, in accordance with ICH-GCP section 4.8. The centre is responsible for 
ensuring that all local policies are followed. 
 
Additionally, in accordance with GCP 4.8.2, NCIC CTG may require that participants/potential 
participants be informed of any new information may impact a participant’s/potential 
participant’s willingness to participate in the study.  
 
Based upon applicable guidelines and regulations (Declaration of Helsinki, ICH-GCP), a 
participating investigator (as defined on the participants list) is ultimately responsible, in terms of 
liability and compliance, for ensuring informed consent has been appropriately obtained. NCIC 
CTG recognizes that in many centres other personnel (as designated on the participants list) also 
play an important role in this process. In accordance with GCP 4.8.5, it is acceptable for the 
Principal Investigator to delegate the responsibility for conducting the consent discussion. 
 
NCIC CTG requires that each participant sign a consent form prior to their enrollment in the 
study to document his/her willingness to take part. NCIC CTG may also require, as indicated 
above, that participants/potential participants be informed of new information if it becomes 
available during the course of the study. In conjunction with GCP 4.8.2, the communication of 
this information should be documented. 
 
NCIC CTG allows the use of translators in obtaining informed consent. Provision of translators is 
the responsibility of the local centre. Centres should follow applicable local policies when 
procuring or using a translator for the purpose of obtaining informed consent to participate in a 
clinical trial.  
 
In accordance with ICH-GCP 4.8.9, if a subject is unable to read then informed consent may be 
obtained by having the consent form read and explained to the subject.  
 
16.4 
Discontinuation of the Trial 
 
If this trial is discontinued for any reason by the NCIC CTG all centres will be notified in writing 
of the discontinuance and the reason(s) why. If the reason(s) for discontinuance involve any 
potential risks to the health of patients participating on the trial or other persons, the NCIC CTG 
will provide this information to centres as well. 
 
If this trial is discontinued at any time by the centre (prior to closure of the trial by the NCIC 
CTG), it is the responsibility of the principal investigator to notify the NCIC CTG of the 
discontinuation and the reason(s) why.  
 
Whether the trial is discontinued by the NCIC CTG or locally by the centre, it is the responsibility 
of the principal investigator to notify the local Research Ethics Board and all clinical trials 
subjects of the discontinuance and any potential risks to the subjects or other persons. 
 
16.5 
Retention of Patient Records and Study Files 
 
All essential documents must be maintained as per C.05.012 and in accordance with ICH-GCP.  


 
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The Principal Investigator must ensure compliance with the Regulations and the GCP Guideline 
from every person involved in the conduct of the clinical trial at the site.  
 
Essential documents must be retained for 25 years following the completion of the trial at the 
centre (25 years post final analysis, last data collected, or closure notification to REB, whichever 
is later), or until notified by NCIC CTG that documents no longer need to be retained.  
 
In accordance with GCP 4.9.7, upon request by the monitor, auditor, REB or regulatory authority, 
the investigator/institution must make all required trial-related records available for direct access.  
 
NCIC CTG will inform the investigator/institution as to when the essential documents no longer 
need to be retained.  
 
16.6 
Centre Performance Monitoring 
 
This study is eligible for inclusion in the Centre Performance Index (CPI). 
 
Forms are to be submitted according to the schedule in the protocol. There are minimum 
standards for performance. 
 
16.7 
On-Site Monitoring/Auditing 
 
NCIC CTG site monitoring/auditing will be conducted at participating centres in the course of the 
study as part of the overall quality assurance program. The monitors/auditors will require access 
to patient medical records to verify the data, as well as essential documents, standard operating 
procedures (including electronic information), ethics and pharmacy documentation (if 
applicable). 
 
As this trial is conducted under a CTA with Health Canada, your site may be subject to an 
inspection by the Health Canada Inspectorate. 
 
Oncolytics Biotech Inc. has reserved the right to audit participating centres. Audits may only be 
conducted after consultation with NCIC CTG. 
 
16.8 
Case Report Forms 
 
A list of forms to be submitted, as well as expectation dates, are to be found in Appendix IV. 
 
This trial will use a web-based Electronic Data Capture (EDC) system for all data collection 
except for Quality of Life. For details of accessing the EDC system and completing the on-line 
Case Report Forms please refer to the “Registration/Randomization and Data Management 
Guidebook” posted on the IND.210 area of the NCIC CTG web-site (www.ctg.queensu.ca). 


 
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AMEND #1: 2013-APR-25; AMEND #2: 2013-JUN-26 
17.0 
TRANSLATIONAL RESEARCH STUDIES  
 
This trial is one of four phase II trials conducted by NCIC CTG with a total of more than 400 
patients planned for accrual and as such will create a rich resource to validate putative biomarkers 
as well as explore discovery of new markers related to the use of biologic therapies for cancer. 
Prognostic biomarkers are of interest, as are biomarkers that may provide evidence of a 
pharmacodynamic effect of reolysin. The identification of predictive markers is an important step 
in allowing patient selection to optimize treatment choices, and ideally would lead to personalized 
and cost effective therapies 
 
 
Tumour* 
Paxgene (DNA)* 
Plasma* 
Serum* 
Baseline 
 
 
 
 
End Cycle 2 
 
 
 
 
Off treatment 
 
 
 
 
Additional samples 
 
 
 
 
* each has mandatory AND optional planned/potential assays 
 
17.1 
Correlative Studies of Archival Paraffin Embedded Tumour Samples– All patients 
 
The collection of a representative block of the diagnostic tumour tissue to enable correlative 
studies is an important part of this trial. Prognostic biomarkers are of interest, as are biomarkers 
that may provide evidence of a pharmacodynamic effect of reolysin. The identification of 
predictive markers is an important step in allowing patient selection to optimize treatment 
choices, and ideally would lead to personalized and cost effective therapies. For this reason, 
collection of a representative tumour block from a biopsy taken prior to study entry, is a 
mandatory part of this study. All additional tumour samples from biopsies that may be taken 
during and/or at end of study should also be submitted. Centres who are unable to submit the 
block immediately MUST consult NCIC CTG prior to randomizing a patient as the routine 
submission of unprepared slides is not acceptable (NCIC CTG will explore whether submission 
of cores, blocks for immediate return, or dipped slides may be an acceptable alternative)  
 
Reovirus depends upon aberrant EGFR/RAS signaling for its replication and cytotoxic activity 
[Thirukkumaran 2009]. Aberrant pathway activation is reported in several malignancies including 
lung, prostate, colon and breast cancers. In the setting of lung cancer (NSCLC), it has been 
demonstrated that selection of patients with KRAS or EGFR mutated/amplified tumors led to a 
clinical benefit rate of 90% for therapy with a Reovirus PLUS paclitaxel/carboplatin combination 
[Villalona-Calero 2011]. Although RAS mutation is not proposed to be an initiating event in the 
malignant evolution of prostate cancer, and observed KRAS mutation rate in primary prostate 
cancer samples is low [Moul 1992], in vivo studies have implicated cross-talk between the 
PTEN/PI3K/AKT pathway and the mitogen activated protein kinase pathway which may 
predispose to reovirus susceptibility [Kinkade 2008]. Furthermore, recent data has shown that ras/raf 
pathway alterations in CRPC metastases (as opposed to primary tissue) were seen in up to 90% of 
cases with a KRAS mutation rate of 32% [Taylor 2010]. While the rationale for reoD in mCRPC is 
predicated on factors outlined above that are independent of the RAS/MEK/ERK pathway, these 
specific observations would support both the evaluation of reovirus in this population and the 
interrogation of KRAS as a potential predictive marker. Further, EGFR alterations are reported in 
30-40% of CRPC samples [de Muga 2010] and so this is another potential predictive marker for 
reovirus therapy in this cohort. In patients with breast cancer, EGFR expression is common, 
although KRAS is mutated in only a minor fraction of breast tumors (5%).  In advanced 
colorectal cancer, KRAS somatic mutations predict resistance to monoclonal antibodies targeting 
epidermal growth factor receptor (EGFR).  


 
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AMEND #1: 2013-APR-25 
Myeloid-derived suppressor cells (MDSCs) expand during cancer, inflammation and infection, 
and suppress T-cell responses. Their presence in the tumor microenvironment has been suggested 
to have a causative role in promoting tumor-associated immune suppression. Preliminary data 
suggest that they may be prognostic. COX2 is a key factor in the activation of MDSC, through 
regulation of arginase 1, iNOS and prostaglandin E2 (PGE2). In an in vivo model of RCC, 
sunitinib decreases MDSC (measured as decrease in splenic MDSC) which was associated with 
an enhanced adaptive anti-tumor response to reolysin (preliminary data from Dr. Morris). In 
ovarian cancer models, treatment with reolysin had antitumor activity and was associated with 
decreased frequency of MDSC [Gujar 2013]. Shojaei et al. reported that accumulation of MDSC 
(CD11b+Gr1+ cells) in tumours renders them refractory to anti-angiogenic blockage by VEGF 
antibodies [Shojael 2007]. We hypothesize that antitumor activity of reolysin will be associated with 
decreased frequency of MDSC and in trials that contain bevacizumab, bevacizumab will decrease 
MDSC and enhance adaptive anti-tumor response to reolysin [Adair 2012]. Quantification of 
MDSCs can be conducted using IHC methods. 
 
Planned studies (mandatory) 
 
1. Assays for Common Tumour Based Mutations. 
 
OncoCarta (Sequenom) mass spectrometry mutation profiling will be performed as a generic 
screen for tissue mutations, including EGFR exons 18, 19, 20 and 21 as well as KRAS 
codons 12, 13 and 61 and Braf.  
 
2. Assays for Copy Number 
 
FISH will be used to evaluate gene copy number for selected genes relevant for the tumour 
type being studied, including EML4-ALK FISH for lung cancer patients and PTEN FISH for 
prostate cancer patients 
 
3. Immunohistochemical assays. 
 
Assays planned include ALK for lung cancer patients and Myeloid Derived Suppressor Cells 
(MDSC) [Gabrilovich 2009].  
 
Future banking (optional) 
 
This trial is one of four phase II trials conducted by NCIC CTG with a total of more than 400 
patients planned for accrual. A pooled tumour bank, from consenting patients will be created and 
other exploratory correlative studies conducted. 
 
Directions 
 
At the same time that the baseline form is submitted, an original tumour block should be sent to 
the NCIC CTG Pathology Coordinator. Centres should contact NCIC CTG if they are unable to 
submit a tumour block, as sufficient tissue is required for the assays described above. Upon 
receipt, the NCIC CTG pathology coordinator will then send appropriate material, along with 
information regarding NCIC CTG protocol number and an assigned unique tumour bank ID 
number to the research laboratory(ies) where these assays will be done.  


 
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AMEND #1: 2013-APR-25 
Ship tumour block along with a copy of the completed Archival Tumour Tissue Submission Form 
to:  
Shakeel Virk 
Pathology Coordinator NCIC Clinical Trials Group  
Richardson Labs Bldg, 4th Floor  
88 Stuart St.  
Queen’s University  
Kingston, ONK7L 3N6 
Tel: 613-533-2906  
Fax: 613-548-2486  
Email: virk@cliff.path.queensu.ca  
 
17.2 
Correlative Studies of  Serum and Plasma Samples – All patients  
 
The NCIC CTG is interested in exploring the use of surrogate tissues such as serum and plasma 
in evaluating potential prognostic or predictive biomarkers, or as evidence of pharmacodynamic 
effects of reolysin. The collection of these samples in these four large phase II trials, with 
matching tissue based biomarkers is an important objective of these trials. Blood, , serum and 
plasma samples will be collected and banked for planned and future studies from all patients. In 
this study, samples will be taken at baseline, end of cycle 2 and at off treatment. 
 
Collection and shipping details will be provided in the Laboratory Manual at start up. 
 
Planned studies (mandatory) 
 
1. KRAS and EGFR mutations 
 
An 8.5 mL blood sample will be drawn at baseline and collected into PAXgene Blood DNA 
tubes. Samples will be batched and shipped to Chi Lab in Vancouver for further analysis. RT-
PCR will be undertaken on isolated DNA to detect the 3 most frequent KRAS (codon 12, 13 
and 61) and EGFR (exons 18 and 21) mutations EntroGen, Tarzana, CA, USA).  
 
2. Serum cytokines, autoimmune/reactive antibodies, anti-viral responses, metabolomics 
 
A growing body of knowledge derived from pre-clinical investigations has strongly 
implicated anti-tumour and anti-viral immune responses as key contributors to the anti-
tumour effects of oncolytic reovirus. Therefore, we will evaluate these parameters using 
serum from patients treated with reolysin. Serological responses (cytokines, antibodies and 
metabolites) provide rich sources of correlative data that can be used to understand the 
biological consequences of this novel therapy and may provide important biomarkers that 
will facilitate future patient management. 
 
Serum will be prepared within 2 hours of phlebotomy and stored at –20 C. At the end of the 
study, sera will be shipped to the Bramson lab on dry ice where they will be subject to a 
variety of analyses. Anti-viral antibodies will be measured using an in vitro neutralizing 
antibody assay. Anti-tumour antibodies will be characterized using a phage-display 
methodology with a phage expression library derived from a collection of human tumors. 
Serum cytokines will be analyzed using the Luminex MAGPIX platform. Finally, metabolic 
changes associated with treatment will be measured in sera using liquid chromatography-
mass spectrometry. 
 
NOTE: It would be preferable to store the materials at –80 C. However, if –80 C freezers are 
not available at all study sites, -20C freezers are acceptable for short-term storage.  


 
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AMEND #1: 2013-APR-25 
Exploratory studies (optional) 
 
1. Evaluation of exosome for potential biomarkers and viral elements  
 
It has been demonstrated that prostate cancer cells secrete exosomes (membrane-bound 
vesicles containing proteins, mRNA and microRNAs derived from the donor cell cytoplasm) 
which can be isolated from the bloodstream. Serum samples will be collected at baseline, end 
of cycle 2 and end of treatment will be batched and shipped to NCIC CTG Tumour Bank. If 
the exosome assays and analyses in the reolysin NCIC CTG Prostate trial (IND.209) are 
promising, similar assays will be performed. Exosomes will be extracted from each sample 
using differential sucrose assisted centrifugation. Exosome abundance will be evaluated by 
Nanosight technology. Exosome content will be determined using Western Blotting, Mass 
Spectroscopy (for protein analysis) and quantitative PCR and micro-arrays (for transcriptome 
analysis). 
 
2. Evaluation of plasma for microRNA as potential biomarkers 
 
Several studies have identified circulating microRNAs (miRNA) as non-invasive markers of 
malignancy. miRNA are small RNA molecules of 21-23 nucleotides that bind with imperfect 
complementarity to sequences in specific mRNA targets and typically silence their expression 
and have been implicated in tumour progression by modulating oncogenic and tumour 
suppressor pathways. In prostate cancer, several circulating miRNAs have been identified as 
having prognostic and predictive potential, including association with development of 
castration resistant disease such as with miR-141, miR-375, and miR-126 [Selth 2012]. This 
study will explore known circulating oncogenic miRNA profiles by low-density PCR arrays 
and correlate with treatment outcomes.  
 
3. Evaluation of plasma or serum  
 
Potential studies include: serum EGFR extracellular domain (ECD), serum HER2 ECD, E-
cadherin ELISAs, TGF-a and HGF. 
 
Please refer to the Correlative Studies Manual for complete instructions. 
 


 
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18.0 
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Maddox JF, et al. Bacterial-and virus-induced inflammation increases sensitivity to acetaminophen 
hepatotoxicity. J Tox and Environm Health Part A, 2010; 73:58-73 
Marcato P, Shmulevitz M, Pan D, Stoltz D, Lee PW. Ras transformation mediates reovirus oncolysis by 
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AMEND #1: 2013-APR-25 
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Wadler S, Yu B, Lane M, Klampfer L, Sasazuki T, Coffey M. The oncolytic reovirus, Reolysin, augments the 
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2010;21:1152-62 


 
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AMEND #1: 2013-APR-25 AMEND #2: 2013-JUN-26; ADMIN UPDATE #1: 2014-MAY-23 (withdrawn);  
 
AMEND #3: 2014-JUN-16; AMEND #4: 2014-NOV-17 
APPENDIX I - PATIENT EVALUATION FLOW SHEET 
 
Required Investigations 
Pre-study 
(within 7 days prior to 
randomization, or as 
noted) 
Day 1 
each 
cycle 
Weekly cycles 
1 and 2 then 
day 1 each 
cycle 
End 
cycle 2 
Day 1 
of 
cycle 
5 
Every 
8 
weeks 
4 Weeks; 
then every 
3 Months until 
Relapse/PD/ death 
History & Physical Exam1 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
 
Performance Status 
X 
X 
 
 
 
 
4 weeks ONLY 
Clinical tumour 
measurements 
X 
 
 
 
 
X 
X  
(if applicable) 
Blood pressure, heart rate 
X 
X 
 
 
 
 
4 weeks ONLY 
Hematology & Biochemistry1 
 
 
 
 
 
 
CBC, differential, platelets 
X 
 
X 
 
 
 
X 
Serum creatinine, bilirubin, 
ALP, AST, ALT, LDH, total 
protein 
X 
X 
X2 
 
 
 
X 
CEA 
X 
 
 
 
 
X3 
X 
Other Investigations 
 
 
 
 
 
 
 
Pregnancy test, in women of 
childbearing potential only 
X 
 
 
 
 
 
 
Urinalysis1 
X4 
X5 
 
 
 
 
X5 
Quality of Life 
X6 
 
 
 
X 
 
X7 
(at off treatment) 
Radiology8 
 
 
 
 
 
 
 
Chest CT 
Abd./ Pelvic CT scan 
Other as clinically indicated 
X 
(within 28 days prior to 
randomization; 35 if 
negative) 
 
 
 
 
X 
X 
Correlative Studies9 
 
 
 
 
 
 
 
Archival tissue block  
(all patients) 
Available prior to 
randomization 
 
 
 
 
 
 
Blood samples  
X 
(AFTER randomization but 
BEFORE cycle 1 day 1)  
 
 
X 
 
 
X 
(at off treatment) 
Adverse Events 
 
 
 
 
 
 
 
Adverse Events/ Baseline 
Symptoms10 
Within 7 days prior to 
randomization 
 
Continuously each visit 
X 
1 
Timing of Day 1 Assessments: Pre-treatment blood draws, physical exams, urinalysis and QoL may be done one working day prior to treatment 
if necessary (e.g. Friday for treatment on Monday, or to accommodate holidays). NOTE: labs do NOT need to be repeated D1C1. 
2 
Biochemistry:  Day 8 cycle 1 and 2 only: bilirubin, ALP, AST, ALT, and LDH. 
3 
CEA must be done end of every second cycle (every 4 weeks). 
4 
 For protein screen using spot testing; if > grade 2 repeat with mid-stream urine - if still > grade 2 then urine collection for 24 hours to confirm 
< 2g/24hrs. 
5 
Initial screening may be done by dipstick. If protein ≥ grade 2, 24 hour urine collection and urine microscopy is mandatory. A urine specimen 
should be taken and frozen for virus shedding studies (contact NCIC CTG for instructions). 
6  
Within 14 days of randomization. 
7 
At 4 week post visit if not done at time off treatment. 
8 
All patients will be seen at 4 weeks. Thereafter, continued follow-up is not required for patients who go off protocol treatment with progressive 
disease, except to document toxicities and death. For patients who go off protocol treatment with CR, PR or SD ongoing, follow-up will be 
required every 3 months until relapse/progression. 
9 
See section 17. 
10 Adverse events will be recorded and graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) (Appendix V). 


 
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APPENDIX II - PERFORMANCE STATUS SCALES/SCORES 
 
PERFORMANCE STATUS CRITERIA 
Karnofsky and Lansky performance scores are intended to be multiples of 10. 
ECOG (Zubrod) 
Karnofsky 
Lansky* 
Score 
Description 
Score 
Description 
Score 
Description 
0 
Fully active, able to carry on all 
pre-disease performance 
without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
100 
Fully active, normal. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
90 
Minor restrictions in physically 
strenuous activity. 
1 
Restricted in physically 
strenuous activity but 
ambulatory and able to carry 
out work of a light or sedentary 
nature, e.g. light housework, 
office work. 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
80 
Active, but tires more quickly. 
70 
Cares for self, unable to carry on 
normal activity or do active work. 
70 
Both greater restriction of and 
less time spent in play activity. 
2 
Ambulatory and capable of all 
selfcare but unable to carry out 
any work activities. Up and 
about more than 50% of waking 
hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
60 
Up and around, but minimal 
active play; keeps busy with 
quieter activities. 
50 
Requires considerable assistance 
and frequent medical care. 
50 
Gets dressed, but lies around 
much of the day; no active play; 
able to participate in all quiet 
play and activities. 
3 
Capable of only limited 
selfcare; confined to bed or 
chair more than 50% of waking 
hours. 
40 
Disabled, requires special care and 
assistance. 
40 
Mostly in bed; participates in 
quiet activities. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
30 
In bed; needs assistance even for 
quiet play. 
4 
Completely disabled. Cannot 
carry on any selfcare. Totally 
confined to bed or chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
20 
Often sleeping; play entirely 
limited to very passive activities. 
10 
Moribund, fatal processes 
progressing rapidly. 
10 
No play; does not get out of bed. 
* The conversion of the Lansky to ECOG scales is intended for NCI reporting purposes only. 
 


 
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AMEND #1: 2013-APR-25 
APPENDIX III - DRUG DISTRIBUTION, SUPPLY AND CONTROL 
 
Drug Distribution 
 
Full details on Drug Distribution will be posted on the IND.210 website. 
 
Reolysin will be supplied by Oncolytics to the distributor, and sent from the distributor to participating 
centres. 
 
Drug Labelling 
 
Drug for this study has been labelled in accordance with Health Canada regulations. 
 
Initial Drug Supply 
 
Once a centre is locally activated (following receipt and review of all required documentation), the NCIC 
CTG will authorize a start-up supply of reolysin to be shipped directly to the centre. The drug will be 
shipped to the centre within 5 working days of local activation. Note: Shipment will not be made on 
Fridays and weekends.  
 
Drug accountability forms will be posted on the trial website. 
 
Drug Ordering (Re-supply) 
 
Subsequent requests for more drug should be made by authorized personnel at each centre as directed on 
the supplied NCIC Request for Drug Shipment form. The drug re-order form can be found on the 
IND.210 website. 
 
Please allow sufficient time for shipment of drug. 
 
Note: Shipment will not be made on Fridays and weekends. Drug accountability and drug re-order forms 
will be posted on the trial website for pharmacists to download. 
 
Drug Accountability 
 
The investigational products are to be prescribed only by the investigator and co-investigators on the 
participants list. Under no circumstances will the investigator allow the drug to be used other than as 
directed by the protocol. Accurate records must be maintained accounting for the receipt of the 
investigational product and for the disposition of the product (Drug Accountability Log).  
 
Drug Destruction 
 
Expired/used study drug may be destroyed as per local standard operating procedures. Destruction of 
expired/used drug must be documented on the Drug Accountability Log and a copy of the destruction 
certificate kept on file in the pharmacy. Instructions for return or destruction of unused drug will be 
supplied at the time of expiry and at trial closure. 
 
** PLEASE NOTE ** 
DRUG FROM THIS SUPPLY IS TO BE USED ONLY 
FOR PATIENTS REGISTERED ON THIS STUDY 
 
Study drug shipped to participating centres may be transferred from the main hospital pharmacy to a 
satellite pharmacy, provided separate drug accountability records are maintained in each pharmacy. 
Investigational agent may NOT however, be transferred to pharmacies or physicians outside the 
participating centre. 


 
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AMEND #1: 2013-APR-25 
APPENDIX IV - DOCUMENTATION FOR STUDY 
 
Follow-up is required for patients from the time of randomization and will apply to all eligible and 
ineligible patients. This trial will use a web-based Electronic Data Capture (EDC) system for all data 
collection including SAE reporting (see Section 11.0 for details regarding SAE reporting). For details 
about accessing the EDC system and completing the on-line Case Report Forms please refer to the Data 
Management Guidebook posted on the IND.210 area of the NCIC CTG web-site (www.ctg.queensu.ca). 
 
Electronic  
Case Report Form 
To be Completed/Submitted Electronically: 
Supporting Documentation 
to be sent by MAIL** 
BASELINE REPORT 
Due within 2 weeks of patient randomization.  
 
Note: Eligibility Checklist must be completed at time of 
randomization to confirm eligibility.  
Copy of consent form 
signature page(s); relevant 
operative, pathology and 
radiology reports. 
TREATMENT 
REPORT  
To be completed every 2 weeks (i.e. after each reporting 
period). Due within 2 weeks of end of reporting period. This 
report documents treatment, adverse events, investigations 
and response assessment for each reporting period. 
Relevant radiology reports 
QUALITY OF LIFE 
To be completed within 14 days prior to randomization, on 
day 1 of cycle 5 and at off treatment 
Original QoL questionnaire 
CORRELATIVE 
STUDIES 
See section 17.0. To be completed and submitted with the 
tumour block at time of Baseline folder completion and with 
correlative samples at time of shipping. 
Archival Tissue Submission 
Form & Request for Payment 
Form 
Correlative Sampling Form 
END OF 
TREATMENT 
REPORT 
To be completed when patient permanently discontinues the 
treatment agent. Due within 2 weeks of end of protocol 
treatment. 
 
4 WEEK POST 
TREATMENT 
REPORT 
To be completed once on all patients, 4 weeks after going 
off protocol treatment. Due within 2 weeks after contact 
with patient. 
Relevant radiology reports  
FOLLOW-UP 
REPORT 
Continued follow-up is not required for patients who go off 
protocol treatment with progressive disease, except to 
document ongoing toxicities (until resolved to < grade 2) and 
late toxicities (including second malignancies). For patients 
who go off protocol treatment with response or stable disease 
ongoing, Follow-up Report to be completed every 3 months 
until relapse/progression. Due within 2 weeks after contact 
with patient. 
Relevant radiology reports. 
RELAPSE/ 
PROGRESSION 
REPORT 
To be completed at the time of disease relapse or 
progression. Due within 2 weeks after contact with patient. 
Relevant radiology reports if 
not previously submitted for 
another folder. 
DEATH REPORT 
Required for all patients.* Due within 2 weeks of knowledge 
of death. 
Autopsy report, if done. 
SERIOUS ADVERSE 
EVENT (SAE) 
REPORT 
All reportable serious adverse events must be reported as 
described in Section 11.0. Preliminary NCIC CTG Serious 
Adverse Event Report due within 24 hours. Updated NCIC 
CTG Serious Adverse Event Report due within 7 days. 
All relevant test reports; 
admission, discharge 
summaries/notes. 
* 
Note: It is the investigator's responsibility to investigate and report the date/cause of death of any patient who dies during this 
period. Any death that occurs during protocol therapy or within 30 days after last dose must also be reported as a Serious Adverse 
Event as described in Section 11. 
** Supporting documents should be mailed immediately after the report they refer to has been submitted electronically. 


 
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APPENDIX V - NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS  
 
The descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for Adverse Event (AE) reporting. All appropriate treatment areas 
should have access to a copy of the CTCAE. A copy of the CTCAE can be downloaded from the CTEP 
web site (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
 


 
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APPENDIX VI - MANAGEMENT OF ANGIOGENESIS INHIBITOR (AI)-INDUCED HYPERTENSION  
 
 


 
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Table 1. Dihydropyridine calcium-channel blockers 
 
Agent 
Initial dose 
Intermediate dose 
Maximum dose 
Hepatic metabolism? 
Nifedipine XL 
30 mg po qd 
60 mg po qd 
90 mg po qd 
CYP 3A4 substrate 
Amlodipine 
2.5 mg po qd 
5 mg po qd 
10 mg po qd 
CYP 3A4 substrate 
Felodipine 
2.5 mg po qd 
 
10 mg po qd 
CYP 3A4 substrate + inhibitor 
 
Table 2: Selective β blockers 
 
Agent 
Initial dose 
Intermediate dose 
Maximum dose 
Hepatic metabolism? 
Metoprolol 
25 mg po bid 
50 mg po bid 
100 mg po bid 
CYP 2D6 substrate 
Atenolol 
25 mg po qd 
50 mg po qd 
100 mg po qd 
No 
Acebutolol 
100 mg po bid 200mg-300 mg po bid 
400 mg po bid 
Yes (possibly cyp 450) 
Bisoprolol 
2.5 mg po qd 
5-10 mg po bid 
20 mg po qd 
Yes (possibly cyp 450) 
 
Table 3. Angiotensin Converting Enzyme Inhibitors (ACEIs) 
 
Agent  
Initial dose 
Intermediate dose 
Maximum dose 
Hepatic metabolism? 
Captopril 
12.5 po tid 
25 mg po tid 
50 mg po tid 
CYP 2D6 substrate 
Enalapril 
5 mg po qd 
10-20 mg po qd 
40 mg po qd 
CYP 3A4 substrate 
Ramipril 
2.5 mg po qd 
5 mg po qd 
10 mg po qd 
Yes (possibly cyp 450) 
Lisinopril 
5 mg po qd 
10-20 mg po qd 
40 mg po qd 
No  
Fosinopril 
10 mg po qd 
20 mg po qd 
40 mg po qd 
Yes (possibly cyp 450) 
Rarely used: 
Perindopril  
4mg po qd 
none 
8mg po qd 
Yes but not cyp-450 
Quinapril 
10mg po qd 
20 mg po qd 
40 mg po /qd 
No 
 
Table 4. Angiotensin II Receptors Blockers (ARBs) 
 
Agent 
Initial dose 
Intermediate dose 
Maximum dose 
Hepatic metabolism? 
Losartan 
25mg po qd 
50 mg po qd 
100 mg po qd 
CYP 3A4 substrate 
Candesartan 
4mg po qd 
8-16 mg po qd 
32mg po qd 
CYP 2C9 substrate  
Irbesartan 
75mg po qd 
150 mg po qd 
300 mg po qd 
CYP 2C9 substrate 
Telmisartan 
40 mg po qd 
none 
80 mg po qd 
Yes but not per cyp-450 
Valsartan 
80 mg po qd 
none 
160mg po qd 
Yes but not per cyp-450 
 
Table 5. α and β blocker 
 
Agent 
Initial dose 
Intermediate dose 
Maximum dose 
Hepatic metabolism? 
Labetolol 
100 mg po bid 
200 mg po bid 
400 mg po bid 
CYP 2D6 substrate and inhibitor 
 
NB. Agents in bold characters are suggested as optimal choices to avoid or minimize potential drug-
interactions 


 
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APPENDIX VII - QUALITY OF LIFE ASSESSMENT 
 
Introduction 
 
The assumption that control of symptoms will automatically improve quality of life is probably true but 
hasn't yet been tested, especially in determining how certain symptoms may or may not affect quality of 
life. Current literature reveals interesting things; two in particular are: 
• 
additional and useful information may be obtained from quality of life measurements 
• 
a growing consensus that the goal of medical care today for most patients is the preservation of 
function and well-being in everyday life. 
 
We have reached the stage where the collection of information about psychological distress, social 
disruption, emotional trauma and painful side-effects is not only necessary but a routine component in 
many protocols. 
 
Quality of life data can be used in a variety of ways: 
• 
to try to achieve the best possible outcome for patients 
• 
to evaluate the extent of change in the quality of life of an individual or group across time 
• 
to evaluate new treatments and technologies 
• 
to support approval of new drug applications 
• 
to try to provide the best value for health care dollars 
• 
to compare costs and benefits of various financial and organizational aspects of health care services 
 
In the future, approval of not only drugs but also new therapies or methods of delivery will most likely be 
based on a combination of quality of life, survival, response, and adverse event data. 
 
Instructions for Administration of a Quality of Life Questionnaire. The instructions below are intended as 
a guide for the administration of the Quality of Life questionnaire. 
 
1. Preamble 
 
Quality of life data are collected for research purposes, and will usually not be used for the patient’s 
individual medical care. The assessment is in the form of a self report questionnaire. Therefore, it 
must be completed by the patient only, without translation, coaching or suggestions as to the "correct" 
answer by relatives or health care personnel. 
 
The usual scheduled times to obtain the questionnaires are as follows: 
• 
pre-randomization or pre-registration (baseline) 
• 
during treatment 
• 
during follow-up 
 
The information provided by the patient in the completed questionnaire is confidential and should not 
be discussed with or shown to anyone who is NOT mentioned in the consent form signed by the 
patient. 
 
If a particular question has not been answered, please document the reason(s) in the appropriate space 
on the questionnaire. If the whole questionnaire has not been completed, please document the 
reason(s) on the appropriate case report forms. 


 
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2. Pretreatment Assessment 
 
It should be explained to the patient that the purpose of the questionnaire is to assess the impact of 
treatment on different areas of the patient's life, e.g.: psychological distress, social disruption, side-
effects, et cetera. 
 
The CRA should collect the questionnaire as soon as it has been completed, check to see that each 
question has been answered and gently remind the patient to answer any inadvertently omitted 
questions. If a patient states that s/he prefers not to answer some questions and gives a reason(s), the 
reason(s) should be noted on the questionnaire. If a specific reason is not given, this also should be 
noted on the questionnaire. 
 
3. Assessments During Treatment 
 
The quality of life questionnaire should be given to the patient before being seen by the doctor, and 
prior to treatment on the day of treatment, as required by the schedule in the protocol. If the patient 
does not have a doctor visit scheduled, or if it was not possible for the patient to complete the 
questionnaire before being seen by the doctor, s/he should still complete the questionnaire prior to 
treatment. 
 
4. Assessments During Follow-up 
 
The quality of life questionnaire should be given to the patient before being seen by the doctor, on 
follow-up visits as required by the schedule. 
 
A patient may, on occasion, be reluctant to complete the questionnaire because they feel 
unwell. In that case, you may express sympathy that things are below par, but state that 
this is exactly the information we require if we are to understand more about how quality 
of life is affected. You may also remind them that it takes only a few minutes to 
complete. 
 
It defeats the whole purpose of the assessment if it is delayed until the patient feels better!  
 
5. What If . . .  
 
The patient should complete the questionnaires at the clinic. The exception is that the design of some 
trials may require the patient to take the questionnaire home with them after leaving the clinic, and 
complete it on the specific day, because a return visit to the clinic is not scheduled. 
 
There may be circumstances when the patient does not complete the questionnaire as required in the 
clinic. Three situations are described below. In these cases, it is beneficial if quality of life data can 
still be collected. 
 
A. The patient leaves the clinic before the questionnaire could be administered, or someone forgets 
to give the questionnaire to the patient.  
 
Contact the patient by phone informing him or her that the questionnaire was not completed. Ask 
the patient if s/he is willing to complete one: 
If yes, mail a blank questionnaire to the patient, and make arrangements for return of the 
questionnaire in a timely fashion. Record the date it was mailed and the date received on the 
questionnaire. 


 
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If this is not feasible, then ask the patient if s/he is willing to complete a questionnaire over 
the phone. If the patient agrees, read out the questions and range of possibilities, and record the 
answers. Make a note on the questionnaire that the questionnaire was completed over the phone. 
 
If no, note the reason why the questionnaire was not completed on the appropriate case report 
form. 
 
B. The patient goes on an extended vacation for several months and won't attend the clinic for 
regular visit(s). 
 
Ensure that the patient has a supply of questionnaires, with instructions about when to complete 
them, and how to return them. If it is known beforehand, give the patient blank questionnaires at 
the last clinic visit; if the extended absence is not known in advance, mail the blank 
questionnaires to the patient. Written instructions may help ensure that the patient stays on 
schedule as much as possible.  
 
C. The patient does not want to complete the questionnaire in clinic. 
 
Should the patient not wish to answer the questionnaire in the clinic but insists on taking it home, and 
failing to comply with the patient's wishes is likely to result in the questionnaire not being completed 
at all, then the patient may take the questionnaire home with instructions that it is to be completed the 
same day. When the questionnaire is returned, the date on which the questionnaire was completed 
should be noted and a comment made on the questionnaire as to why the patient took it away from the 
clinic before completion.  
 
6. Waiving the Quality of Life Component 
 
The only time that we will not require a patient to complete the quality of life questionnaires is if s/he 
is not literate in either English or French (or other languages that the questionnaire may be available 
in). In other words, if the assistance of a translator is required to comprehend the questions and reply, 
the questionnaires should not be completed. Translation of the questions is not acceptable. Please 
indicate on questionnaire. 
 
7. Unwillingness to Complete Quality of Life Questionnaire 
 
If a patient speaks and reads English or French (or other languages that the questionnaires may be 
available in), but does not wish to complete the questionnaires then s/he is NOT eligible and should 
NOT be put on study. 
 
8. Inability to Complete Quality of Life Questionnaire (for reason other than illiteracy in English or 
French) 
 
An eligible patient may be willing but physically unable to complete the questionnaires, because of 
blindness, paralysis, etc. If the patient is completing the QOL assessment in the clinic, the 
questionnaire should be read to them and the answers recorded by a health care professional (e.g. 
preferably the clinical research associate assigned to the trial, but another clinic nurse, a doctor or 
social worker who is familiar with the instructions for administering the questionnaires would be 
acceptable). If the patient is completing the questionnaire at home, and a telephone interview by the 
clinical research associate is not possible, then a spouse or friend may read the questions to the patient 
and record the answers. However, this method should be a last resort, and the spouse or friend should 
be instructed to not coach or suggest answers to the patient. Whichever method is used, it should be 
recorded on the questionnaire. 
 
If these special arrangements are not possible or feasible, then the patient would not be required to 
complete the questionnaires, and this should be reported on the appropriate case report form. 
 


 
 
Quality of Life Questionnaire – ENGLISH 
 
NCIC CTG Trial: IND.210 
 
This page to be completed by the Clinical Research Associate 
 
Patient Information 
NCIC CTG Patient Serial No: ___________ 
Hospital No.: 
_XXXXXXXXX_ 
 
(if permitted by REB) 
Patient Initials: ____ ____ ____ 
 
(first-middle-
last)  
Institution: ___________________________________________ 
Investigator: ______________________________ 
 
Scheduled time to obtain quality of life assessment: please check (3) 
 Prior to randomization 
During chemotherapy:  
 Day 1 cycle 5  
Off Treatment: 
 Off Study      week 4 (only if not completed at time off study) 
Were ALL questions answered? ___ Yes ___ No If no, reason: ________________________________________ 
 
Was assistance required? ___ Yes ___ No If yes, reason: ________________________________________ 
Where was questionnaire completed:  home      clinic      another centre 
Comments: ____________________________________________________________________________________ 
_____________________________________________________________________________________________ 
 
 
Date Completed:  __ __ __ __ - __ __ __ - __ __ 
 
       yyyy            mmm         dd 
 
PLEASE ENSURE THIS PAGE IS FOLDED BACK BEFORE HANDING 
TO THE PATIENT FOR QUESTIONNAIRE COMPLETION. 
 
 
 
 
 
 
 
NCIC CTG use only 
Logged: _______ 
______ - ____ - ____ 
Study Coord: _______ 
______ - ____ - ____ 
Res Assoc: _______ 
______ - ____ - ____ 
Data Ent’d: 
_________ 
Verif: 
_________ 


This box to be completed by the clinical research associate:     Pt. Serial #: _____________      Pt. Initials: ____ ____ 
____ 
 
NCIC CTG Trial IND.210 
Page 1 of 3 
Please go on to the next page 
 
EORTC QLQ-C30 (Core 30 Questionnaire Version 3.0 © copyright 1995 EORTC Quality of Life Study Group. All rights reserved.) 
European Organization for Research and Treatment of Cancer (EORTC) 
 
 
Quality of Life Questionnaire (IND.210) 
 
We are interested in some things about you and your health. Please answer all the questions yourself by circling 
the number that best applies to you. There are no 'right' or 'wrong' answers. Choose the best single response that 
applies to you. The information that you provide is for research purposes and will remain strictly confidential. 
The individuals (e.g. doctors, nurses, etc.) directly involved in your care will not usually see your responses to 
these questions -- if you wish them to know this information, please bring it to their attention. 
 
 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
1. 
Do you have any trouble doing strenuous activities, like 
carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4 
 
 
 
 
 
2. 
Do you have any trouble taking a long walk? 
1 
2 
3 
4 
 
 
 
 
 
3. 
Do you have any trouble taking a short walk outside of 
the house? 
1 
2 
3 
4 
 
 
 
 
 
4. 
Do you need to stay in a bed or a chair during the day? 
1 
2 
3 
4 
 
 
 
 
 
5. 
Do you need help with eating, dressing, washing 
yourself or using the toilet? 
1 
2 
3 
4 
During the past week: 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
6. 
Were you limited in doing either your work or other 
daily activities? 
1 
2 
3 
4 
 
 
 
 
 
7. 
Were you limited in pursuing your hobbies or other 
leisure time activities? 
1 
2 
3 
4 
 
 
 
 
 
8. 
Were you short of breath? 
1 
2 
3 
4 


This box to be completed by the clinical research associate:     Pt. Serial #: _____________      Pt. Initials: ____ ____ 
____ 
 
NCIC CTG Trial IND.210. EORTC QLQ-C30 
Page 2 of 3 
Please go on to the next page 
During the past week: 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
9. 
Have you had pain? 
1 
2 
3 
4 
 
 
 
 
 
10. Did you need to rest? 
1 
2 
3 
4 
 
 
 
 
 
11. Have you had trouble sleeping? 
1 
2 
3 
4 
 
 
 
 
 
12. Have you felt weak? 
1 
2 
3 
4 
 
 
 
 
 
13. Have you lacked appetite? 
1 
2 
3 
4 
 
 
 
 
 
14. Have you felt nauseated? 
1 
2 
3 
4 
 
 
 
 
 
15. Have you vomited? 
1 
2 
3 
4 
 
 
 
 
 
16. Have you been constipated? 
1 
2 
3 
4 
 
 
 
 
 
17. Have you had diarrhea? 
1 
2 
3 
4 
 
 
 
 
 
18. Were you tired? 
1 
2 
3 
4 
 
 
 
 
 
19. Did pain interfere with your daily activities? 
1 
2 
3 
4 
 
 
 
 
 
20. Have you had difficulty in concentrating on things, like 
reading a newspaper or watching television? 
1 
2 
3 
4 
 
 
 
 
 
21. Did you feel tense? 
1 
2 
3 
4 
 
 
 
 
 
22. Did you worry? 
1 
2 
3 
4 


This box to be completed by the clinical research associate:     Pt. Serial #: _____________      Pt. Initials: ____ ____ 
____ 
 
NCIC CTG Trial IND.210 EORTC QLQ-C30 
Page 3 of 3 
During the past week: 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
23. Did you feel irritable? 
1 
2 
3 
4 
 
 
 
 
 
24. Did you feel depressed? 
1 
2 
3 
4 
 
 
 
 
 
25. Have you had difficulty remembering things? 
1 
2 
3 
4 
 
 
 
 
 
26. Has your physical condition or medical treatment 
interfered with your family life? 
1 
2 
3 
4 
 
 
 
 
 
27. Has your physical condition or medical treatment 
interfered with your social activities? 
1 
2 
3 
4 
 
 
 
 
 
28. Has your physical condition or medical treatment 
caused you financial difficulties? 
1 
2 
3 
4 
 
 
For the following questions please circle the number between 1 and 7 that best applies to you. 
29. How would you rate your overall health during the past week? 
1 
Very Poor 
2 
3 
4 
5 
6 
7 
Excellent 
 
30. How would you rate your overall quality of life during the past week? 
1 
Very Poor 
2 
3 
4 
5 
6 
7 
Excellent 
 
Please check to make sure you have answered all the questions. 
 
 
Please fill in your initials to indicate that you have completed this questionnaire: ______________ 
 
Today's date (Year, Month, Day): ________________________________ 
 
 
Thank you. 
 


 
PROTOCOL DATE: 2012-MAY-03 
 
NCIC CTG TRIAL: IND.210 
 
 
CONFIDENTIAL 
Final Page 
CONFIDENTIAL 
 
AMEND #1: 2013-APR-25; ADMIN UPDATE #1: 2014-MAY-23 (withdrawn); AMEND #3: 2014-JUN-16 
LIST OF CONTACTS 
 
PATIENT RANDOMIZATION 
All patients must be randomized as described in Section 7.0 before any treatment is given. 
 
 
Contact 
Tel. # 
Fax # 
STUDY SUPPLIES 
Data Management Guidebook, 
Protocol, Safety Information 
Available on NCIC CTG Website: 
http://www.ctg.queensu.ca 
under: Clinical Trials 
613-533-6430 
613-533-2411 
PRIMARY CONTACTS FOR 
GENERAL PROTOCOL 
RELATED QUERIES 
(including eligibility questions 
and protocol management) 
Ashley Theis 
Study Coordinator 
NCIC CTG 
Email: atheis@ctg.queensu.ca 
or:  
Lesley Seymour 
Director, NCIC CTG 
Investigational New Drug Program 
Email: lseymour@ctg.queensu.ca 
STUDY CHAIRS 
Dr Patricia Tang 
Email: 
patricia.tang@albertahealthservices.ca 
403-521-3688 
403-283-1651 
Dr Derek Jonker 
Email: 
djonker@ottawahospital.on.ca 
613-737-7700 
x 70168 
613-247-3511 
 
SERIOUS ADVERSE EVENT 
REPORTING 
See protocol Section 11.0 for 
details of reportable events. 
Dr. Lesley Seymour 
NCIC CTG 
Investigational New Drug Program 
613-533-6430 
613-533-2411 
or 
Ashley Theis 
Study Coordinator 
NCIC CTG 
DRUG ORDERING 
See Appendix III and trial website at 
http://www.ctg.queensu.ca 
under: Clinical Trials 
 
 
ELECTRONIC DATA 
CAPTURE (EDC) 
(technical support) 
NCIC CTG Help Desk Home Page 
https://scooby.ctg.queensu.ca/helpdesk/ 
 
Email Support Staff at: 
support@ctg.queensu.ca 
 
 
 

SAP_001.pdf: 
A RANDOMIZED PHASE II STUDY OF REOLYSIN IN COMBINATION WITH FOLFOX6/BEVACIZUMAB OR 
FOLFOX6/BEVACIZUMAB ALONE IN PATIENTS WITH METASTATIC COLORECTAL CANCER 
NCIC CTG Protocol Number: IND.210 
NCT01622543 
Statistical Analysis Plan 
Date: March 20, 2015 


 
 
STATISTICAL ANALYSIS PLAN for 
 
A RANDOMIZED PHASE II STUDY OF REOLYSIN IN COMBINATION 
WITH FOLFOX6/BEVACIZUMAB OR FOLFOX6/BEVACIZUMAB ALONE 
IN PATIENTS WITH METASTATIC COLORECTAL CANCER 
 
NCIC CTG Protocol Number: IND.210 
 
Prepared by: 
Signature 
Date 
 
NCIC CTG/Queen’s Statistician  
 
 
            
 
 
 
  
 
 
 
Dongsheng Tu 
 
 
Reviwed by: 
Signature 
Date 
 
NCIC CTG/Queen’s 
Senior Investigator       
 
 
 
 
            
 
 
 
 
 
 
 
 
 
 
 
Lesley Seymour 
 
 


ABBREVIATIONS 
 
AE  
 
Adverse Event 
ALT 
 
Alanine Aminotransferase 
AST 
 
Serum Glutamic Oxaloacetic Transaminase 
BSA 
 
Body Surface Area 
C. I. 
 
Confidence Interval 
CMH 
 
Cochran-Mantel-Haenszel 
CR  
 
Complete Response 
CRF 
 
Case Report Form 
CTCAE  
Common Toxicity Criteria for Adverse Events 
CTG 
 
Clinical Trials Group 
DR  
 
Duration of Response 
ECOG  
Eastern Cooperative Cancer Group 
EORTC  
European Organization for Research and Treatment of Cancer 
IN  
 
Inevaluable 
LDH 
 
Serum Lactate Dehydrogenase 
LKA 
 
Last day the patient is Known Alive 
LNL 
 
Lower Normal Limit 
MPV 
 
Major Protocol Violation 
NA  
 
Not Assessed or Not Applicable 
NC  
 
Not Computed 
NCI 
 
National Cancer Institute 
OS  
 
Overall Survival 
PD  
 
Progression Disease 
PFS 
 
Progression Free Survival 
PR  
 
Partial Response 
QLQ 
 
Quality of Life Questionnaire  
QOL 
 
Quality of Life 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RR  
 
Response Rate 
SAS 
 
Statistical Analysis System 
SD  
 
Stable Disease 
STD 
 
Standard Deviation 
UNL 
 
Upper Normal Limit 
WBC 
 
White Blood Cells 
 


TABLE OF CONTENTS 
 
1. 
Introduction ___________________________________________________ 6 
2. 
Study Description _______________________________________________ 6 
2.1 
Study Design ______________________________________________________ 6 
2.2 
Treatment Allocation _______________________________________________ 6 
3. 
Objectives _____________________________________________________ 6 
3.1 
Primary___________________________________________________________ 6 
3.2 
Secondary _________________________________________________________ 7 
4. 
Endpoints _____________________________________________________ 7 
4.1 
Primary Efficacy ___________________________________________________ 7 
4.2 
Secondary Efficacy _________________________________________________ 7 
4.3 
Safety ____________________________________________________________ 7 
5. 
Sample Size and Power __________________________________________ 7 
6. 
Data Set Descriptions ____________________________________________ 7 
7. 
Statistical Analysis ______________________________________________ 8 
7.1 
General Methods ___________________________________________________ 8 
7.2 
Study Conduct _____________________________________________________ 9 
7.2.1 
Patient Disposition and Follow-up _________________________________________ 9 
7.2.2 
Accrual Patterns _______________________________________________________ 9 
7.2.3 
Eligibility Violations/Protocol Deviations ___________________________________ 9 
7.3 
Study Population ___________________________________________________ 9 
7.3.1 
Patient Pretreatment Characteristics ________________________________________ 9 
7.3.2 
Prior Surgery ________________________________________________________ 10 
7.3.3 
Prior radiotherapy _____________________________________________________ 10 
7.3.4 
Prior Systemic Therapy ________________________________________________ 10 
7.3.5 
Extent of Disease _____________________________________________________ 10 
7.3.6 
Baseline Exams ______________________________________________________ 10 
7.4 
Extent of Exposure ________________________________________________ 11 
7.4.1 
Duration of Study Therapy ______________________________________________ 11 
7.4.2 
Modifications of Protocol Therapy ________________________________________ 11 
7.4.3 
Cumulative dose, dose intensity and relative dose intensity _____________________ 11 
7.4.4 
Off Study Therapy ____________________________________________________ 12 
7.5 
Efficacy __________________________________________________________ 12 
7.5.1 
Progression Free Survival _______________________________________________ 12 
7.5.2 
Progression Free Survival by Subsets______________________________________ 14 
7.5.3 
CEA Levels _________________________________________________________ 14 
7.5.4 
Overall survival ______________________________________________________ 14 
7.5.5 
Overall Survival by Subsets _____________________________________________ 14 
7.5.6 
Treatment Response ___________________________________________________ 15 
7.5.7 
Treatment Response by Subsets __________________________________________ 15 
7.5.8 
Duration of Response __________________________________________________ 16 
7.6 
Safety ___________________________________________________________ 16 
7.6.1 
Adverse Events _______________________________________________________ 16 
7.6.2 
Laboratory Evaluations ________________________________________________ 17 
7.6.2.1 
Hematology _______________________________________________________ 17 


7.6.2.2 
Biochemistry_______________________________________________________ 17 
7.6.3 
Deaths on Study/Adverse Events Leading to Discontinuations due to Toxicity _____ 17 
5.6.3 
Other Safety _________________________________________________________ 17 
5.6.3.1 
Hospitalizations ____________________________________________________ 17 
5.6.3.2 
Transfusions _______________________________________________________ 17 
7.7 
Concomitant Medications and Other Anti-Cancer Treatments ____________ 17 
7.8 
Quality of Life ____________________________________________________ 18 
7.8.1 
Scoring Algorithms for EORTC QLQ-C30 and Skindex-16 ____________________ 18 
7.8.2 
Data Sets ____________________________________________________________ 19 
7.8.3 
Compliance __________________________________________________________ 19 
7.8.4 
Analyses of QOL _____________________________________________________ 19 
7.8.5.1 
Baseline and Change Score Analysis ____________________________________ 19 
7.8.5.3 
Proportions of Deterioration and Improving or Stable for EORTC QLQ-C30 at 
Post-baseline Assessment _____________________________________________________ 19 
8. 
Data Conventions ______________________________________________ 19 
9. 
Appendices ___________________________________________________ 20 
Appendix 1: Tables and Figures __________________________________________________ 20 
 
 
Tables 
Table 1:  Patient Disposition ................................................................................................................20 
Table 2:  Follow-up of Patients.............................................................................................................20 
Table 3:  Accrual by Center ..................................................................................................................21 
Table 4:  Accrual by Stratification Factor at Randomization ...............................................................21 
Table 5:  Eligibility and Reasons for Ineligibility and Major Protocol Violations ...............................22 
Table 6:  Treatment as Randomized Versus as Treated ........................................................................22 
Table 7:  Pretreatment Characteristics at Baseline ..............................................................................23 
Table 8:  Prior Surgery .........................................................................................................................24 
Table 9:  Prior Radiotherapy ................................................................................................................24 
Table 10:  Prior Systemic Therapy .......................................................................................................25 
Table 11:  Extent of Disease (Target Lesions) ......................................................................................26 
Table 12:  Extent of Disease (All Non-Target Lesions) ........................................................................27 
Table 13:  Baseline Hematology ...........................................................................................................28 
Table 14:  Baseline Chemistry ..............................................................................................................29 
Table 15:  Baseline Symptoms Status ....................................................................................................30 
Table 16:  Prior Concomitant Medications (Baseline) .........................................................................30 
Table 17:  Past or Current Major Medical Problems ...........................................................................30 
Table 18:  Number of Patients by Cycle ................................................................................................31 
Table 26:  Log Rank and Cox Regression Model for Progression Free Survival .................................34 
Table 27:  Progression Summary ..........................................................................................................35 
Table 28:  Progression-free survival by Subsets ...................................................................................35 
Table 29:  Summary Baseline CEA values and Change from Baseline at Each Time Period*.............36 
Table 30:  Log Rank and Cox Regression Model for Overall Survival (OS) ........................................37 
Table 31:  Overall Survival by Subsets .................................................................................................38 
Table 32:  Treatment Response .............................................................................................................39 
Table 33:  Cochran Mantel Haenszel and Logistic Regression Model for Response ...........................40 
Table 34:  Response According to Pretreatment Characteristics .........................................................41 
Table 36:  All Acute Non-Hematologic Adverse Events in ARM A .......................................................42 
Table 37:  Severe Acute Non-Hematologic Adverse Events in ARM A .................................................42 
Table 38:  Acute (On-treatment) Adverse Events Related to Bevacizumab ..........................................43 
Table 39:  Severe Delayed Non-Hematologic Adverse Events in ARM A .............................................43 
Table 40:  Hematology by arm: Worst Grade per Patient ....................................................................44 
Table 41:  Biochemistry Tests by Arm:  Worst per Patient ..................................................................45 
Table 42:  All Deaths ............................................................................................................................46 
Table 43:  Deaths within 4 Weeks of Last Treatment ............................................................................46 
Table 44:  Adverse Event leading to Treatment Discontinuation..........................................................46 


Table 47:  Concomitant Medication ......................................................................................................48 
Table 48:  Anti-Cancer Treatment ........................................................................................................48 
Table 49:  Compliance Rate with QoL Assessment by Treatment Arm .................................................49 
Table 50:  QoL: Summary Baseline Scores ...........................................................................................49 
Table 51:  Summary QOL Change Scores from Baseline for Scale/Domain/Item at Each Time Period*
 ................................................................................................................................................................50 
Table 52:  Proportion of Patients with Deterioration, Improvement or Stable EORTC QLQ-C30 
domains/items and Global QLQ scales* ................................................................................................50 
 
 
Figures 
Figure 1:  Accrual by Calendar Time ..................................................................................................21 
 
 
 
 
 
 
 
 
 


1. Introduction 
This analysis plan is to describe the final analyses performed by NCIC Clinical Trials 
Group (NCIC CTG) for I210 trial.  It will be used for the writing of NCIC Clinical 
Trials Group study report. 
2. Study Description 
2.1 
Study Design 
I210 is an open-label, randomized, non-blinded, phase II clinical study of Reolysin 
day 1-5 (cycles 1, 2, 4, 6, 8 and alternate cycles thereafter) plus q2 weekly 
FOLFOX6/bevacizumab versus q2 weekly FOLFOX6/bevacizumab as first line 
palliative treatment for patients with advanced or metastatic colorectal cancer. Prior to 
the randomized component 6-9 additional patients will be accrued to ensure safety 
and tolerability of the combination. The study is being conducted by the NCIC 
Clinical Trials Group, with support of Oncolytics Biotech Inc. Patients are stratified 
by KRAS mutation status (if known) and prior adjuvant chemotherapy prior to 
randomization.       
 
A total of 100 patients would be enrolled (50 on each arm).  The final analyses will 
be conducted respectively after at least 50 progression or deaths have been recorded.  
This analysis plan describes the analyses performed at the completion of the study.     
 
This study was open to accrue patients on June 11, 2012.  The safety run-in 
component of the study was completed in early 2013 with a total of six patients 
enrolled. The required minimum number of events for the analysis (50) was observed 
in February 2015 among a total of 109 patients randomized.  March 11, 2015 was 
decided as the date of data cut-off date and the final analysis will be performed after 
all data observed up to and including March 11, 2015 are cleaned. 
 
The NCIC CTG DSMC has been reviewing safety data every six months (usually at 
the time of the bi-annual NCIC CTG Spring and Fall meetings) and as otherwise 
required.  These analyses have been prepared by a NCIC CTG/Queen’s Senior 
Biostatistician.   
2.2 
Treatment Allocation 
The study is planned to randomize 100 subjects with using a 1:1 allocation to 
Reolysin in combination with FOLFOX6/bevacizumab (ARM A) or FOLFOX6/ 
bevacizumab alone (ARM B).  The randomization is dynamically balanced by 
KRAS mutation status (if known) and prior adjuvant chemotherapy using the 
minimization method.  A centralized system is used to randomize all patients in this 
study. 
3. Objectives 
3.1 
Primary 
The primary objective of this study is to compare the progression free survival (PFS) 
of patients with metastatic colorectal cancer treated with Reolysin in combination 
with FOLFOX6/bevacizumab or FOLFOX6/ bevacizumab alone.  


3.2 
Secondary 
Secondary objectives are to: 
 
• Compare change in CEA level between two treatment arms. 
• Compare objective response rates (RR) between the two treatment arms. 
• Compare overall survival (OS) between the two treatment arms. 
• Compare quality of life between the two treatment arms. 
• Evaluate the safety profile of Reolysin in combination with FOLFOX6/ 
bevacizumab in comparison with FOLFOX6/bevacizumab alone. 
• To explore potential molecular factors which may be prognostic, or predictive of 
response, by assessment of archival tumour tissue and serial blood samples  
 
[Note: The last objective (study of molecular markers) will be addressed separately 
from this analysis plan]. 
4. Endpoints 
4.1 
Primary Efficacy 
The primary efficacy endpoint is progression free survival.  
4.2 
Secondary Efficacy 
The secondary efficacy endpoints (covered in this analysis plan) are: 
• Change in CEA levels 
• Objective Response Rate 
• Overall Survival 
• Quality of Life (using EORTC QLQ-C30) 
4.3 
Safety 
The safety endpoints are serious and non-serious adverse events (clinical and 
laboratory), laboratory parameters, dosing data (including dose interruptions, total 
delivered dose and dose modifications) and reasons off treatment.  
5. Sample Size and Power 
The expected median progression free survival for FOLFOX6/bevacizumab is 8.5 
months. With a total sample size of 100 accrued in around 13 months and followed 
for 6 months to observe 50 PFS events before the final analysis, we will have 80% 
power to detect a difference between two treatment groups in PFS from 8.5 to 15.5 
months (i.e. hazard ratio of 0.55) with a one-sided alpha 0.1.     
6. Data Set Descriptions 
Three types of analysis samples will be used: 
 
All Randomized Patients: 
All patients who have been randomized in the study with the treatment arm will be as 
randomized.  The patients in the safety run-in phase are excluded. 
 
All Accrued Patients: 
All patients who have been accrued in the study with the treatment arm will be as 


randomized for those who have been randomized.  The patients in the safety run-in 
phase are included in the ARM A. 
 
Response-Evaluable Patients: 
All patients with at least one target lesion who have at least one disease assessment 
after baseline will be considered evaluable for response.  In addition, patients who 
develop progressive disease prior to the scheduled first post-baseline assessment will 
also be considered evaluable for response. 
 
All Treated Patients: 
All patients who received at least one dose of study treatment including patients 
enrolled in safety run-in phase. 
7. Statistical Analysis 
7.1 
General Methods 
All comparisons between treatment arms will be carried out using a one-sided test at 
an alpha level of 10% unless otherwise specified.   
 
When appropriate, discrete variables are summarized with the number and proportion 
of subjects falling into each category, and compared using Fisher’s exact test.   
Continuous and ordinal categorical variables are summarized using the mean, median, 
standard error, minimum and maximum values and when appropriate, compared 
using the Wilcoxon test.  All confidence intervals are computed based on normal 
approximations except those for rates, which will be computed based on the exact 
method. 
 
Time to event variables are summarized using Kaplan-Meier plots.  Primary 
comparisons of the treatment groups are made using the stratified log-rank test.   
Primary estimates of the treatment differences are obtained with the hazard ratios and 
95% confidence intervals from stratified Cox regression models using treatment arm 
as the single factor.  
 
Percentages given in the summary tables will be rounded and may therefore not 
always add up to exactly 100%.  Listings, tabulations, and statistical analyses will be 
carried out using the SAS (Statistical Analysis System, SAS Institute, North Carolina, 
USA) software. 
 
Unless otherwise specified, date of randomization and stratification factors will be 
taken from the Centralized Randomization File.  
 
Baseline evaluations will be those collected on CRF ELIGIBILITY WORKSHEET 
and BASELINE REPORT and closest to, but no later than, the first day of study 
medication for treated subjects and closest to, but no later than, the date of 
randomization, for subjects who were randomized but who never received treatment. 
 
Laboratory results, adverse events, and other symptoms are coded and graded using 
the NCI CTCAE when available.  


7.2 
Study Conduct 
All randomized patients are included in the analyses of study conduct.  Information 
will be tabulated by randomized treatment (unless otherwise indicated) and pooled 
treatments. 
7.2.1 
Patient Disposition and Follow-up 
• Number of patients randomized, treated (on study, off study), never treated 
(Table 1)  
• Number of alive patients (Table 2) 
• Median (estimated by Kaplan-Meier method) and range (minimum and maximum) 
(Table 2) of the follow-up time (months) defined as time from the day of 
randomization (as recorded in centralized randomization file) to the last day the 
patient is known alive (LKA) as the last recorded date known alive or censored at 
the time of death and calculated as  
 
[(date of death or LKA − date of randomization) + 1)]/30.4375. 
7.2.2 
Accrual Patterns 
• Number of patients randomized by center (Table 3)  
• Number of patients by stratification factor at randomization (Table 4)  
• Accrual of patients by calendar time pooled across two treatment arms (Figure 1) 
7.2.3 
Eligibility Violations/Protocol Deviations 
Eligibility violations of inclusion or exclusion criteria are centrally reviewed by 
NCIC CTG; a field (y/n) for eligibility status and reason for ineligibility is entered in 
the database.  A major protocol violation (MPV) is defined as a deviation from the 
protocol, initiated by the centre or the investigator, serious enough to mean that the 
patient's data contributes little, if any, information on the efficacy or toxicity of the 
regimen under study. MPVs are coded by NCIC CTG based on its standard codes.  
• Number of patients eligible, not eligible (Table 5) 
• Reasons for ineligibility (Table 5)   
• Major protocol violations: % for each type of violations (Table 5). 
 
Deviations from randomization will be summarized as follows:  
• Treatment as randomized versus as treated (Table 6) 
7.3 
Study Population 
All randomized patients are included in the study population analyses.  Information 
will be tabulated by randomized treatment (unless otherwise indicated) and pooled 
treatments. 
7.3.1 
Patient Pretreatment Characteristics  
• Gender: male, female (Table 7) 
• Age: median, minimum, maximum values; <65, ≥65 (Table 7) 
• ECOG Performance Status: 0, 1, 2 (Table 7) 
• Months from first histological diagnosis of colorectal cancer to randomization: 
median, minimum, maximum values (Table 7) 


• Months from first relapse to randomization: median, minimum, maximum values 
• Type of malignancy: colon only, rectum only, colon and rectum (Table 7) 
• Histology: adeno-carcinoma, etc. (Table 7) 
• Grade at diagnosis: low, moderate, high, unknown . (Table 7) 
• K-ras mutation status: wild-type, mutated, unknown (Table 7) 
• EGFR protein: positive, negative, unknown . (Table 7) 
• EGFR copy number: normal, increased-amplified, unknown (Table 7) 
• EGFR mutation: yes, no, unknown (Table 7) 
• BRAF mutation status: wild-type, mutated, unknown (Table 7) 
• PIK3CA mutation status: wild-type, mutated, unknown (Table 7) 
7.3.2 
Prior Surgery 
• Number of patients with prior surgery for colorectal cancer (Table 8) 
• Procedure/site of prior surgery (Table 8)   
7.3.3 
Prior radiotherapy 
• Number of patients with prior radiotherapy (Table 9) 
• Prior radiotherapy by site (Table 9) 
• Total dose of radiotherapy (cGy): median, minimum, maximum values (Table 9) 
• Best response: CR/PR, SD, PD (Table 9) 
7.3.4 
Prior Systemic Therapy 
• Number of subjects with prior systemic therapy and setting/intent of prior 
systemic therapy (adjuvant, neo-adjuvant, advanced/recurrent/metastatic) (Table 
10) 
• Prior fluoropyrimidine-based therapy regimens: yes, no (Table 10)  
• Number of patients with prior systemic drug/agent (Table 10) 
7.3.5 
Extent of Disease 
• Number of patients with target lesions, number of target lesions, largest measure, 
site of target lesions, evaluation procedure (Table 11) 
• Number of patients with non-target lesions, number of non-target lesions, site of 
non-target lesions, evaluation procedure (Table 12) 
 
In both tables, site of disease will be taken from the target (non-target lesions at 
baseline section in CRF BASELINE REPORT. 
7.3.6 
Baseline Exams 
• Baseline hematology: WBC, absolute neutrophil count (ANC), platelets, 
lymphocytes (Table 13) 
• Baseline biochemistry: total bilirubin, alkaline phosphatase, ALT, AST, lactate 
dehydrogenase (LDH), serum creatinine, total protein (Table 14)  
• Baseline symptom status (Table 15) 
• Concomitant medications (Table 16) 
• Other past and current major medical problems ongoing at baseline (Table 17) 


7.4 
Extent of Exposure 
Patients included are those who received at least one dose of protocol therapy as 
defined in Section 6. 
7.4.1 
Duration of Study Therapy 
During protocol treatment, the patients on both treatment arms are planned to receive 
FOLFOX6/bevacizumab infusion on day 1 of a 14 day cycle (IV bevacizumab 
5mg/kg over 1 hour, oxaliplatin 85mg/m2
 and leucovorin 400 mg/m2 concurrently 
over 2 hours, bolus fluorouracil 400 mg/m2 after leucovorin, and continuous infusion 
of fluorouracil 2400 mg/m2 over 46 hours).  Patients on ARM A will receive 
Reolysin 3x1010 TCID50 over 1 hour on days 1-5 of cycle 2, 4, 6, 8 and alternate 
cycles thereafter.     
 
Duration of a treatment (in weeks) during the study is defined as follows: 
 
[last date of the treatment− first date of the treatment+ 1]/7, 
 
where the first and last date of the treatment is taken from respective treatment 
administration section of CRF TREATMENT REPORT.  
 
The following variables will be summarized using the data set of all treated patients: 
• Number of patients by cycle of therapy (Table 18) 
• Total number of cycles of treatment per patient (Table 19) 
• Total treatment duration (weeks) per patient (Table 20) 
7.4.2 
 Modifications of Protocol Therapy  
The administration of a drug in a cycle may be modified (delayed, omitted, reduced, 
interrupted, increased) because of toxicity or other reasons. For each drug, the 
following variables will be summarized using the data set of all treated patients: 
• Number of patients with at least one cycle delayed, reduced, omitted, reduced, 
interrupted, increased (Table 21) 
• Number of patients delayed, delayed, reduced, omitted, reduced, interrupted, 
increased by cycle and dose (Table 21) 
• Reason for these dose modifications (Table 21) 
7.4.3 
Cumulative dose, dose intensity and relative dose intensity  
The cumulative dose (TCID50) per patient for Reolysin is the total dose (TCID50) that 
the patient received. The cumulative dose (mg/kg) per patient for bevacizumab is 
defined as the sum over all cycles of total actual doses that patient received divided 
by the weight in a given cycle. The cumulative dose (mg/m2) per patient for 
oxaliplatin, leucovorin and fluorouracil (bolus and continuous) is defined as the sum 
over all cycles of the total actual dose received divided by the BSA in a given cycle. 
 
The actual dose intensity of Reolysin (TCID50/week) per patient is defined as: 
 
Reolysin Dose Intensity
= Cumulative dose of Reolysin (TCID50) −first cycle dose ofReolysin (TCID50) 
[last Reolysin dosing date −second Reolysin dosing date + 34]/7
. 


 
The actual dose intensity (mg/kg/week or mg/m2/week) per patient for bevacizumab, 
oxaliplatin, leucovorin and fluorouracil (bolus and continuous) is defined as the 
cumulative dose (mg/kg or mg/m2) divided by “treatment duration” (in weeks), where 
“treatment duration” per patient is defined as the duration from first day of drug 
administration to the last day of drug administration plus 14 days over all cycles in 
which the given drug is prescribed.   
 
The median and range of cumulative dose and actual dose intensity will be 
summarized in respectively Table 22 and Table 23.   
 
The relative dose intensity per patient is defined as the actual dose intensity 
(TCID50/week, mg/kg/week, mg/m2/week) divided by the planned weekly dose as 
assigned in the protocol, which is 0.75 TCID50/week for Reolysin (after first cycle), 
2.5/mg/kg/week for bevacizumab, 42.5 mg/m2/week for oxaliplatin, 200 mg/m2/week 
for leucovorin, 200 mg/m2/week for bolus fluorouracil, and 1200 mg/m2/week for 
continuous fluorouracil.  The patient relative dose intensities will be grouped 
according to the following categories: < 60%,  ≥ 60% - <80%, ≥ 80% - < 90%, ≥ 90% 
(Table 24).  
7.4.4 
Off Study Therapy 
The reason for off of each study therapy will be taken from End of Treatment Section 
of CRF END OF TREATMENT REPORT. 
 
The following information will be summarized for each of protocol treatment (Table 
25): 
• Number of patients off study treatment 
• Reason off protocol therapy 
7.5 
Efficacy 
7.5.1 
Progression Free Survival 
Progression Free Survival (PFS) will be calculated for all patients from the day of 
randomization until the first observation of objective disease relapse or progression 
(as recorded in CRF RELAPSE/PROGRESSION REPORT) or death due to any 
cause (CRF DEATH REPORT) as the (difference+1).   
 
A patient who goes on to receive anti-cancer therapy prior to documentation of 
disease relapse/progression or death will be censored on the earliest date cancer 
treatment began. 
 
If a patient has not relapsed/progressed, died, or receive anti-cancer therapy, PFS will 
be censored on the date of last disease assessment defined as the earliest test date of 
target lesion or non-target lesions (if patient has no target lesions). 
 
The comparison of PFS between the two treatment arms is the primary objective of 
this study.  The primary analysis will be the log-rank test (Table 26) stratified by the 
factors coded as: 
 


Stratification Factor (at randomization) 
 
 
KRAS status  
1 
= 
Wild 
Type 
3=Unknown 
2 = Mutated 
Adjuvant fluoropyrimidine-based therapy  
0 =Yes  
1 = No 
 
The hazard ratio of Reolysin combined with FOLFOX6/Bevacizumab (ARM A) over 
FOLFOX6/Bevacizumab alone (ARM B) and two-sided 95% CI will be calculated 
(Table 26) based on the Cox regression model stratified by KRAS status and whether 
djuvant fluoropyrimidine-based therapy was received, and with treatment arm coded 
as ARM A=1 and ARM B=0.  A Kaplan-Meier curve for proportions of patients 
alive and free of progression in each treatment arm will be displayed.  The 95% 
confidence intervals for the median PFS will be computed using the method of 
Brookmeyer and Crowley [2].  One-year PFS rates, based on Kaplan-Meier 
estimates, will be calculated by treatment arm.  
 
The primary analysis of PFS will include all randomized patients, with patients in the 
safety run-in phase excluded.  A sensitive analysis will be performed to include all 
patients with patients in the safety run-in phase included in ARM A for analysis. 
   
In order to assess the influence of the potential prognostic factors shown and coded 
below on the comparison of PFS between treatment arms in an explorative 
multivariate analysis, a stratified Cox regression model will be used with all variables 
(treatment arm and prognostic factors) included to estimate hazard ratios and 95% 
confidence intervals. 
 
Prognostic factors (at baseline) 
 
 
Gender 
0 = Female 
1 = Male 
Age 
0 = ≥ 65 
1 = <65 
LDH 
0 = >UNL  
1 = ≤ UNL  
Alkaline phosphatase 
0 = >UNL 
1 = ≤ UNL  
Hemoglobin 
0 = >LLN  
1 = ≤ LLN  
 
No interactions will be considered in the model.  Univariate comparisons of PFS 
between levels of prognostic factors listed above will be performed using the 
stratified log-rank test (Table 26).   
 
A frequency table will also be provided describing PFS events and censorings as 
follows (Table 27): 
• Number of patients who had a PFS event (objective relapse/progression, 
death without documented relapse/progression) 
• Number of patients censored with reasons of censoring (other cancer 
treatment, alive at the clinical cut-off without progression, lost to 
follow-up) 
 
Since patients are still assessed after receiving other cancer treatments, a sensitivity 
analysis will be performed by not censoring patients who received other anti-cancer 
therapy. 


7.5.2 
Progression Free Survival by Subsets 
For each level of the following baseline variables, a Kaplan-Meier plot of PFS by 
treatment arm will be produced as well as medians with 95% C.I. and the hazard ratio 
(unstratified) with 95% CI of ARM A over ARM B(Table 28): 
 
• Performance status at baseline: ECOG 0-1, 2 
• Age: <65, ≥65 
• Gender: female, male 
7.5.3 
CEA Levels 
CEA is measured at baseline, every 4 weeks (end of every second cycle) during 
protocol treatment, four weeks after completion of protocol therapy, and every three 
months thereafter until relapse/PD for patients with CR, PR, or SD ongoing. The 
mean and standard deviation of CEA levels at baseline and the change of CEA levels 
from baseline at each assessment time during protocol treatment and 4 weeks after 
completion of protocol treatment will be presented.  The change of CEA levels from 
baseline at each time during and 4 weeks after protocol treatment between treatment 
groups will be assessed using a Wilcoxon rank sum test (Table 29).   
7.5.4 
Overall survival 
For all randomized patients, survival is calculated from the day of randomization (as 
recorded in Centralized Randomization File) to death (CRF DEATH REPORT).  For 
alive patients, survival is censored at the last day the patient is known alive (LKA) as 
the last recorded date known alive.  Survival time (in months) is defined as  
 
[(date of death or LKA − date of randomization) + 1)]/30.4375. 
 
Analyses for survival will be similar to that for PFS as previously described. A 
Kaplan-Meier curve for survival in each treatment arm will be displayed.  In the 
primary analysis, median survival for the two treatments will be compared using the 
stratified log-rank test (Table 30).  A stratified Cox regression model will estimate 
the ARM A over ARM B PFS hazard ratio and 95% CI (Table 30).  In addition, a 
stratified Cox regression model adjusted for covariates will be applied to verify the 
impact of the prognostic factors on the treatment effect (Table 30).  Univariate 
comparisons of survival between levels of prognostic variables listed will be 
performed using the stratified log-rank test (Table 30). 
 
Coding for treatment arm, stratification variables and prognostic factors is identical to 
that presented in Section 7.5.1. 
7.5.5 
Overall Survival by Subsets 
Subset analyses performed for PFS will also be performed for survival (Table 31). 


7.5.6 
Treatment Response 
All patients will have their best response on study classified every 8 weeks during 
protocol treatment, using the RECIST (Response Evaluation Criteria in Solid Tumors) 
criteria 1.1.  The best response to protocol treatment is determined by investigators 
for patients who permanently discontinued protocol treatment and collected in “best 
objective response (overall) to protocol therapy” section of CRF END OF 
TREATMENT REPPORT.  For patients who are still on treatment and followed for 
response at final clinical cut-off, their best response is defined as the “best verified” 
response they have achieved up to the time of clinical cut-off determined by NCIC 
CTG Senior Investigator based on data on “Response Assessment” section of CRF 
TREATMENT REPORT. 
Best response to protocol treatment will be summarized for all randomized patients 
(Table 32). 
 
The primary analysis of response will be the comparison of the objective response 
rate (CR+PR) between treatment arms among all the randomized patients using the 
Cochran-Mantel-Haenszel (CMH) statistic adjusted for stratification factor for all 
randomized patients (Table 33).   
 
Objective response rate will also be compared between treatment arms using the 
CMH statistic adjusted for stratification factors for all response evaluable patients. 
 
In addition, a stratified logistic regression model adjusted for covariates will be 
applied to verify the impact of the prognostic factors on the treatment effect (Table 
33).  Univariate comparisons of response between levels of prognostic variables will 
be performed using stratified logistic regression (Table 33).  For all stratified 
logistic regression models, estimates of the odds ratio(s) and 95% confidence 
interval(s) will be given. 
 
Stratified logistic regression odds ratios will be estimated using PROC PHREG in 
SAS.  A dummy time variable will be created, where all responders will be classified 
as events with an arbitrary time = t0, and non-responders as censored with time t1, 
where t1 > t0.  The DISCRETE option will be used for tied observations. 
 
Coding for treatment, stratification variable and prognostic factors is identical to that 
presented in Section 7.5.1. 
7.5.7 
Treatment Response by Subsets  
For all randomized patients, the objective response rate will be presented for each 
treatment arm in the subgroups defined by the categorical variables listed below 
(Table 34).  The same table will be presented for all response evaluable patients. No 
formal comparisons are planned: 
 
• gender (male, female) 
• age (<65 years, ≥65 years) 
• performance status at baseline (ECOG 0-1, ECOG 2) 


7.5.8 
Duration of Response 
For patients whose best responses are classified as CR or PR at any reporting period 
during the study, the duration of response is calculated as the time from CR or PR is 
documented (whichever is the first) until first observation of objective disease relapse 
or progression or death due to any cause.  If a patient has not relapsed/progressed or 
died, duration of response will be censored on the date of last disease assessment 
defined as the earliest test date of target lesion or non-target lesions (if patient has no 
target lesions, whichever is latest. 
 
All randomized patients with CR or PR are included in this analysis.  The median 
duration of response and associated 95% confidence intervals will be computed and 
compared by the stratified log-rank test adjusting for stratification factors at 
randomization (Table 35).   
7.6 
Safety  
 
The safety analyses will base on the All Treated population defined in Section 6.   
Adverse events and laboratories are graded and categorized using the NCI CTCAE 
except where CTCAE grades are not available. 
7.6.1 
Adverse Events 
Adverse events (AEs) will be recorded on the Adverse Events (AE) sections of CRF 
TREATMENT REPORT, 4-WEEK POST TREATMENT REPORT, and FOLLOW 
UP REPORT (ongoing or new grade 3 or higher AEs which are thought to be related 
to protocol treatment).  Severity grade 5 will be combined with grade 4 for the 
purpose of this report. Adverse events reported on study treatment (“AE” sections in 
CRF TREATMENT REPORT and 4-WEEK POST TREATMENT REPORT) are 
defined as acute (on treatment) adverse events.  Adverse events reported on “AE” 
section of CRF FOLLOW UP REPORT will be defined as delayed (late) AEs.  
 
Drug (Reolysin, bevacizumab, or FOLFFOX6) related adverse events are those 
events with a relation to protocol therapy of 3=possible, 4=probable or 5=definite. 
 
Severe adverse events are those events reported with a NCI CTC Grade of 3 or 
higher. 
 
Comparisons between treatment arms on acute and delayed adverse events (severe vs. 
other) will be carried out using a two sided Fisher’s exact test at an alpha level of 5% 
for adverse events with incidence of at least 10% at grade 3 or higher in one of 
treatment arms. 
 
The following variables are summarized.  Tabulations of overall adverse events will 
be presented by treatment group. 
 
• Acute adverse events: worst CTC grade per patient by arm (Table 36) 
• Any acute adverse events, severe acute adverse events: worst CTC grade per 
patient by arm (Table 37) 
• Drug related acute adverse events: worst CTC grade per patient (Table 38) 
• Delayed adverse events: worst CTC grade per patient by arm (Table 39) 


7.6.2 
Laboratory Evaluations 
Laboratory evaluations obtained reported on CRF TREATMENT REPORT and 
4-WEEK POST TREATMENT REPORT) and on CRF FOLLOW UP REPORT will 
be included in the calculation for respective acute and late laboratory adverse events.  
Laboratory results will be classified according to the NCI CTCAE. Tabulations of 
laboratory adverse events will be presented by treatment group. 
 
7.6.2.1 Hematology 
• Hemoglobin, platelets, WBC, Neutrophils, lymphocytes: worst CTC grade 
per patient (Table 40) 
 
7.6.2.2 Biochemistry 
• Serum creatinine, bilirubin, alkaline phosphatase, AST, ALT, LDH, total 
protein: worst CTC grade per patient (Table 41) 
7.6.3 
Deaths on Study/Adverse Events Leading to Discontinuations due to 
Toxicity 
• All Deaths: number of patients who died and cause of death, by treatment group, 
from CRF DEATH REPORT (Table 42) 
• Deaths within 4 weeks of last treatment: number of patients who died and cause 
of death from CRF DEATH REPORT, by treatment group (Table 43) 
• Adverse events leading to discontinuations of Reolysin, bevcizumab, FOLFFOX6: 
number of patients with adverse events leading to discontinuations of treatment as 
identified from CRF END OF TREATMENT REPORT, by treatment group 
(Table 44)  
 
5.6.3 
Other Safety 
 
5.6.3.1 Hospitalizations 
Number of patients and cycles for which patients were hospitalized will be 
summarized by treatment group (Table 45).  
 
5.6.3.2 Transfusions 
Patients who received transfusions during protocol therapy will be summarized as 
follows: 
• Number of patients who received any blood transfusions (red blood cells, platelets, 
and/or other) (Table 46)  
7.7 
Concomitant Medications and Other Anti-Cancer Treatments 
 
Concomitant medication is defined as medication, other than protocol therapy, which 
is taken by patients any time on treatment or after end of treatment. Patients may also 
receive any other anti-cancer treatment after being taken off protocol treatment. 
 
• Concomitant medications for patients during protocol treatment by treatment 
group (Table 47) 
• Anti-cancer treatments for patients during protocol treatment or 4 weeks after 
completion of protocol treatment, by treatment group (Table 48) 


• Anti-cancer treatments for patients during follow-up, by treatment group (Table 
48) 
7.8 
Quality of Life 
 
The quality of life of patients in this study is assessed by using EORTC QLQ-C30 
(version 3.0) at baseline, during chemotherapy (Day 1 cycle 5), off treatment (off 
study or week 4 after completion of protocol treatment). The following are the 
scoring algorithms for EORTC QLQ-C30 and Skindex-16.  
7.8.1 
Scoring Algorithms for EORTC QLQ-C30 and Skindex-16 
The EORTC core questionnaire, QLQ-C30 (version 3.0), consists of five Functional 
Scales, Global Health Status, and nine Symptoms Scales. Each scale in the 
questionnaire will be scored (0 to 100) according to the EORTC recommendations in 
the EORTC QLQ-C30 Scoring Manual.  The scoring method for EORTC QLQ-C30 
is summarized below.  In this summary Qi refers to the i-th question on the 
QLQ-C30. 
 
Functional scale’s scores: 
• Physical functioning: 
 
(1 - ((Q1+Q2+Q3+Q4+Q5)/5 -1)/3) * 100 
• Role functioning: 
 
 
(1 - ((Q6+Q7)/2-1)/3) * 100 
• Emotional functioning:  
(1 - ((Q21+Q22+Q23+Q24)/4-1)/3) * 100 
• Cognitive functioning: 
 
(1 - ((Q20+Q25)/2-1)/3) * 100 
• Social functioning:  
 
(1 - ((Q26+Q27)/2-1)/3) * 100 
 
Global health status score: 
• Global QOL: 
((Q29+Q30)/2-1)/6 * 100 
 
Symptom scale’s scores: 
• Fatigue: 
 
 
 
 
((Q10+Q12+Q18)/3-1)/3 * 100 
• Nausea and vomiting: 
 
((Q14+Q15)/2-1)/3 * 100 
• Pain: 
 
 
 
 
 
((Q9+Q19)/2-1)/3 * 100 
• Dyspnea: 
 
 
 
 
((Q8-1)/3 * 100 
• Insomnia:  
 
 
 
(Q11-1)/3 * 100 
• Appetite loss: 
 
 
 
(Q13-1)/3 * 100 
• Constipation: 
 
 
 
(Q16-1)/3 * 100 
• Diarrhea: 
 
 
 
 
(Q17-1)/3 * 100 
• Financial difficulties: 
 
(Q28-1)/3 * 100 
 
Missing items in a scale will be handled by the following methods: Values will be 
imputed for missing items by “assuming that the missing items have values equal to 
the average of those items which are present” for any scale in which at least half the 
items are completed.  A scale in which less than half of the items are completed will 
be treated as missing. 


7.8.2 
Data Sets 
The analyses of quality of life data will be restricted to randomized patients who have 
a measurement at baseline and at least one measurement after baseline.  
7.8.3 
Compliance 
Compliance will be described, by time of evaluation, by the number and percentage 
of subjects who filled out a questionnaire (per subject, at least one question answered) 
in that period of evaluation. The denominator used in calculating the percentage for 
baseline will be all randomized subjects.  The number of subjects who are treated on 
day 1 cycle 5) or who were off treatment and had assessment at time of off protocol 
treatment or 4 weeks after completion of protocol treatment will be used for other two 
time points (Table 49).   
7.8.4 
Analyses of QOL 
 
7.8.5.1 Baseline and Change Score Analysis 
Descriptive statistics for EORTC QOL-C30 scores (mean, standard deviation) will be 
presented for each scale at baseline.  The same statistics will be generated at each 
time of post-baseline evaluation.  The change scores from baseline at each time of 
post-baseline evaluation between treatment groups will be assessed using a Wilcoxon 
rank sum test for each EORTC QOL-C30 (Table 50 and Table 51). 
 
7.8.5.3 Proportions of Deterioration and Improving or Stable for EORTC 
QLQ-C30 at Post-baseline Assessment 
The deterioration is defined as a change score from baseline which is –10 points or 
lower.  Fisher’s exact test will be used to compare the proportions of patients with 
deterioration in each of QLQ domains, items, and scales at two post-baseline 
assessment time points between two treatment arms (Table 52). 
 
The proportions of patients who had improving (defined as change score from 
baseline of 10 points or higher) or stable (defined as change score from baseline of 
between –10 and 10 points) QOL domain, items, and scales at two post baseline 
assessment time points will also be compared between two treatment arms using 
Fisher’s exact test (Table 52). 
8. Data Conventions 
 
When converting a number of days to other units, the following conversion factors 
will be used: 
1 year = 365.25 days 
1 month = 30.4375 days 
 
When either day or month of a date is missing, the missing day and/or month will be 
imputed by the midpoint within the smallest known interval.  For example, if the day 
of the month is missing for any date used in a calculation, the 15th of the month will 
be used to replace the missing day.  If the month and day of the year are missing for 
any date used in a calculation, the first of July of the year will be used to replace the 
missing date. 


9. Appendices 
 
Appendix 1: Tables and Figures 
 
Table 1:  Patient Disposition 
 
Data set:  All Randomized Patients 
 
Number of patients (%) 
 
ARM A 
ARM B 
Total 
Randomized  
N=*** 
N=*** 
N=*** 
 
 
 
 
Treated 
*** (**) 
*** (**) 
*** (**) 
  On study 
*** (**) 
*** (**) 
*** (**) 
  Off study (1)   
*** (**) 
*** (**) 
*** (**) 
 
 
 
 
Never Treated 
*** (**) 
*** (**) 
*** (**) 
(1) Off all study therapy 
 
Table 2:  Follow-up of Patients 
 
Data set:  All Randomized Patients 
 
Number of patients (%) 
 
ARM A 
ARM B 
Total 
Number of patients alive 
*** (%) 
*** (%) 
*** (%) 
 
 
 
 
Fellow-up (months) 
 
 
 
 
median 
** 
** 
** 
  
Minimum-maxiumu   
**-**  
**-** 
**-** 
 
 
 
 
 
 


Table 3:  Accrual by Center 
 
Data set:  All Randomized Patients 
 
Number of patients (%) 
 
ARM A 
N=*** 
ARM B 
N=*** 
Total 
N=*** 
Center #1 
*** (**) 
*** (**) 
*** (**) 
Center #2 
*** (**) 
*** (**) 
*** (**) 
Center #3 
*** (**) 
*** (**) 
*** (**) 
... 
*** (**) 
*** (**) 
*** (**) 
 
 
Table 4:  Accrual by Stratification Factor at Randomization 
 
Data set:  All Randomized Patients 
 
Number of patients (%) 
 
ARM A 
N=*** 
ARM B 
N=*** 
Total 
N=*** 
KRAS Status 
 
 
 
 
Wild type 
** (**) 
** (**) 
** (**) 
 
Mutated 
** (**) 
** (**) 
** (**) 
 
Unknown 
** (**) 
** (**) 
** (**) 
Adjuvant fluoropyrimidine-based therapy 
 
 
 
 
Yes 
** (**) 
** (**) 
** (**) 
 
No 
** (**) 
** (**) 
** (**) 
Source:  Centralized Randomization File 
 
 
Figure 1:  Accrual by Calendar Time 
 
 
 
 
 


Table 5:  Eligibility and Reasons for Ineligibility and Major Protocol Violations 
Data set:  All Randomized Patients 
 
Number of Patients (%) 
 
ARM A 
N=*** 
ARM B 
N=*** 
Total 
N=*** 
Eligible 
*** (**) 
*** (**) 
*** (**) 
Not Eligible 
*** (**) 
*** (**) 
*** (**) 
Reason for ineligibility  
 
 
 
 
<Reason 1> 
** 
** 
** 
 
<Reason 2> 
** 
** 
** 
 
... 
** 
** 
** 
Major protocol violation 
 
<violation type 1> 
 
<violation type 2> 
 
… 
 
** 
** 
 
** 
** 
 
** 
** 
 
Table 6:  Treatment as Randomized Versus as Treated 
Data set:  All Randomized Patients 
 
Number of Patients (%) 
Randomized Arm 
 
ARM A 
N=*** 
ARM B 
N=*** 
Total 
N=*** 
Treatment received 
 
 
 
 
Reolysin+FOLFOX6/bevacizumab 
*** (**) 
*** (**) 
*** (**) 
 
FOLFOX6/bevacizumab 
*** (**) 
*** (**) 
*** (**) 
 
Reolysin only 
*** (**) 
*** (**) 
*** (**) 
 
FOLFOX6 only 
*** (**) 
*** (**) 
*** (**) 
 
bevacizumab only 
*** (**) 
*** (**) 
*** (**) 
 
Not treated 
*** (**) 
*** (**) 
*** (**) 
 
 
 


Table 7:  Pretreatment Characteristics at Baseline 
Data set:  All Randomized Patients 
 
Number of patients (%) 
 
ARM A 
ARM B 
Total 
Gender  
 
 
 
    Female 
** (**) 
** (**) 
** (**) 
    Male 
** (**) 
** (**) 
** (**) 
Age (years) 
 
 
 
    N 
    Median 
    Min - Max 
** 
** 
** - ** 
** 
** 
** - ** 
** 
** 
** - ** 
     < 65 
     ≥ 65 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
ECOG Performance Status 
 
 
 
    0 
** (**) 
** (**) 
** (**) 
    1 
** (**) 
** (**) 
** (**) 
    2 
** (**) 
** (**) 
** (**) 
Type of Malignancy 
 
 
 
    Colon only 
**(**) 
** (**) 
** (**) 
    Rectum only 
 
** (**) 
** (**) 
** (**) 
    Colon and rectum 
** (**) 
** (**) 
** (**) 
Months from First Histological Diagnosis to Randomization 
 
 
 
    N 
    Median 
    Min - Max 
** 
** 
** - ** 
** 
** 
** - ** 
** 
** 
** - ** 
Months from First Relapse to Randomization 
 
 
 
    N 
    Median 
    Min - Max 
** 
** 
** - ** 
** 
** 
** - ** 
** 
** 
** - ** 
Histology  
 
Adeno-carcinoma 
 
Squamous  
 
Other 
 
**(**) 
** (**) 
** (**) 
 
**(**) 
** (**) 
** (**) 
 
** (**) 
** (**) 
** (**) 
Grade at diagnosis 
 
 
 
 
Low 
 
Moderate 
 
High 
 
Unknown 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
K-ras mutation status 
 
 
 
 
Wild-type 
 
Mutated 
 
Unknown 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
EGFR Protein 
 
Positive 
 
Negative 
 
Unknown 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 
** (**) 
** (**) 
** (**) 
EGFR Copy Number 
 
Normal 
 
Increased-Amplified 
 
Unknown 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 
** (**) 
** (**) 
** (**) 


EGFR Mutation 
 
Yes 
 
No 
 
Unknown 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
BRAF mutation status 
 
Wild 
 
Mutated 
 
Unknown 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
PIK3CA mutation status 
 
Wild 
 
Mutated 
 
Unknown 
 
** (**) 
** (**) 
** (**) 
 
** (**) 
** (**) 
** (**) 
 
** (**) 
** (**) 
** (**) 
 
Table 8:  Prior Surgery 
Data set:  All Randomized Patients 
 
Number of Patients (%) 
 
ARM A 
N=*** 
ARM B 
N=*** 
Total 
N=*** 
Prior surgery 
 
 
 
 
No 
*** (**) 
*** (**) 
*** (**) 
 
Yes 
*** (**) 
*** (**) 
*** (**) 
 
 
 
 
Procedure / Site 
 
 
 
 
Procedure / Site 1 
*** (**) 
*** (**) 
*** (**) 
 
Procedure / Site 2 
*** (**) 
*** (**) 
*** (**) 
              .... 
*** (**) 
*** (**) 
*** (**) 
 
Table 9:  Prior Radiotherapy 
Data set:  All Randomized Patients 
Number of patients (%) 
 
ARM A 
N=*** 
ARM B 
N=*** 
Total 
N=*** 
Any Prior Radiotherapy 
No 
Yes  
 
*** (**) 
*** (**) 
 
*** (**) 
*** (**) 
 
*** (**) 
*** (**) 
Site of Any Prior Radiotherapy(1) 
 
 Site #1 
 
Site #2  
 
Site #3 
... 
 
*** (**) 
*** (**) 
*** (**) 
 
*** (**) 
*** (**) 
***(**) 
 
*** (**) 
*** (**) 
***(**) 
Total Dose of radiotherapy (cGy) 
*** (**) 
***(**) 
***(**) 
Best Response 
 
 CR/PR 
 
SD  
 
PD 
 
*** (**) 
*** (**) 
*** (**) 
 
*** (**) 
*** (**) 
***(**) 
 
*** (**) 
*** (**) 
***(**) 
(1) Patient may have more than one site of radiotherapy 
 
 


Table 10:  Prior Systemic Therapy 
Data set:  All Randomized Patients 
Number of patients (%) 
 
ARM A 
N=*** 
ARM B 
N=*** 
Total 
N=*** 
With at least one prior systemic therapy 
*** (**) 
*** (**) 
*** (**) 
Therapy setting/intent (1) 
 
Adjuvant 
 
Neo-adjuvant 
 
Advanced/recurrent/metastatic 
 
Other 
 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
 
Prior adjuvant fluoropyrimidine-based therapy regimens 
 
Yes 
 
No 
 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
Prior systemic drug /agent(2) 
 
Drug 1 
 
Drug 2 
 
… 
 
*** (**) 
*** (**) 
… 
 
*** (**) 
*** (**) 
… 
 
*** (**) 
*** (**) 
… 
(1) Patients may have more than one setting/intent (2) Patient may have more than one drug or regimen 
 
 
 


Table 11:  Extent of Disease (Target Lesions) 
Data set:  All Randomized Patients 
 
Number of Patients with Target Lesions (%) 
 
ARM A 
N=*** 
ARM B 
N=*** 
Total 
N=*** 
Presence of Target Lesions 
 
 
 
    Patients with at least one target lesion 
*** (**) 
*** (**) 
*** (**) 
 
 
 
 
Number of Target Lesions 
 
 
 
              1 
*** (**) 
*** (**) 
*** (**) 
              2 
*** (**) 
*** (**) 
*** (**) 
              3 
*** (**) 
*** (**) 
*** (**) 
              4 
*** (**) 
*** (**) 
*** (**) 
… 
 
 
 
 
 
 
 
Largest Target Lesion in cm 
 
 
 
              < 2 
*** (**) 
*** (**) 
*** (**) 
              2-5 
*** (**) 
*** (**) 
*** (**) 
              > 5-10 
*** (**) 
*** (**) 
*** (**) 
              > 10 
*** (**) 
*** (**) 
*** (**) 
 
 
 
 
 Site of Target Lesion(1) 
 
 
 
 
Abdomen 
*** (**) 
*** (**) 
*** (**) 
 
Adrenals 
*** (**) 
*** (**) 
*** (**) 
 
Bone 
*** (**) 
*** (**) 
*** (**) 
 
Brain 
*** (**) 
*** (**) 
*** (**) 
 
Liver 
*** (**) 
*** (**) 
*** (**) 
 
Lung 
*** (**) 
*** (**) 
*** (**) 
 
Nodes 
*** (**) 
*** (**) 
*** (**) 
 
Pleura 
*** (**) 
*** (**) 
*** (**) 
 
Skin 
*** (**) 
*** (**) 
*** (**) 
 
Subcutaneous Tissue 
*** (**) 
*** (**) 
*** (**) 
              .... 
*** (**) 
*** (**) 
*** (**) 
 
 
 
 
Procedures for Evaluating Target Lesions 
 
 
 
 
Imaging (2) 
*** (**) 
*** (**) 
*** (**) 
 
Clinical Exam 
*** (**) 
*** (**) 
*** (**) 
 
Imaging (2) and Physical Exam 
*** (**) 
*** (**) 
*** (**) 
 
 
 
 
(1) Patients may have target lesions at more than one site 
(2) Bone scan, CT scan, MRI, PET-CT, or X-Ray 
 
 


Table 12:  Extent of Disease (All Non-Target Lesions) 
Data set:  All Randomized Patients 
 
Number of Patients (%) 
 
ARM A 
N=*** 
ARM B 
N=*** 
Total 
N=*** 
Presence of Non-Target Lesions 
 
 
 
 
Patients with at least one non-target lesion 
*** (**) 
*** (**) 
*** (**) 
 
 
 
 
Site of Non-target lesion(1)  
 
 
 
 
Abdomen 
*** (**) 
*** (**) 
*** (**) 
 
Adrenals 
*** (**) 
*** (**) 
*** (**) 
 
Bone 
*** (**) 
*** (**) 
*** (**) 
 
Brain 
*** (**) 
*** (**) 
*** (**) 
 
Liver 
*** (**) 
*** (**) 
*** (**) 
 
Lung 
*** (**) 
*** (**) 
*** (**) 
 
Nodes 
*** (**) 
*** (**) 
*** (**) 
 
Pleura 
*** (**) 
*** (**) 
*** (**) 
 
Skin 
*** (**) 
*** (**) 
*** (**) 
 
Subcutaneous Tissue 
*** (**) 
*** (**) 
*** (**) 
 
Other 
*** (**) 
*** (**) 
*** (**) 
 
 
 
 
Number of disease sites 
 
 
 
              1 
*** (**) 
*** (**) 
*** (**) 
              2 
*** (**) 
*** (**) 
*** (**) 
              3 
*** (**) 
*** (**) 
*** (**) 
              4 
*** (**) 
*** (**) 
*** (**) 
              ≥5 
*** (**) 
*** (**) 
*** (**) 
Procedures for Evaluating Target Lesions 
 
 
 
 
Imaging (2) 
*** (**) 
*** (**) 
*** (**) 
 
Clinical Exam 
*** (**) 
*** (**) 
*** (**) 
 
Imaging (2) and Physical Exam 
*** (**) 
*** (**) 
*** (**) 
(1) Patients may have non-target lesions at more than one site 
(2) Bone scan, CT scan, MRI, PET-CT, or X-Ray 
 
 
 


Table 13:  Baseline Hematology 
 
Data set:  All Randomized Patients 
 
Number of Patients (%) 
 
 
ARM A N = *** 
ARM B 
N = *** 
Total 
N=*** 
 
 
 
 
WBC 
 
 
 
 
Grade 0 
** (**) 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
 
 
 
 
Absolute neutrophil count (ANC) 
 
 
 
 
Grade 0 
** (**) 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
 
 
 
 
Platelet 
 
 
 
 
Grade 0 
** (**) 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
 
 
 
 
Lymphocytes 
 
 
 
 
Grade 0 
** (**) 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
 
 
 
 
(1) Not done or outside the 7-day window prior to start of therapy 
 


Table 14:  Baseline Chemistry 
Data set:  All Randomized Patients 
 
Number of Patients (%) 
 
ARM A N = *** 
ARM B 
N = *** 
Total 
N=*** 
Total bilirubin 
 
 
 
 
Grade 0 
** (**) 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
Alkaline phosphatase 
 
 
 
 
Grade 0 
** (**) 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
ALT 
 
 
 
 
Grade 0 
** (**) 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
AST 
 
 
 
 
Grade 0 
** (**) 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
LDH 
 
 
 
 
Grade 0 
** (**) 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
Serum Creatinine 
 
 
 
 
Grade 0 
** (**) 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
Total Protein 
 
 
 
 
Grade 0 
** (**) 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
(1) Not done or outside the 7-day window prior to start of therapy 
 
 


Table 15:  Baseline Symptoms Status 
Data set:  All Randomized Patients (ARM A arm) 
 
Number of patients (%) 
N=*** 
 
Worst grade 
Any grade 
 
NR 
1 
2 
3 
4 
 
Patients with any symptom/ 
finding at baseline 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
Patients 
with 
particular 
symptom/finding, 
within 
body system:  
Body System 1(1) 
Event 1 
Event 2 
Event 3 
...  
Body System 2(1) 
Event 1  
...  
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
(1) Patients may have more than one event within a body system 
 
NOTE:  Same table to be made for ARM B arm 
 
Table 16:  Prior Concomitant Medications (Baseline) 
Data set:  All Randomized Patients 
 
Number of patients (%) 
 
ARM A 
N=*** 
ARM B 
N=*** 
Total 
N=*** 
Any prior concomitant medication (1)  
 
 
 
    No 
** (**) 
** (**) 
** (**) 
    Yes 
** (**) 
** (**) 
** (**) 
Drug Name 1                 
** (**)    
** (**)     
 
** (**)      
Drug Name 2 
** (**) 
** (**) 
** (**) 
.... 
 
 
 
 
Table 17:  Past or Current Major Medical Problems  
Data set:  All Randomized Patients 
 
Number of patients (%) 
 
ARM A 
N=*** 
ARM B 
N=*** 
Total 
N=*** 
Patients Reporting at least one past or current  major 
medical problem at baseline 
** (**) 
** (**) 
** (**) 
Medical Problem(1) 
 
 
 
... 
** (**) 
** (**) 
** (**) 
(1) patients may report more than one medical problem reported 
 


Table 18:  Number of Patients by Cycle 
Data Set: All Treated Patients  
 
Number of Patients (%) 
 
 
ARM A 
N=*** 
ARM B 
N=*** 
Cycle 
1 
** (**) 
** (**) 
 
 
2 
** (**) 
** (**) 
 
 
3 
** (**) 
** (**) 
 
 
... 
 
 
 
 
 
 
 
 
Table 19:  Number of Cycles of Protocol Therapy per Patient 
Data Set: All Treated Patients  
 
ARM A 
ARM B 
Number of Cycles: 
 
 
 
N 
*** 
*** 
 
Median  
* 
* 
 
Min – Max 
* - * 
* - * 
 
 
 
 
 
 
Table 20:  Total treatment Duration of Protocol Therapy 
Data Set: All Treated Patients  
 
ARM A 
ARM B 
Duration in weeks: 
 
 
 
N 
*** 
*** 
 
Median  
* 
* 
 
Min – Max 
* - * 
* - * 
 
 
 
 
Note: Table will be done for each of protocol treatments.  
 
 


Table 21:  Number of Patients with Modifications of Protocol Therapy  
Data Set: All Treated Patients 
 
ARM A 
 
Reolysi
n 
Bevacizu
mab 
Oxalipl
atin 
Leucovarin 
Bolos 
Fluorouracil 
Continuous 
Fluorouracil 
Patients with at least one 
cycle with (type of 
modification) over all cycles 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 
 
 
 
 
 
 
Reason for (type of 
modification) 
 
 
 
 
 
 
 
Reason 1 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 
… 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 
 
 
 
 
 
 
Dose reduction by cycle 
 
 
 
 
 
 
 
Cycle 
1 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 
 
 
2 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 
 
 
... 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
Note: Similar table will be done for ARM B and each type of dose modification 
 
Table 22:  Cumulative Dose 
Data Set: All Treated Patients 
 
ARM A 
 
Reolysin 
Bevaci
zumab 
Oxaliplatin 
 
Leucovarin 
Bolos 
Fluorouracil 
Continuous 
Fluorouracil 
Cumulative dose 
per patient 
(<unit>) 
 
 
 
 
 
 
 
N 
*** 
*** 
*** 
*** 
*** 
*** 
 
Mean (SD) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 
Median 
** 
** 
** 
** 
** 
** 
 
Min-Max 
** - ** 
** - ** 
** - ** 
** - ** 
** - ** 
** - ** 
Note: Similar table will be done for ARM B 
 
Table 23:  Actual Dose Intensity 
Data Set: All Treated Patients 
 
ARM A 
 
Reolysin 
Bevacizu
mab 
Oxaliplatin 
 
Leucovarin 
Bolos 
Fluorouracil 
Continuous 
Fluorouracil 
Dose intensity 
 
 
 
 
 
 
 
N 
*** 
*** 
*** 
*** 
*** 
*** 
 
Mean (SD) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 
Median 
** 
** 
** 
** 
** 
** 
 
Min-Max 
** - ** 
** - ** 
** - ** 
** - ** 
** - ** 
** - ** 
Note: Similar table will be done for ARM B 
 
 
 


Table 24:  Relative Dose Intensity 
 
Data Set: All Treated Patients 
 
 
ARM A 
 
Reolysin 
Bevacizu
mab 
Oxaliplatin 
 
Leucovarin 
Bolos 
Fluorouracil 
Continuous 
Fluorouracil 
Relative Dose 
intensity  
 
 
 
 
 
 
 
 
 
 
 
 
 
 ≥ 90% planned 
intensity  
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 ≥ 80% - < 90% 
planned intensity  
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 ≥ 60% - < 80% 
planned intensity 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 < 60% planned 
intensity   
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
 
 
 
 
 
 
 
 
Note: Similar table will be done for ARM B 
 
Table 25:  Off Protocol Therapy Summary 
Data set:  All Treated Patients 
 
Number of patients (%) 
 
ARM A 
N = *** 
ARM B 
N = *** 
Patients off (type of) protocol therapy 
 
N = ** (**) 
 
N = ** (**) 
       Reason off protocol therapy 
Treatment Completed 
Progressive Disease (objective) 
Symptomatic Progression 
Intercurrent Illness – adverse events unrelated to 
 treatment 
Adverse events related to protocol therapy 
Patient Refusal (not related to adverse event) 
Death 
Other Reason 
 
 
** 
** 
** 
** 
** 
** 
 
** 
** 
** 
** 
** 
 
** 
** 
** 
** 
** 
** 
 
** 
** 
** 
** 
** 
 
Note: Table will be done for each of protocol regiments (bevacizumab, FOLFOX6, 
Reolysin) 
 
 
 
 


Table 26:  Log Rank and Cox Regression Model for Progression Free Survival 
 
Data set:  All Randomized Patients 
 
N 
Univariate Analysis(1) 
Multivariate Analysis(2) 
Treatment Arm/ 
Prognostic Factors at  
Baseline 
 
Median PFS 
(Months) 
1 year PFS Rate 
(95% C. I.) 
Hazard 
Ratio(4) 
(95% CI) 
Log-rank 
p-value 
Hazard 
Ratio(4)  
(95% C.I.) 
P-value 
from Cox 
regression 
Treatment arm 
 
 
 
 
0.*** 
 
0.*** 
 
ARM A 
*** 
**.** 
0.*** (0.***-0.***) 
**.** 
 
**.** 
 
 
ARM B 
*** 
**.** 
0.*** (0.***-0.***) 
(**.**,**.**) 
 
(**.**,**.**) 
 
 
 
 
 
 
 
 
 
Gender 
 
 
 
 
0.*** 
 
0.*** 
 
Male 
*** 
**.** 
0.*** (0.***-0.***) 
NC (3) 
 
**.** 
 
 
Female 
*** 
**.** 
0.*** (0.***-0.***) 
 
 
(**.**,**.**) 
 
 
 
 
 
 
 
 
 
Age 
 
 
 
 
0.*** 
 
0.*** 
 
<65 
*** 
**.** 
0.*** (0.***-0.***) 
NC 
 
**.** 
 
 
≥65 
*** 
**.** 
0.*** (0.***-0.***) 
 
 
(**.**,**.**) 
 
 
 
 
 
 
 
 
 
LDH 
 
 
 
 
0.*** 
 
0.*** 
 
UNL 
*** 
**.** 
0.*** (0.***-0.***) 
NC 
 
**.** 
 
 
>UNL 
*** 
**.** 
0.*** (0.***-0.***) 
 
 
(**.**,**.**) 
 
 
 
 
 
 
 
 
 
 
Alkaline phosphatase 
 
 
 
 
0.*** 
 
0.*** 
 
UNL 
*** 
**.** 
0.*** (0.***-0.***) 
NC 
 
**.** 
 
 
> UNL 
*** 
**.** 
0.*** (0.***-0.***) 
 
 
(**.**,**.**) 
 
 
 
 
 
 
 
 
 
Hemoglobin 
 
 
 
 
0.*** 
 
0.*** 
 
LLN  
*** 
**.** 
0.*** (0.***-0.***) 
NC 
 
**.** 
 
 
>LLN  
*** 
**.** 
0.*** (0.***-0.***) 
 
 
(**.**,**.**) 
 
 
 
 
 
 
 
 
 
(1) Stratified; (2) Stratified Cox regression with all factors included; (3) NC = not computed 
(4) Hazard ratio of first category over second category 
 


Table 27:  Progression Summary 
 
Data set:  All Randomized Patients 
 
Number of Patients (%) 
ARM A 
N=*** 
ARM B 
N=*** 
 
 
 
Patients who had PFS event 
*** (**) 
*** (**) 
 
 
 
 
Relapse/Progression on treatment 
** 
** 
 
Relapse/Progression during follow-up 
** 
** 
 
Death (without relapse/progression) 
** 
** 
 
 
 
Patients who were censored 
 
*** (**) 
*** (**) 
   Reason Censored 
 
 
 
Received other cancer treatment  
 
Alive at the clinical cut-off without progression 
** 
** 
 
Lost to follow-up 
** 
** 
 
Table 28:  Progression-free survival by Subsets 
 
Data set:  All Randomized Patients 
 
 
Factors 
 
 
Value 
ARM A 
ARM B 
 
 
N 
Median 
PFS 
95% C.I. 
 
N 
Median 
PFS 
95% C.I. 
Hazard Ratio(1) 
95% C.I. 
 
 
 
 
 
 
 
Performance Status 
at baseline 
ECOG 0-1 
** 
**.** 
(**.**,**.**) 
** 
**.** 
(**.**,**.**) 
**.** 
(**.**,**.**) 
 
ECOG 2 
** 
**.** 
(**.**,**.**) 
** 
**.** 
(**.**,**.**) 
**.** 
(**.**,**.**) 
 
 
 
 
 
 
 
Age 
<65 
** 
**.** 
(**.**,**.**) 
** 
**.** 
(**.**,**.**) 
**.** 
(**.**,**.**) 
 
 
≥65 
** 
**.** 
(**.**,**.**) 
** 
**.** 
(**.**,**.**) 
**.** 
(**.**,**.**) 
 
 
 
 
 
 
 
Female 
Female 
** 
**.** 
(**.**,**.**) 
** 
**.** 
(**.**,**.**) 
**.** 
(**.**,**.**) 
 
Male 
** 
**.** 
(**.**,**.**) 
** 
**.** 
(**.**,**.**) 
**.** 
(**.**,**.**) 
(1) ARM A over ARM B hazard ratio (Unstratified) 
 
 
 


Table 29:  Summary Baseline CEA values and Change from Baseline at Each 
Time Period* 
 
ARM A 
ARM B 
 
P Value* 
 
 
CEA 
 
 
 
Baseline 
 
 
. 
 
N 
*** 
*** 
 
 
Mean 
*** 
*** 
 
 
STD 
*** 
*** 
 
Change from baseline at Week 4 during treatment 
 
 
.** 
 
N 
*** 
*** 
 
 
Mean 
*** 
*** 
 
 
STD 
*** 
*** 
 
 
… 
 
 
 
 
 
 
 
 
 
**Wilcoxon rank sum test 


Table 30:  Log Rank and Cox Regression Model for Overall Survival (OS) 
Data set:  All Randomized Patients 
 
N 
Univariate Analysis(1) 
Multivariate Analysis(2) 
Treatment Arm/ 
Prognostic Factors at  
Baseline 
 
Median OS 
(Months) 
1 year Survival Rate 
(95% C. I.) 
Hazard 
Ratio(4) 
(95% CI) 
Log-rank 
p-value 
Hazard 
Ratio(4)  
(95% C.I.) 
P-value 
from Cox 
regression 
Treatment arm 
 
 
 
 
0.*** 
 
0.*** 
ARM A 
*** 
**.** 
0.*** (0.***-0.***) 
**.** 
 
**.** 
 
ARM B 
*** 
**.** 
0.*** (0.***-0.***) 
(**.**,**.**) 
 
(**.**,**.**) 
 
 
 
 
 
 
 
 
 
Gender 
 
 
 
 
0.*** 
 
0.*** 
 
Male 
*** 
**.** 
0.*** (0.***-0.***) 
NC (3) 
 
**.** 
 
 
Female 
*** 
**.** 
0.*** (0.***-0.***) 
 
 
(**.**,**.**) 
 
 
 
 
 
 
 
 
 
Age 
 
 
 
 
0.*** 
 
0.*** 
 
<65 
*** 
**.** 
0.*** (0.***-0.***) 
NC 
 
**.** 
 
 
≥65 
*** 
**.** 
0.*** (0.***-0.***) 
 
 
(**.**,**.**) 
 
 
 
 
 
 
 
 
 
LDH 
 
 
 
 
0.*** 
 
0.*** 
 
UNL 
*** 
**.** 
0.*** (0.***-0.***) 
NC 
 
**.** 
 
 
>UNL 
*** 
**.** 
0.*** (0.***-0.***) 
 
 
(**.**,**.**) 
 
 
 
 
 
 
 
 
 
 
Alkaline phosphatase 
 
 
 
 
0.*** 
 
0.*** 
 
UNL 
*** 
**.** 
0.*** (0.***-0.***) 
NC 
 
**.** 
 
 
> UNL 
*** 
**.** 
0.*** (0.***-0.***) 
 
 
(**.**,**.**) 
 
 
 
 
 
 
 
 
 
Hemoglobin 
 
 
 
 
0.*** 
 
0.*** 
 
UNL  
*** 
**.** 
0.*** (0.***-0.***) 
NC 
 
**.** 
 
 
> UNL  
*** 
**.** 
0.*** (0.***-0.***) 
 
 
(**.**,**.**) 
 
 
 
 
 
 
 
 
 
(1) Stratified; (2) Stratified Cox regression with all factors included; (3) NC = not computed (4) Hazard ratio of first category over second category 
 
 
 


Table 31:  Overall Survival by Subsets 
 
Data set:  All Randomized Patients 
 
 
Factors 
 
 
Value 
ARM A 
ARM B 
 
 
N 
Median 
OS 
95% C.I. 
 
N 
Median 
OS 
95% C.I. 
Hazard Ratio(1) 
95% C.I. 
 
 
 
 
 
 
 
Performance Status 
at baseline 
ECOG 0-1 
** 
**.** 
(**.**,**.**) 
** 
**.** 
(**.**,**.**) 
**.** 
(**.**,**.**) 
 
ECOG 2 
** 
**.** 
(**.**,**.**) 
** 
**.** 
(**.**,**.**) 
**.** 
(**.**,**.**) 
 
 
 
 
 
 
 
Age 
<65 
** 
**.** 
(**.**,**.**) 
** 
**.** 
(**.**,**.**) 
**.** 
(**.**,**.**) 
 
 
≥65 
** 
**.** 
(**.**,**.**) 
** 
**.** 
(**.**,**.**) 
**.** 
(**.**,**.**) 
 
 
 
 
 
 
 
Female 
Female 
** 
**.** 
(**.**,**.**) 
** 
**.** 
(**.**,**.**) 
**.** 
(**.**,**.**) 
 
Male 
** 
**.** 
(**.**,**.**) 
** 
**.** 
(**.**,**.**) 
**.** 
(**.**,**.**) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(1) ARM A over ARM B hazard ratio (Unstratified) 
 


Table 32:  Treatment Response 
 
Data set:  All Randomized Patients 
 
Number of Patients (%)a 
N=*** 
ARM A 
N=*** 
ARM B 
N=*** 
 
 
 
Patients with at least one target lesion 
 
 Response-evaluable  
N=*** 
 
N=*** 
N=*** 
 
N=*** 
 
Complete response (CR) 
** (**) 
** (**) 
 
Partial response (PR) 
** (**) 
** (**) 
 
Stable disease (SD) 
** (**) 
** (**) 
 
Progressive disease (PD) 
** (**) 
** (**) 
 
Inevaluable for response (IN) 
<Reason 1> 
<Reason 2> 
.... 
** (**) 
** 
** 
... 
** (**) 
** 
** 
.... 
 
 
 
 
Not response evaluable 
N=*** 
N=*** 
 
Never treated  
** 
** 
 
Not assessed (NA)  
** 
** 
 
Patients with no target lesions 
 
 
N=*** 
 
N=*** 
 
Progressive disease (PD) 
** 
** 
 
Inevaluable for response (IN) 
<Reason 1> 
<Reason 2> 
.... 
** 
** 
** 
... 
** 
** 
** 
.... 
 
Not assessed (NA) 
** 
** 
 
Never treated  
** 
** 
 
 
 
a percentages are calculated out of the number of randomized patients 
 
 
 
 
 
 
 


Table 33:  Cochran Mantel Haenszel and Logistic Regression Model for 
Response 
Data set:  All Randomized Patients 
 
Univariate Analysis (1) 
Multivariate Analysis (2) 
 
Treatment/ Prognostic Factors 
Odds Ratio(4) 
(95%CI) 
CMH 
p-value 
Odds Ratio (4)  
(95% C.I.) 
p-value 
from logistic 
regression 
 
 
 
 
 
Treatment arm 
 
0.*** 
 
0.*** 
 
ARM A: ARM B 
**.** 
 
**.** 
 
 
(**.**,**.**) 
 
(**.**,**.**) 
 
 
 
 
 
 
 
 
 
 
 
Gender 
 
0.*** 
 
0.*** 
 
Male: Female 
NC 
 
**.** 
 
 
 
 
(**.**,**.**) 
 
 
 
 
 
 
Age 
 
0.*** 
 
0.*** 
 
<65: ≥65 
NC 
 
**.** 
 
 
 
 
 
(**.**,**.**) 
 
 
 
 
 
 
LDH 
 
0.*** 
 
0.*** 
 
≤UNL:  >UNL 
NC 
 
**.** 
 
 
 
 
 
(**.**,**.**) 
 
 
 
 
 
 
 
Alkaline phosphatase 
 
0.*** 
 
0.*** 
 
≤ UNL: >UNL 
NC 
 
**.** 
 
 
 
 
 
(**.**,**.**) 
 
 
 
 
 
 
Hemoglobin 
 
0.*** 
 
0.*** 
 
≤ LLN: >LLN 
NC 
 
**.** 
 
 
 
 
 
(**.**,**.**) 
 
 
 
 
 
 
(1) Stratified 
(2) Stratified Logistic regression, all factors included 
(3) NC = not computed 
(4) Odds ratio of first category over second category 
 
NOTE:  Same table to be made for all response evaluable patients. 
 
 


Table 34:  Response According to Pretreatment Characteristics 
 
Data set:  All Randomized Patients 
 
Number of Responses/Number of Patients (%) 
ARM A 
N=*** 
ARM B 
N=*** 
 
 
 
 
 
 
Gender 
 
 
 
Male 
**/** (**) 
**/** (**) 
 
Female 
**/** (**) 
**/** (**) 
 
 
 
Age 
 
 
 
< 65 years 
**/** (**) 
**/** (**) 
 
≥ 65 years 
**/** (**) 
**/** (**) 
 
 
 
Baseline performance status 
 
 
 
ECOG 0-1 
**/** (**) 
**/** (**) 
 
ECOG 2 
**/** (**) 
**/** (**) 
 
 
 
 
 
NOTE:  Same table to be made for all response evaluable patients. 
 
Table 35:  Duration of Response 
 
Data set:  All Randomized Patients with CR or PR 
 
ARM A 
N=*** 
ARM B 
N=*** 
P-value(1) 
Median Duration of Response (months) 
(95% CI) 
***  
(**-**) 
***  
(**-**) 
.** 
(1) Stratified 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Table 36:  All Acute Non-Hematologic Adverse Events in ARM A 
 
Data set:  All Treated Patients in ARM A 
 
Number of patients in ARM A (%) 
N=*** 
 
Worst grade 
Any 
grade 
 
NR 
1 
2 
3 
4 
5 
 
Patients with any AE 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
Patients with AE within 
category 
 
Category 1(1) 
Event 1 
Event 2 
Event 3 
...  
 
Category 2(1) 
Event 1  
...  
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
(1) Patients may have more than one event within a category. 
 
NOTE:  Same table to be made on ARM B.  
 
Table 37:  Severe Acute Non-Hematologic Adverse Events in ARM A 
 
Data set:  All Treated Patients in ARM A 
 
Number of patients in ARM A (%) 
N=*** 
 
Worst grade 
Any grade 3 
or higher AE 
 
 
 
 
3 
4 
5 
 
Patients with any AE 
 
 
 
** (**) 
** (**) 
** (**) 
** (**) 
Patients with AE within 
category 
 
Category 1(1) 
Event 1 
Event 2 
Event 3 
...  
 
Category 2(1) 
Event 1  
...  
 
 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
(1) Patients may have more than one event within a category. 
 
NOTE:  Same table to be made on ARM B.  
 
 


Table 38:  Acute (On-treatment) Adverse Events Related to Bevacizumab  
 
Data set:  All Treated Patients in ARM A 
 
Number of patients in ARM A (%) 
N=*** 
 
Worst grade 
Any 
grade 
 
NR 
1 
2 
3 
4 
5 
 
Patients 
with 
any 
drug 
related AE 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
Patients with AE within 
category 
 
Category 1(1) 
Event 1 
Event 2 
Event 3 
...  
 
Category 2(1) 
Event 1  
...  
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 (1) Patients may have more than one event within a category. 
 
NOTE:  Same type of table to be made on ARM B and also adverse events 
related to FOLFOX6 on both arms and related to Reolysin on ARM A. 
 
Table 39:  Severe Delayed Non-Hematologic Adverse Events in ARM A 
 
Data set:  All Treated Patients in ARM A 
 
Number of patients in ARM A (%) 
N=*** 
 
Worst grade 
Any grade 3 
or higher AE 
 
 
 
 
3 
4 
5 
 
Patients with any AE 
 
 
 
** (**) 
** (**) 
** (**) 
** (**) 
Patients with AE within 
category 
 
Category 1(1) 
Event 1 
Event 2 
Event 3 
...  
 
Category 2(1) 
Event 1  
...  
 
 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
(1) Patients may have more than one event within a category. 
 
NOTE:  Same table to be made on ARM B.  
 


Table 40:  Hematology by arm: Worst Grade per Patient 
Data set:  All Randomized Patients 
 
Number of Patients (%) 
 
 
ARM A 
N=*** 
ARM B 
N=*** 
 
 
 
WBC 
 
 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
 
 
Lymphocyte 
 
 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
 
 
Platelet 
 
 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
 
 
Anemia (Hemoglobin) 
 
 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
 
 
Neutrophil 
 
 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Table 41:  Biochemistry Tests by Arm:  Worst per Patient 
Data set:  All Randomized Patients 
 
Number of Patients (%) 
 
ARM A 
N = *** 
ARM B 
N = *** 
Total bilirubin 
 
 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
 
 
Alkaline phosphatase 
 
 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
 
 
ALT 
 
 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
 
 
AST 
 
 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
 
 
LDH 
 
 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
 
 
Creatinine 
 
 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
 
 
 
 
 
 
 
 


  
Table 42:  All Deaths 
Data set:  All Treated Patients 
 
Number of Patients 
(%) 
 
ARM A 
N = ** 
ARM B 
N = ** 
Number of Patients who died 
** (**) 
** (**) 
 
 
 
Cause of Death 
 
 
 
Study-specific malignant disease only 
** 
** 
 
Adverse event possibly, probably or definitely related to protocol treatment 
** 
** 
 
Complication from a non-protocol treatment for this malignancy  
** 
** 
 
Other primary malignancy 
** 
** 
 
Other condition or circumstance 
** 
** 
 
Table 43:  Deaths within 4 Weeks of Last Treatment 
Data set:  All Treated Patients 
 
Number of Patients 
(%) 
 
ARM A 
N = *** 
ARM B 
N = *** 
Number of Patients who died within 30 days of last cetuximab treatment 
** (**) 
** (**) 
 
 
 
Cause of Death 
 
 
 
Study-specific malignant disease only 
** 
** 
 
Adverse event possibly, probably or definitely related to protocol treatment 
** 
** 
 
Complication from a non-protocol treatment for this malignancy  
** 
** 
 
Other primary malignancy 
** 
** 
 
Other condition or circumstance 
** 
** 
 
 
Table 44:  Adverse Event leading to Treatment Discontinuation 
Data set:  All Treated Patients 
 
Number of patients (%) 
 
ARM A 
N = *** 
ARM B 
N = *** 
Number discontinued from adverse events 
 
      <Adverse event 1>(a) 
      <Adverse event 2> 
      .... 
 
** (**) 
 
** 
** 
** (**) 
 
** 
** 
(a): one patient may have more than one adverse event 
 
NOTE:  Table will be made for each component of protocol therapy. 
 
 


Table 45:  Hospitalization 
 
Data set:  All Treated Patients  
 
Arm 1 
N=*** 
Arm 2 
N=*** 
Number (%) cycles with hospitalization 
**/*** (**) 
**/*** (**) 
 
 
 
Number (%) of patients hospitalized  
*** (**) 
*** (**) 
 
 
 
 
 
 
Table 46:  Transfusion 
Data set:  All Treated Patients 
 
Number of patients (%) 
 
Arm 1 
N=*** 
Arm 2 
N=*** 
Number (%) of patients transfused 
*** (**) 
*** (**) 
 
 
 
Type of transfusion (1) 
 
 
 
Number of patients received Red Blood Cells 
** 
** 
 
Number of patients received Platelets 
** 
** 
 
Number of patients received Other Transfusions 
** 
** 
(1) All cycles 
 
 
 
 


Table 47:  Concomitant Medication 
Data set:  All Treated Patients 
 
Number of patients (%) 
 
ARM A 
N = *** 
ARM B 
N = *** 
Any concomitant medication during and 4 weeks after protocol treatment 
No 
Yes 
 
** (**) 
** (**) 
 
** (**) 
** (**) 
Type of concomitant medications during protocol treatment* 
 
Medication A 
 
… 
 
** (**) 
** (**) 
 
** (**) 
** (**) 
* one patient may have more than one medication. 
 
Table 48:  Anti-Cancer Treatment 
 
Data set:  All Randomized patients 
 
Number of patients (%) 
 
ARM A 
N = *** 
ARM B 
N = *** 
Number of patients with any other anti-cancer 
treatment during and 4 weeks after protocol 
treatment  
*** (**) 
*** (**) 
 
Chemotherapy (1) 
 
 
Drug 1 … 
 
Radiotherapy (1) 
 
Hormonal therapy (1) 
 
 
Drug 1 … 
 
Immunotherapy (1) 
 
 
Drug 1 … 
 
Other (1) 
 
 
Drug 1 … 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
Number of patients with any anti-cancer treatment 
during follow-up 
*** (**) 
*** (**) 
 
Chemotherapy (1) 
 
 
Drug 1 … 
 
Radiotherapy (1) 
 
Hormonal therapy (1) 
 
 
Drug 1 … 
 
Immunotherapy (1) 
 
 
Drug 1 … 
 
Other (1) 
 
 
Drug 1 … 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
 
(1) Patients could have more than one type of anti-cancer treatment. 


Table 49:  Compliance Rate with QoL Assessment by Treatment Arm 
 
ARM A 
N = *** 
ARM B 
N = *** 
 
N 
received (%) 
N 
received (%) 
Baseline 
*** 
** (**) 
*** 
** (**) 
During chemotherapy (Day 1 cycle 5) 
*** 
** (**) 
*** 
** (**) 
Off treatment (off study or week 4 
after completion of protocol treatment) 
*** 
** (**) 
*** 
** (**) 
 
 
Table 50:  QoL: Summary Baseline Scores 
 
ARM A 
ARM B 
EORTC QLQ-C30 
 Functional scales 
 
 
Physical 
 
 
 
N 
*** 
*** 
 
Mean 
*** 
*** 
 
STD 
*** 
*** 
... 
... 
... 
EORTC QLQ-C30  
Global QOL 
 
 
 
N 
*** 
*** 
 
Mean 
*** 
*** 
 
STD 
*** 
*** 
EORTC QLQ-C30 
 Symptom scales 
 
 
Fatigue 
 
 
 
N 
*** 
*** 
 
Mean 
*** 
*** 
 
STD 
*** 
*** 
… 
… 
… 
 


Table 51:  Summary QOL Change Scores from Baseline for Scale/Domain/Item 
at Each Time Period* 
 
ARM A 
ARM B 
 
P Value** 
 
 
Scale/Domain/Item 
 
 
 
During Chemotherapy (Day 1 cycle 5) 
 
 
.** 
 
N 
*** 
*** 
 
 
Mean 
*** 
*** 
 
 
STD 
*** 
*** 
 
Off treatment (Off study or week 4 after 
completion of protocol treatment) 
 
 
.** 
 
N 
 
 
 
 
Mean 
*** 
*** 
 
 
STD 
*** 
*** 
 
* Table will be provided for each EORTC QLQ-C30 scale/domain/item. 
** Wilcoxon rank sum test 
 
Table 52:  Proportion of Patients with Deterioration, Improvement or Stable 
EORTC QLQ-C30 domains/items and Global QLQ scales* 
 
N 
ARM A 
N (%) 
ARM B 
N (%) 
P value** 
 
Deterioration 
 
 
 
 
   Physical function 
 
 
 
 
 
During Chemotherapy (Day 1 cycle 5) 
*** 
*** (**.**) 
*** (**.**) 
0.*** 
 
Off treatment (Off study or week 4 after 
completion of protocol treatment) 
*** 
*** (**.**) 
*** (**.**) 
0.*** 
 
 
 
 
 
 
Improvement 
 
 
 
 
   Physical function 
 
 
 
 
 
During Chemotherapy (Day 1 cycle 5) 
*** 
*** (**.**) 
*** (**.**) 
0.*** 
 
Off treatment (Off study or week 4 after 
completion of protocol treatment) 
*** 
*** (**.**) 
*** (**.**) 
0.*** 
 
 
 
 
 
Stable 
 
 
 
 
   Physical function 
 
 
 
 
 
During Chemotherapy (Day 1 cycle 5) 
*** 
*** (**.**) 
*** (**.**) 
0.*** 
 
Off treatment (Off study or week 4 after 
completion of protocol treatment) 
*** 
*** (**.**) 
*** (**.**) 
0.*** 
* Table will be provided for each EORTC QLQ-C30 scale/domain/item 
**Fisher’s exact test