Clinical trial NCT01652196
Conditions: Mucinous Adenocarcinoma of the Colon Mucinous Adenocarcinoma of the Rectum Signet Ring Adenocarcinoma of the Colon Signet Ring Adenocarcinoma of the Rectum Stage IV Colon Cancer Stage IV Rectal Cancer
Keywords: colorectal cancer rectal cancer FOLFOX Aflibercept
Sponsor: John Hays
Start date: 2012-11-14; Completion date: 2022-08-30
Enrollment: 56 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well giving aflibercept together with combination chemotherapy works in treating patients with previously untreated colon or rectal cancer that is metastatic or locally advanced and cannot be removed by surgery. Aflibercept may stop the growth of colon or rectal cancer by blocking blood flow to the tumor. Drugs used in chemotherapy, such as leucovorin calcium, fluorouracil, and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving aflibercept together with combination chemotherapy may kill more tumor cells

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate the progression free survival (PFS) of patients with untreated metastatic colorectal cancer (mCRC) receiving the combination of modified leucovorin calcium, fluorouracil, oxaliplatin (FOLFOX6) (mFOLFOX6) and aflibercept.

SECONDARY OBJECTIVES:

I. To evaluate the objective response rate (complete response \[CR\] + partial response \[PR\]) and the disease control rate (CR + PR + stable disease \[SD\]), as determined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria, of patients with untreated mCRC receiving the combination of mFOLFOX6 and aflibercept.

II. To evaluate overall survival of patients with untreated mCRC receiving the combination of mFOLFOX6 and aflibercept.

III. To further characterize the safety and toxicity of the combination of mFOLFOX6 and aflibercept, including 60 day all-cause mortality.

IV. To describe patients with mCRC whose disease is rendered resectable as a consequence of therapy with the combination of mFOLFOX 6 and aflibercept.

TERTIARY OBJECTIVES:

I. To assess the use of dynamic imaging modalities including dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI) and fluorodeoxyglucose (FDG)-positron emission tomography (PET) to evaluate changes in vascular permeability and FDG avidity and correlate with clinical efficacy (PFS, overall survival \[OS\], and response by RECIST 1.1).

II. To evaluate circulating levels of vascular endothelial growth factor A (VEGFA), phosphatidylinositol glycan anchor biosynthesis, class F (PlGF), soluble vascular endothelial growth factor receptor 2 (VEGF-R2), chemokine (C-X-C motif) ligand 12 (CXCL12) and chemokine (C-X-C motif) receptor 4 (CXCR4) as potential biomarkers for efficacy of aflibercept.

III. To evaluate for the presence of VEGF single nucleotide polymorphisms (SNPs) and whether any SNP(s), when detected, may be predictive of efficacy and/or toxicity of aflibercept.

IV. To assess microvessel density/tumor blood flow, capillary permeability and vessel normalization by tumor biopsy pre and post treatment with aflibercept.

V. To evaluate the presence of hypertension as a predictive biomarker for clinical efficacy of aflibercept.

OUTLINE:

Patients receive aflibercept intravenously (IV) over 1 hour followed by oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV over 5-15 minutes and then continuously over 46 hours on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 4 weeks.

Arms: arm 1: Patients receive aflibercept and fluorouracil and then continuously over 46 hours on days 1 and 15.If leucovorin is not available due to drug shortages the regimen should be administered with the leucovorin omitted. Correlative Studies are required to be available before enrolling on the study. A fresh biopsy is only required if there is insufficient material for analysis. Repeat tumor biopsies after 8 weeks of therapy are optional and will only be performed at the Ohio State University Medical Center.DCE MRI (dynamic contrast-enhanced magnetic resonance imaging)images at weeks 0, and after 8 weeks +/- 1 week of treatment(after Cycle 2). 18FDG-PET is a functional imaging technique that relies on tumor uptake of radiolabeled tracer 18 fluorodeoxyglucose (18FDG).FDG-PET is a widely-used imaging modality in the detection and monitoring of a variety of metastatic cancers,including colorectal cancer (99-102).
Interventions: intervention 1: aflibercept intervention 2: oxaliplatin intervention 3: leucovorin intervention 4: fluorouracil intervention 5: Correlative Studies intervention 6: DCE MRI intervention 7: f18FDG-PET intervention 8: PET (positron emission tomography)
Intervention descriptions: intervention 1: 4 mg/kg as a 1-hour IV(intervenous) infusion intervention 2: 85 mg/m2 IV infused over 2 hours intervention 3: 200 mg/m2 (Or levoleucovorin 100 mg/m2. If leucovorin is not available due to drug shortages the regimen should be administered with the leucovorin omitted) IV over 2 hours. Alternatively, leucovorin may be administered (via separate infusion lines) concurrently with oxaliplatin intervention 4: 400 mg/m2 IV bolus over 5-15 minutes, then 2400 mg/m2 continuous IV infusion over 46 hours. intervention 5: Patients are required to have tissue available before enrolling on the study. A fresh biopsy is only required if there is insufficient material for analysis. Repeat tumor biopsies after 8 weeks of therapy are optional and will only be performed at the Ohio State University Medical Center. intervention 6: Images at weeks 0, and after 8 weeks +/- 1 week of treatment (after Cycle 2). intervention 7: 18FDG-PET is a functional imaging technique that relies on tumor uptake of radiolabeled tracer 18 fluorodeoxyglucose (18FDG). FDG-PET is a widely-used imaging modality in the detection and monitoring of a variety of metastatic cancers, including colorectal cancer (99-102). intervention 8: Correlative studies

Protocol documents:
Prot_SAP_000.pdf: 
IRB Protocol Number: 2012C0055 
 
  
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TITLE:  A Phase II Study of the Combination of Aflibercept (VEGF-Trap) plus Modified 
FOLFOX 6 in Patients with Previously Untreated Metastatic Colorectal Cancer 
 
 
Coordinating Center: 
 
       
The Ohio State University  
 
Principal Investigator: 
    
John Hays, MD, PhD 
 
  
460 W 12th Ave, 
 
 
Columbus OH 43210 
T (614) 685-6700 
F (614) 292-6356 
 
 
 
John.Hays@osumc.edu 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
Multi-Center Trial Program:                                                               
Clinical Trials Office  
     
The Ohio State University                                       
 
        
Fax: (614) 366-6652  
Email: OSUCCC-CTO-MCTP@osumc.edu                                  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participating Centers: 


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Roswell Park cancer Institute 
PI: WenWee Ma, MD 
Elm and Carlton Streets 
Buffalo, NY 14228 
Phone: (716) 845-8916 
Email: wenwee.ma@roswellpark.org 
 
University of North Carolina 
PI: Autumn McRee, MD 
101 Manning Drive 
Chapel Hill, NC 27599-7600 
Phone: (919) 966-5902  
Email:  autumn_mcree@med.unc.edu  
 
University of Michigan                                      
PI: John Krauss, MD                                           
3216 Cancer Center, SPC 5934                           
1500 E. Medical Center Drive    
Ann Arbor, MI 48109                
Phone: (734) 615-3969       
Email: jkrauss@med.umich.edu 
 
Montefiore Medical Center                            Virginia Commonwealth University 
PI: Sanjay Goel                                                 PI: Khalid Matin, MD 
1825 Eastchester Road                                      1201 E. Marshal St. 11th Floor 
Montefiore Medical Center                                P.O. Box 980070 
Albert Einstein College of Medicine                 Richmond, VA 23298-0070 
Bronx, NY 10461 
Phone: 719-904-2488 
 
 
 
 
Protocol Type / Version # / Version Date: 
Original / 1.0 / November 4, 2011 
 
 
 
 
 
Revision/1.1/ April 30, 2012 
 
 
 
 
 
Revision/1.2/ August 12, 2012 
 
 
 
 
 
Revision/1.3/April 8, 2013 
 
 
 
 
 
Revision/1.4/December 11, 2013 
 
 
 
 
 
Revision/1.5/April 29, 2014  
 
 
 
 
 
Revision/1.6/October 13, 2014 
 
 
 
 
 
Revision/1.7/January 28, 2015 
 
 
 
 
 
Revision/1.8/December 27, 2016 
 
 
 
 
 
Revision/1.9/June 21, 2017 
 
 
 
 
 
Revision/1.10/May 15, 2018 
 
 
 
 
 


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SCHEMA 
 
Registration 
 
 
 
mFOLFOX6 a + afliberceptb  
 
Days 1 and 15c 
 
 
 
Response assessment q8 week 
 
 
 
Continue treatment as long as treatment criteria are metd   
 
 
a.  mFOLFOX6= oxaliplatin 85 mg/m2 IV with leucovorin 400 mg/m2 
(levoleucovorin 200 mg/m2 if standard leucovorin is not available, omit leucovorin if 
neither standard or levoleucovorin is available) IV followed by 5FU 400mg/m2 IV 
bolus over 5-15 minutes  followed by 5FU 2400 mg/m2 continuous IV infusion over 
46 hours  
 
b.  Aflibercept dosing= 4 mg/kg IV 
 
c.  1 cycle = 28 days 
 
d.  Discontinue treatment in the event of disease progression, unacceptable toxicity,   
intercurrent illness rendering the patient unacceptable for further treatment, or patient       
refusal              
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
Page 
 
SCHEMA ........................................................................................................................................4 
 
1. OBJECTIVES ..........................................................................................................................8 
1.1 
Primary Objectives ......................................................................................................8 
1.2 
Secondary Objectives ..................................................................................................8 
 
2. BACKGROUND ......................................................................................................................8 
2.1 
Colorectal Cancer (CRC) ............................................................................................8 
 
2.1.1 Angiogenesis in CRC ............................................................................................9 
 
2.1.2 VEGF ....................................................................................................................9 
 
2.1.3 Targeting VEGF in CRC .....................................................................................10 
2.2 
5-FU, Leucovorin, and Oxaliplatin ...........................................................................11 
 
2.2.1 5-FU and leucovorin ...........................................................................................11 
 
2.2.2 Oxaliplatin ...........................................................................................................11 
 
2.2.3 FOLFOX .............................................................................................................11 
 
2.3 
Aflibercept ..................................................................................................................12 
2.4 
Correlative Studies Background ..............................................................………….23 
 
2.4.1 Biologic correlative studies .................................................................................23 
 
2.4.2 Radiographic correlative studies .........................................................................27 
2.5    Study Rationale…………………………………………………………………….....28 
 
3. PATIENT SELECTION .......................................................................................................29 
3.1 
Eligibility Criteria  .....................................................................................................29 
3.2 
Exclusion Criteria ......................................................................................................30 
3.3 
Inclusion of Women and Minorities .........................................................................32 
 
4. REGISTRATION PROCEDURES ......................................................................................32 
4.1  
General Guidelines.....................................................................................................32 
4.2  
Registration Process...................................................................................................32 
 
5. TREATMENT PLAN ............................................................................................................33 
5.1  
Agent Administration ................................................................................................33 
 
5.2  
General Concomitant Medication and Supportive Care 
Guidelines 
34  
      5.3  
Duration of Therapy ..................................................................................................35 
5.4       Duration of Follow Up ...............................................................................................36 
5.5       Criteria for Removal from Study .............................................................................36 
 
6. DOSING DELAYS/DOSE MODIFICATIONS ..................................................................36 
6.1  
Dose Delays/Modifications for FOLFOX .................................................................37 
 
 
6.1.1 Selected Hematologic and Non-Hematologic Toxicities ....................................37 


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6.1.2 Neurotoxicity ......................................................................................................39 
6.2  
Dose Delays/Modifications for Aflibercept ..............................................................40 
 
 
6.2.1 Hypertension Therapy .........................................................................................42 
 
 
6.2.2 Proteinuria ...........................................................................................................42 
 
 
6.2.3 Reversible Posterior Leuko-encephalopathy ......................................................43 
 
 
6.2.4 Gastrointestinal Perforation ................................................................................43 
 
 
6.2.5 Hypersensitivity Reactions .................................................................................44 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................46 
7.1  
Expected AEs for Aflibercept ...................................................................................46 
7.2  
AE List for Commercial Agents ...............................................................................48 
7.3  
AE Characteristics .....................................................................................................48 
7.4  
Monitoring for AEs ....................................................................................................48 
7.5 
Recording and Reporting ..........................................................................................50 
7.6 
Data Safety Monitoring Plan ....................................................................................50 
 
8. PHARMACEUTICAL INFORMATION ............................................................................51 
8.1  
Investigational Agents ................................................................................................51 
 
 
8.1.1 Aflibercept .......................................................................................................51 
8.2  
Commercial Agents ....................................................................................................54 
 
      8.2.1 5-FU .................................................................................................................54 
 
 
8.2.2 Leucovorin .......................................................................................................55 
 
 
8.2.2.1 Levoleucovorin …………………………………………………………….. 56  
 
 
8.2.3 Oxaliplatin........................................................................................................57 
8.3  
Agent Ordering ..........................................................................................................60 
8.4  
Agent Accountability .................................................................................................61 
 
9. CORRELATIVE STUDIES ..................................................................................................61 
9.1 
Collection of Tumor Specimen(s) .............................................................................61 
 
9.1.1 Tissue requirements .........................................................................................61 
 
9.1.2 Shipping of Specimens ....................................................................................62 
9.2 
Biologic Correlative Studies ......................................................................................63 
 
9.2.1 Measurement of VEGF, VEGFR, P1GF, CXCL12, CXCR4 ..........................63 
 
9.2.2 Relationship Between Hypertension and Efficacy ..........................................63 
 
9.2.3 SNP Analysis ...................................................................................................63 
 
9.2.4 Measurement and Quantification of Tumor Microvessel Density ...................64 
9.3 
Radiographic Correlative Studies ............................................................................64 
 
9.3.1 DCE-MRI .........................................................................................................64 
 
9.3.2 FDG-PET .........................................................................................................65 
 
10. STUDY CALENDAR ............................................................................................................67 
 
11. MEASUREMENT OF EFFECT ..........................................................................................70 
11.1 
Antitumor Effect – Solid Tumors ............................................................................70 
 
11.1.1 Definitions........................................................................................................70 
 
11.1.2 Disease Parameters ..........................................................................................70 


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11.1.3 Methods for Evaluation of Measurable Disease ..............................................71 
 
11.1.4 Response Criteria .............................................................................................72 
 
11.1.5 Duration of Response .......................................................................................73 
 
11.1.6 Progression-Free Survival ................................................................................74 
 
11.1.7 Overall Survival ...............................................................................................74 
 
11.1.8  Response Rate................................................................................................ 74 
 
11.1.9  Disease Control Rate.......................................................................................74  
 
12. DATA/SAE REPORTING & REGULATORY REQUIREMENTS ................................74 
12.1 
Serious Adverse Event Reporting .............................................................................74 
12.1.1 SAEs Reportable to the FDA ...........................................................................74 
12.1.2 Actions Toward the FDA .................................................................................75 
12.1.3 Actions Toward Sanofi-Aventis ......................................................................75 
12.1.4 Actions Toward Co-Investigators ....................................................................75 
12.1.5 Actions Toward Other Manufacturers .............................................................76 
12.1.6 Follow-up Reports ...........................................................................................76 
12.1.7  Multicenter Coordination .................................................................................76 
12.1.8  Coordinating Center Responsibilities ..............................................................77 
 
13. STATISTICAL CONSIDERATIONS .................................................................................77 
 
13.1 
Study Design/Endpoints ............................................................................................77 
 
13.2 
Sample Size, Accrual Rate, and Study Duration ....................................................78 
 
13.3 
Study Design and Primary Endpoint Analysis ........................................................78 
 
13.4 
Secondary Endpoint Analysis ...................................................................................79 
 
13.5 
Reporting and Exclusions .........................................................................................80 
 
REFERENCES .............................................................................................................................82 
 
APPENDICES 
 
APPENDIX A 
Performance Status Criteria ...............................................................................................89 
 
APPENDIX B 
 
Instructions for Preparation and Handling of Aflibercept .................................................90 
 
APPENDIX C 
 
DCE MRI and FDG-PET Imaging Protocol ......................................................................92 
 
APPENDIX D 
 
Blood Pressure Log ............................................................................................................93 
 
 
 
 
 


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1. OBJECTIVES 
 
1.1. 
Primary Objectives 
 
• To evaluate the progression free survival (PFS) of patients with untreated metastatic 
colorectal cancer (mCRC) receiving the combination of modified FOLFOX6 
(mFOLFOX6) and aflibercept.  
      
1.2. 
Secondary Objectives 
 
• To evaluate the objective response rate (CR+PR) and the disease control rate 
(CR+PR+SD), as determined by RECIST 1.1 criteria, of patients with untreated mCRC 
receiving the combination of mFOLFOX6 and aflibercept. 
• To evaluate overall survival of patients with untreated mCRC receiving the combination 
of mFOLFOX6 and aflibercept. 
• To further characterize the safety and toxicity of the combination of mFOLFOX6 and 
aflibercept, including 60 day all-cause mortality. 
• To describe patients with mCRC whose disease is rendered resectable as a consequence of 
therapy with the combination of mFOLFOX 6 and aflibercept. 
• Biologic and radiographic correlative objectives 
o To assess  the use of dynamic imaging modalities including DCE MRI and FDG-
PET to evaluate changes in vascular permeability and FDG avidity and correlate 
with clinical efficacy (PFS, OS, and response by RECIST 1.1) 
o To evaluate circulating levels of VEGFA, PlGF, soluble VEGF-R2, CXCL12 and 
CXCR4 as potential biomarkers for efficacy of aflibercept. 
o To evaluate for the presence of VEGF single nucleotide polymorphisms (SNPs) 
and whether any SNP(s), when detected, may be predictive of efficacy and/or 
toxicity of aflibercept. 
o To assess microvessel density/tumor blood flow, capillary permeability and vessel 
normalization by tumor biopsy pre and post treatment with aflibercept. 
o To evaluate the presence of hypertension as a predictive biomarker for clinical 
efficacy of aflibercept 
 
2. BACKGROUND 
 
2.1. Colorectal cancer 
 
Colorectal cancer (CRC) remains the 3rd leading cause of cancer death in the United States, 
with an estimated 142,000 new cases and 50,000 deaths in 2010 (1).  Roughly 15% of patients 


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present with metastatic disease, and another 40-50% will develop distant metastases during 
their disease course (2).  A small percentage of patients with limited metastatic disease can be 
cured with surgical resection (3), but for the majority of patients with metastatic colorectal 
cancer (mCRC), treatment is palliative. For decades, single-agent 5-fluorouracil (5-FU) was 
the only active treatment available.  In the recent years, the addition of oxaliplatin or irinotecan 
to 5-FU,  as well as the development of the novel monoclonal antibodies bevacizumab, 
cetuximab, and panitumumab, has provided extended survival for these patients, with a median 
survival of around 18-22 months (4-13). 
 
 
  
 
2.1.1. Angiogenesis in CRC 
 
 
Angiogenesis is necessary for normal organ development and differentiation, as well as 
adult blood vessel formation, and organ and tissue repair.  Aberrant angiogenesis is 
associated with a variety of pathologic conditions, including cancer.  For solid tumors to 
grow beyond 1-2 mm, neoangiogenesis is necessary to maintain adequate tumor tissue 
oxygenation (14).   In CRC, the process of neovascularization plays an important role in 
cancer progression.  Increased angiogenesis in the primary tumor has been associated with 
relapse, metastases, and overall poor prognosis in CRC patients (15-18). 
 
2.1.2. VEGF 
 
Vascular endothelial growth factor (VEGF) is a protein which is critical to angiogenesis 
(19, 20).  The VEGF family of proteins consists of VEGF A-D as well as placental growth 
factor (PlGF) (21).  VEGF-A in particular functions to activate endothelial cells and 
promote their survival, and thus plays a crucial role in tumorigenesis.   The biologic effects 
of VEGF are mediated via its receptor tyrosine kinases, VEGFR1-3, which are expressed 
on the surface of vascular endothelial cells.  VEGFR1 functions predominantly to 
upregulate macrophage and monocyte regulation and effects vascular permeability, and 
can also positively or negatively regulate VEGFR2 expression.  VEGFR2 is the most active 
promoter of tumor angiogenesis.  VEGFR3 is involved in development of lymphatic 
endothelial cells (21).  Binding of VEGF to its receptor initiates a cascade of events 
promoting angiogenesis, such as endothelial cell proliferation and migration, and increased 
vascular permeability (22-24).  Phosphorylated VEGFR2 is capable of activating numerous 
cell signaling pathways implicated in cancer growth, including the MAPK and PI3K/Akt 
pathways, Src, and HSP27 which promote proliferation, survival and chemotaxis in 
endothelial cells and ultimately produce the characteristic effects of VEGF on vessels, 
including increased vascular permeability and angiogenesis (21, 25).  Overexpression of 
VEGF has been shown to induce activation of Akt, STAT3, and ERK and increases 
proliferation of vascular endothelial cells (25). Both VEGFA and VEGFR2 are upregulated 
in the setting of tissue hypoxia (21), which constitutes a potential mechanism for tumor 
resistance to anticancer therapy.  VEGF pathway interruption can be achieved via various 
mechanisms, including soluble decoy receptors that prevent VEGF from binding to its 
normal receptors (26-28), small molecule VEGFR TKIs (29-31), and antibodies against 
VEGF (32-34) or its receptors (35).  Blockade of VEGF-mediated signaling suppresses 
tumor growth in vivo (33). In preclinical studies, preventing VEGF from binding to its 
receptor was one of the most effective ways of blocking the VEGF signaling pathway (36). 


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2.1.3. Targeting VEGF in CRC  
 
VEGF is expressed on about 50% of CRCs, with little to no expression on normal colonic 
mucosa.  In CRC, VEGF expression has been correlated with tumor size, tumor stage, 
lymph node metastases, and distant metastases (37, 38), as well as depth of tumor invasion 
(39), and appears to be an adverse prognostic factor (38, 40).  The efficacy of VEGF as a 
therapeutic target is well-established in this disease, but currently anti-VEGF monoclonal 
antibodies are the only approved method of VEGF inhibition.  Bevacizumab, a humanized 
monoclonal antibody that binds to VEGF and prevents its interaction with its receptor, is 
the only commercially available anti-angiogenic therapy for mCRC.  Addition of 
bevacizumab to fluoropyrimidine and oxaliplatin-based therapy improves outcomes in 
mCRC. In the E3200 trial, bevacizumab was shown to significantly prolong overall 
survival (13 vs 10 months) and improved response (9% vs 3%) when combined with 
FOLFOX4 as compared to FOLFOX4 alone in patients with previously treated mCRC (7). 
These results led to the phase III NO16966 trial, which investigated the role of 
bevacizumab versus placebo in the first-line setting when added to fluoropyrimidine and 
oxaliplatin-based chemotherapy with FOLFOX or XELOX for the treatment of mCRC (41, 
42).  The primary endpoint of the study was met, with a significant improvement in 
progression-free survival in patients receiving oxaliplatin-based therapy plus bevacizumab 
versus placebo (9.4 vs 8 months, respectively). In subset analysis of FOLFOX versus 
XELOX, the PFS benefit was only significant for XELOX, however, the results may have 
been affected by the discontinuation of chemotherapy before evidence of disease 
progression in a substantial number of patients. There was no significant overall survival 
benefit for the addition of bevacizumab versus placebo to chemotherapy (21.3 vs 19.9 
months).  Objective response rates were similar (47% vs 49%), and 8.4% of patients 
receiving bevacizumab were able to undergo attempted curative metastatectomy (42).  
Bevacizumab also improves outcomes when added to irinotecan plus fluoropyrimidine 
therapy.  In a randomized phase III study of patients with untreated mCRC, the addition of 
bevacizumab to the combination of bolus 5FU, leucovorin and irinotecan (IFL) 
significantly improved overall survival to a median of 20.3 months versus 15.6 months 
with IFL alone, with an overall response rate of 44% (4).  Interestingly, the even patients 
who did not have objective responses by RECIST on this study still benefitted as much 
from the addition of bevacizumab as those who had an objective response. The phase III 
BICC-C study showed a significant survival benefit for the addition of bevacizumab to 
FOLFIRI in the first line setting of mCRC with a median OS of 28 months, versus 23 
months for FOLFIRI alone and 19 months for IFL plus bevacizumab (9, 43).  While the 
toxicity profile of bevacizumab does not seem to overlap with chemotherapy, commonly 
observed toxicities included proteinuria and hypertension, and an increased rate of 
thrombotic events are also seen.  Based on the results of these studies, bevacizumab is 
approved for the treatment of mCRC in the untreated or refractory setting, in combination 
with 5-FU based cytotoxic chemotherapy.  The clinical benefit observed from anti-VEGF 
therapy with bevacizumab highlights the need for further investigation to discover novel 
methods of optimizing blockade of this pathway in mCRC, in order to continue to improve 
clinical outcomes. 
 


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2.2.   5-Fluorouracil, Leucovorin and Oxaliplatin 
 
 
 
2.2.1.   5-Fluorouracil and Leucovorin 
 
 
 
 
5-fluorouracil (5-FU) is a pyrimidine antimetabolite which is metabolized 
intracellularly into its active form.  Its subsequent incorporation into DNA and RNA 
inhibits thymidylate synthase and thus interferes with DNA synthesis and 
replication.  Leucovorin is a reduced form of folic acid which enhances the 
cytotoxicity of 5-FU by stabilizing the binding of 5-dUMP and thymidylate 
synthase.  5-FU and leucovorin have been the backbone of CRC chemotherapy for 
more than the past decade.  Standard leucovorin is a racemic mixture of the d and 
l-isomers and only the l-isomer is active. A preparation containing the l-isomer, 
known a levoleucovorin is commercially available. The standard dose of 
levoleucovorin is 50% of the dose of standard leucovorin. It is unknown whether 
leucovorin is a necessary component of FOLFOX. Recent shortages of leucovorin 
have required administration of the regimen without leucovorin commonly both on 
study and in clinical practice. Given the short half-life of 5FU, infusional regimens 
appear to provide the maximal dose intensity when administered over 24-48 hours.  
Improvement in response, PFS, toxicity, and a trend toward improved OS were seen 
with 5-FUadministered as a short continuous infusion, versus bolus (44). 
 
 
 
 
 
2.2.2.   Oxaliplatin 
 
Oxaliplatin is a platinum derivative with a 1,2-diaminocyclohexane carrier ligand.  
While its exact mechanism of action is unknown, oxaliplatin is thought to exert its 
cytotoxic effects through the formation of DNA adducts.  Oxaliplatin is distributed 
extensively in the plasma, although the elimination of total platinum in the urine is 
slow, with approximately 33% eliminated in 48 hours.  Fecal elimination accounts 
for a trivial amount of clearance.  As a single agent, oxaliplatin has minimal activity 
in advanced CRC.  
 
 
2.2.3. FOLFOX 
 
Oxaliplatin and 5-FU appear to be at least additive in their antitumor activity, 
although the mechanism of synergy is unclear.  The combination of 5FU, 
leucovorin and oxaliplatin (FOLFOX) was initially approved as second line therapy 
for patients who had failed first-line IFL, based on a 9% ORR versus 0% with 
5FU/LV or oxaliplatin alone, as well as improved time to progression and palliation 
of symptoms (45).  A subsequent study of the combination in the first-line setting 
versus 5FU/LV (46) resulted in significantly improved PFS (9 vs 6.2 m) and ORR 
(51% vs 22%). Although OS benefit was not significant, a trend toward improved 
OS was seen with FOLFOX, suggesting that this regimen was beneficial in 
untreated mCRC. The role of FOLFOX as frontline therapy for mCRC was further 
solidified by the Intergroup N9741 study in 2004, which showed a significant 
improvement in time to progression (8.7 vs 6.9 m), ORR (45% vs 31%), and OS 
(19.5 vs 15m) versus IFL (12, 46).  There have been multiple variations in the 


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FOLFOX regimen, based on the dose and schedule of 5FU, LV and oxaliplatin.  
The FOLFOX6 regimen consists of oxaliplatin 100 mg/m2 over 120 minutes, 
followed by LV 400 mg/m2 over 2 hours, followed by 5-FU 400 mg/m2 bolus, then 
5-FU 2400 mg/m2 continuous infusion over 46-48 h, repeated every 2 weeks.  A 
modified version of this regimen is currently in use (modified FOLFOX6 or 
mFOLFOX6) which includes a decrease in the dose of oxaliplatin to 85 mg/m2 (as 
in the FOLFOX4 regimen). Oxaliplatin-related peripheral neuropathy, which is 
cumulative after 4-5 months of therapy, tends to be the treatment-limiting toxicity 
with this regimen.  The OPTIMOX1 and 2 trials were conducted for this reason to 
evaluate the impact on toxicity and efficacy of a stop-and-go administration of 
oxaliplatin in patients with mCRC receiving FOLFOX.  The OPTIMOX1 trial 
revealed oxaliplatin can be safely discontinued after 3 months of FOLFOX therapy, 
and safely re-initiated following a period of maintenance therapy with infusional 
5FU/LV upon resolution of toxicity or at disease progression, with achievement of 
objective response or stabilization of disease in 69% of patients at reintroduction, a 
trend toward less neurotoxicity and no adverse impact on OS, PFS, or duration of 
disease control (47).  The follow-up OPTIMOX2 trial confirmed that maintenance 
therapy is required, as it improves outcomes versus no therapy, during the 
oxaliplatin-free period (48) 
 
 
2.3   Aflibercept (VEGF Trap) 
 
Aflibercept is a novel recombinant human fusion protein comprised of domain 2 of 
VEGFR1 fused with domain 3 from VEGFR2, attached to the hinge region of the Fc(a) 
domain of human IgG1.  Aflibercept binds to VEGF and prevents it from interacting with 
its receptors (VEGFR), thus inhibiting the growth of new blood vessels that supply 
tumors. Aflibercept binds VEGF A and B in the picomolar (pmol/L) range, and also binds 
placental growth factor (PlGF), although with lower affinity. The binding of aflibercept 
to these ligands in vivo to block tumor angiogenesis and vascular permeability is the 
anticipated mechanism of activity of aflibercept.  Aflibercept would be expected to lead 
to reduced tumor growth by a dual mechanism: reducing the density of tumor vasculature 
and reducing the supply of available nutrients and tissue matrix components escaping 
from leaky tumor vessels. 
 
2.3.1Preclinical Studies 
 
 
2.3.1.1 In Vitro Activity Studies  
 
 
In vitro single-agent activity of VEGF Trap 
 
In vitro binding assays of VEGF Trap revealed a binding affinity for VEGF of about 
1 pM.  VEGF Trap also showed increased binding affinity for VEGF-A 
(dissociation constant [Kd] of 0.5 pM for VEGF-A).  When added to cultured 
endothelial cells, VEGF-Trap completely blocked VEGF-induced VEGFR2 
phosphorylation when added at a 1.5-fold molar excess compared with the added 
VEGF, which is consistent with a very high-affinity binding to VEGF.  In addition, 


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VEGF Trap also binds PlGF1 and 2 (49). 
 
2.3.1.2 In vivo activity studies 
 
In vivo pharmacology studies have indicated that treatment with aflibercept 
effectively inhibits tumor growth of a wide variety of rodent and human tumor 
cell lines implanted either subcutaneously or orthotopically in mice. Aflibercept 
treatment inhibited the growth of tumors representing a variety of tissue types 
including melanoma, glioma, rhabdomyosarcoma, Wilms tumor, neuroblastoma, 
Ewing sarcoma, lymphoma, and ovarian, pancreatic, prostate, mammary, gastric, 
and colon tumor tissues with a broad pharmacological index. Antitumor activity 
was observed from 2.5 to 40 mg/kg (49-52).  Aflibercept treatment significantly 
decreased the vessel density in tumors, an indication that tumor-induced 
angiogenesis was inhibited. In order to compare the efficacy of this method of 
VEGF blockade with other known VEGF blockers, aflibercept was compared at 
equimolar doses to DC101, a well-characterized monoclonal antibody that targets 
VEGFR2, in a mouse melanoma model.  The doses of DC101 required to inhibit 
tumor growth were much higher than that of aflibercept, and the dose of DC101 
required to be equally efficacious accumulated at 60-fold higher serum levels than 
aflibercept, suggesting that a much lower dose could be potentially efficacious in 
humans (49, 52). 
 
2.3.1.3 Pharmacokinetics  
 
Pharmacokinetic (PK) parameters of aflibercept in the mouse, rat, and monkey are 
summarized in Table 1.  Inhibition of tumor growth was observed in mouse 
xenografts tumor models with aflibercept doses > 2.5 mg/kg.  This dose 
corresponds to a free aflibercept Cmax  concentrations of 10 µg/mL, about 10-fold 
higher than bound aflibercept concentrations. This suggests that levels of free 
aflibercept in excess of bound aflibercept may be necessary for pharmacological 
activity. Accordingly, the target pharmacological exposure in humans is proposed 
to be a safely administered dose of aflibercept, where maximal bound levels of 
aflibercept are achieved and an excess of free aflibercept is sustained.  
 
Table 1.  Summary of nonclinical pharmacokinetics for aflibercept 
IV Route 
Species  
Dose 
(mg/kg ) 
Cmax 
(µg/mL)  
AUC 
(µg.h/mL)  
t1/2 (h)  Clearance 
(mL/h/ Kg) 
Volume 
(mL/kg)  
Mouse 
1 
19.5 
306 
48 
3.31 
226 
Rat 
1 
20.8±2.4 
463±65 
54±9 
2.21±0.34 
168 
Monkey 
5 
181.7±46.4 
10235±1532 
98±31 
0.5±0.07 
69.1 
AUC=area under the curve 
 
Following IV administration, free aflibercept was characterized by a low clearance 
(0.5-3 mL/hr/kg) and low volume of distribution (69 to 226 mL/kg), and a long 
apparent elimination half-life (48 to 98 hours) in all animal species evaluated. 


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2.3.1.4 Toxicology 
 
Preclinical toxicology was evaluated in rats after a single IV administration and SC 
administration for 13 weeks as well as in cynomolgus monkeys after SC and IV 
administration for 4 and 13 weeks and IV administration for 26 weeks. 
 
Single administration 
A single IV injection (30-minute infusion) of aflibercept at 0, 50, 150, or 500 
mg/kg to rats resulted in lesions at the injection site (tail vein) and a moderate 
decrease in mean body weight gain in males at all dose levels. The Lethal Dose 
was above 500 mg/kg and the No-Observable Adverse Effect Level (NOAEL) 
was 150 mg/kg.  
 
Repeated administration  
In the 13-week rat study, SC administration of aflibercept 3 times per week was 
associated with morbidity and mortality at 1 and 2 mg/kg/administration. The 
most prominent microscopic findings were observed in the kidney (glomerular 
mesangial thickening and tubular protein casts) from 0.5 mg/kg/administration 
and were associated at 1 and 2 mg/kg/administration with increased serum BUN 
and urinary protein levels, and decreased serum protein levels. Renal toxicity of 
aflibercept observed in normal immunocompetent rats that produced antibodies to 
aflibercept, was due, at least in part, to the deposition of immune complexes in 
renal glomeruli. Microscopic changes in the femur (decrease and/or loss of 
metaphyseal bone trabeculae and metaphyseal capillaries, thinning of cortical 
bone) were observed at doses ≥1 mg/kg/administration. The NOAEL was 
determined to be 0.1 mg/kg/administration. 
 
In the monkey studies, the main compound-related microscopic findings were 
observed in the bone, nasal cavity, kidney, ovary, and adrenal gland. In the bone, 
aflibercept-induced effects consisted mainly of thickening of the growth plate and 
osteocartilaginous exostoses observed on the axial and appendicular skeleton that 
correlated with hunched posture at clinical examination. In the nasal cavities, 
degeneration/regeneration of the respiratory and olfactory epithelium, and 
atrophy/loss of nasal septum and/or turbinates was often associated with 
hemorrhage and suppurative exudate. Histopathologic findings in the kidneys 
(increased glomerular mesangial matrix) were associated in a few animals with 
decreased serum total protein and albumin levels and increased serum BUN and 
urine protein and/or microalbumin levels. In the ovaries, the decreased number of 
maturing follicles, granulosa cells, and/or theca cells was associated with an 
overall inhibition of the female reproductive function. The histopathologic 
changes in the bone growth plate and ovary were considered related to the 
pharmacological activity of aflibercept. In the adrenals, a decreased vacuolation 
of adrenal zona fasciculata cells with cytoplasmic eosinophilia was observed. In 
addition, focal vascular proliferation/degeneration was noted in a range of organs, 
including in particular the digestive system, urinary bladder, heart, and brain of a 
few monkeys. Main clinical pathology changes consisted of slight increases in red 


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blood cell parameters, fibrinogen, globulin, BUN, and decreases in albumin. In 
addition, increased liver enzyme (GGT, AST, ALT, ALP) levels were noted in a 
few monkeys with portal inflammation and necrosis. Aflibercept administration 
also resulted in a decrease in sperm motility and increased incidence of abnormal 
spermatozoa morphology. Most aflibercept-related findings were noted from the 
lowest doses tested (1.5 to 3 mg/kg/administration). With the exception of 
osteocartilaginous exostoses and nasal cavity findings, aflibercept related findings 
were reversible within 5 months. Aflibercept was not highly immunogenic in 
monkeys treated by either the SC or IV route for 13 weeks, while the incidence of 
antibody response increased in monkeys treated for 26 weeks. 
 
Reproductive Toxicology 
The SC administration of aflibercept at 25 mg/kg to adult female marmosets 
during the follicular or luteal phase inhibited antral follicle development and 
ovulation. When administered in the luteal phase, aflibercept induced functional 
luteal involutions.  Single IV injections of aflibercept at 0.25, 1, 4, or 12.5 mg/kg, 
at defined stages of menstrual cycle to adult female stumptail macaques led at all 
doses to rapid dose-dependent and reversible suppression of ovarian function. 
 
The effects of aflibercept on male and female fertility parameters were also 
evaluated in sexually mature cynomolgus monkeys treated at 3, 10 and 30 
mg/kg/administration once a week for 15 weeks and then every other week up to 
Week 26. In females, the abrogation of ovarian function and follicular 
development was evidenced from 3 mg/kg/administration. Aflibercept-induced 
inhibition of ovarian function was reversible within 3 to 18 weeks after the last 
injection. In males, the main aflibercept-induced effects consisted of a decrease in 
sperm motility and an increase in incidence of spermatozoa morphological 
abnormalities from 3 mg/kg/administration. These effects were fully reversible 
after a 13 week recovery period. 
 
The effects of aflibercept on embryofetal development were evaluated in pregnant 
rabbits treated IV at doses of 3, 15, or 60 mg/kg/administration on gestation Days 
6, 9, 12, 15, and 18 (total of 5 administrations) during organogenesis. Aflibercept 
at 60 mg/kg/administration induced abortion, minimal to moderate maternal 
toxicity, and embryolethality. External, visceral (affecting mainly the heart and 
great vessels), and/or skeletal malformations were observed in fetuses from dams 
treated at 3 mg/kg/administration (corresponding to a plasma exposure of 1935 
μg.h/mL, which is approximately 1.3 times the systemic exposure in patients at 
the recommended human dose). The visceral and skeletal malformations are 
likely related to the pharmacological activity of aflibercept. 
 
Genotoxicity 
No studies are planned to evaluate genotoxicity of aflibercept because 
genotoxicity assays are not applicable for biologics. 
 


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2.3.2 Clinical Experience with Aflibercept  
 
Aflibercept has been administered IV and SC to healthy subjects, and IV and SC to 
oncology patients. Available information is described in this CIB. Additional studies 
sponsored by the National Cancer Institute – Cancer Therapy Evaluation Program (NCI-
CTEP) are ongoing. 
 
The PK profiling of aflibercept has been determined: 
• in healthy subjects, after 1 hour single IV administration at doses of 1 to 4 mg/kg, and 
after single SC administration at 2 mg/kg. 
• in cancer patients, after SC administration (single and repeated doses) at doses of 25 
μg/kg once weekly to 800 μg/kg twice weekly. 
• in cancer patients, after IV administration after 1 hour infusion at doses of 0.3 mg/kg to 
7 mg/kg every 2 weeks, and up to 9 mg/kg every 3 weeks, following both single and 
repeated administrations. 
 
Concentrations of free aflibercept, bound aflibercept, and anti-aflibercept antibodies were 
measured by ELISA. Concentrations of total aflibercept were derived from measurements 
of free and bound aflibercept. 
 
No metabolism studies of aflibercept have been performed since it is a protein. 
 
2.3.2.1Clinical Pharmacokinetics 
 
The kinetics of aflibercept were determined in healthy subjects in two studies, 
PDY6655 and PDY6656.  The primary objective of these studies was to evaluate 
the blood pressure effects of a single dose of aflibercept. In study PDY6656, the 
pharmacokinetics of aflibercept have been evaluated following a single IV 
administration at the doses of 1, 2, and 4 mg/kg versus placebo in four parallel 
groups of twelve healthy subjects. In study PDY6655, the absolute bioavailability 
of the aflibercept SC formulation based on free and bound aflibercept levels in 
healthy male subjects was determined following administration of a single dose of 
2 mg/kg. 
 
Mean plasma concentration-time profiles for study PDY6656 are shown in Figure 
1. 
 
The PK profile of free aflibercept was biphasic with concentrations detectable up 
to 35 days in a majority of subjects at a dose of 1 mg/kg and up to 42 days at the 
doses of 2 and 4 mg/kg. Free aflibercept was characterized by dose dependent 
clearance, and a volume distribution of about 6 L. Dose dependent clearance is 
consistent with a saturation of the rapid clearance pathway of binding 
endogenously produced VEGF. The elimination half-life of free aflibercept was 
about 5 days. 
 


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Bound aflibercept Cmax and AUC increased proportionally with doses between 1 
and 2 mg/kg, then plateaued between 2 and 4 mg/kg, suggesting that free 
aflibercept was present in sufficient amounts to bind all endogenous VEGF at the 
higher dose levels. Median tmax of bound aflibercept increased with dose from 14 
days at the dose of 1 mg/kg to 28 days at the dose of 4 mg/kg. 
 
Free VEGF levels in plasma increased from below the limit of quantitation (15 
pg/mL) during the two first weeks after infusion to a mean concentration of 48.7 
pg/mL, 42 days after administration of the 4 mg/kg dose. 
 
Following administration of 1, 2, and 4 mg/kg doses, free aflibercept levels 
remained in excess of bound aflibercept levels for approximately 10, 18, and 28 
days, respectively. 
 
Absolute bioavailability of free aflibercept SC was 54.9 %, with an elimination 
half-life of approximately 5 days, comparable to that estimated after IV infusion. 
 
The current clinical development program is focused on IV administration. 
 
Figure 1.  Mean free and bound aflibercept concentration-time profiles (µg/mL) 
 
The pharmacokinetics of aflibercept were studied in patients receiving aflibercept 
as an IV single agent during Cycle 1 (TED6115) and during repeated cycles 
(extension study TED6116). Patients received 2 doses IV, administered two 
weeks apart, in study TED6115. Patients enrolled in the extension study 
(TED6116) continued to receive aflibercept every other week at their assigned 
dose, or at a lower dose if toxicity was encountered. 
 
Mean PK parameters of free aflibercept are summarized in Table 2.  
 
Table 2.  Mean (CV%) pharmacokinetic parameters of free aflibercept in study TED6115 (Cycle 1) 


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Free aflibercept exposure increased more than proportionally in the dose range 0.3 
to 2 mg/kg, then approximately proportionally to dose in the dose range 2 to 7 
mg/kg. The apparent elimination half-life increased with doses from 1.70 days at 
0.3 mg/kg to 3.76 days at 2 mg/kg, reaching 5.14 days at 7 mg/kg. Mean 
clearance values of free aflibercept decreased from 1.95 L/day estimated at the 
dose of 0.3 mg/kg to 1.13 L/day at the dose of 2 mg/kg. These dose dependent 
values are in agreement with a saturation of the rapid clearance pathway of 
binding endogenously produced VEGF. 
 
Mean PK parameters of bound aflibercept are summarized in Table 3.  
 
Table 3.  Mean (CV%) pharmacokinetic parameters of bound aflibercept in study TED6115 (Cycle 
1) 
 
The concentrations of bound aflibercept increased with doses between 0.3 and 2 
mg/kg, then plateaued between 2 and 7 mg/kg, suggesting that bound 
concentrations were limited by the endogenous production of VEGF. Free 
aflibercept levels remained in excess of bound aflibercept levels during the two 
weeks from the dose of 2 mg/kg. 
 
Sources of pharmacokinetic variability 
Intrinsic factors which could impact PK have not been evaluated to date; 
aflibercept is not metabolized by hepatic CYP enzymes and the renal elimination 
of aflibercept corresponds to approximately 1% of the glomerular filtration rate. 
 


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Extrinsic factors as sources of PK variability, such as cytotoxic agents given in 
combination with aflibercept, have been evaluated (Table 4).  Pharmacokinetic 
data are presented in table 5. 
 
Table 4.  Clinical oncology studies assessing drug-drug interactions 
 
 
Table 5. Mean (CV%) pharmacokinetic parameters of free and bound aflibercept in 
combination studies. 
Free and bound aflibercept concentrations determined in combination studies are 
in the same order of magnitude of those observed in the monotherapy study 
TED6115, suggesting that cytotoxic combinations (FOLFOX 4, irinotecan, 5-FU, 
docetaxel, and gemcitabine) have no influence on the PK of aflibercept. Anti-
aflibercept antibodies have been reported using ELISA methods. These findings 
are not unexpected, as aflibercept is a recombinant protein product. The 
immunogenicity testing with present methods showed that less than 1% of 
patients evaluated developed anti-aflibercept antibodies. Further assay 
development is ongoing and the implications and understanding of anti-
aflibercept antibodies is under evaluation. 


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2.3.2.2 Clinical Efficacy 
 
Phase I studies have a demonstrated safety in advanced solid tumors, as well as 
phase II efficacy data in second line mCRC including patients refractory to 
bevacizumab.   Recent phase III data showed a survival benefit for the addition of 
aflibercept over placebo to second-line chemotherapy in mCRC. 
 
 
2.3.2.2.1 Phase I Trials of Aflibercept 
Aflibercept has been studied in as a single agent and in combination with 
chemotherapy in the phase I setting. 
 
In a phase I study of patients with refractory advanced solid tumors, 47 patients 
were enrolled and received escalating doses of single-agent aflibercept from 0.3 to 
7 mg/kg IV every 2 weeks (53).  DLTs included grade 3 ALT elevation at 1 
mg/kg, grade 3 dyspnea and arthralgia at 2 mg/kg, and grade 3 hypertension at 4 
mg/kg.  At the 7 mg/mg dose, DLTs included proteinuria (n=1) and rectal 
ulceration (n=1).  The most common drug-related AEs were fatigue (63%), 
nausea (36%) and vomiting (27%), which were generally grade 1 and resolved 
with discontinuation of the drug.  Toxicities commonly associated with 
antiangiogenic therapy that were seen with aflibercept included dysphonia (46%), 
hypertension (38%) and proteinuria (10%).  The incidence of grade 3-4 
hypertension increased with increasing doses of aflibercept (42% at 4 mg/kg, 75% 
at 5 mg/kg, and 46% at 7 mg/kg).  Based on this toxicity profile, the 
recommended phase II dose of aflibercept was 4 mg/kg every 2 weeks as a single 
agent.  Evidence of activity was observed, with 3 patients achieving confirmed PR 
and an additional patient with an unconfirmed PR.  Correlative DCE MRI showed 
evidence of decreased tumor perfusion and vascularity with increasing dose levels 
of aflibercept. 
 
TCD6117 (AVE0005A/1001) was an open-label, phase 1, dose-escalation, 
sequential-cohort study of the safety, tolerability, and pharmacokinetics of IV 
aflibercept administered every 2 weeks in combination with FOLFOX4 
(oxaliplatin 85 mg/m2 on Day 1, leucovorin 200 mg/m2 on Day 1 and Day 2, 5-
FU bolus/infusion 400/600 mg/m2 on Day 1 and Day 2 of a 2-week cycle) in 
patients with advanced solid malignancies. Thirty-two patients (male/female: 
9/23, median age 59 years [range 25 to 79], ECOG performance status 0/1: 11/21) 
were enrolled at 3 aflibercept dose levels: 2 mg/kg (n = 4), 4 mg/kg (n = 18), and 
5 mg/kg (n = 10). Primary tumors were mainly gastrointestinal (16, including 8 
pancreas, 3 cholangiocarcinoma, and 3 gastric), breast (5), ovarian (4), and others 
(7). Most patients (75%) were heavily pretreated, with a median number of prior 
lines of chemotherapy of 3 (range 1 to 9). Patients received a median number of 
3.5 treatment cycles (range 2 to 8), 7.0 (range 2 to 20), 5.5 (range 1 to 20) at the 2, 
4, and 5 mg/kg dose levels, respectively. 
 
 
2.3.2.2.2 Phase II Trials of Aflibercept in CRC 


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A second line, 2-stage phase II trial evaluated aflibercept monotherapy in two 
cohorts of previously-treated mCRC patients, a cohort of patients previously 
treated with bevacizumab and a cohort of bevacizumab-naïve patients (54). 
Aflibercept 4mg/kg IV every 2 weeks was administered. Among the bevacizumab 
naïve patients, the disease control rate (DCR = PR + SD > 16 weeks) was 29% 
and median PFS was 2 m; among bevacizumab pretreated patients, there was one 
partial response, with a disease control rate of 30% and median PFS of 3.4 m. 
Only the bevacizumab pretreated cohort met the prespecified response criteria to 
proceed with further trials. Aflibercept was well tolerated in these patients (54). 
 
 
2.3.2.2.3 Phase III Trials of Aflibercept in CRC 
Data were recently presented from a randomized phase III trial (VELOUR) in 
which patients with mCRC who had failed oxaliplatin-based therapy were 
randomized to receive FOLFIRI plus aflibercept 4 mg/kg or placebo every 2 
weeks.  30% of patients had failed prior bevacizumab therapy as well. The 
primary endpoint of the trial was OS, which was met with a statistically 
significant improvement in the aflibercept arm (13.5m vs 12 m).  PFS (6.9m vs 
4.7 m) and ORR (20% vs 11%) were also significantly improved with the addition 
of aflibercept (55).  These results were remarkably similar to the 2nd-line E3200 
trial with FOLFOX and bevacizumab (7), further supporting the role of anti-
VEGF therapy in this disease.   Grade 3-4 AEs observed in VELOUR with >2% 
higher incidence with aflibercept versus placebo were diarrhea, asthenia/fatigue, 
stomatitis/ulceration, infections, hypertension, GI/abdominal pain, 
neutropenia/neutropenic complications, and proteinuria.  AEs led to treatment 
discontinuation in 26.6% of patients receiving aflibercept, versus 12.1% of 
patients receiving placebo.  
 
2.3.2.3 Clinical Toxicology  
 
To date, aflibercept has been administered to 76 healthy subjects and 
approximately 2000 patients with advanced solid malignancies in clinical 
oncology trials. In company sponsored trials, doses have been administered up to 
800 μg/kg twice weekly SC, 7 mg/kg every 2 weeks, and 9 mg/kg IV every 3 
weeks. In company-sponsored Phase 1 and Phase 2 single agent trials >400 
patients have been dosed with aflibercept for >2000 cycles, primarily on an every 
2 week schedule. In company-sponsored Phase 1 combination trials, >200 
patients have been dosed for >1000 cycles in either an every 2 or 3 week 
schedule. Phase 3 combination trials evaluating 4 mg/kg every 2 weeks and 6 
mg/kg every 3 weeks of aflibercept are recently completed/ongoing. 
 
The most frequent TEAEs (all grades, regardless of relationship to study 
medication) observed across all doses were: 
• overall incidence >25%: fatigue, nausea, diarrhea, vomiting, anorexia, 
hypertension, headache, constipation, mucosal inflammation, dysphonia, 
epistaxis, and abdominal pain 
• overall incidence 10-25%: peripheral sensory neuropathy, pharyngolaryngeal 


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pain, temperature intolerance, abdominal pain upper, arthralgia, chills, dyspepsia, 
dyspnea, neuropathy peripheral, palmoplantar erythrodysesthesia syndrome, pain 
in extremity, back pain, bone pain, dehydration, gastroesophageal reflux disease, 
edema peripheral, skin discoloration, alopecia, dizziness, insomnia, and pyrexia. 
The profile of AEs reported is overall consistent with what has been reported 
with VEGF blockade and FOLFOX4. A dose of 4mg/kg of aflibercept was 
selected based on similar free and bound aflibercept levels in single agent and in 
combination with FOLFOX4 (56). 
 
Overall, based upon treatment-related serious or severe AEs in clinical trials, the 
following toxicities may occur with IV aflibercept as a single agent or in 
combination with other drugs: 
• Hematological disorders and resistance: anemia, thrombocytopenia, 
thrombotic microangiopathy; additionally in combination with cytotoxic 
chemotherapy: neutropenia including febrile neutropenia, neutropenic colitis, 
and sepsis 
• Cardiac disorders: cardiac failure 
• Digestive toxicity: abdominal pain, gastrointestinal hemorrhage, intestinal 
perforation, intestinal obstruction, enteric fistula, peritonitis, pneumatosis 
intestinalis, nausea, vomiting, diarrhea, constipation, mucosal inflammation or 
ulceration, stomatitis, hepatic enzymes increased 
• General disorders: asthenia, fatigue, musculoskeletal pain, injection site 
reaction 
• Immune system disorders: hypersensitivity 
• Metabolic disorders: dehydration 
• Musculoskeletal: arthralgia, myalgia, osteonecrosis 
• Nervous system: headache, dizziness, encephalopathy (including reversible 
posterior leukoencephalopathy syndrome), cerebral ischemia, cerebral 
hemorrhage, cerebral venous thrombosis 
• Renal disorders: proteinuria (including nephrotic syndrome), hematuria, renal 
failure 
• Respiratory disorders: dysphonia, dyspnea, epistaxis, hemoptysis, pulmonary 
embolism, tracheo-esophageal fistula 
• Skin disorder in combination with cytotoxic chemotherapy: palmar-plantar 
erythrodysaesthia syndrome, erythema 
• Vascular disorders: hypertension (including malignant hypertension), deep vein 
thrombosis, and phlebitis 
  
Developmental/Reproductive Toxicity 
As angiogenesis is critical to fetal development, the inhibition of angiogenesis 
following administration of aflibercept is likely to result in adverse effects on 
pregnancy. There are no adequate and well-controlled studies in pregnant women 
using aflibercept. Women of childbearing potential should be advised to avoid 
becoming pregnant while receiving aflibercept, and advised to use effective 
contraception (including abstinence and double-barrier methods) during and up to 
a minimum of 6 months after the last dose of treatment. Developmental and 


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reproductive toxicity studies of aflibercept have not been performed thus far.  
Aflibercept has not been tested in breastfeeding women, however IgG1s are 
secreted into breast milk, and aflibercept should not be administered to women 
who are breastfeeding.  No genotoxicity studies have been conducted with 
aflibercept. 
 
If a patient becomes pregnant while receiving aflibercept, therapy should be 
discontinued immediately and the patient should be apprised of the potential 
hazard to the fetus and/or the potential risk of loss of pregnancy. Patients who 
discontinue aflibercept should also be counseled concerning the prolonged 
exposure following discontinuation of therapy (half-life of approximately 20 
days) and the possible effects of aflibercept on fetal development.   
 
Immunogenicity and Infusion Reactions 
As of February 12, 2009, a total of 3923 serum samples from 1254 cancer patients 
treated with aflibercept (as monotherapy or in combination with cytotoxic 
chemotherapy) were assessed for immunogenicity using ELISA methods. To date, 
anti-aflibercept antibodies have been detected in 11 samples from 11 different 
patients (incidence: 0.9% across the 1254 patients in single and combination agent 
studies.) 
 
As of 12 February 2009, 9 SAEs of hypersensitivity, all recovered, have been 
reported. Two of the 9 cases were not related to aflibercept but rather to additional 
medication (non-protocol paclitaxel in one case and protocol oxaliplatin in the 
second case). The remaining 7 cases of hypersensitivity were assessed by the 
Investigators as related to study treatment. The majority of the events were of 
moderate severity. 
 
 
2.4 Correlative Studies Background 
 
2.4.1 Laboratory/Biologic Correlative Studies  
 
 
Specific Aim: To identify novel predictive markers of response to therapy in 
 
patients with untreated metastatic colorectal cancer receiving aflibercept. The  
 
tissue and blood correlative studies from this trial will include, but are not   
 
limited to the following listed below. Any leftover tissue or blood will  
 
 
be kept for future unknown research. Note that consent for future unknown  
 
research for the tissue banking and blood banking parts are optional to enroll on  
 
this study.  . 
 
Measurement of Serum VEGF, VEGFR, and P1GF (Cynthia Timmers, PhD) 
There remains a critical need to identify biomarkers to predict which patients 
will benefit from anti-angiogenic therapy, and which patients will not respond.  
The majority of prior clinical trials conducted with bevacizumab have included 
biomarker studies. Previous studies have shown that plasma VEGFA may be a 
prognostic biomarker in mCRC, with high levels associated with worse OS than 


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low levels, but predictive value of VEGF was not observed for bevacizumab-
based treatment (57).  It was previously demonstrated that VEGF and VEGFR2 
may be predictive for efficacy with bevacizumab in breast cancer patients, with 
high expression correlating with better PFS (58).  Similarly, VEGFA and 
VEGFR2 were found to be potentially predictive of efficacy for pancreas cancer 
patients treated with bevacizumab, with high levels correlating with improved 
survival with treatment (59).  To further investigate predictive markers, samples 
from several previously conducted trials were re-analyzed to evaluate potential 
predictive value of plasma VEGFA, using a novel ELISA-based assay favoring 
shorter isoforms VEGFA121 and VEGFA110.  Results were presented at the 2011 
ESMO meeting and showed a potential predictive value of high levels of 
VEGFA for efficacy with bevacizumab, with high plasma VEGFA levels 
correlating with improved PFS and OS following treatment with bevacizumab 
in pancreas, breast and gastric cancers, but this effect was not seen in CRC (60), 
suggesting that further investigation is needed to study these and other novel 
predictive biomarkers for efficacy in this disease.  It was also hypothesized that 
certain VEGFA isoforms such as VEGFA121 and/or VEGFA110 may be driving 
predictive value and may vary in different tumor types, which may be a reason 
for the predictive value of VEGF observed in some cancers and not others on 
this  (60).   
 
Predictive biomarkers for aflibercept were investigated in a phase II study.  In 
recurrent glioblastoma multiforme (GBM) patients treated with aflibercept, 
circulating VEGF levels were significantly decreased within 24 hours of 
treatment with aflibercept, and correlated with radiographic response on MRI.  
These data suggest that decreased levels of VEGF may predict response to 
therapy with aflibercept (61).  PIGF levels initially decreased following 
aflibercept treatment, but increased significantly by day 28.  Lower baseline 
levels of P1GF were also associated with improved response suggesting 
potential value as a predictive marker (61).  These data suggest that VEGF and 
its receptor and P1GF may be potential predictive biomarkers for response to 
therapy with aflibercept.  We will measure serum levels of VEGFA, VEGFR2, 
and P1GF during treatment, which will be correlated with clinical outcomes. 
 
2.4.1.1 Measurement of Serum CXCL12 and CXCR4 (Cynthia Timmers, PhD) 
Several studies have shown that chemokines (chemoattractant cytokines) are 
major regulators of cancer cell trafficking and adhesion, and are an important 
factor in organ-selective metastases.  CXCR4 and its only known ligand 
CXCL12 (SDF1) have a known role in the metastatic spread of colorectal cancer 
(62).  In preclinical models, CXCL12-induced CXCR4 activation results in 
migration and survival of colorectal cancer cells (63, 64)  CXCR4 
overexpression is associated with lymph node metastases in colon cancer (65) 
and its expression has been associated with adverse outcome including 
increased risk of recurrence, development of metastatic disease, and inferior 
survival (63, 65).  Inhibition of CXCL12-CXCR4 signaling results in marked 
inhibition of solid tumor metastases in animal models (62, 66, 67). 


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There is evidence to suggest that VEGF upregulates the CXCR4 expression on 
vascular endothelial cells (VEC), and is synergistic with CXCL12-mediated 
VEC migration (68). Additionally, due to the mechanism of action of VEGF, 
tumor changes in blood flow/microvessel density, capillary permeability, and 
blood vessel normalization are potentially impacted by anti-VEGF therapies 
(68).  Inhibition of VEGF may therefore lead to decreased expression of 
CXCR4.  CXCL12/CXCR4 inhibition has been shown to decrease the growth 
of gastrointestinal tumors (68).  We hypothesize that VEGF inhibition may alter 
chemokine expression and that pretreatment levels of chemokine expression 
may be prognostic or predictive for response to therapy with aflibercept. We 
will obtain serum measurements of CXCR4 and CXCL12 at various timepoints 
of treatment and correlate these levels with clinical outcomes to test this 
hypothesis. 
 
2.4.1.2 Single nucleotide polymorphisms (SNPs) (Cynthia Timmers, PhD) 
Previous attempts to identify tumor-related biomarkers that predict efficacy of 
bevacizumab (such as tumor expression of VEGF) have been largely 
unsuccessful- a possible reason being that angiogenesis is a host-related 
process.  However, there is a significant amount of inherited genetic variability 
within VEGF and its receptor including multiple single-nucleotide 
polymorphisms (SNPs) (69, 70) which may have prognostic and/or predictive 
value.  The VEGF gene is located on chromosome 6p12-p21 and is made up of 
8 exons separated by 7 introns that exhibit alternative splicing to form a family 
of proteins (71, 72).  There have been several polymorphisms identified in the 
VEGF gene, some of which are associated with variations in VEGF protein 
production (69, 73, 74).  These polymorphisms include [-2578C>A,-1154G>A, 
and-634G>C (translation start site counted as +1) in the promoter or 5’ 
untranslated region and +936C>T in the 3’-untranslated region].  VEGF gene 
polymorphisms have been associated with the development of cancers in which 
angiogenesis plays a critical role (75-78), and recent data shows that the 
presence of certain VEGF SNPs can be predictive of clinical outcome in breast 
and ovarian cancers (79-81).  In a study of 446 of colorectal cancer patients who 
had undergone prior surgical resection for stage II or III disease, VEGF gene 
polymorphisms were shown to be an independent prognostic marker (82).  
Specifically, 3 genotypes were analyzed: -2578C>A, -634G>C, and +936C>T.  
On univariate analysis, all 3 had a survival effect.  On multivariate analysis, 
patients with the -634G>C polymorphism, the G/C genotype or C/C genotype 
exhibited significantly superior OS and PFS compared with the G/G genotype.  
For patients with the +936C>T polymorphism, survival was significantly worse 
if the C/T or T/T genotype was present, versus the C/C genotype.  The -
2578C>A polymorphism was not significantly associated with outcome on 
multivariate analysis (82).  Subsequent haplotype analysis evaluated the 
combined prognostic effect of the 3 polymorphisms.  Haplotype CCC was 
associated with significantly improved survival versus CGC, and in turn CGC 
was associated with improved survival over AGT haplotype.  These data 


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suggest a prognostic influence of certain VEGF gene SNPs in patients with 
CRC.   
 
The predictive value of VEGF SNPs for response to anti-angiogenic therapy 
with bevacizumab was also recently demonstrated in breast cancer, where 
patients with the VEGF genotypes -2578 AA and -1154 AA had superior OS 
with bevacizumab treatment versus other VEGF genotypes.  In addition, VEGF 
SNP genotypes -634 CC and -1498 TT were strongly associated with less grade 
3-4 hypertension with bevacizumab therapy (70, 83).   Recently presented 
preliminary data suggest that VEGF SNPs may have predictive value across a 
wide variety of cancers treated with bevacizumab including CRC (84).   Patients 
with VEGF-2578 AA genotype had a trend toward improved clinical efficacy 
and genotypes -1498 TT and -634CC had a trend toward less grade 3-4 
toxicities.  
 
We will analyze VEGF SNPs in patients with mCRC treated with aflibercept to 
identify any SNPs that may be prognostic or predictive of clinical efficacy 
and/or toxicity.  We will also compare our results to those of patients previously 
treated with bevacizumab.  
 
2.4.1.3 Measurement and Quantification of Tumor Vasculature (Cynthia Timmers, 
PhD)  
In preclinical mouse models, treatment with VEGF-Trap resulted in decline in 
tumor vascular patency and blood flow with a marked decrease in tumor blood 
vessel density by more than 70% in seven days, and decreased VEGFR2 and 
VEGFR3 expression in surviving vascular endothelial cells.  In addition, the 
sprouting of new blood vessels was also inhibited (85).  A second study in mice 
bearing human colorectal cancer xenograft tumors also showed that VEGF-Trap 
resulted in a decrease in tumor vasculature in just 3 days, and also induced a 
decrease in the caliber of tumor vessels and inhibited proliferation of vascular 
endothelial cells and formation of new blood vessels (25).  We will measure the 
effect 
of 
treatment 
with 
aflibercept 
on 
tumor 
vasculature 
by 
immunohistochemistry performed on tumor biopsies pretreatment, and post–
cycle 2 (tumor biopsies after cycle 2 will only be performed at Ohio State 
University Medical Center) with aflibercept.  Results will also be correlated 
with measurements of tumor vasculature by DCE-MRI and serum markers of 
angiogenesis.  
 
2.4.1.5 Hypertension  
Hypertension is a well-known toxicity of anti-angiogenic therapy.  Several 
studies have also shown that hypertension may be a predictive biomarker for 
efficacy of anti-angiogenic therapy (68, 70, 86-90) however this has not been 
shown in all studies (91) and warrants further investigation.  We will 
characterize hypertension as a treatment-related toxicity according to CTCAE 
v. 4.0 and evaluate for correlation with clinical outcomes to determine if 
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2.4.2   Radiographic Correlative Studies (Dr. Michael Knopp) 
 
2.4.2.1 DCE-MRI  
Tumor treatment evaluation needs to address as the tumor are a truly three-
dimensional, continuously evolving process and during their development and 
therapy, neoplastic lesions change their properties (i.e. neoangiogenesis, 
metabolism and necrosis). These changes can occur simultaneously in various parts 
of a tumor that leads to lesion heterogeneity. Three-dimensional detailed 
assessment with dynamic contrast enhanced MRI (DCE-MRI) is able to 
demonstrate changes in tumor vascularity and viability in all parts of a tumor. 
Furthermore, anti-angiogenic therapy can lead to early changes in tumor 
vasculature and tissue perfusion without corresponding changes in tumor size.  
This is a limitation of using traditional RECIST criteria alone to measure 
response to anti-angiogenic therapy.  In clinical trials of bevacizumab, objective 
response lack of response RECIST or did not necessarily predict clinical 
outcome (92), highlighting the need for new imaging modalities to supplement 
the inadequacies of RECIST in this area. DCE-MRI provides the ability to 
measure effect of therapy on tumor heterogeneity, microcirculation, vascularity 
and viability and is a promising imaging modality both for the measurement of 
anti-angiogenic effects of therapy, and prediction of early response to treatment.  
The value of such an approach in cancer diagnosis and treatment evaluation has 
been extensively shown (93-97).  Dose dependent blood vessel changes have 
been noted on DCE-MRI with anti-angiogenic therapy (68).  A study in a GBM 
population treated with aflibercept demonstrated evidence of decreased 
vascular permeability on DCE-MRI, which correlated with decreased free 
VEGF levels and tumor response (98).   We will perform DCE-MRI at week 0 
(pre-therapy) and after 8 weeks (2 cycles) of therapy to evaluate changes in 
tumor vasculature with aflibercept therapy, and assess for relationships between 
DCE MRI findings and clinical outcomes. DCE-MRI will only be performed at 
sites that have the technology available. DCE-MRI is optional for participating 
sites that are unable to perform the imaging due to financial restrictions. We 
will also evaluate for relationships between circulating markers of angiogenesis 
(see Section 2.4.1) and changes in tumor vasculature observed on DCE-MRI. 
 
2.4.2.2 FDG-PET  
While the use of RECIST criteria is the standard approach to assessment of 
response to anticancer therapy, there are limitations to this method in the setting 
of anti-angiogenic therapy, when tumors can exhibit necrosis and changes in 
vascularity without changes in size.  18FDG-PET is a functional imaging 
technique that relies on tumor uptake of radiolabeled tracer 18 
fluorodeoxyglucose (18FDG). FDG-PET is a widely-used imaging modality in 
the detection and monitoring of a variety of metastatic cancers, including 
colorectal cancer (99-102).  18FDG is a radiopharmaceutical analog of glucose 
that is taken up by metabolically active tumor cells using a facilitated transport 
similar to that used by glucose. FDG-6-phosphate is effectively “trapped” 
within these cells, as it is not a substrate for the subsequent enzymatically-


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driven pathways for glucose and the rate of dephosphorylation is slow. 
Increased tumor FDG uptake as measured by PET, although a function of 
proliferative activity, also reflects viable tumor cell number. Several factors can 
lead to changes in FDG uptake in a tumor, including alterations in tumor 
perfusion as a result of the effects of anti-angiogenic therapy on tumor 
vasculature (103), which makes PET scanning an attractive potential adjunct to 
traditional CT scan in the assessment of response to anti-angiogenic therapy.   
In fact, various PET techniques can be used to directly evaluate a variety of 
parameters relating to tumor neovasculature, including hemodynamic 
parameters (blood flow,  blood volume) and tissue properties (glucose 
metabolism, hypoxia) (103). It has been demonstrated in several cancers that 
changes in tumor metabolism can be seen on PET after just a few weeks of 
effective therapy (104-107) and that these findings may predict clinical 
outcome. 
 
In rectal cancer, decrease or loss in FDG avidity has been correlated with 
responses to anti-VEGF therapy (108), and in metastatic colon cancer patients 
treated with anti-angiogenic therapy, the use of FDG-PET along with DCE MRI 
was able to detect changes in tumor vasculature that predicted response to 
therapy after just 3 cycles of treatment in one case series (109), and in a second 
study, decreased FDG uptake on PET correlated with significantly improved 
progression-free survival in patients treated with FOLFOX plus bevacizumab 
(110).  Integration of PET with conventional imaging techniques may therefore 
provide a useful adjunct to assessment of response to anti-angiogenic therapy 
in CRC (111).  To further investigate the utility of FDG-PET in this setting, we 
will perform FDG-PET scans on all patients at week 0 (pre-therapy) and after 
8 weeks (2 cycles) of therapy and correlate results with clinical efficacy and 
DCE MRI findings. FDG-PET will only be performed at sites that have the 
technology available. FDG-PET is optional for participating sites that are 
unable to perform the imaging due to financial restrictions. 
 
 
2.5       Study Rationale 
 
Colon cancer remains a therapeutic challenge despite advances in both our understanding 
of the disease as well as development of new biologic and targeted therapies.   
Angiogenesis and particularly VEGF have a known pathogenic role in colon cancer and 
are well-established as a valid therapeutic target in this disease.  As bevacizumab is the 
only approved anti-VEGF therapy for mCRC, further investigation into anti-VEGF 
targeted therapy is warranted in an effort to improve outcomes in these patients.  
Aflibercept represents a novel approach to targeting VEGF with a different mechanism of 
action than bevacizumab (including a higher affinity for VEGF-A than bevacizumab), and 
has shown activity in patients refractory to bevacizumab.  Aflibercept is safe and tolerable 
in phase I and II studies with a toxicity profile similar to bevacizumab.  Results of the 
recent phase III VELOUR study with aflibercept + FOLFIRI as second line therapy, 
including a patient population in which 28% of patients had received prior bevacizumab, 


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were comparable to previously conducted studies of FOLFOX + bevacizumab as second 
line therapy.  These results provide further validation of VEGF as a therapeutic target in 
mCRC and provide rationale for bringing the combination of aflibercept +FOLFOX to the 
first-line setting. 
 
The rationale for the correlative science stems from the information provided above.  There 
remains an unmet need to identify predictive biomarkers for anti-angiogenic therapy, in 
order to better select patients who are likely to benefit from treatment, and detect early in 
the treatment course those patients who will not respond.   Our proposed work outlined 
above will investigate circulating markers of angiogenesis and SNPs that have been shown 
to be potential predictive markers for anti-angiogenic therapy, in patients treated with 
aflibercept.  Our radiographic correlative studies are designed to further investigate the 
utility of DCE-MRI and FDG-PET as adjunctive imaging modalities and potential early 
predictors of response to anti-angiogenic therapy. Development of additional methods of 
response assessment, particularly those which may be able to predict early responders and 
spare non-responders the added toxicity of anti-angiogenic agents, is crucial in the setting 
of anti-angiogenic therapy, given the limitations of traditional RECIST criteria.   
 
3. PATIENT SELECTION 
 
3.1  
Eligibility Criteria 
 
3.1.1 Patients must have histologically confirmed adenocarcinoma of colorectal 
origin that is metastatic or locally advanced and unresectable. 
 
3.1.2 Patients must have measurable disease, as defined by RECIST 1.1 criteria:  
one lesion that can be accurately measured in at least one dimension (longest 
diameter to be recorded) as >10 mm with spiral CT scan (CT scan slice 
thickness no greater than 5 mm) Malignant lymph nodes will be considered 
measurable if they are ≥15 mm in short axis.  See Section 11 for the 
evaluation of measurable disease.  
 
3.1.3    Patients must not have received any prior systemic therapy for metastatic or 
locally advanced CRC.   Prior VEGF inhibitors are not allowed. 
 
3.1.4 Prior adjuvant therapy for CRC including fluoropyrimidines either alone or in 
combination with oxaliplatin is allowed, provided that all therapy was 
completed > 12 months from cancer recurrence, therapy duration was < 6 
months, and all prior toxicities have completely resolved (residual grade 1 
neuropathy is allowed). 
 
3.1.5 Patients who have received prior locoregional therapy for metastatic disease 
including surgical resection, microwave ablation, cytoreductive surgery with 
hyperthermic intraperitoneal chemotherapy, or radiation are eligible providing 
the measurable disease is clearly manifest and is outside of the radiation port 
or ablation field. Patients who have received liver directed treatments such as 


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yttrium-90 radioembolization or transarterial chemoembolization are eligible 
if their measurable disease is outside of the liver. 
 
3.1.6 Age >18 years.   
 
3.1.7 Life expectancy > 12 weeks.  
 
3.1.8 ECOG performance status 0-1 (see Appendix A).   
 
3.1.9 Patients must have adequate organ and marrow function as defined below: 
 
- 
hemoglobin 
 
 
 
 
> 9 g/dL (blood transfusion permitted to 
attain this value) 
- 
absolute neutrophil count  
>1,500/µL 
- 
platelets 
 
 
 
 
 
>100,000/µL 
- 
total bilirubin  
 
 
 
<1.5 X institutional ULN 
- 
AST (SGOT)/ALT(SGPT) 
 
<2.5 X institutional ULN (may be < 5x 
ULN if increase is due to metastatic disease) 
- 
creatinine  
 
 
 
 
< 1.5 x institutional ULN 
 
 
 
OR  
- 
Creatinine Clearance           
≥60 mL/min/1.73 m2 for patients with  
 
 
 
 
creatinine  levels above institutional ULN 
- 
urinalysis  
 
 
 
 
UPCR < 1  or <1000 mg protein/24 hr  
- 
Blood Pressure 
 
 
 
< 160/90 
 
3.1.10 Ability to understand and the willingness to sign a written informed consent 
document. 
 
3.2  
Exclusion Criteria 
 
3.2.1 Patients may not be receiving any other investigational agents.   
 
3.2.2 Patients with known or suspected brain metastases, carcinomatous meningitis, 
uncontrolled seizure disorder, active intracranial bleeding or active neurologic 
disorder are excluded. 
 
3.2.3 Patients with an active second primary malignancy or history of malignancy 
within 5 years of enrollment are excluded, with the exception of non-
melanoma skin cancers and cervical cancer which has been treated with 
curative therapy.  
 
3.2.4 Grade > 2 sensory neuropathy at the time of enrollment. 
 
3.2.5 Major surgery within 4 weeks of enrollment.  Any and all surgical incisions 
must be fully healed prior to study enrollment. *Note: Recent port placement 


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for chemotherapy administration is not considered an exclusionary surgical 
incision. 
 
3.2.6 Female or male patients of reproductive capacity unwilling to use methods 
appropriate to prevent pregnancy are excluded.  Effective contraception is 
required for at least 6 months following the last administration of aflibercept. 
 
3.2.8 Uncontrolled intercurrent illness including, but not limited to, ongoing or 
active infection, uncontrolled hypertension (BP > 160/90), unstable angina 
pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would 
limit compliance with study requirements, or any condition that the PI feels 
would make the patient ineligible.  
 
3.2.9 Positive pregnancy screening test with a minimum sensitivity of 25 IU/L of 
hCG within 72 hours of registration.   Breastfeeding women are also excluded.  
 
3.2.10 History of pulmonary embolus within 3 months or DVT within 4 weeks of 
enrollment.   Patients on anticoagulation must be on a stable dose of warfarin 
with a therapeutic-range INR or on a stable dose of low molecular weight 
heparin.  
 
3.2.11  Active congestive heart failure (NYHA class II-IV). 
 
3.2.12  History of an arterial thrombotic vascular event including CVA, MI, unstable 
angina, coronary or peripheral arterial bypass graft, or TIA within 6 months. 
 
3.2.13  Serious or non-healing wound, ulcer or bone fracture. If patient develops a 
serious or non-healing wound, ulcer or bone fracture after enrollment, but 
prior to study drug initiation, patient is not eligible to begin protocol therapy. 
 
3.2.14  History of treatment-resistant peptic ulcer disease, erosive esophagitis, 
gastritis, or diverticulitis within 3 months. 
 
3.2.15  History of GI perforation within 5 years or patient has a current or prior 
intestinal fistula.  
 
3.2.16  Known chronic infectious disease including, but not limited to, HIV/AIDS 
 
3.2.17  History of major hemorrhage including gastrointestinal bleeding (grade 2-4), 
pulmonary hemorrhage, or clinically significant hemoptysis (>1 tsp in 24 
hours) within the last 5 years.  Patients with underlying conditions that 
predispose to bleeding, such as bleeding diathesis, known esophageal varices, 
or tumor involving major vessels, are also excluded.  
 
3.2.18  Inability to understand or comply with study protocol. 
 


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3.2.19  Known hypersensitivity to Chinese hamster ovary cell products or to 
recombinant human or murine antibodies, or any of the treatments in this 
protocol.  
 
 
3.3  
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this 
trial.  
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines 
 
OSU patients will be registered by the OSU research coordinator. 
 
Subsite patients will have eligibility verified and will be entered on study centrally at 
The Ohio State University by the Subsite Coordinator.  All subsites should call the 
Subsite Coordinator (Jennifer Sexton) at 614-366-5642, to verify enrollment 
availability. The required registration forms (Eligibility Checklist and Registration Form) 
can be found in the Supplemental Forms Document. 
 
Following registration, patients should begin protocol treatment within 5 days.  Issues 
that would cause treatment delays should be discussed with the Principal Investigator.  
If a patient does not receive protocol therapy following registration, the patient’s 
registration on the study may be canceled.  The Subsite Coordinator should be notified 
of cancellations as soon as possible.  
 
 
4.2 
Registration Process 
 
To register a subsite patient, the following documents should be completed by the 
research nurse or data manager and faxed or securely e-mailed to the Subsite 
Coordinator (Jennifer Sexton): 
• Copy of all required laboratory tests per the protocol calendar. Screening tests 
must be within the specified window. 
• Signed patient consent form 
• HIPAA authorization form 
• Eligibility Checklist (refer to Supplemental Forms Document)  
• Registration Form (refer to Supplemental Forms Document)  
• Source documents verifying every inclusion & exclusion criteria 
• Additional source documents pertaining to verification of eligibility (emails, other 
signed forms, etc) 
 
The Subsite Coordinator will email the research nurse or data manager to confirm 
receipt of the registration request and supporting documents. The research nurse or data 


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manager at the participating site should call the Subsite Coordinator if the email 
confirming receipt of the registration request is not received within 2 hours.  To 
complete the registration process, the Subsite Coordinator will 
• assign a patient study number 
• register the patient on the study 
• fax or securely e-mail the patient study number and dose information to the 
participating site 
• call the research nurse or data manager at the participating site to verbally 
confirm registration. 
 
5. TREATMENT PLAN 
 
5.1  
Agent Administration 
 
Treatment will be administered on an outpatient basis.  Appropriate dose modifications 
for FOLFOX and aflibercept are described in Section 6.  Reportable adverse events and 
for FOLFOX and aflibercept are described in Section 7.  No investigational or 
commercial agents or therapies other than those described below may be administered 
with the intent to treat the patient's malignancy.  For the purposes of this study, 1 
treatment cycle = 28 days. 
 
Agents will be administered in the following order on days 1 and 15 of each cycle: 
 
1. Aflibercept 4 mg/kg as a 1-hour IV infusion, followed by: 
 
2. mFOLFOX6 
• Oxaliplatin 85 mg/m2 intravenously infused over 2 hours, followed by 
• Leucovorin 400 mg/m2 (Or levoleucovorin 200 mg/m2. If leucovorin is not 
available due to drug shortages the regimen should be administered with the 
leucovorin omitted) IV over 2 hours.  Alternatively, leucovorin may be 
administered (via separate infusion lines) concurrently with oxaliplatin, 
followed by  
• 5-FU 400 mg/m2 IV bolus over 5-15 minutes, then 2400 mg/m2 continuous IV 
infusion over 46 hours. 
 
At the investigator’s discretion, Ca++ and Mg++ (1g each) may be administered prior 
to oxaliplatin and again prior to 5-FU. 
 
Instructions for the preparation, handling, and administration of aflibercept are 
provided in Appendix B.  Treatment must be administered through a tunneled central 
line.  For the evaluation, a cycle will be defined as 28 days.   
 
5.2  
General Concomitant Medication and Supportive Care Guidelines 
 
o Antiemetic prophylaxis: symptomatic management of nausea is at the discretion 
of the treating investigator with the following recommended guidelines: 


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 Oxaliplatin is emetogenic. All patients receiving oxaliplatin  
should be pre-medicated with an acceptable antiemetic regimen. Patients 
may receive dexamethasone 10-20 mg IV as pre-treatment antiemetic 
unless there is a relative or absolute contraindication to corticosteroids. 
Other antiemetics may be used in addition to the suggested regimen, if 
clinically indicated. 
 
 Patients should have anti-emetic available as needed. 
 
 The use of additional antiemetics prophylactically or as needed should be 
prescribed and administered as needed and adjusted during the study at the 
discretion of the treating investigator. 
 
o Diarrhea Management: Symptomatic management of diarrhea is at the discretion 
of the treating investigator. The following guidelines are recommended: 
 
 All patients should be instructed to take anti-diarrheal medications at the 
earliest sign of diarrhea or abdominal cramping after beginning the study 
medications. These signs can include (a) loose stool, (b) the occurrence of 
one or two more bowel movements than usual in one day, or (c) unusually 
high volume of stool.  A low dose of anti-diarrheal medication may be 
required chronically while patients are receiving treatment.  
 
 If an anti-diarrheal medication is needed, the following options are 
suggested: 
 
• Loperamide: 4 mg at the first onset of diarrhea, then 2 mg every 2 
hours around the clock until diarrhea free for at least 12 hours.  
Patient may take 4 mg every 4 hours during the night. 
 
• Diphenoxylate/Atropine: two tablets at the first onset of diarrhea, 
then two tablets four times a day until diarrhea-free for at least 12 
hours. 
 
• If diarrhea continues >7 days, consider sending stool for C. difficile 
assay. 
 
o Management of hypertension: The optimal choice of antihypertensive agents to 
control hypertension induced by aflibercept has not been established.  Clinical 
management of hypertension should be at the discretion of the treating physician.  
Acceptable antihypertensives noted to be effective include angiotensin-converting 
enzyme (ACE) inhibitors, calcium channel blockers, diuretics, and beta blockers. 
 


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o Management of pharyngo-laryngodysesthesias: Oxaliplatin may cause 
discomfort in the larynx or pharynx associated with dyspnea, anxiety, swallowing 
difficulty and 
is exacerbated by cold. Appropriate therapy includes use of anxiolytics, cold 
avoidance and monitoring. 
 
o Management of oxaliplatin hypersensitivity reactions: Platinum 
hypersensitivity can cause dyspnea, bronchospasm, itching and hypoxia. 
Appropriate treatment includes supplemental oxygen, steroids, antihistamines, 
and epinephrine; bronchodilators and vasopressors may be required. Platinum 
hypersensitivity a rare but potentially life-threatening event and should be treated 
promptly according to institutional guidelines. Grade 3-4 oxaliplatin 
hypersensitivity occurs in 2-3% of patients receiving this agent and incidence 
increases with multiple courses of therapy. 
 
o Management of aflibercept infusion reactions: Symptomatic and supportive 
treatment should be administered according to each participating institution’s 
local procedures for treating infusional reactions to other protein therapeutic 
agents.  See section 6.2.5 for information regarding the management of infusion 
reactions related to aflibercept. 
 
o Anticoagulation: Patients requiring therapeutic anticoagulation should be 
carefully monitored while receiving therapy with aflibercept.  For patients 
receiving anticoagulation with warfarin, INR must be kept in the therapeutic 
range and should be checked prior to every dose of aflibercept. 
 
5.3  
Duration of Therapy 
 
In the absence of treatment delays due to adverse events, treatment may continue until 
one of the following criteria applies: 
 
• Disease progression, 
 
• Intercurrent illness that prevents further administration of treatment, 
 
• Unacceptable adverse events(s), 
 
• Patient decides to withdraw from the study, or 
 
• General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
 
• Patients may be removed from study to undergo surgical resection. 
 
5.4 
Duration of Follow Up 
 


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Patients will be followed every 3 months after removal from treatment until death. 
Adverse event reporting should continue for 30 days after last dose of protocol 
therapy. Patients removed from treatment for unacceptable adverse events will be 
followed until resolution or stabilization of the adverse event. 
 
 
5.5 
Criteria for removal from Study 
 
Patients will be removed from study when any of the criteria listed in Section 5.3 
applies.  The reason for study removal and the date the patient was removed must be 
documented in the Case Report Form. 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Additional cycles of therapy may be administered provided that the patient meets the 
following criteria on Day 1 of each cycle:  
 
o ANC >  1500/µL  
o Platelets > 75,000/µL  
o Non-hematologic toxicity recovered to less than or equal to grade 1 (or tolerable 
grade 2 or baseline)  
o No evidence of progressive disease  
o If the initiation of a new cycle, or therapy during a cycle, is delayed for > 4 
weeks, treatment with FOLFOX and aflibercept should be discontinued. 
 
• Subjects with adverse events that are manageable with supportive therapy may not require 
dose reductions (e.g., nausea/vomiting may be treated with antiemetics, diarrhea may be 
treated with loperamide, electrolyte abnormalities may be corrected with supplements 
rather than by dose reduction).  However, toxicity persists despite optimum supportive 
measures, dose reductions should be implemented. 
 
• Subjects will be withdrawn from the study if they fail to recover to CTC Grade 0-1 or 
tolerable grade 2 (or within 1 grade of starting values for pre-existing laboratory 
abnormalities) from a treatment-related adverse event within 28 days OR they experience 
agent related adverse events requiring dose modification despite three previous dose 
reductions (i.e. would require a fourth dose reduction) unless the principal investigator 
agrees that the subject should remain in the study because of evidence that the patient 
is/may continue deriving benefit from continuing study treatment (i.e. patient has PR, CR, 
SD > 3 months). The appropriate reduced dose will be determined after discussion with the 
principal investigator .  
 
Table 6.  Dose Levels for FOLFOX and Aflibercept 
Agent 
Initial dose 
Level -1 
Level -2 
Level -3 
Oxaliplatin 
85 mg/m2 
65 mg/m2 
50 mg/m2 
40 mg/m2 
5-FU bolusa 
400 mg/m2 
discontinue 
--- 
--- 
5-FU infusionb 
2400 mg/m2 
1920 mg/m2 
1600 mg/m2 
1360 mg/m2 
Aflibercept 
4 mg/kg 
2 mg/kg 
discontinue 
--- 


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a Leucovorin (LV) dose is always 400 mg/m2 (Or if levoleucovorin is used the dose is 200 mg/m2) given prior to 5-
FU bolus.  If 5-FU bolus is held or discontinued, LV is also held or discontinued.  
b5-FU infusion is delivered continuously over 46-48 hours. 
 
6.1 Dose Modifications for FOLFOX 
 
In order for a treatment cycle to begin, all criteria in section 6.0 must be met. 
 
6.1.1 Selected hematologic and nonhematologic adverse events (excluding neurotoxicity) 
Toxicity NCI CTCAE v 4.0 Grade 
Note: Dose Modifications are based on AEs observed during a cycle 
(i.e., after day 1 of a cycle).  Dose modifications must be based on the 
AE requiring the greatest modification.  Skipped doses are not made 
up. 
Current cycle 
Next cycle 
No toxicity 
Maintain dose level 
Maintain dose level 
Neutrophils (ANC) 
Grade 1 (ANC <LLN- 1500/mm3) 
 
Grade 2 (ANC <1500-1000/mm3) 
 
Grade 3 (ANC <1000-500/mm3) 
 
 
 
 
 
Grade 4 (ANC <500/mm3) 
 
Maintain dose level 
 
Maintain dose level 
 
Skip 5FU and oxaliplatin.  If 
toxicity resolves to < grade 1 
during the cycle, 5-FU and 
oxaliplatin may be resumed with 
omission of bolus 5-FU. 
 
Skip 5-FU and oxaliplatin.  If 
toxicity resolves to < grade 1 
during the cycle, 5-FU and 
oxaliplatin may be resumed with 
omission of bolus 5-FU and 
reduction of oxaliplatin by 1 dose 
level. 
 
Maintain dose level 
 
Maintain dose level 
 
Discontinue bolus 5FU, and reduce 
oxaliplatin by 1 dose level or add 
Neulasta 
 
 
 
 
Discontinue bolus 5-FU and 
continue oxaliplatin at reduced 
dose level from previous cycle (or 
add Neulasta or reduce oxaliplatin 
by 1 dose level if treatment was not 
resumed in previous cycle).  
Plateletsa 
Grade 1 (Plt <LLN-75,000/ mm3) 
 
Grade 2 (Plt <75,000-50,000/ mm3) 
 
 
 
Grade 3 (Plt <50,000-25,000/ mm3) 
 
 
 
 
 
Grade 4 (Plt <25,000) 
 
Maintain dose level 
 
Omit bolus 5-FU and reduce 
oxaliplatin 1 dose level for 
remainder of current cycle 
 
Skip 5-FU and oxaliplatin.   If plts 
recover to > 75,000 during the 
cycle, 5-FU and oxaliplatin may be 
resumed with omission of bolus 5-
FU. 
 
Skip 5-FU and oxaliplatin.  If plts 
recover to < 75,000 during the 
cycle, 5-FU and oxaliplatin may be 
resumed with omission of bolus 5-
FU and reduction of oxaliplatin by 
1 dose level. 
 
Maintain dose level 
 
Resume 5FU and oxaliplatin at the 
previous dose levels. 
 
 
Discontinue bolus 5-FU  
 
 
 
 
 
Discontinue bolus 5-FU and 
continue oxaliplatin at reduced 
dose level from previous cycle (or 
reduce oxaliplatin by 1 dose level if 
treatment was not resumed in 
previous cycle). 
Febrile Neutropenia (ANC <1000 
Skip 5FU and oxaliplatin.  If fever 
Discontinue bolus 5-FU and 


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and T >  38.5°C) 
 
and neutropenia resolve during the 
current cycle, 5-FU and oxaliplatin 
may be resumed with omission of 
bolus 5-FU and reduction of 
oxaliplatin  by 1 dose level, 
provided ANC and platelets < 
grade 1. 
continue oxaliplatin at the reduced 
dose level from previous cycle (or 
reduce oxaliplatin by 1 dose level if 
treatment was not resumed in 
previous cycle). 
Other hematologic toxicities (e.g. anemia, lymphopenia) do not require dose modification; however, red blood 
cell transfusion should be strongly considered for hemoglobin < 8 g/dL 
Diarrhea 
Grade 1 
 
Grade 2 
 
 
 
Grade 3 
 
 
 
 
 
 
Grade 4 
 
Maintain dose level 
 
Reduce 5-FU 1 dose level for 
remainder of cycle.  Oxaliplatin is 
not reduced. 
 
Skip 5-FU and oxaliplatin.  If 
diarrhea resolves to < grade 1 
during the current cycle, 5-FU is 
resumed at 1 lower dose level with 
omission of bolus 5-FU.  
Oxaliplatin is not reduced. 
 
Skip 5-FU and oxaliplatin.  If 
diarrhea resolves to < grade 1 
during the current cycle, 5-FU and 
oxaliplatin are resumed at 1 lower 
dose level with omission of bolus 
5-FU. 
 
Maintain dose level 
 
Resume 5-FU at previous dose 
level. Maintain oxaliplatin dose. 
 
 
Discontinue bolus 5-FU and 
continue 5-FU at reduced dose 
from previous cycle (or reduce by 1 
dose level if not resumed in 
previous cycle).  Maintain 
oxaliplatin dose.  
 
 
Discontinue bolus 5-FU and 
continue 5-FU and oxaliplatin at 
reduced doses from previous cycle 
(or reduce by 1 dose level if not 
resumed in previous cycle).   
Mucositis/Stomatitis 
Grade 1 
 
Grade 2 
 
 
Grade 3 
 
 
 
 
 
 
Grade 4 
 
Maintain dose level 
 
Reduce 5FU one dose level for 
remainder of cycle. 
 
Skip 5-FU and oxaliplatin.  If 
mucositis resolves to < grade 1 
during the cycle, 5-FU and 
oxaliplatin are resumed at one 
lower dose level with omission of 
bolus 5-FU.   
 
Skip 5-FU and oxaliplatin.  If 
mucositis resolves to < grade 1 
during the cycle, 5-FU and 
oxaliplatin are resumed at one 
lower dose level with omission of 
bolus 5-FU.   
 
Maintain dose level 
 
Resume treatment at previous dose 
level. 
 
Discontinue bolus 5-FU and 
continue 5-FU at reduced dose 
from previous cycle (or reduce by 1 
dose level if not resumed in 
previous cycle).  Maintain 
oxaliplatin dose at previous (non-
reduced) dose level.  
 
Discontinue bolus 5-FU and 
continue 5-FU and oxaliplatin at 
reduced doses from previous cycle 
(or reduce by 1 dose level if not 
resumed in previous cycle).   
Nausea/Vomiting (despite 
antiemetics) 
Grade 1 
 
Grade 2 
 
Grade 3 
 
 
 
Maintain dose 
 
Maintain dose 
 
Hold oxaliplatin and continue 5-
FU.  If toxicity resolves to < grade 
 
 
Maintain dose 
 
Maintain dose 
 
Continue oxaliplatin at reduced 
dose level from previous cycle.  5-


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Grade 4 
1 during the cycle, resume 
oxaliplatin at 1 lower dose level for 
remainder of cycle 
 
Hold 5-FU and oxaliplatin.  If 
toxicity resolves to < grade 1 
during the cycle, reduce 5-FU and 
oxaliplatin 1 dose level and omit 
bolus 5-FU for remainder of cycle. 
FU is not reduced. 
 
 
 
Discontinue bolus 5-FU.  Continue 
5-FU and oxaliplatin at reduced 
dose levels from previous cycle (or 
reduce by 1 dose level of treatment 
not resumed in previous cycle). 
Pulmonary Toxicity 
 
Grade > 3 cough, dyspnea, hypoxia, 
pneumonitis, or pulmonary 
infiltrates 
 
 
Hold all therapy until interstitial 
lung disease is ruled out.   
 
 
Oxaliplatin may be resumed at the 
physician’s discretion if interstitial 
lung disease is ruled out, infection 
has resolved, and dyspnea or 
hypoxia are resolved to < grade 1.  
If ILD is confirmed, all protocol 
therapy is discontinued.  
All other non-hematologic 
toxicities (except neurologic)*b,c, 
Dose modifications for other nonhematologic adverse events at the start 
of 
subsequent cycles of therapy, and at time of retreatment are the same as 
recommended for nausea/ vomiting (above) with the following exception: 
Omit bolus 5-FU and decrease infusion 5-FU by one dose level for 
other Grade>3 
non-hematologic events 
*Exceptions: alopecia, anorexia, fatigue, nausea if can be controlled by antiemetics, clinically insignificant 
metabolic/laboratory abnormalities. 
a Hemolytic Uremic Syndrome (HUS)/Thrombotic Thrombocytopenic Purpura (TTP): The hemolytic uremic syndrome should be 
suspected in individuals who experience unexplained severe hemolysis, hemoglobinemia and renal failure as demonstrated by an 
increase in serum creatinine. Patients suspected of experiencing HUS or demonstrating symptoms of TTP should have the following 
laboratory analyses conducted: creatinine, BUN, urinalysis with microscopic evaluation, CBC with differential and platelets, PT/PTT, 
Fibrinogen, Fibrinogen Degradation Products (FDP), Anti-thrombin III (ATIII), von Willenbrand Factor (VWF), anti-nuclear antibodies 
(ANA), rheumatoid factor (RhF), C3, C4, CH50, anti-platelet antibodies, platelet associated IgG, circulating immune complexes. 
Oxaliplatin should be discontinued for any suspected occurrence of HUS or TTP. 
b With any suspicion of veno-occlusive disease (VOD) of the liver (hyperbilirubinemia, ascites, unexplained weight gain, 
hepatomegaly, splenomegaly, esophageal varices or other sign of portal hypertension), chemotherapy must be held. If VOD is 
diagnosed clinically, chemotherapy must be discontinued. 
c Dose modifications should only be applied for those untoward events (including but not limited to metabolic or vascular 
toxicities) that might bear some relationship to study treatment. 
 
 
 
 
6.1.2  Neurotoxicity 
Paresthesias/Dysesthesias 
1-7 day duration 
>7 day duration 
Grade 1: paresthesias/dysesthesias 
that resolve and do not interfere with 
function 
Maintain dose 
Maintain dose 
Grade 2: paresthesias/dysesthesias 
interfering with function, but not 
ADL’s 
Maintain dose* 
Decrease oxaliplatin 1 dose level* 
Grade 3: paresthesias/dysesthesias 
with pain or with functional 
impairment that also interfere with 
ADL’s 
First episode: decrease oxaliplatin 
1 dose level 
Second episode: stop oxaliplatin 
Stop oxaliplatin 
Grade 4: persistent paresthesias/ 
dysesthesias that are disabling or 
life-threatening 
Stop oxaliplatin 
Stop oxaliplatin 


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*Hold oxaliplatin for >grade 2 neurotoxicity. When < grade 1, resume treatment with dose modifications. If 
> grade 1 toxicity persists after 4 weeks’ hold, discontinue oxaliplatin. Continue 5-FU and aflibercept at previous 
doses while oxaliplatin is held. 
Laryngeal Dysesthesia 
 
 
Grade 1-2 (Mild, moderate) 
Maintain dose and consider 
increasing duration of oxaliplatin 
infusion to 6 hours 
Maintain dose and consider 
increasing duration of oxaliplatin 
infusion to 6 hours 
Grade 3 (Severe) 
At physician’s discretion, either 
stop oxaliplatin or increase 
duration of infusion to 6 hours 
Stop oxaliplatin 
Patients may also discontinue oxaliplatin following multiple cycles even in the absence of dose-limiting 
neurotoxicity if, in the treating physician’s judgement, neurotoxicity is likely to become problematic. Patients 
should continue to receive other protocol therapy and the oxaliplatin may be reintroduced subsequently. 
 
 
 
 
 
 
 
6.2  Dose Delays and Modifications for Aflibercept  
Toxicity  
NCI CTCAE v 
4.0 Grade 
Note: Dose Modifications are based on AEs observed during a 
cycle (i.e., after day 1 of a cycle).  Dose modifications must be 
based on the AE requiring the greatest modification.  Skipped 
doses are not made up. 
Action to be taken 


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Hypertension  
 
 
 
Grade <  2 
 
 
 
Initiate antihypertensive drug therapy (see recommendation below) 
and close monitoring of blood pressure for further adjustment, as 
needed.  
No dose modification and no delay. 
 
Grade 3 (requiring 
more than one 
drug or more 
intensive therapy 
than previously) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Modify antihypertensive drug therapy (see recommendation below).  
Delay the administration of both FOLFOX and aflibercept for a 
maximum of 4 weeks, until recovery to blood pressure (BP) ≤ 
150/100 or to systolic BP < 180 if diastolic BP < 90 for patients with 
known history of isolated systolic hypertension: 
• 
If BP is controlled within 4 weeks delay: 
-First episode: readminister FOLFOX and aflibercept at the 
same dose. 
- 
Second episode: readminister FOLFOX and aflibercept 
with Aflibercept reduced to dose level-1. 
-Third episode, discontinue aflibercept. 
• 
If BP is still uncontrolled despite appropriate anti 
hypertensive treatment and after 4 weeks delay: 
Administer FOLFOX and discontinue aflibercept for 1 
cycle; the reintroduction of aflibercept at a dose reduced to 
dose level – 1 will be reconsidered at the time of the 
administration of the subsequent cycle (in combination with 
FOLFOX), only if BP is controlled at the time of re-
administration.  
• 
In case of re-occurrence of grade 3 BP despite dose 
reduction of aflibercept, or if BP is still uncontrolled despite 
1 omission of administration of Aflibercept, the patients 
will be permanently discontinued from aflibercept. 
FOLFOX may be continued at investigator discretion if 
he/she believes the patient is deriving clinical benefit.  
Grade 4 
Permanently discontinue aflibercept.  Seek cardiologist opinion. 
Arterial 
thromboembolic 
events (e.g.: 
myocardial infarction, 
or stroke) documented 
by appropriate tests 
Grade 3-4 
Permanently discontinue aflibercept.   
Hemorrhagea 
Grade 3-4 
Permanently discontinue study treatment. 
GI perforation/fistula 
formation 
Any grade 
Permanently discontinue study treatment. 
Reversible posterior 
leukoencephalopathy 
syndrome 
documented with 
appropriate tests 
Any grade 
Permanently discontinue study treatment. 
Venous 
Thromboembolic 
events documented by 
appropriate tests 
Grade 3  
First episode: Treat with heparins and continue study treatmentb 
 
Second episode despite appropriate anticoagulation: Permanently 
discontinue aflibercept 
Grade 4 
Permanently discontinue aflibercept 


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Hypertriglyceridemia 
(Not an identified risk; 
however, observed in 2 
patients receiving 
Aflibercept in this 
ongoing study: A 
Phase II Study of 
VEGF-Trap plus 
Modified FOLFOX 6 
in Previously 
Untreated Patients with 
Metastatic Colorectal 
Cancer) 
 
 
 
Grade <  2 
 
 
 
Medically manage per institutional guidelines. No dose modification 
and no delay. 
Grade 3 
At first occurrence, omit Aflibercept that day and medically manage 
toxicity per institutional guidelines. 
If toxicity persists at next dosing time point (despite optimal medical 
management), hold until grade , <  or = 2 and reduce Aflibercept by 
1 dose level (table 6) for subsequent doses. If recurrent grade 3 
occurs after dose reduction and despite optimal medical 
management, permanently discontinue aflibercept. 
Grade 4 
At first occurrence, omit Aflibercept that day and medically manage 
toxicity per institutional guidelines. 
If toxicity persists at next dosing time point (despite optimal medical 
management), hold until grade , <  or = 2 and reduce Aflibercept by 
1 dose level (table 6) for subsequent doses. If recurrent grade 3 
occurs after dose reduction and despite optimal medical 
management, permanently discontinue aflibercept. 
Hypercholesterolemia 
 
(Not an identified risk; 
however, observed in 2 
patients receiving 
Aflibercept in this 
ongoing study: A Phase 
II Study of VEGF-Trap 
plus Modified 
FOLFOX 6 in 
Previously Untreated 
Patients with 
Metastatic Colorectal 
Cancer) 
 
Grade <  2 
 
 
 
Medically manage per institutional guidelines. No dose modification 
and no delay. 
 
Grade 3 
At first occurrence, omit Aflibercept that day and medically manage 
toxicity per institutional guidelines. 
If toxicity persists at next dosing time point (despite optimal medical 
management), hold until grade , <  or = 2 and reduce Aflibercept by 
1 dose level (table 6) for subsequent doses. If recurrent grade 3 
occurs after dose reduction and despite optimal medical 
management, permanently discontinue aflibercept. 
Grade 4 
At first occurrence, omit Aflibercept that day and medically manage 
toxicity per institutional guidelines. 
If toxicity persists at next dosing time point (despite optimal medical 
management), hold until grade , <  or = 2 and reduce Aflibercept by 
1 dose level (table 6) for subsequent doses. If recurrent grade 3 
occurs after dose reduction and despite optimal medical 
management, permanently discontinue aflibercept. 
a In case of grade 3 hemorrhage, continuation of aflibercept may be considered depending on individual Benefit/Risk 
assessment. 
 b Based on investigator’s judgement in assessing potential risk of extension and/or embolization in case of DVT 
 
6.2.1 Hypertension therapy recommendations: 
• If the patient is found to have asymptomatic grade 1 or higher hypertension during home 
monitoring, they should be seen within 24-48 hours so the blood pressure measurement can be 
confirmed and antihypertensive therapy initiated. 
• For patients without prior antihypertensive therapy, at the time of the hypertensive episode the 
initiation of calcium-channel blockers should be considered as a first-intent treatment. A close 
monitoring of the BP should be initiated for further adjustment in treatment, as needed. 
Ultimately, antihypertensive treatment must be individualized based on the presence of 
comorbidity factors such as diabetes, cardiovascular or renal disease, additionally taking into 


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account the safety and the efficacy of any prior antihypertensive therapy received. In addition, 
oral and/or intravenous sodium intake should be carefully monitored in these patients. 
• For patients already under anti-hypertensive therapy efforts should be done to optimize the 
existing therapy before adding other agents as required to control the BP.  
• When hypertension is accompanied by signs or symptoms of end organ damage such as 
hypertensive retinopathy, kidney function abnormalities (like progressive proteinuria), or any 
signs or symptoms of cardiovascular morbidity or central nervous system (CNS) morbidity, 
treatment with aflibercept should be interrupted. 
 
6.2.2 Proteinuria: 
Determination and management of proteinuria: 
Prior to each administration of aflibercept, perform UPCR and urinalyses. 
Urinary protein creatinine ratio (UPCR) corresponds to the ratio of urinary protein and urinary 
creatinine concentrations (expressed in mg/dL). There is a high correlation between morning 
UPCR and 24-hour proteinuria in patients with normal or reduced renal function, UPCR 
demonstrated very good to excellent performance for the diagnosis of both abnormal and nephrotic 
proteinuria at all renal function levels. This ratio provides an accurate quantification of 24-hour 
urinary protein excretion. 
 
UPCR to detect proteinuria, will be done on a random urine sample. If UPCR > 1, 24-hour urine 
collection to grade proteinuria will be performed. In addition, in case UPCR is greater than 2 or in 
case of proteinuria of renal origin (according to urinary protein electrophoresis) is associated with 
hematuria (microscopic or macroscopic), then a blood work-up in search for hemolytic anemia of 
microangiopathic origin should be initiated and a nephrologist consultation should be considered 
as detailed in Table 8. 
 
This blood work-up could include schistocytes, haptoglobin, LDH and orosomucoïd whenever 
possible. Delay in availabilty of part of the results should not delay consultation to the nephrologist 
 
Proteinuria should always be assessed taking into account the presence or absence of 
hematuria and the blood pressure status of the patient. 
 
Table 8 summarizes the course of action with regard to aflibercept dosing, which will depends on 
the presence of hematuria and the level of 24-hour proteinuria results. Only one dose level 
reduction is permitted for aflibercept. 
 
6.2.3 Reversible posterior leuko-encephalopathy (RPLS) or clinical symptoms related to 
vasogenic edema of the white matter:  
Clinical presentations are variable and may include headache, altered mental status, seizure and 
cortical visual deficit. Hypertension is a risk factor. MRI scans are key to diagnosis and typically 
demonstrate vasogenic edema (hyperintensity in T2 and FLAIR images and hypodensity in T1 
images) predominantly in the white matter of the posterior parietal and occipital lobes; less 
frequently, the anterior distributions and the gray matter may also be involved. RPLS should be 
in the differential diagnosis in patients presenting with unexplained mental status change, visual 
disturbance, seizure, or other CNS findings. RPLS is potentially reversible with early recognition 


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of symptoms and timely correction of the underlying causes, including control of BP and 
interruption of the offending drug, which are important in order to prevent progression to 
irreversible tissue damage. 
 
6.2.4 Gastrointestinal perforation: 
In case a patient reported abdominal pain or increase in severity of pre-existing abdominal pain, 
with or without associated symptoms (such as nausea, vomiting, constipation), he/she should be 
evaluated by a physician for possible gastro-intestinal perforation, as this has been reported with 
anti-VEGF agents. 
 
6.2.5 Hypersensitivity reaction: 
In case of hypersensitivity reaction, institutional treatment guidelines for this type of AEs, or the 
following proposed guideline in Table 4 can be applied. 
For Grade ≥2 event, initiate anti-aflibercept Ab detection process. 
 
 
 
 
Table 7.  Management of Hypersensitivity Reactions 
Symptom Severity 
Intervention Recommendation 
Mild-Moderate 
E.g., NCI CTCAE grade ≤ 2 cutaneous reaction, pruritus, 
flushing, rash, dyspnea, tachycardia, hypotension, anxiety, 
headache, myalgias, edema, nausea 
Stop aflibercept infusion; 
Give diphenhydramine 50 mg IV and/or IV 
dexamethasone 10 mg; 
Resume aflibercept infusion after subject 
recovery. 
Severe 
e.g., symptomatic bronchospasm, generalized urticaria, systolic 
BP ≤ 80 mm Hg, angioedema, anaphylaxis 
Stop aflibercept infusion; 
Give IV diphenhydramine 50 mg and/or IV 
dexamethasone 10 mg and/or epinephrine as 
needed; 
Permanently discontinue aflibercept. 


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Prior to cycle n 
aflibercept 
administration 
Aflibercept dosing 
for cycle n 
During cycle n 
Repeat 24-h proteinuria as 
necessarya 
Aflibercept dosing 
for cycle n +1 
During cycle n + 1 
Repeat 24-h proteinuria as 
necessary a 
Aflibercept dosing for 
cycle n + 2 
UPCR [1-2]  
Presence of 
hematuria 
 
Or 
 
UPCR >2 
 
Omit dosing 
aflibercept 
Perform  nephrologic work-upb 
and seek nephrologist opinion :  
 
 
 
 
- TMA ruled out and ≤2g/24-h 
prior n+1 dosing 
: 
Administer aflibercept 
 
 
- TMA ruled out and >2 ≤ 
3.5g/24-h prior n+1 dosing : 
 
Omit dosing aflibercept 
≤2g/24-h prior n+2 dosing 
: 
Resume aflibercept  level –1c 
>2g/24-h prior n+2 dosing 
: 
Permanently discontinue 
aflibercept 
- TMA ruled out and >3.5g/24-h  
prior n+1 dosing 
: 
Permanently discontinue aflibercept 
- TMA diagnosed 
: 
Permanently discontinue aflibercept, seek nephrologist opinion for continuation of chemotherapy 
Nephrotic syndrome  Permanently discontinue aflibercept, perform nephrologic work-upb, seek nephrologist opinion for continuation of chemotherapy 
 
 
 
Aflibercept dosing 
for cycle n 
During cycle n 
Repeat 24-h proteinuria as 
necessarya 
Aflibercept dosing 
for cycle n +1 
During cycle n + 1 
Repeat 24-h proteinuria as 
necessary a 
Aflibercept dosing for 
cycle n + 2 
UPCR [0-1] 
Administer 
aflibercept 
 
UPCR [1-2] 
Absence of hematuria 
Administer 
aflibercept, then 
perform 24-h 
proteinuria: 
 
 
- if ≤3.5g/24-h 
≤2g/24-h prior n+1 dosing    : 
Administer aflibercept 
 
 
>2g/24-h prior n+1 dosing   : 
 
Omit dosing aflibercept 
≤2g/24-h prior n+2dosing   : 
Resume aflibercept level –1c 
>2g/24-h prior n+2 dosing  : 
Permanently discontinue 
aflibercept 
 
 
- if > 3.5g/24-h 
≤2g/24-h prior n+1 dosing   : 
Administer aflibercept level 
-1c 
 
 
>2 ≤ 3.5g/24-h prior n+1 dosing: 
 
Omit dosing aflibercept 
≤2g/24-h prior n+2 dosing :  
Resume aflibercept level –1c 
>2g/24-h prior n+2 dosing : 
Permanently discontinue 
aflibercept 
>3.5g/24-h prior n+1 dosing    : 
Permanently discontinue aflibercept 
Table 8.  Management of Proteinuria 


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TMA: Thrombotic micro-angiopathy 
a: Patients can be monitored with UPCR as necessary, however 24-hour proteinuria should be performed prior to make dosing decision. 
b: 24-hour proteinuria, urinary protein electrophoresis, haptoglobin, orosomucoid, schistocytes and LDH 
c: When a patient is already treated at dose level -1, aflibercept should be discontinued 
 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Serious AEs (SAEs), judged by the Investigator or Sponsor to be unexpected and reasonably 
associated with the use of the study drug(s), are reported directly to the FDA in accordance with 
applicable law, regulations and Study protocol with a copy submitted to Sanofi-Aventis.  If the 
FDA does not require the sponsor (investigator) to submit SAEs that are unexpected and related, 
SAE reports should be sent to Sanofi-Aventis when discovered. 
 
In addition, disease progression, or lack of efficacy, should be considered as expected and will, 
therefore, be excluded from expedited reporting requirements. 
 
When investigational product is administered in combination with 1 or more approved anticancer 
agents, the expectedness determination should take into account the labeling of each specific 
marketed drug taken in combination based upon reference documents as defined in the protocol. 
 
Preferred terms of comparable or lower specificity/severity should be considered expected. An 
event more severe than those included in this list will be considered unexpected. 
 
7.1 Expected Adverse Events for Aflibercept 
 
Table 9.  Expected adverse events in treatment with intravenous aflibercept. 
MedDRA SOC 
Preferred Term 
Blood  and lymphatic system disorders 
Anemia 
Thrombotic microangiopathy 
Cardiac disorders 
Cardiomyopathy (incl. cardiac failure) 
Gastrointestinal disorders 
Abdominal pain 
Diarrhea 
Enterocutaneous fistula 
Gastrointestinal hemorrhage (incl. fatal) 
Gastrointestinal perforation (incl. fatal) 
Intestinal obstruction 
Mucositis 
Nausea 
Peritonitis 
Rectal ulcer 
Stomatitis 
Vomiting 
General disorders and administration site 
conditions 
Asthenia (incl. fatigue and malaise 
Pyrexia 
Immune system disorders 
Drug hypersensitivity (incl. flushing, rigors) 
Infections and Infestations 
Abdominal abscess 
Investigations 
Hepatic enzyme increased (incl. ALT, AST, Alk. Phos: 
<5X ULN 
Metabolism and nutrition disorders 
Dehydration 
Hypokalemia 
Hypomagnesemia 


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Hyponatremia 
Musculoskeletal and connective tissue disorders 
Arthralgia 
Osteonecrosis 
Neoplasm benign, malignant and unspecified 
(including cysts and polyps) 
Tumor hemorrhage 
 
 
MedDRA SOC 
Preferred term 
Nervous system disorders 
Cerebral hemorrhage (incl. fatal) 
Cerebral ischemia (incl. fatal) 
Encephalopathy (incl. Reversible Posterior 
Leukoencephalopathy 
Syndrome [RPLS]) 
Headache 
Psychiatric disorders 
Anxiety 
Renal and urinary disorders 
Proteinuria (incl. nephrotic syndrome) 
Renal failure 
Reproductive system and breast disorders 
Female genital tract fistula 
Respiratory, thoracic, and mediastinal disorders 
Dysphonia (hoarseness) 
Dyspnea 
Epistaxis 
Hemoptysis (incl. fatal) 
Pulmonary embolism (incl. fatal) 
Tracheo-esophageal fistula 
Vascular disorders 
Deep vein thrombosis 
Hypertension 
 
 
Based upon treatment-related serious or severe AEs in clinical trials, the following toxicities may 
occur with IV aflibercept as a single agent or in combination with other drugs: 
• Hematological disorders and resistance: anemia, thrombocytopenia, thrombotic 
microangiopathy; additionally in combination with cytotoxic chemotherapy: neutropenia 
including febrile neutropenia, neutropenic colitis, and sepsis 
• Cardiac disorders: cardiac failure 
• Digestive toxicity: abdominal pain, gastrointestinal hemorrhage, intestinal perforation, 
intestinal obstruction, enteric fistula, peritonitis, pneumatosis intestinalis, nausea, vomiting, 
diarrhea, constipation, mucosal inflammation or ulceration, stomatitis, hepatic enzymes 
increased 
• General disorders: asthenia, fatigue, musculoskeletal pain, injection site reaction 
• Immune system disorders: hypersensitivity 
• Metabolic disorders: dehydration 
• Musculoskeletal: arthralgia, myalgia, osteonecrosis 
• Nervous system: headache, dizziness, encephalopathy (including reversible posterior 
leukoencephalopathy syndrome), cerebral ischemia, cerebral hemorrhage, cerebral venous 
thrombosis 
• Renal disorders: proteinuria (including nephrotic syndrome), hematuria, renal failure 
• Respiratory disorders: dysphonia, dyspnea, epistaxis, hemoptysis, pulmonary embolism, 
tracheo-esophageal fistula 
• Skin disorder in combination with cytotoxic chemotherapy: palmar-plantar erythrodysaesthia 
syndrome, erythema 
• Vascular disorders: hypertension, (including malignant hypertension), deep vein thrombosis, 


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and phlebitis 
 
Note: aflibercept  in combination with other agents could cause an exacerbation of any adverse event currently 
known to be caused by the other agent, or the combination may result in events never previously associated with 
either agent. 
 
7.2 Adverse Event List for Commercial Agents 
 
 
5-Fluorouracil 
For a comprehensive list of adverse events please refer to the package insert. Section 
8.2.1 provides an overview of toxicities related to 5-FU. 
 
Leucovorin 
For a comprehensive list of adverse events please refer to the package insert. Section 
8.2.2 provides an overview of toxicities related to leucovorin. 
 
Oxaliplatin 
For a comprehensive list of adverse events please refer to the package insert. Section 
8.2.3 provides an overview of toxicities related to oxaliplatin. 
 
7.3 
Adverse Event Characteristics  
CTCAE term (AE description) and grade:  The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4 will be utilized for AE reporting.  All appropriate treatment areas 
should have access to a copy of the CTCAE version 4.  A copy of the CTCAE version 
4 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
7.4 
Monitoring for Adverse Events 
 U.S. regulations require that a sponsor reports Serious Adverse Events (SAEs) 
occurring with use of its product in a clinical trial if it is unexpected, and felt to be 
related to use of the drug.  During the conduct of Investigator Sponsored Trials 
(ISTs), where the investigator holds the Investigational New Drug (IND) application, 
all SAEs that occur will be evaluated by the investigator for reportability to FDA. An 
Adverse Event should be identified, Serious Adverse Event and Expectedness 
determined and causality assessed by the investigator using the definitions that 
follow. 
 
7.4.1 Definitions 
An Adverse Event is any untoward medical occurrence in a patient 
administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with the treatment.  For marketed 
products in the U.S., a Serious Adverse Event is an adverse event 
occurring at any dose that results in any of the following outcomes: 
 


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a. Death 
b. Life-threatening1 
c. Persistent or significant disability/incapacity2 
d. In patient hospitalization or prolongation of existing hospitalization 
e. Congenital anomaly/birth defect 
 
An event may not meet any of the above seriousness criteria but still 
be judged as medically serious.  That is, important medical events 
that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience 
when based upon appropriate medical judgment, they may jeopardize 
the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes (a-e) listed above.  Some 
examples of this type of event are: 
 
• 
blood dyscrasia without inpatient hospitalization 
• 
convulsions without inpatient hospitalization 
• 
intensive treatment in an emergency room or at home for allergic 
bronchospasm without inpatient hospitalization 
• 
development of drug dependency 
• 
drug abuse 
• 
overdose with an associated serious event, or required intervention to 
prevent impairment/damage 
 
An Unexpected Adverse Event is not listed in the current US Package Insert 
(USPI) or an event that may be mentioned in the USPI, but differs from the event 
because of greater severity or specificity.  
 
Causality is a determination of whether there is a reasonable possibility that the 
drug may have caused or contributed to an adverse event. It includes assessing 
temporal relationships dechallenge/rechallenge information, association (or lack 
of association) with underlying diseases, and the presence (or absence) or a lack 
of one or more likely causes. 
 
The Investigator must determine if an adverse event is in some way related to the 
use of the study drug.  This relationship should be described as follows: 
 
Unlikely:  The event is clearly due to causes distinct from the use of the study 
drug, such as a documented pre-existing condition, the effect of a concomitant 
medication, a new condition which, based on the pathophysiology of the 
                                                 
1 The term "life-threatening" in the definition of "serious" refers to an event in which in the view of the initial reporter the patient was at immediate 
risk of death from the adverse experience as it occurred; it does not refer to an event which had it occurred in a more severe form, might have 
caused death. 
2 A substantial disruption of a person’s ability to conduct normal life functions. 


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condition, and the pharmacology of the study drug, would be unlikely related to 
the use of the study drug. 
 
 
Possible: The event follows a reasonable temporal sequence from administration 
of the study drug or the event follows a known response pattern to the study drug 
BUT the event could have been produced by an intercurrent medical condition 
which, based on the pathophysiology of the condition, and the pharmacology of 
the study drug, would be unlikely related to the use of the study drug or the event 
could be the effect of a concomitant medication 
 
 
 
Probable: The event follows a reasonable temporal sequence from administration 
of the study drug and the event follows a known response pattern to the study 
drug AND the event cannot have been reasonably explained by an intercurrent 
medical condition or the event cannot be the effect of a concomitant medication 
 
 
Definite: The event follows a reasonable temporal sequence from administration 
of the study drug, the event follows a known response pattern to the study drug 
and based on the known pharmacology of the study drug, the event is clearly 
related to the effect of the study drug 
 
 
 
Unknown: Based on the evidence available, causality cannot be ascribed 
 
7.5  Recording and Reporting 
 
 
Information on the recording and reporting of adverse events is provided in Section 
12. 
 
7.6      Data Safety Monitoring Plan 
 
The data and safety monitoring plan will involve the continuous evaluation of safety, 
data quality and data timeliness. Investigators will conduct continuous review of data 
and patient safety at their regular Disease Group meetings (at least monthly) and the 
discussion will be documented in the minutes. The PI of the trial will review toxicities 
and responses of the trial where applicable at these disease center meetings and 
determine if the risk/benefit ratio of the trial changes. Frequency and severity of 
adverse events will be reviewed by the PI and compared to what is known about the 
agent/device from the other sources; including published literature, scientific meetings 
and discussions with the sponsors, to determine if the trial should be terminated before 
completion. Serious adverse events and responses will also be reviewed by the 
OSUCCC Data and Safety Monitoring Committee (DSMC). The PI will also submit a 
progress report (biannually for Phase II) that will be reviewed by the committee per the 
DSMC plan. All reportable Serious Adverse Events (SAE) will also be reported to the 
IRB of record as per the policies of the IRB. 
 
For OSU  
All Serious Adverse events are to be submitted to the DSMC for their review. 


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Submissions are made via OnCore.  
  
For Participating Sites  
Participating sites will review patients enrolled at their institution for phase II 
investigator initiated studies quarterly. All reportable SAE will also be reported to 
the lead PI (at OSU) for review and reporting to the IRB and DSMC at OSUCCC. 
SAE’s need to be faxed to OSU Medical Center utilizing SAE Submission Form 
(refer to Supplemental Forms Document). It is the responsibility of the OSU PI to 
obtain information on a quarterly basis on all patients on trial regardless of clinical 
trial site. These materials will be submitted to the OSUCCC DSMC by the OSU PI. 
Refer to section 12 for additional reporting requirements. Subsite institutions are 
required to report SAEs to their local IRBs per their institutional and IRB policies. 
  
Regulatory Guidelines  
This study will be performed in accordance with United States Investigational New 
Drug (IND) regulations (21 Code of Federal Regulations [CFR] 56), the guidelines 
of the International Conference on Harmonisation (ICH), and the most recent 
guidelines of the Declaration of Helsinki.  
Institutional Review Board/Independent Ethic Committee Conduct of the study must 
be approved by an appropriately constituted institutional review board (IRB) or 
independent ethics committee (IEC). Approval is required for the study protocol, 
investigational drug brochure, protocol amendments, informed consent forms, 
patient information sheets, and advertising materials. No study drug will be shipped 
to a site until written IRB or IEC authorization has been received by the sponsor or 
its representative. 
 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events associated with the investigational or commercial agents 
administered in this study can be found in Section 7.1. 
 
8.1  Investigational Agents 
 
8.1.1 Aflibercept  
 
Other Names:  AVE0005; VEGF Trap 
 
Classification: antineoplastic agent (VEGF trap) 
 
Molecular Formula: Aflibercept is a recombinant fusion protein consisting of human 
vascular endothelial growth factor (VEGF) receptor extracellular domains fused to 
the Fc portion of human immunoglobulin G1 (IgG1). Aflibercept contains portions of 
the extracellular domains of 2 different vascular endothelial growth factor receptors 
(VEGFRs): VEGFR1 (also known as Flt-1) and VEGFR2 (also known as KDR or 
Flk-1). 
 


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M.W.:  115 
 
Mode of Action:  Aflibercept is a specific antagonist that binds and inactivates 
circulating VEGF. Aflibercept was designed to prevent the growth of primary and 
metastatic tumors by blocking tumor angiogenesis and vascular permeability. 
 
Description:  Aflibercept is a fusion protein consisting of extracellular domains of 
human VEGF receptors (VEGFRs) fused to the Fc portion of human IgG1. 
Aflibercept contains portions of the extracellular domains of two different VEGFRs: 
VEGFR1 (Flt-1) and VEGFR2 (KDR or Flk-1).  VEGFR1 and VEGFR2 are native 
receptors containing 7 Ig domains in the extracellular domain and an intracellular 
tyrosine kinase. 
 
Aflibercept binds VEGF in the picomolar (pmol/L) range, and also binds placental 
growth factor (PlGF), although with lower affinity. The affinity constants (Kd) for 
binding to 2 human isoforms of VEGF, VEGF165 and VEGF121, are 0.50 pmol/L and 
0.36 pmol/L, respectively. The Kd for human PlGF2 is 39 pmol/L. The binding of 
aflibercept to its ligands in vivo is expected to block tumor angiogenesis and vascular 
permeability. 
 
How Supplied:  Aflibercept is supplied as a clear, colorless solution for IV infusion.  
Excipients include sodium chloride, sodium citrate dihydrate, citric acid 
monohydrate, polysorbate 20, sodium phosphate dibasic heptahydrate, sodium 
phosphate monobasic monohydrate, and water for injection. 
 
Storage:  The aflibercept concentrate for solution for infusion in its original unopened 
container under refrigerated conditions (2 to 8°C). 
 
Stability:   Shelf life of aflibercept is 36 months if properly stored under the above 
conditions. 
 
Route(s) of Administration: Intravenous 
 
Method of Administration: Multiple vials of aflibercept concentrate for solution for 
infusion may be required depending on the patient’s weight and the intended dose. 
The necessary volume of aflibercept should be withdrawn from the vials and injected 
directly into the infusion bag. Aflibercept concentrate should be diluted for infusion 
with 0.9% sodium chloride solution or 5% dextrose by a healthcare professional. The 
dilution must be carried out under aseptic conditions. Any unused portion left in a 
vial must be discarded, as the investigational drug product does not contain any 
preservatives. 
 
Potential Drug Interactions:  No formal crossover design drug-drug interaction 
studies with antineoplastic agents have been conducted. However, the existing data of 
aflibercept in combination Phase 1 trials suggest that aflibercept does not affect the 
pharmacokinetics of 5-FU, oxaliplatin, gemcitabine, irinotecan, or docetaxel. 


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Patient Care Implications:   
 
 
Pregnancy and lactation 
Angiogenesis is critical to fetal development and the inhibition of angiogenesis 
following administration of aflibercept is likely to result in adverse effects on 
pregnancy. There are no adequate and well-controlled studies in pregnant women. 
All patients should be counseled regarding the potential risk of aflibercept to the 
developing fetus prior to initiation of therapy.  
 
If the patient becomes pregnant while receiving aflibercept, she should be apprised 
of the potential hazard to the fetus and/or the potential risk of loss of pregnancy. 
Patients who discontinue aflibercept should also be counseled concerning the 
prolonged exposure following discontinuation of therapy (half-life of 
approximately 20 days) and the possible effects of aflibercept on fetal development. 
 
No information is available regarding the safety of aflibercept in pregnant women 
and their fetuses, or in women who are breast feeding. It is not known whether 
aflibercept is excreted in human or animal milk and the potential for absorption and 
harm to the nursing infant is unknown. However, IgG1s are secreted into the breast 
milk of nursing mothers. The Investigator must make every effort to ensure 
aflibercept is not administered to women who are pregnant or breast feeding. 
Lactating women should be advised to discontinue nursing during aflibercept 
treatment and to not resume until at least 6 months following the last administration 
of aflibercept. 
 
Prior to enrollment in a clinical trial of aflibercept, patients of childbearing potential 
must have a negative serum pregnancy test (within 7 days). In the event of 
pregnancy while on aflibercept treatment, aflibercept should be discontinued and 
the Sponsor informed immediately. Follow-up of the pregnancy will be mandatory 
until the outcome has been determined. Information related to the pregnancy must 
be given on a “Drug Exposure Via Parent-Data Collection” form that will be 
provided by the Sponsor. Effective contraceptive measures are required for 6 
months following the last administration of aflibercept. 
 
Overdose 
There is no information on the safety of aflibercept given at doses exceeding 7 
mg/kg every 2 weeks, or 9 mg/kg every 3 weeks. 
 
Osteonecrosis of the jaw 
For patients receiving aflibercept, good oral hygiene and regular dental follow-up 
is recommended. Patients should not undergo invasive dental procedures while 
receiving aflibercept without first consulting with the treating oncologist. If 
osteonecrosis develops, aflibercept should be permanently discontinued and the 
patient referred to an oral surgery specialist for further management. 
 


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Availability 
 
Aflibercept is an investigational agent supplied to the investigators by Sanofi-
Aventis. 
 
8.2  Commercial Agents  
 
 
8.2.1 5-Fluorouracil: please see package insert for additional information 
 
Chemical Name: 2,4-Dihydroxy-5-fluoropyrimidine 
 
 
 
Other Names: 5-FU, Adrucil 
 
 
 
Classification: Antimetabolite 
 
 
 
Molecular Formula: C4H3FN2O2 
 
Molecular Weight: 130.08 
 
 
 
Mode of Action: fluorouracil is a pyrimidine antagonist that interferes with 
nucleic acid biosynthesis.  The deoxyribonucleotide of the drug inhibits 
thymidylate synthase, thus inhibiting formation of thymidylic acid from 
deoxyuridylic acid and thus interfering with the synthesis of DNA. It also 
interferes with RNA synthesis. 5FU is cell-cycle specific (S-phase). 
 
 
 
How supplied: Commercially available in 500 mg/10mL ampoules and vials, and 
1 gram/20 mL, 2.5 gram/50mL and 5 gram/100 mL vials. 
 
 
 
Storage and stability: Stable for prolonged period of time at room temperature if 
protected from light. Inspect for precipitate; if apparent, agitate vial vigorously or 
gently heat to not greater the 140°F in a water bath. Do not allow to freeze. 
 
Route of Administration: intravenous 
 
Drug Administration: 5-FU will be administered at 400 mg/m2 IV bolus over 5-
15 minutes, followed by 2400mg/m2 continuous infusion over 46 hours. 
 
Patient Care Implications: Reported Adverse Events and Potential Risks 
Hematologic: Leukopenia, thrombocytopenia, anemia; can be dose 
limiting; less common with continuous infusion. 
Dermatologic: Dermatitis, nail changes, hyperpigmentation, Hand-
Foot Syndrome with protracted infusions, alopecia. 
Gastrointestinal: Nausea, vomiting, anorexia, diarrhea, can be 
dose limiting; mucositis occasionally dose limiting; severe, 
cholera-like diarrhea which can be fatal when given with 
leucovorin. 
Neurologic: Cerebellar Syndrome (headache and cerebellar 
ataxia). 


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Cardiac: Angina, noted with continuous infusion. 
Ophthalmic: Eye irritation, nasal discharge, watering of eyes, 
blurred vision. 
 
 
Drug Interactions: Chronic administration of cimetidine may decrease the 
clearance of 5-FU. Within individuals, interferon alpha may decrease 5-FU 
clearance in a dose and schedule-dependent manner. Dipyridamole 57 increases 
5-FU clearance and lower Cpss during continuous infusion. No pharmacokinetic 
interaction between 85 mg/m2 oxaliplatin and 5-FU/LV has been observed in 
patients treated every 2 weeks. Increases of 5-FU plasma concentrations by 
approximately 20% have been observed with doses of 130 mg/m2 oxaliplatin 
dosed every 3 weeks.  Leucovorin enhances the cytotoxicity of 5-FU by forming a 
more stable tertiary complex with thymidylate synthase. Concomitant 
administration of 5-FU with warfarin has been reported to result in increased 
INR/prolonged prothrombin time.  Patients receiving both drugs should be 
followed with weekly INRs. 
 
Note: 5-FU in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination 
may result in events never previously associated with either agent. 
 
 
 
Availability: Commercially available 
 
 
 
8.2.2 Leucovorin: please see package insert for additional information. 
 
Other Names: Folinic acid, Citrovorum factor, or 5-formyl-5,6,7,8-
tetrahydrofolic acid 
 
Classification: Chemically reduced derivative of folic acid 
 
Mode of Action:  Leucovorin can enhance the therapeutic and toxic effects of 
fluoropyrimidines used in cancer therapy, such as 5-fluorouracil. 5-Fluorouracil is 
metabolized to fluorodeoxyuridylic acid, which binds to and inhibits the enzyme 
thymidylate synthase (an enzyme important in DNA repair and replication). 
Leucovorin is readily converted to another reduced folate, 5,10-
methylenetetrahydrofolate, which acts to stabilize the binding of 
fluorodeoxyuridylic acid to thymidylate synthase and thereby enhances the 
inhibition of this enzyme. 
 
How Supplied: Leucovorin calcium for injection is supplied in sterile, single-use 
vials. 
 
Storage and Stability: Store at 25°C (77°F); excursions permitted to 15-30°C 
(59°-86°F). Protect from light. 
 
Route of Administration: Intravenous 
 


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Drug Administration: Leucovorin 400mg/m 2 in 250cc D5W is to be given over 
2 hours. Leucovorin can be administered following oxaliplatin, or at the same 
time as oxaliplatin in separate bags using a Y-line.  
 
Patient Care Implications: Known potential toxicities include nausea, diarrhea, 
thrombocytosis, rash, hives, pruritus, headache, and wheezing 
 
Drug Interactions: May potentiate the toxic effects of fluoropyrimidines (5-
fluorouracil) therapy, resulting in increased hematologic and gastrointestinal 
(diarrhea, stomatitis) 
adverse effects. Monitor closely. 
 
Availability: Commercially available 
 
8.2.2.1       Levoleucovorin: please see package insert for additional information. 
 
Other Names: Fusilev, or (6S)-N-{4-[[(2-amino-5-formyl-1,4,5,6,7,8-hexahydro-
4-oxo-6pteridinyl)methyl] amino]benzoyl}-L-glutamate pentahydrate . 
 
Classification: Chemically reduced derivative of folic acid 
 
Mode of Action: Levoleucovorin can enhance the therapeutic and toxic effects of 
fluoropyrimidines used in cancer therapy such as 5-fluorouracil. 5-fluorouracil is 
metabolized to 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP), which 
binds to and inhibits thymidylate synthase (an enzyme important in DNA repair 
and replication). Levoleucovorin is readily converted to another reduced folate, 
5,10-methylenetetrahydrofolate, which acts to stabilize the binding of FdUMP to 
thymidylate synthase and thereby enhances the inhibition of this enzyme.   
 
How Supplied: Levoleucovorin Each 50 mg single-use vial of Fusilev for 
Injection contains a sterile lyophilized powder consisting of 64 mg levoleucovorin 
calcium pentahydrate (equivalent to 50 mg levoleucovorin) and 50 mg mannitol.  
50 mg vial of freeze-dried powder – NDC 68152-101-00. 
 
Storage and Stability: Store at 25° C (77 °F) in carton until contents are used. 
Excursions permitted from 15-30° C (59-86 °F). Protect from light. 
 
Route of Administration: Intravenous 
 
Drug Administration: Levoleucovorin 200mg/m 2 in 250cc D5W is to be given 
over 2 hours. Leucovorin can be administered following oxaliplatin, or at the 
same time as oxaliplatin in separate bags using a Y-line.  
 
                        Patient Care Implications: Known potential toxicities include nausea, vomiting,  
 
 
diarrhea, stomatitis, Abdominal Pain, Asthenia/Fatigue/Malaise ,   
 
 
 
Anorexia/Decreased Appetite, Dermatitis, Alopecia, 


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Drug Interactions: Folic acid in large amounts may counteract the antiepileptic 
effect of phenobarbital, phenytoin and primidone, and increase the frequency of 
seizures in susceptible children. It is not known whether folinic acid has the same 
effects. However, both folic and folinic acids share some common metabolic 
pathways. Caution should be taken when taking folinic acid in combination with 
anticonvulsant drugs. Preliminary human studies have shown that small quantities 
of systemically administered leucovorin enter the CSF, primarily as its major 
metabolite, 5-methyltetrahydrofolate (5-MTHFA). In humans, the CSF levels of 
5-MTHFA remain 1-3 orders of magnitude lower than the usual methotrexate 
concentrations following intrathecal administration.  
Fusilev increases the toxicity of 5-fluorouracil. 
 
Availability: Commercially available 
 
8.2.3 Oxaliplatin: Please see package insert for additional information 
 
 
Chemical Name: Trans-l-1,2-diaminocyclohexane oxalatoplatinum 
 
 
Other Names: Eloxatin 
 
 
Classification: Platinum Analogue 
 
 
Molecular Formula: C8H12N2O4Pt  
Molecular Weight: 359.3 
 
Mode of Action: Oxaliplatin undergoes nonenzymatic conversion in physiologic 
solutions to active derivatives via displacement of the labile oxalate ligand. 
Several transient reactive species are formed, including monoaquo and diaquo 
DACH platinum, which covalently bind with macromolecules. Both inter and 
intrastrand Pt-DNA crosslinks are formed. Crosslinks are formed between the N7 
positions of two adjacent guanines (GG), adjacent adenineguanines (AG), and 
guanines separated by an intervening nucleotide (GNG). These crosslinks inhibit 
DNA replication and transcription. Cytotoxicity is cell-cycle nonspecific. 
 
How Supplied: Powder for solution for infusion: 
ELOXATIN is supplied in clear, glass, single-use vials with gray 
elastomeric stoppers and aluminum flip-off seals containing 50 mg 
or 100 mg of oxaliplatin as a sterile, preservative-free lyophilized 
powder for reconstitution. Lactose monohydrate is also present as 
an active ingredient. 
 
NDC 0024-0596-02: 50 mg single-use vial with green flip-off seal 
individually packaged in a carton. 
 
NDC 0024-0597-04: 100 mg single-use vial with dark blue flip-off 
seal individually packaged in a carton. 


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Concentrate for solution for infusion: 
ELOXATIN is supplied in clear, glass, single-use vials with gray 
elastomeric stoppers and aluminum flip-off seals containing 50 
mg, 100 mg or 200 mg of oxaliplatin as a sterile, preservative-free, 
aqueous solution at a concentration of 5 mg/ml. Water for 
Injection, USP is present as an inactive ingredient. 
 
NDC 0024-0590-10: 50 mg single-use vial with green flip-off seal 
individually packaged in a carton. 
 
NDC 0024-0591-20: 100 mg single-use vial with dark blue flip-off 
seal individually packaged in a carton. 
 
NDC 0024-0592-40: 200 mg single-use vial with orange flip-off 
seal individually packaged in a carton. 
 
Storage and Stability: Powder for solution for infusion:  
Store under normal lighting conditions at 25°C (77°F); 
excursions permitted to 15-30°C (59-86°F) [see USP 
controlled room temperature]. 
 
Concentrate for solution for infusion: 
Store at 25°C (77°F); excursions permitted to 15-30°C (59-
86°F). Do not freeze and protect from light (keep in 
original outer carton). 
 
Route of Administration: Intravenous 
 
Drug Administration: ELOXATIN 85 mg/m2 IV infusion in 500 mL 5% 
Dextrose injection, USP (D5W) given over 120 minutes. Leucovorin 400 mg/m2 
IV infusion in D5W can be given at the same time in separate bags using a Y-line.  
Premedication with antiemetics, including 5-HT3 blockers with or without 
dexamethasone, is recommended. When oxaliplatin is administered with 5-
fluorouracil, the oxaliplatin infusion should precede that of 5-fluorouracil. Ensure 
the infusion lines are adequately flushed with 5% Dextrose between 
administration of the two drugs. 
 
Patient Care Implications: Reported Adverse Events and Potential Risks 
Allergy/Immunology: Allergic/Hypersensitivity reaction (including 
drug fever) 
Auditory: Middle ear/hearing (ototoxicity, mild), inner ear/hearing 
(mild hearing loss). 
Blood/Bone Marrow: decreased hemoglobin, hemolysis (e.g., 
immune hemolytic anemia, drug related hemolysis), decreased 
leukocytes, decreased platelets, neutropenia. 


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Cardiovascular (Arrhythmia): Sinus tachycardia, supraventricular 
arrhythmias (SVT/atrial fibrillation/flutter), ventricular 
arrhythmias 
(PVCs/bigeminy/trigeminy/ventricular tachycardia). 
Cardiovascular (General): Edema, hypertension, phlebitis 
(superficial), thrombosis/embolism (including pulmonary 
embolism). 
Coagulation: DIC (disseminated intravascular coagulation). 
Constitutional Symptoms: Fever (in the absence of neutropenia, 
where neutropenia is defined as AGC <1.0 x 109L), weight loss, 
fatigue (lethargy, malaise, asthenia). 
Dermatology/Skin: Erythema or skin eruptions, alopecia, hand-foot 
skin reaction, injection site reaction, rash/desquamation 
Endocrine: Hot flashes/flushes 
Gastrointestinal: Anorexia, constipation, dehydration, dysphagia, 
diarrhea, esophagitis, odynophagia (painful swallowing), 
gastrointestinal reflux, enteritis, ascites (not otherwise specified), 
intestinal obstruction, stomatitis/pharyngitis (oral/pharyngeal 
mucositis), taste disturbance (dyspepsia), nausea, vomiting, colitis, 
ileus, typhlitis. 
Hematologic: Single-agent oxaliplatin produces only mild 
myelosuppression with minimal to severe neutropenia, anemia, or 
thrombocytopenia. In combination, more grade 3/4 neutropenia or 
thrombocytopenia may be noted. 
The hemolytic uremic syndrome (HUS) should be suspected in 
individuals who experience the following unexplained severe 
hemolysis, hemoglobinemia, and renal failure as demonstrated 
by an increase in serum creatinine. Patients suspected of 
experiencing HUS should have a thorough laboratory evaluation.  
Oxaliplatin should be discontinued for any suspected 
occurrence of HUS. 
Hemorrhage: CNS hemorrhage/bleeding, hemoptysis, 
hemorrhage/bleeding with grade 3 or 4 thrombocytopenia, 
melena/GI bleeding, rectal bleeding/hematochesia, other 
(hemorrhage NOS). 
Hepatic: Increase alkaline phosphatase, increased bilirubin, 
increase GGT, hepatic enlargement, increase SGOT (AST), 
increase SGPT (ALT) 
Infection/Febrile Neutropenia: Febrile neutropenia (fever of 
unknown origin) without clinically or microbiologically 
documented fever (ANC <1.0 x 109L fever >38.5°C), infection 
(documented clinically or microbiologically) with grade 3 or 4 
neutropenia (ANC<1.0 x 109L), infection with unknown ANC, 
infection without neutropenia. 
Metabolic/Laboratory: Acidosis (metabolic or respiratory), 
hyperuricemia, hypokalemia, hypophosphatemia, hyponaturemia, 


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hypomagnesemia, hypocalcemia. 
Musculoskeletal: Involuntary muscle contractions. 
Neurology: Ataxia (incoordination, including abnormal gait), 
insomnia, mood alteration (depression, anxiety), neuropathy 
cranial (ptosis), vertigo, acute sensory neuropathy induced or 
exacerbated by cold (including acute laryngopharyngeal 
dysesthesias, Lhermitte’s sign, upper extremity paresthesias), 
chronic peripheral neuropathy. 
Ocular/Visual: Conjunctivitis, vision abnormalities including 
blindness, optic neuritis, papilledema, hemianopsia, visual field 
defect, transient blindness. 
Pain: Abdominal pain or cramping, arthralgia (joint pain), bone 
pain, chest pain (non-cardiac and nonpleuritic), headache 
(including migraine), Myalgia (muscle pain including cramps and 
leg cramps). 
Pulmonary: Pulmonary fibrosis, cough, Dyspnea (shortness of 
breath, hiccoughs (hiccups, singultus), pneumonitis/pulmonary 
infiltrates (including eosinophilic pneumonia, interstitial 
pneumonitis, and interstitial lung disease), laryngospasm. 
Renal/Genitourinary: Increased creatinine, renal failure, urinary 
retention, hemolytic uremic syndrome (HUS). 
 
A life threatening constellation of renal failure, anemia, and 
thrombocytopenia, has been reported in oxaliplatin trials. Also 
reported on oxaliplatin trials but with the relationship to oxaliplatin 
still undetermined: tongue paralysis, anemia, aphasia, abnormal 
hepatic dysfunction, hyporeflexia, anxiety, depression, dysarthria, 
insomnia, increase sweating, rhinitis, epistaxis, gout, pancreatitis, 
idiopathic thrombocytopenia (5 cases), thrombocytopenia 
associated with hemolytic anemia (2 cases). 
 
Note: Oxaliplatin in combination with other agents could cause an 
exacerbation of any adverse event currently known to be caused by 
the other agent, or the combination may result in events never 
previously associated with either agent. 
 
Availability: Commercially Available 
 
8.3 
Agent Ordering 
 
Aflibercept ordering will be completed through the Sanofi-Aventis IST Portal. 
Fluorouracil, leucovorin and oxaliplatin are commercially available.   
 
8.4 
Agent Accountability 
 
Agent Inventory Records – The investigator, or a responsible party designated by 


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the investigator, must maintain a careful record of the inventory and disposition 
of all agents received. 
 
9. CORRELATIVE STUDIES  
 
 
9.1. 
Collection of Specimen(s). Patients are required to have tissue available before 
enrolling on the study. A fresh biopsy is only required if there is insufficient 
material for analysis.   Repeat tumor biopsies after 8 weeks of therapy are 
optional and will only be performed at the Ohio State University Medical 
Center.  In addition to tumor tissue, whole blood, plasma and serum will be 
collected at various timepoints outlines below. 
 
9.1.1. 
Blood and Tissue Requirements:  
 
• A whole blood sample should be collected prior to treatment on Cycle 1 Day 1 
for subsequent DNA extraction for SNP analysis.  Whole blood 
(approximately 5 mL) should be collected in an EDTA tube, aliquoted into 
two 1.5-2.0 mL cryovials and stored at -70oC or lower until shipping. 
 
• A 10mL whole blood sample will be collected to obtain a plasma sample for 
all patients on C1D1 (prior to treatment), week 3, week 9, week 13 and 4 
weeks after the patient goes off treatment.  Whole blood should be collected in 
an EDTA tube (lavender top), inverted 8-10 times and placed on ice until 
centrifugation at 1200g for 10 minutes at +4oC.  This should be done within 1 
hour of collection to limit degradation and lysis.  Plasma supernatant should 
be carefully aspirated without disturbing the buffy coat layer. About 4-5 mL 
of plasma can be obtained. Aliquot plasma into 4 properly labeled 1.5-2.0 mL 
cryovials (1 to 1.25 mL per tube).  Store at -70oC or lower until shipping.  
Detailed instructions for this procedure are provided in the Laboratory Manual 
(provided separately). 
 
• Additionally, one 10 mL red top or serum separator tube (SST) should also be 
collected at the same time points listed above (weeks 1, 3, 9, 13 and 4 weeks 
after going off treatment).  This tube should be inverted five times and then 
allowed to sit at room temperature until a clot has formed (60 minutes for red 
top tubes or 30 for SST).  Tubes should then be centrifuged at 1200g for 10 
minutes at room temperature or +4 oC.  Serum can be either poured or pipetted 
off into 4 properly labelled 1.5-2.0 mL cryovials (1 to 1.25 mL per tube) and 
stored at -70oC or lower until shipping. Detailed instructions for this procedure 
are provided in the Laboratory Manual (provided separately). 
 
• An archival tissue block verified to contain tumor or a minimum of 10 slides 
cut at 4-5 microns (unstained and placed onto poly-l-lysine-coated or plus (+) 


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slides) will be required for IHC.  An additional H&E stained 4-micron slide 
will also be required if sending slides.   
 
• Fresh core biopsies are required upon study entry if sufficient archival 
material in not available.  In addition, patients treated at The Ohio State 
University may undergo an optional biopsy after 8 weeks of treatment.  This 
biopsy can be performed up to 7 days prior to C3D1.  Biopsies will be 
performed preferably under image-guidance, although biopsy method will be 
chosen based on feasibility for each individual patient and tumor location.  
Four to five core needle biopsies will be taken depending on the size of the 
tumor.  These cores should be immediately placed in 10% neutral buffered 
formalin, processed using standard operating procedures and embedded in 
paraffin.  Detailed instructions for this procedure are provided in the 
Laboratory Manual (provided separately).  Blocks should be labeled with the 
protocol number, subject number, date and institution.   
 
 
   9.1.2.  
Shipping of Specimen(s): 
 
Specimens to be collected and prepared in this study include whole blood, plasma, 
serum and archival FFPE blocks or slides (FFPE core biopsies if required).  
Samples should be shipped in batches according to instructions listed below along 
with the “RESEARCH SPECIMEN REQUEST FORM” (included in the 
laboratory manual). 
 
• All frozen specimens should be packed in dry ice in styrofoam shippers with 
enough dry ice to ensure that the samples will not thaw within a 48-hour period.  
A minimum 5 kg of dry ice should be used.  Dry ice should be placed along the 
bottom of the styrofoam container.  Each set of frozen specimens should be 
placed in a plastic resealable bag, grouped according to the subject.  A paper 
towel should be wrapped around the samples.  Each plastic bag for each patient 
should be identified with the following information:  protocol number, 
institution name, patient study ID number.  Before plastic bags are placed into 
the styrofoam box a layer of paper towels should be placed on top of the dry 
ice.  The plastic bag should then be placed into the box, and additional dry ice 
should be placed along its sides.  The styrofoam container should be sealed with 
strapping tape and placed into a sturdy cardboard mailing box.  Copies of all 
completed “RESEARCH SPECIMEN REQUEST FORMS” (included in 
laboratory manual) should be included in a plastic resealable bag and placed on 
top of the Styrofoam container.  The box should subsequently be sealed but in 
a way that will permit carbon dioxide to escape as the dry ice sublimates.  
Frozen specimens should be shipped overnight by carrier of choice on Monday, 
Tuesday, or Wednesday.  Shipments should not be made on Thursday or Friday. 
Deliveries on Weekends and holidays will not be accepted. 
 
• FFPE core biopsies should be placed in a resealable plastic bag (separate bags 
per patient) and can be shipped with the frozen samples but on the outside of 


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the styrofoam container.  If not shipping with the frozen samples, place bags in 
a cardboard box and place in a padded envelope.  These specimens with the 
specimen submission form can be sent by regular US mail or UPS ground. 
 
• FFPE slides should be packaged in a slide holder and shipped in a well 
cushioned box. These specimens with the relevant pathological report/s can be 
sent by regular US mail or UPS ground.  
 
Blood and Tissue Specimens should be shipped to the following address: 
 
 
 
 
 
 
 
Cynthia Timmers, Ph.D. 
 
 
 
 
 
 
Room 460B Biomedical Research Tower 
 
 
 
 
460 West 12th Avenue 
 
 
Columbus, Ohio 43210 
 
 
 
Tel. (614)-366-9041 
Cynthia.timmers@osumc.edu 
 
 
9.2 
Biologic Correlative Studies 
 
9.2.1 Measurement of serum levels of VEGF, VEGFR, P1GF, CXCL12 and CXCR4  
 
We will use a very sensitive ELISA kit from R&D Systems (Minneapolis, Minnesota, 
USA) to measure serum levels of the PIGF, VEGFA and it receptor VEGFR2 and also 
CXCL12 and its receptor CXCR4. We will correlate the serum levels of these proteins 
before and after treatment with any clinical responses observed. Any differences in the 
serum levels of these proteins will be statistically analyzed. We will collect these 
samples on the same schedule as DCE-MRI scans so that our values may be correlated 
with DCE-MRI analysis. 
 
 
  9.2.2 Relationship between hypertension and clinical efficacy          
 
   
Blood pressure will be measured weekly for the first 6 weeks and at each therapeutic 
visit and will be graded according to NCI CTCAE v. 4.0.  Results will be collected, 
analyzed, and correlated with response as outlined in Section 13. 
 
9.2.3 SNP analysis 
 
To evaluate genetic markers as potential predictive biomarker for treatment outcome, 
genomic DNA will be extracted from whole blood collected in EDTA tubes at baseline 
(week 1 pre-treatment).   DNA will be purified using the Promega Maxwell 16 Blood 
DNA Purification kit on the Maxwell 16 automated extraction instrument.  and 
quantified using PicoGreen fluorescence using Molecular Probes Quant-IT broad range 
dsDNA kit.  Concentration will be based on the standard curve provided in the Quant-
IT kit.   


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Single nucleotide polymorphisms (SNPs) in VEGFA, VEGFR1, VEGFR2, IL8 and 
CXCR2 will be assessed using TagMan SNP Genotyping Assays.  Genotypes will be 
determined using the TaqMan Genotyper Software. 
 
9.2.4 Measurement and quantification of tumor microvessel density 
 
Immunochemistry and quantitative image analysis will be performed as quantitative 
measure of ongoing tumor associated angiogenesis. This assessment will be performed 
on tumor biopsies pretreatment and after 8 weeks of therapy. For these studies, anti-
CD31 antibody will be used. CD31 is a cell surface glycoprotein on endothelial cells 
that mediate adhesion between vascular cells and their extracellular matrix and is 
involved in transmitting the signals from VEGF. It is strongly expressed by all 
endothelial cells and weakly by leukocytes. CD31 has been used successfully as a 
marker for microvessel density in our laboratory. This is the approach that will be used 
to stain sections of tumor biopsies taken from patients that have been treated with 
aflibercept and FOLFOX. Tumor sections (4-5 microns) will be stained with rat anti-
mouse platelet endothelial cell adhesion molecule-1 antibody (PECAM-1, CD31; 
5ug/ml). After applying the biotinylated secondary antibody, the avidin biotin 
peroxide complex (ABC) method using Vectastatin kit (Vector Laboratories) will be 
used for visualization and quantitation. Staining of blood vessels with CD31 is suitable 
for identification of angiogenesis in tumor biopsy samples. The stained slides will then 
be quantified using the Image J software provided by NIH. 
 
9.3 
Radiographic Correlative Studies 
 
We are in the process of developing a trial-specific standard imaging manual that will 
be distributed to all participating sites.  All DCE-MRI and FDG-PET images must be 
obtained according to the Imaging Protocol outlined in Appendix C.  DCE-MRI and 
FDG-PET will only be performed at sites that have the technology available. DCE-
MRI and FDG-PET are optional for participating sites that are unable to perform the 
imaging due to financial restrictions. Images will be uploaded to a central database and 
reviewed centrally at OSUMC by Dr. Knopp and his group. 
 
9.3.1 DCE MRI  
 
We will obtain DCE MRI images at weeks 0, and after 8 weeks +/- 1 week of 
treatment (after Cycle 2- see study calendar). Patients enrolled at sites where this 
technology is unavailable and/or patients with contraindications to MRI imaging, 
will not undergo this part of imaging. Dr. Michael Knopp and his group will be 
directly involved in the development and the conduct of the radiographic 
correlates for this study in collaboration with our group. 
 
Patients will be imaged with conventional T2- and T1-weighted sequences prior to 
contrast agent application and with T1-weighted sequences after contrast agent 
application for tumor localization and volumetry. In addition, dynamic contrast 


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enhanced (DCE) images will be acquired to demonstrate tumor heterogeneity, 
microcirculation, vascularization and viability. DCE MRI will be carried out using 
a standard, commercially available, FDA approved contrast agent (Gd-chelate) and 
a power injector (Spectris, MedRad, Indianola, PA). All patients will be imaged on 
a 3 Tesla MR system (Achieva; Philips, Cleveland, OH) using a surface coil. 
Images will be acquired with a 3D fast spoiled gradient echo sequence covering the 
lesion with a time resolution in the range of seconds.  For patients treated at OSU, 
the core lab of the Wright Center of Innovation will perform the lesion tracking 
assessment, uni-dimensional lesion measurement (RECIST) as well as 3-D volume 
segmentation. 
 
The DCE-MRI data analysis will be performed using in-house developed software 
based on the IDL environment (Interactive Data Language; ITT, Boulder, CO). 
Regions of interest (ROIs) will be drawn on dynamic imaging data sets including  
tumor and artery. The ROIs for each time point will be co-registered to compensate 
for subject motion during scans. The ROI placement will be carried out by an 
experienced reader and confirmed by a radiologist. The tumor time-enhancement 
curves will be quantitatively analyzed. The adjusted Brix’s model-based 
pharmacokinetic parameters (Amp, kep, kel) will be determined by using the 
MINPACK-1 method for fitting the tracer kinetics equation to the tissue time-signal 
intensity curves 
 
9.3.2 FDG-PET 
 
18FDG-PET will be performed using whole-body technique at week 0 (pre-therapy) 
and after 8 weeks +/- 1 week of treatment (after cycle 2). Patients enrolled at sites 
where this technology is unavailable, will not undergo this part of imaging. It is crucial 
that the 18FDG-PET studies are acquired and processed using the same protocol at 
all sites.  Subjects must fast 4-6 hours before the procedure, but can freely drink 
water, in order to diminish physiologic glucose uptake and reduce serum insulin 
levels to near basal level. Blood sugar cannot exceed 200 mg/dL at the time of the 
18FDG-PET study. Subjects should be injected with approximately 10-20 mCi of 
18FDG and remain still during an 18FDG uptake period of at least 60 minutes. The 
18FDG uptake period of the post week 8 (cycle 3) PET scans should be within 15 
minutes of the uptake period of the baseline PET scan. After the 18FDG uptake 
period, two or three dimensional whole body emission scans encompassing the 
region between the earlobes and the proximal thighs will be obtained in several bed 
positions (usually 6-8) using a PET/CT system for several minutes (usually 3-5) 
per bed position (in accordance with the manufacturer’s recommendations). The 
total scanning time for each patient usually ranges from 20-45 minutes. PET/CT 
may be performed with or without oral or IV contrast, but should be performed 
consistently for the baseline and post- week 8 scan. The PET projection data are 
corrected for random coincidences, scatter, and attenuation in accordance with 
manufacturer’s recommendations. Transaxial images will be reconstructed into at 
least 128 x 128 pixel images with a pixel size according to manufacturer’s 
recommendations, preferably of 5 mm or less. The reconstructed PET/CT images 
will be displayed on a computer workstation so that transaxial, sagittal, and coronal 


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images can be simultaneously viewed. All scans should be performed on calibrated 
PET/CT scanners and each subject should have the baseline and post-cycle 2 scans 
on the same scanner. Coincidence imaging using hybrid SPECT/PET systems is 
unacceptable. For each subject’s PET scan, the following parameters must be 
recorded during the PET procedure: assay time, 18FDG assay dose, injection time, 
residual time, residual dose, PET emission scan start time, subject weight 
(measured on the day of the scan). All clocks used to record time must be 
synchronized with the PET scanner computers. The 18FDG-PET scans at baseline 
and at follow-up will be interpreted by an experienced nuclear medicine physician 
at each participating site who will be responsible for image interpretation. The 
images will be interpreted together with pertinent clinical and CT findings. 
Interpreting the PET scan in this fashion mimics the usual clinical situation, in 
which this information is incorporated into the interpretation, especially in the  case 
of an equivocal scan finding that may be easily explained by the CT scan result 
(e.g., anatomic variation of the bowel or bladder) or clinical information (e.g., 
increased uptake at a site of recent surgery or biopsy). In addition, all PET/CT 
images will be sent to the Ohio State University for central analysis.  Images 
obtained at baseline and cycle 3 will be compared to DCE-MRI images obtained at 
the same time points for combined evaluation of the effects of anti-angiogenic 
therapy and correlation with RECIST response by CT scan. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10. STUDY CALENDAR 
Baseline evaluations are to be conducted within 2 weeks prior to start of protocol therapy.  
Scans and x-rays must be done ≤4 weeks prior to the start of therapy.  In the event that the 


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patient's condition is deteriorating, laboratory evaluations should be repeated within 48 hours 
prior to initiation of the next cycle of therapy. All study visits and evaluations have a +/- 3 
day window.  
   
Pre-
Study 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Wk 
13 
Continued 
Treatment 
Follow 
Upo 
Off 
Treatment 
 
Aflibercept  
mFOLFOX 6b 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Xn 
 
 
 
Informed 
consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent 
meds 
 
X 
X------------------------------------------------------------------------------------------------X 
 
 
 
Physical exam 
 
X 
 
Xq 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Xn 
 
X 
 
Vital signsl 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Xn 
 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Xn 
 
X 
 
Performance 
status 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Xn 
 
X 
 
CBC w/diff, 
plts PT/INRc 
 
X 
 
Xq 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Xn 
 
X 
 
Serum 
chemistryd 
X 
 
Xq 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Xn 
 
X 
Urine studiese 
X 
Xq 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Xn 
 
 
LDH/ 
Phosphorous 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest X ray 
 
As Medically Indicated 
 
 
 
Adverse Event 
Evaluation 
 
X ------------------------------------------------------------------------------------------------X 
 
 
X 
 
Tumor 
measurements 
 
 
X 
 
Tumor measurements are repeated every 8 weeks.  Documentation (radiologic) must be 
provided for patients removed from study for progressive disease. 
 
X 
 
Radiologic 
evaluationm 
 
X 
 
Radiologic measurements should be performed every 8 weeks. 
 
X 
 
B-HCGf 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CEA 
X 
CEA measurements to be performed every 4 weeks 
X 


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Pre-
Study 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Wk 
13 
Continued 
Treatment 
Follow 
Upo 
Off 
Treatment 
Lipid Studiesp 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Xp 
 
X 
Whole blood 
for SNP 
analysis 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum and 
plasma 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
Assessment 
for 
resectabilityg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
DCE-MRIi 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
FDG-PETi 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Tumor biopsyj, 
k 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
a: 
Patients will continue to receive therapy on study until any of the following: disease progression, unacceptable toxicity, 
intercurrent illness, death, or refusal/withdrawal of consent to receive treatment.  
b:  Aflibercept will be administered at a dose of 4 mg/kg intravenously every 2 weeks.  mFOLFOX 6 is administered intravenously 
every 2 weeks and consists of oxaliplatin 85 mg/m2 plus leucovorin 400 mg/m2 given together over 2 hours, followed by bolus 
5-FU 400 mg/m2 over 5-15 minutes, followed by continuous infusion 5-FU 2400 mg/m2 over 46 hours. 
c: 
For patients requiring therapeutic anticoagulation with warfarin, PT/INR should be assessed prior to each aflibercept infusion. 
d: 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose,  potassium, total 
protein, SGOT[AST], SGPT[ALT], sodium. 
e: 
Urinalysis for hematuria, protein and creatinine measurements.  24-hour urine collection for quantitative protein determination 
should be obtained for a urine protein/creatinine ratio >1. 
f: 
Serum pregnancy test (women of childbearing potential).  This must be obtained within 7 days of treatment initiation. 
g: 
For patients with limited hepatic metastatic disease only, at each interval radiographic evaluation, a determination of 
possibility of R0 resection of all metastatic disease should be considered 
h.    Two 10mL tubes of blood will be obtained for purification of serum and plasma for pharmacodynamic correlates pre-dose on 
day 1 of weeks 1, 3, 9 and 13 and at the time of progression or when patient goes off study. 
i:  
DCE-MRI and FDG-PET will be obtained at week 0 (pre-therapy) and after 8 weeks +/- 1 week (2 cycles) of therapy  at sites 
with the technology available. DCE-MRI and FDG-PET are optional for participating sites that are unable to perform the 
imaging due to financial restrictions. 
j:    Patients are required to have paraffin embedded tissue available before enrolling on the study. A biopsy is only required if there 
is insufficient material for analysis. The tissue will be used for correlative studies that include measurement of tumor 
vascularity and SNPs. 
k: 
At 8 weeks post-treatment, patients will have the option to undergo tumor biopsy (OSU patients only) to assess for changes in 
tumor vascularity. 
l.     Blood Pressure will be checked at home by the patient with two separate measurements at least 1 minute apart on C1D8, 
C1D22 and C2 Day 8 and the lower reading should be reported to the study coordinator by phone. If the patient has a home 
blood pressure monitoring device (wrist cuffs are allowed) they should bring it in on their 1st visit (for calibration), otherwise 
one will be provided to them.  


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m. Radiologic evaluation to include CT scan of Chest, Abdomen, and Pelvis 
n. 
Patients may continue on treatment past 13 weeks so long as criteria in section 5.3 has not been met. Treatment schedule will 
remain the same as weeks 1-13. Physical exams will only be required to be done monthly. All other assessments will be every 
2 weeks on treatment days. 
o. 
After being taken off treatment, patient will be followed every 3 months until death. Adverse event reporting should continue 
for 30 days after last dose of protocol therapy. Patients removed from treatment for unacceptable adverse events will be 
followed until resolution or stabilization of the adverse event. After removal from treatment, follow up may be done by phone, 
if needed. Radiologic evaluation frequency should occur per local standard of care. Patients are not required to continue to 
have radiologic evaluations per protocol schedule. 
p. 
Lipid studies are to be performed at baseline and then monthly during protocol therapy and are to include LDL-cholesterol, 
HDL-cholesterol, and Triglycerides 
q. 
If pre-study physical exam and labs were performed within 3 days prior to C1D1, these assessments do not need to be repeated 
on C1D1. 
 


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11. MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 8 weeks.   
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee, Version 
1.1 [58].  Changes in only the largest diameter (unidimensional measurement) of the tumor 
lesions are used in the RECIST criteria. 
 
11.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their first 
treatment with aflibercept and mFOLFOX6 
 
Evaluable for objective response.  Only those patients who have measurable disease present 
at baseline, have received at least two cycles of therapy, and have had their disease re-
evaluated will be considered evaluable for response.  These patients will have their response 
classified according to the definitions stated below.  (Note:  Patients who exhibit objective 
disease progression prior to the end of cycle 2 will also be considered evaluable.) 
 
11.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as at least one lesion that can be 
accurately measured in at least one dimension (longest diameter to be recorded) as >10 mm 
with spiral CT scan (CT scan slice thickness no greater than 5 mm) Malignant lymph nodes 
will be considered measurable if they are ≥15 mm in short axis.   
 
Note:  Tumor lesions that are situated in a previously irradiated area will not be considered 
measurable.   
 
Non-measurable disease.  All other lesions, including small lesions (longest diameter 
<10mm or pathological lymph nodes with >10 to <15mm short axis as well as truly non-
measurable lesions. Lesions considered truly non-measurable include: leptomeningeal 
disease, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung, abdominal masses/abdominal organomegaly identified by 
physical exam that is not measurable by reproducible imaging techniques. 
 
Target lesions.  A sum of the diameters (longest for non-nodal lesions, short axis for nodal 
lesions) for all target lesions will be calculated and reported as the baseline sum diameters. 
If lymph nodes are to be included in the sum, then as noted above, only the short axis is 
added into the sum. The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including pathological lymph nodes 
should be identified as non-target lesions and should also be recorded at baseline. 
Measurements are not required and these lesions should be followed as ‘present’, ‘absent’, 


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or in rare cases ‘unequivocal progression’. In addition, it is possible to record multiple 
nontarget lesions involving the same organ as a single item on the case record form (e.g. 
‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 
 
11.1.3 Methods for Evaluation of Measurable Disease 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation 
should always be done rather than clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial and ≥10mm diameter as assessed using calipers (e.g. skin nodules). For the case 
of skin lesions, documentation by color photography including a ruler to estimate the size of 
the lesion is suggested. As noted above, when lesions can be evaluated by both clinical exam 
and imaging, imaging evaluation should be undertaken since it is more objective and may 
also be reviewed at the end of the study. 
 
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions. However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung.  
 
Conventional CT and MRI  This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness.  MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease.  Furthermore, as with CT, the modality used at follow-up should be 
the same as was used at baseline and the lesions should be measured/assessed on the same 
pulse sequence.  It is beyond the scope of the RECIST guidelines to prescribe specific MRI 
pulse sequence parameters for all scanners, body parts, and diseases.  Ideally, the same type 
of scanner should be used and the image acquisition protocol should be followed as closely 
as possible to prior scans.  Body scans should be performed with breath-hold scanning 
techniques, if possible. 
 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as 
a method of measurement. Ultrasound examinations cannot be reproduced in their entirety 
for independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to 
the next (described in greater detail in Appendix C). If new lesions are identified by 
ultrasound in the course of the study, confirmation by CT or MRI is advised. If there is 
concern about radiation exposure at CT, MRI may be used instead of CT in selected 


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instances. 
 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor evaluation 
is not advised. However, they can be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in trials where recurrence following complete 
response or surgical resection is an endpoint. 
 
Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. If 
markers are initially above the upper normal limit, however, they must normalize for a 
patient to be considered in complete response. 
 
11.1.4 Response Criteria 
 
11.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR): 
Disappearance of all target lesions. Any pathological 
lymph nodes (whether target or non-target) must have 
reduction in short axis to <10 mm. 
 
Partial Response (PR): 
At least a 30% decrease in the sum of diameters of 
target lesions, taking as reference the baseline sum 
diameters 
 
Progressive Disease (PD): 
At least a 20% increase in the sum of diameters of 
target lesions, taking as reference the smallest sum on 
study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase 
of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note: the appearance of one 
or more new lesions is also considered progression). 
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as 
reference the smallest sum diameters while on study. 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR): 
Disappearance 
of 
all 
non-target 
lesions 
and 
normalization of tumor marker level. All lymph nodes 
must be non-pathological in size (<10mm short axis). 
 
Incomplete Response/ 
Stable Disease (SD): 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal 
limits. 
 
Progressive Disease (PD): 
Unequivocal progression of existing non-target 
lesions. (Note: the appearance of one or more new 


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lesions is also considered progression). 
When the patient also has measurable disease, to achieve ‘unequivocal progression’ 
on the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease such that, even in presence of SD or PR in target 
disease, the overall tumor burden has increased sufficiently to merit discontinuation 
of therapy. A modest ‘increase’ in the size of one or more non-target lesions is 
usually not sufficient to quality for unequivocal progression status. The designation 
of overall progression solely on the basis of change in non-target disease in the face 
of SD or PR of target disease will therefore be extremely rare. In such circumstances, 
the opinion of the treating physician should prevail, and the progression status should 
be confirmed at a later time by the review panel (or Principal Investigator). 
 
11.1.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Note: 
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”.  Every effort should be made to document 
the objective progression even after discontinuation of treatment. 
 
 
 
11.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date 
that recurrent or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for 
CR until the first date that recurrent disease is objectively documented. 
 
 


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Duration of stable disease:  Stable disease is measured from the start of the treatment until 
the criteria for progression are met, taking as reference the smallest measurements recorded 
since the treatment started.  
 
11.1.6 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of documented 
progression or death whichever occurs first. 
 
11.1.7 Overall Survival 
 
Time from study initiation to time of death will be followed and documented for all patients. 
 
11.1.8 Response Rate 
 
  
Response rate is defined as the rate of complete response + partial response as defined by 
RECIST criteria. 
 
11.1.9 Disease Control Rate 
 
  
Disease control rate is defined as the rate of complete response + partial response + stable 
disease, as defined by RECIST criteria. 
 
12. 
DATA/SAE REPORTING & REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and additional instructions for AE reporting can be found in 
Section 7.0 (Adverse Events: List and Reporting Requirements). 
 
12.1 
Serious Adverse Event Reporting 
 
12.1.1. Serious Adverse Events Reportable to the FDA 
In the context of an Investigator Sponsored Trial being conducted under an IND, CFR 312.32 
states the FDA needs to be informed of unexpected and related SAEs (SUSARs) as soon as 
possible or within 15 calendar days. In addition, the investigator must notify the FDA of any 
unexpected, fatal or life-threatening experience associated with the use of the drug as soon as 
possible, or within 7 calendar days by telephone or facsimile.   
 
Subsite institutions are NOT permitted to report directly to the FDA or Sanofi-Aventis. Subsite 
institutions must report all SAEs to the Principal Investigator and the Subsite Coordinator 
within 24 hours of knowledge of the event. A brief description may be initially sent via secure 
email or fax. A complete report is then required to be submitted with SAE Submission Form 
(refer to Supplemental Forms Document) via secure email or fax to the Principal Investigator 
and Subsite Coordinator within 3 days. Follow up reports must be submitted per section 
12.1.6. Subsite institutions are required to submit SAEs to their local IRBs as per their 
institutional and IRB policies. 
 
When the principal investigator has determined that a Serious Adverse Event requires 
reporting to the FDA (unexpected and possibly related to study drug), the following actions 


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must be completed: 
 
12.1.2 Actions towards FDA:  
 
1. The Ohio State University will be the ONLY entity reporting SAEs to the FDA. Subsite 
institutions will NOT report SAEs the FDA. They should send SAEs to OSU for review 
and reporting to the FDA. Refer to section 12.1.1 for details. 
 
2. Telephone the FDA immediately (day of awareness), in the case of reportable death or 
life-threatening events. 
 
3. Complete FDA Form MedWatch 3500A.   
 
4. Send the completed MedWatch 3500A form to the FDA (preferably by fax at 1-800-
FDA-0178) within the timelines mentioned above. 
 
5. Attach the photocopy of all examinations, medical notes and records related to the 
Serious Adverse Event and document the dates these were made. For laboratory results, 
include the laboratory normal ranges. For hospitalizations, Admission H&P, Discharge 
Summary, Consultative reports, etc. could be very helpful. In the case of a Fatal event, 
provide an autopsy report, when it becomes available.   
 
12.1.3 Actions towards Sanofi-Aventis [Aflibercept]: 
 
The Ohio State University will be the only entity reporting SAEs to Sanofi-Aventis. 
Subsite institutions will report SAEs to OSU, which will in turn report to the Sanofi-
Aventis. Refer to section 12.1.1 for details. 
 
Concurrently provide a copy of the information sent to FDA to sanofi-aventis by fax 
(908-203-7783)  or email USPVMailbox@sanofi-aventis.com within 24 hours after the 
FDA submission (initial and follow-up information) 
 
 
 
 
For IST contracts of recently approved new chemical/biological entities include the 
following: 
       
• In addition to SUSARs, all SAEs shall be sent to sanofi-aventis on an ongoing  
 
basis. 
 
• Results of any relevant complementary exams performed to obtain the final  
diagnosis of any SAE (e.g. hospital discharge summary, autopsy report, consultations, 
etc.), will be made available to sanofi-aventis upon request. 
 
 
 
12.1.4 Actions towards co/sub-investigators (participating on this protocol and IRBs: 
 
The principal investigator is responsible for providing all Serious Adverse Events (on 
MedWatch form 3500A) submitted to the FDA to the OSU IRB and co/sub-investigators 


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(via Dear Investigator Letter) participating on this protocol. This applies to initial and 
follow-up information. The Subsite Coordinator will be responsible for submitting subsite 
SAEs the OSU IRB. All SAEs will be sent to the subsite co-investigators by the Subsite 
Coordinator. Subsite institutions are required to submit SAEs to their local IRBs as per 
their institutional and IRB policies. 
 
12.1.5 Actions towards other manufacturers (as relevant): 
 
For reportable Serious Adverse Events (completed MedWatch form 3500A) that have 
occurred in patients treated with products other than of sanofi-aventis, the principal 
investigator must also transmit the information to the manufacturer of the suspect product 
within 24 hours.  
 
12.1.6 Follow-up Reports 
 
• The investigators should take all appropriate measures to ensure the safety of the subjects. 
Notably they should follow-up to determine the outcome of any Adverse Events (clinical 
signs, laboratory values or other, etc.) until the patient has recovered, abnormal values 
have returned to normal or until progression has been stabilized. This may imply that 
follow-up will continue after the subject has left the study and that additional 
investigations may be necessary.  
 
• In the case of a Death or a Life-threatening event, the investigator should provide a follow-
up report, with positive or negative findings within 5 days of the awareness of the initial 
observation.  
 
• Any reportable Serious Adverse Events brought to the attention of the Investigator at any 
time after cessation of the trial and considered by him/her to be reasonably associated with 
medication administered during the period should also be submitted to the FDA.  A copy 
should be provided to sanofi-aventis, if a sanofi-aventis product was involved or the 
appropriate manufacturer of another product within 24 hours after FDA submission (see 
above). 
 
• The MedWatch form 3500A providing follow-up information about a reportable SAE must 
be submitted to the FDA as soon as possible or within 15 calendar days. As with the initial 
submission to the FDA of the MedWatch form 3500A, the principal investigator is also 
responsible for providing all follow-ups for reportable Serious Adverse Events (on 
MedWatch form 3500A) to the IRB and co/sub-investigators (via Dear Investigator Letter) 
participating on this protocol. 
 
 
12.1.7 Multi-center Coordination  
Principal Investigator Responsibilities:  
The principal investigator is responsible for the coordination, development, submission, and 
approval of the protocol as well as its subsequent amendments. The protocol must not be 
rewritten or modified by anyone other than the principal investigator. There will be only one 
version of the protocol, and each participating institution will use that document. The 
principal investigator is responsible for assuring that all participating institutions are using 


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the correct version of the protocol.  
• The principal investigator is responsible for the overall conduct of the study at all 
participating institutions and for monitoring its progress. All reporting requirements are the 
responsibility of the Principal investigator.  
• The principal investigator is responsible for the timely review of Adverse Events (AE) to 
assure safety of the patients.  
• The principal investigator will be responsible for the review of and timely submission of 
data for study analysis. 
  
12.1.8 Coordinating Center Responsibilities (The Ohio State University)  
• Each participating institution will have an appropriate assurance on file with the Office for 
Human Research Protection (OHRP), NIH. The Coordinating Center is responsible for 
assuring that each participating institution has an OHRP assurance and must maintain copies 
of IRB approvals from each participating site.  
• Prior to the activation of the protocol at each participating institution, documentation of 
IRB approval must be submitted to the Coordinating Center. The Coordinating Center is 
responsible for assuring that IRB approval has been obtained at each participating site prior 
to the first patient registration from that site.  
• The Coordinating Center is responsible for central patient registration. The Eligibility 
Worksheet and requested supporting documentation will be faxed by the collaborating site 
to the OSU Subsite Coordinator. Patients will not begin treatment until a confirmation of 
eligibility by the OSU Subsite Coordinator has been performed and registration is received 
from the coordinating institution (OSU). A registration number will be given to each patient 
and will be used as a unique identifier on all patient materials and data sheets submitted 
thereafter. Every effort will be made to ensure that collaborating sites are notified of protocol 
eligibility and patient registration information within approximately 48 hours. 
• The Coordinating Center will maintain documentation of all SAE reports including ones 
from collaborating sites. Participating institutions will report all serious adverse events in 
accordance with Sections 7 & 12 Adverse Event Reporting of the protocol.  
• The Coordinating Center will provide Case Report Folders (CRFs) to all sites. The 
collaborating sites are responsible for the preparation of data for patients enrolled at their 
site. All data requested in the CRF must be provided to the principal investigator upon 
request. Source documents and research records for patients enrolled on the study must be 
made available for monitoring purposes upon request by the principal investigator. 
 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 Study Overview 
This is a single arm single stage phase II study to evaluate the clinical efficacy of treatment 
with FOLFOX + aflibercept in patients with untreated metastatic colorectal cancer.  The 
primary goal of this study is to assess the proportion of patients who are alive and progression-
free at 15 months after treatment the combination of aflibercept plus mFOLFOX6 relative to 
the historical comparator of FOLFOX alone in the first line treatment of mCRC. In a 
secondary manner we will also evaluate response rates and tolerability and toxicity associated 
with this regimen as well as correlative endpoints such as angiogenic markers and how 
changes in these markers correspond to clinical outcomes.  
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progression-free proportion, as measured by the proportion of patients alive and progression-
free at 15 months from initiation of therapy.  All eligible patients who have begun treatment 
will be included for evaluation of the primary endpoint. In addition, those patients who go on 
to undergo surgery will be excluded from the calculation of the primary endpoint to avoid 
potential bias. Based on prior experience and rates, we expect about 10% of these patients will 
be able to undergo surgery. These patients will be analyzed separately from the primary 
endpoint evaluation.  
 
13.2 Sample Size, Accrual, and Study Duration  
 
 
A maximum of 70 eligible patients will be enrolled on this trial and treated with the 
combination of aflibercept and mFOLFOX6. We anticipate that the annual accrual rate across 
all participating sites will be about 40 patients; therefore, the accrual period is expected to be 
approximately 21 months. These estimates are based on previous clinical trial experience in 
this patient population and practice history as well as the fact that patients will be accrued at 
the other participating institutions. The primary endpoint analyses will require 62 evaluable 
patients; the total number of 70 eligible patients reflects the overaccrual to account for about 
10% of patients who are expected to be able to undergo surgery and thus excluded from the 
primary endpoint evaluation to avoid potential bias. Final efficacy analyses will begin after all 
patients have been followed for at least 15 months or until they have a defined event of interest 
(disease progression and/or death).  
 
13.3 
Study design and primary endpoint analysis plans 
 
 
Based on historical data (41, 42), we would expect that treatment with FOLFOX alone in this 
setting would lead to a median progression-free survival (PFS) of around 8 months. Assuming 
that PFS is exponentially distributed, our null hypothesis is that the proportion of patients who 
are alive and progression-free at 15 months with FOLFOX alone (i.e. historical control) is at 
most 25%. We would consider this combination regimen of aflibercept+FOLFOX6 to be 
clinical promising if the true rate was 40% or higher. With these assumptions and constraining 
our one -sided type I error rate to 5% and type II error rate to 20%, this single stage phase II 
study design will require 62 evaluable patients. In other words, we will have at least 80% 
power to determine that this regimen is promising if in fact the true 15-month PFS rate is 40% 
or higher. As discussed above, we expect about 10% of patients to be able to undergo surgery. 
Since these patients have a much different clinical outcome than would be reflective of the 
treatment regimen itself, they will be excluded from our primary endpoint evaluation. 
However, as described below under secondary endpoint analyses, these patients will be 
evaluated in terms of toxicity and tolerability and for other secondary outcome measures.  
 
 
 
Decision Rule: In the final analysis of all 62 evaluable patients, we will need to observe 22 or 
more patients (~35%) who are progression-free and alive at 15 months to determine that this 
regimen is promising. Otherwise, if 21 or fewer of these 62 evaluable patients are alive and 
progression-free at 15 months, we will consider this regimen to not warrant further study in 
this patient population.  
 
 
 
Primary endpoint analysis: The proportion of patients who are alive and progression-free at 15 
months will be evaluated and analyzed using all patients who received at least one day of 
treatment on study. The proportion will be calculated as the number of patients who are alive 
and progression-free at 15 months divided by the total number of evaluable patients (again, 
excluding those who go on to surgery prior to disease progression). Assuming that the number 


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of treatment successes (alive and progression-free) is binomially distributed, proportion 
estimates along with their corresponding exact 95% confidence intervals will be calculated.  
 
13.4 
Analysis of secondary endpoints  
In addition, several secondary clinical and correlative endpoints will be evaluated in these 
subjects.  
 
• Objective response rate (ORR) and percentage of patients able to undergo surgery: each 
of these dichotomous outcomes will be evaluated across all evaluable patients and 
summarized as a proportion with corresponding 95% confidence interval in a manner similar 
to that described for the primary endpoint. Overall response rate will be defined as the 
proportion of patients who achieve a partial response (PR) or complete response (CR) based 
on RECIST 1.1 criteria (112) divided by the total number of evaluable patients. The 
proportion of patients who are able to undergo surgery will be calculated in a similar manner, 
where the number of patients who go on to surgery will be divided by the total number of 
evaluable patients. This latter categorization of patients (ability to undergo surgery) will also 
be considered in conjunction with the primary endpoint analysis as a treatment success 
outcome but in a secondary manner and not used in the decision rule associated with the 
primary endpoint. In this secondary set of analyses, the treatment success proportion will be 
calculated with those able to undergo surgery specifically included in the numerator of the 
proportion.  
 
• Progression-free and overall survival:  In addition to looking at the dichotomized outcome 
of PFS rate at 15 months, we will also evaluate progression-free survival as a time-to-event 
outcome. PFS will be defined as the time from study entry to the time of progressive disease 
and/or death. Patients will be censored at their last evaluation for these analyses if they were 
alive and progression-free at that time. In addition, those who go on to surgery or other 
treatment prior to disease progression will be censored at that timepoint. Overall survival 
will also be calculated for these patients, where overall survival will be defined as the time 
from study entry to time of death due to any cause. These time-to-event outcomes will be 
evaluated using the methods of Kaplan and Meier.   
• Toxicity and Tolerability: As per NCI CTCAE v4.0, the term toxicity is defined as adverse 
events that are classified as either possibly, probably, or definitely related to study treatment. 
The maximum grade for each type of toxicity will be recorded for each patient, and frequency 
tables will be reviewed to determine toxicity patterns. In addition, we will review all adverse 
event data that is graded as 3, 4, or 5 and classified as either “unrelated” or “unlikely to be 
related” to study treatment in the event of an actual relationship developing. The incidence of 
severe (grade 3+) adverse events or toxicities will be described. We will also assess tolerability 
of the regimens through assessing the number of patients who required dose modifications and/or 
dose delays. In addition, we will also capture the proportion of patients who go off treatment due 
to adverse reactions or even those who refuse further treatment for lesser toxicities that inhibit 
their willingness to continue participation on the trial. These tolerability measures will be 
assessed within each of the treatment arms and we will explore differences in these measures 
between the arms. All patients who have received at least one dose of any of the therapeutic 
agents in a treatment arm will be evaluable for toxicity and tolerability.  


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• Levels of circulating VEGF, VEGFR, PIGF, CXCL12 and CXCR4: these markers will be 
evaluated before and after initiation of therapy. Baseline levels as well as change in these 
levels will be quantitatively summarized and graphically explored, in particular in terms of 
how they relate to clinical outcomes of interest. Analyses exploring differences in these 
angiogenic markers in relation to clinical outcomes will be largely hypothesis-generating. If 
deemed clinically active, we do expect at least 22 patients to have a positive clinical outcome 
as defined by the primary endpoint decision rule. Two-sample t-tests will be used to assess 
differences in these markers (baseline and after 8 weeks of treatment) between positive vs. 
negative clinical outcome groups. With limited numbers of patients we will primarily look 
for patterns of difference using graphical analyses; these can include scatterplots of baseline 
vs. change in markers with those with positive vs. negative clinical outcomes reflected 
through different plotting characters to identify potential patterns of interest.  
• Identification of SNPs and correlation with response to treatment. SNP markers will also 
be summarized in an exploratory manner in relation to clinical outcomes of interest. Cross 
tabulation tables and bar graphs will be used to assess potential patterns of allelic expression 
of certain SNPs between those with positive vs. negative clinical outcomes. SNP-based 
expression will also be explored in relation to time-to-event outcomes; given the limited 
numbers of patients, these analyses will be primarily hypothesis-generating.  
• Measurement of tumor vascularity pre and post-treatment with aflibercept: this will be 
analyzed and summarized in a manner similar to that described above for the angiogenic 
marker evaluations and their relationship to clinical outcomes of interest.  
• Correlation between hypertension as a toxicity and response to treatment in patients in 
which it is observed: incidence of hypertension along with severity score (i.e. grade) will be 
evaluated in relation to whether or not patients had a positive vs. negative clinical outcome. 
In particular, we will assess the percentage of those who had any treatment-related 
hypertension between the positive vs. negative clinical outcome patients, where they 
hypothesis is that treatment-related hypertension is reflective of the agent hitting its target.   
• DCE-MRI and FDG-PET and correlation with response, clinical outcome, and serum 
biomarkers of angiogenesis: Imaging outcomes (positive vs. negative; max SUV) will be 
evaluated in relation to positive vs. negative clinical outcomes of interest as well as change 
in angiogenic markers from baseline to 8 weeks into treatment. These relationships will be 
summarized quantitatively as well as explored graphically. Overall, factors that may affect 
the incidence of a positive clinical outcome (i.e. progression-free and alive at 15 months) 
will be explored using a logistic regression model, with change in VEGF (or another 
angiogenic marker) from baseline to 8 weeks into therapy and with imaging outcome.  
 
13.5 
Reporting and Exclusions 
 
13.5.1 Evaluation of toxicity.  All patients will be evaluable for toxicity from the time of their 
first treatment with FOLFOX and aflibercept. 
 
13.5.2 Evaluation of the primary endpoint.  Patients must have received at least 2 cycles of 
therapy and have undergone radiographic response assessment to be considered 
evaluable for the primary endpoint of PFS.  However, patients who are removed from 
study due to progressive disease or death prior to completion of 2 cycles of therapy will 


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be considered evaluable for the primary endpoint.  Patients who are considered non-
evaluable for the primary endpoint will be replaced.  Patients removed from study to 
undergo surgery will not be evaluable for primary endpoint and will be replaced. 
 
 
 
13.5.2 Evaluation of response.  All patients included in the study must be assessed for 
response to treatment, even if there are major protocol treatment deviations or if they 
are ineligible.  Each patient will be assigned one of the following categories:  1) 
complete response, 2) partial response, 3) stable disease, 4) progressive disease, 5) 
early death from malignant disease, 6) early death from toxicity, 7) early death because 
of other cause, or 9) unknown (not assessable, insufficient data).  [Note:  By arbitrary 
convention, category 9 usually designates the “unknown” status of any type of data in a 
clinical database.] 
 
All of the patients who met the eligibility criteria (with the possible exception of those 
who received no study medication) should be included in the main analysis of the 
response rate.  Patients in response categories 4-9 should be considered to have a 
treatment failure (disease progression).  Thus, an incorrect treatment schedule or drug 
administration does not result in exclusion from the analysis of the response rate.  
Precise definitions for categories 4-9 will be protocol specific.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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APPENDIX A 
 
Performance Status Criteria 
 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 
 
 


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APPENDIX B 
Instructions for preparation, handling, and administration of aflibercept 
 
Multiple vials of aflibercept concentrate for solution for infusion may be required depending on 
the patient’s weight and the intended dose. The necessary volume of aflibercept should be 
withdrawn from the vials and injected directly into the infusion bag. 
 
Aflibercept concentrate should be diluted for infusion with 0.9% sodium chloride solution or 5% 
dextrose by a healthcare professional. The dilution must be carried out under aseptic conditions. 
Any unused portion left in a vial must be discarded, as the investigational drug product does not 
contain any preservatives. 
 
Infusion bags made of the following materials may be used: 
• PVC containing DEHP 
• Polyolefin (PVC free DEHP free) 
 
The final concentration of the diluted solution can range between 0.6 mg/dL and 8 mg/dL. This 
concentration allows for: 
 
Polypropylene syringes may be used. 
 
Chemical and physical stability of the diluted aflibercept solutions in polypropylene syringe or 
infusion bags has been demonstrated for up to 24-hours under refrigerated conditions (2° to 8°C) 
or for up to 8 hours at room temperature (approximately 25°C). 
 
From a microbiological point of view, the product should be used immediately. In-use storage 
times and conditions are the responsibility of the user. Dilution under aseptic conditions should 
be applied. 
 
Diluted solutions of aflibercept should be administered using infusion tubing made of the 
following materials: 
• PVC containing DEHP 
• DEHP-free PVC containing TOTM 
• polypropylene 
• polyethylene lined PVC 
• polyurethane 
 
The infusion sets must contain a 0.2 μM polyethersulfone inline filter. PVDF or Nylon filters 
should not be used. 
 
Infusion can be conducted by gravity, with an IV infusion pump, or with a syringe pump using 


IRB Protocol Number: 2012C0055 
 
  
OSU 11182 
 
Version: 5/15/2018 
 
90 
administration sets made of the above materials. 
 
The aflibercept IV dose should be infused over 1 hour. The infusion should not exceed 2 hours at 
ambient temperature (approximately 25° C). 
 
Parenteral investigational drug products must be inspected visually for particulate matter and 
discoloration prior to administration. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


IRB Protocol Number: 2012C0055 
 
  
OSU 11182 
 
Version: 5/15/2018 
 
91 
 
 
 
 
APPENDIX C 
 
Imaging Protocol for DCE-MRI and FDG-PET 
 
See PDF attachment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


IRB Protocol Number: 2012C0055 
 
  
OSU 11182 
 
Version: 5/15/2018 
 
92 
 
 
APPENDIX D 
 
Blood Pressure Log 
 
Instructions: Clinical Research Coordinator 
 
The Clinical Research Coordinator will provide one log to the subject prior to the C1D8, C1D22, 
and C2D8, circling for the patient the correct upcoming study visit, and entering the date for the 
patient that the blood pressures should be completed.  The patient will take the log home, and 
record their blood pressure at home using either their home blood pressure monitoring device, or 
the device provided to them by the study.  If the subject is using a home device, the device must 
be calibrated at the study clinic prior to use.  Wrist cuffs may be used. 
Prior to allowing the study subject to leave the clinic, the study subject and Clinical Research 
Coordinator should discuss a date and time that either the patient will call the coordinator, or the 
coordinator will contact the patient to receive the blood pressure recordings.  The Clinical 
Research Coordinator will indicate the discussed plans on the log below.  The patient should be 
asked to bring the log back with them when they return to their next study visit. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


IRB Protocol Number: 2012C0055 
 
  
OSU 11182 
 
Version: 5/15/2018 
 
93 
Blood Pressure Log 
 
Instructions: Study Patient 
 
Dear Study Patient,  
Please sit resting for 5 minutes prior to taking your blood pressure.  Sitting upright, with both 
feet on the floor if you are able, please follow the instructions on your blood pressure cuff to take 
a reading.  The blood pressure measurement should be recorded in the space labeled Blood 
Pressure Measurement #1 below, along with the time of the measurement in the space labeled 
“Time”. 
After at least one minute after the first blood pressure has been taken, a second blood pressure 
should be taken following the same directions.  The second measurement should be recorded 
with the time as well in the space labeled “Blood Pressure Measurement #2”. 
 
Study Visit: 
C1D8 
C1D22 
C2D8 
 Date: 
____ / ____ / ________ 
____ / ____ / ________ 
____ / ____ / ________ 
 Time #1: 
______ : ______ AM / 
PM 
______ : ______ AM / 
PM 
______ : ______ AM / 
PM 
Blood Pressure 
Measurement 
#1: 
_______ / _______ 
_______ / _______ 
_______ / _______ 
Time #2 
______ : ______ AM / 
PM 
______ : ______ AM / 
PM 
______ : ______ AM / 
PM 
Blood Pressure 
Measurement 
#2: 
_______ / _______ 
_______ / _______ 
_______ / _______ 
 
After you have completed both measurements, please contact your Clinical Research 
Coordinator at the time indicated above with this information, or, be sure to have this 
information available if the Coordinator is scheduled to contact you.  Be sure to remember to 
bring this log with you to your next study visit. 
If you have any questions about these instructions, please do not hesitate to contact your 
Coordinator at the contact listed below. 
 
On the following date: _______________________________  
 
your Study Coordinator, ___________________________________, will collect the blood  
 
pressure information you have recorded above. He/she 
 
 Will call you at Phone # ( ______ ) ______ - __________ 
 
 Would like you to call him/her at Phone # ( ______ ) ______ - __________ 
 
Please have the table above completed and available for review during the phone call.   

ICF_001.pdf: 
C O N S E N T  
Bi o m e di c al/ C a n c er  
O S U 1 1 1 8 2  
 
 
I R B Pr ot o c ol N u m b er: 
2 0 1 2 C 0 0 5 5  
I R B A p pr o v al d at e:  
0 1/ 0 6/ 2 0 1 7  
V er si o n:  2 7 D e c. 2 0 1 6  
 
 
P a g e 1  of 2 1  
F or m d at e:  0 2/ 1 0/ 1 2   
 
T he O hi o St ate U ni versit y C o nse nt t o P artici p ate i n Rese arc h  
 
 
St u d y Title:  
A P h ase II St u d y of t he C o m bi n ati o n of Afli berce pt ( V E G F -
Tr a p) pl us M o difie d F O L F O X 6 i n P atie nts wit h Pre vi o usl y 
U ntre ate d Met ast atic C ol orect al C a ncer  
Pri nci p al I n vesti g at or:  
J o h n H a ys, M D, P h D 
S p o ns or:  
T he O hi o St ate U ni versit y  
 
•  T his is a c o nse nt f or m  f or rese arc h p artici p ati o n.  It c o ntai ns i m p orta nt i nf or mati o n 
a b o ut t his st u d y  a n d w hat t o e x pect if y o u deci de t o partici pate .  Please c o nsi der t he 
i nf or mati o n caref ull y. Feel free t o disc uss t he st u d y wit h y o ur frie n ds a n d fa mil y a n d t o 
as k q uesti o ns bef ore ma ki n g y o ur decisi o n w het her or n ot t o partici pate.  
•  Y o ur p artici p ati o n is v ol u nt ar y.  Y o u ma y ref use t o partici pate  i n t his st u d y.  If y o u 
deci de t o ta ke part i n t he st u d y, y o u ma y lea ve t he st u d y at a n y ti me.  N o matter w hat 
decisi o n y o u ma ke,  t here will be n o pe nalt y t o y o u a n d y o u will n ot l ose a n y of y o ur 
us ual be nefits.   Y o ur decisi o n will n ot affect y o ur f ut ure relati o ns hi p wit h T he O hi o 
State U ni versit y.  If y o u are a st u de nt or e m pl o yee at O hi o State, y o ur decisi o n will n ot 
affect y our gra des or e m pl o y me nt stat us. 
•  Y o u  m a y  or  m a y  n ot  be nefit  as  a  res ult  of  p artici p ati n g  i n  t his st u d y.    Als o,  as 
e x plai ne d bel o w, y o ur partici pati o n ma y res ult i n u ni nte n de d or har mf ul effects f or y o u 
t hat ma y be mi n or or ma y be seri o us de pe n di n g o n t he nat ure of t he researc h. 
•  Y o u will be pr o vi de d wit h a n y ne w i nf or m ati o n t h at de vel o ps d uri n g t he st u d y t h at 
m a y affect y o ur decisi o n w het her or n ot t o c o nti n ue t o p artici p ate.   If y o u deci de t o 
partici pate , y o u will be as ke d t o si g n t his f or m a n d will recei ve a c o p y of t he f or m.  Y o u 
are bei n g as ke d t o c o nsi der partici pati n g i n t his st u d y f or t he reas o ns e x plai ne d bel o w.   
 
1.    W h y  is t his st u d y bei n g d o ne ? 
Y o u  ha ve  bee n  as ke d  t o  ta ke  part  i n  t his  st u d y  beca use  y o u  ha ve u ntreate d  metastatic 
c ol orectal ca ncer.  T his st u d y is bei n g d o ne t o see if t he a d diti o n of t he dr u g, Afli berce pt  i n 
c o m bi nati o n wit h  a m o difie d F O L F O X 6 ( m F O L F O X 6) c he m ot hera p y r e gi me n is effecti ve 
i n t he treat me nt of y o ur ca ncer t hat has s prea d t o l y m p h n o des or ot her or ga ns. F O L F O X 
is  a  c o m bi nati o n  of t hree dr u gs, O xali plati n ,  Fl u or o uracil ( 5-F U)  a n d  Le uc o v ori n. 
F O L F O X is a p pr o ve d b y t he F o o d a n d Dr u g A d mi nistrati o n  ( F D A) f or t he treat me nt of 
metastatic c ol orectal ca ncer, h o w e ver t he c o m bi nati o n of F O L F O X wit h  Afli berce pt  is n ot. 
 
Afli berce pt  is a n i n vesti gati o nal dr u g (a dr u g t hat has n ot bee n a p pr o ve d f or ge neral use 
b y t he F D A  b ut is u n der i n vesti gati o n i n cli nical trials re g ar di n g its safet y a n d efficac y). It 
has bee n a p pr o ve d b y t he F D A  f or t he treat me nt of patie nts wit h a disease of t he e ye calle d  
Ne o vasc ular  ( Wet)  A ge -Relate d  Mac ular  De ge nerati o n  ( A M D).  Afli be rce pt  tar gets  t he 
vasc ular e n d ot helial gr o wt h fact or ( V E G F) w hic h is i m p orta nt f or  a t u m or’s bl o o d s u p pl y. 


C O N S E N T  
Bi o m e di c al/ C a n c er  
O S U 1 1 1 8 2  
 
 
I R B Pr ot o c ol N u m b er: 
2 0 1 2 C 0 0 5 5  
I R B A p pr o v al d at e:  
0 1/ 0 6/ 2 0 1 7  
V er si o n:  2 7 D e c. 2 0 1 6  
 
 
P a g e 2  of 2 1  
F or m d at e:  0 2/ 1 0/ 1 2   
 
B y i nterferi n g wit h t his gr o wt h fact or, t he st u d y dr u g c o ul d decrease t he bl o o d s u p pl y t o 
y o ur t u m or a n d p ossi bl y pre ve nt its gr o wt h a n d s prea d.  
 
2.    H o w m a n y pe o ple will t a ke p art i n t his st u d y ? 
A t otal of 5 5 patie nts will be e nr olle d o n t his st u d y at T he O hi o State U ni versit y.                                 
 
3.    W h at will h a p pe n if I t a ke p art i n t his st u d y ? 
B y a greei n g t o ta ke part i n t his st u d y, y o u are a greei n g t o f oll o w t he st u d y re q uire me nts 
liste d bel o w. I n or der t o fi n d o ut if y o u ca n ta ke part i n t he st u d y, y o u will ha ve a me dical 
e val uati o n d o ne  after y o u si g n t he c o nse nt f or m.  A descri pti o n of tests a n d visits re q uire d 
f or t he me dical e val uati o n is bel o w.  
 
Me dic al E v al u ati o n a n d Pre -tre at me nt Tests: 
Bef ore starti n g  treat me nt wit h  t he  st u d y dr u gs,  y o u  will  ha ve  t he  f oll o wi n g  tests  a n d 
pr oce d ures t o ma ke s ure t hat y o u are eli gi b le t o recei ve st u d y treat me nt. T hese tests a n d 
pr oce d ures will c o nfir m t he a m o u nt of ca ncer t hat y o u ha ve a n d t he y will esta blis h y o ur 
“ baseli ne” or starti n g p oi nt bef ore bei n g treate d : 
 
•  Hist or y a n d P h ysical  E xa m  
•  Vital  Si g ns:   Bl o o d  press ure,  p ulse  rate,  res pirat or y  rate,  te m perat ure  i ncl u di n g 
hei g ht, wei g ht a n d h o w well y o u perf or m e ver y da y tas ks. 
•  Bl o o d tests: C o m plete bl o o d c o u n t i ncl u di n g bl o o d cl otti n g tests, bl o o d c he mistries 
t o c hec k t he le vels of vari o us electr ol ytes a n d c he micals i n y o ur bl o o d, bl o o d test 
t hat tells h o w y o ur li ver is w or ki n g a n d L D H/ P h os p h or o us test. 
•  Bl o o d sa m pl es f or p har mac o d y na mic bl o o d test 
•  If  y o u  are  a  w o ma n  w h o  is  a ble  t o  ha ve  c hil dre n,  y o u  m ust  ha ve  a  ne gati ve 
pre g na nc y bl o o d test i n or der t o e nr oll. 
•  C T Sca n (c o m p ute d t o m o gra p h y - a series of pict ures of areas i nsi de t he b o d y ta ke n 
fr o m  differe nt  a n gles.  T he  pict ures  are  ma de  b y  a  c o m p uter  li n ke d  t o  a n  x-ra y 
mac hi ne)  
•  Electr ocar di o gra p h y- ( E K G- a li ne gra p h t hat s h o ws c ha n ges i n t he electrical acti vit y 
of t he heart o ver ti me) 
•  Re vie w t he c urre nt me dicati o n s y o u are ta ki n g  
•  A d verse E ve nt E val uati o n 
•  Y o u will re q uire t he place me nt of a te m p orar y t u be i nt o a vei n i n y o ur c hest or y o ur 
ar m  d uri n g  t he  c o urse  of  y o ur  treat me nt.  T his  t u be  will  be  attac he d  t o  a  s mall 
p orta ble p u m p. T he dr u g, 5 -F U, will be gi ve n usi n g t his p u m p. T he p u m p is s mall 
e n o u g h  t o  all o w  it  t o  be  attac he d  t o  y o ur  cl ot hi n g,  s o  it  ca n  be  use d  wit h o ut 
restricti n g m ost m o ve me nts a n d acti vities. Y o u will wear t his p u m p f or a 4 6- h o ur 
peri o d e ver y t w o wee ks  
•  T u m or mea s ure me nts o n r o uti ne C T sca ns of t he c hest, a b d o me n a n d pel vis 
•  Ser u m Pre g na nc y test f or w o me n of c hil d beari n g p ote ntial 
•  T u m or bi o ps y- o nl y if paraffi n e m be d de d tiss ue is n ot a vaila ble 


C O N S E N T  
Bi o m e di c al/ C a n c er  
O S U 1 1 1 8 2  
 
 
I R B Pr ot o c ol N u m b er: 
2 0 1 2 C 0 0 5 5  
I R B A p pr o v al d at e:  
0 1/ 0 6/ 2 0 1 7  
V er si o n:  2 7 D e c. 2 0 1 6  
 
 
P a g e 3  of 2 1  
F or m d at e:  0 2/ 1 0/ 1 2   
 
•  Bl o o d f or ge ne a nal ysis (t o c hec k f or n or mal variati o ns i n D N A bases wit hi n t he 
V E G F ge ne t o a nal yze w het her t he y pre dict res p o nse t o t hera p y) 
•  C E A Bl o o d Test  ( T u m or Test Mar ker) 
•  D C E -M RI -( d y na mic c o ntrast en ha nce d  ma g netic res o na nce i ma gi n g ) t y pe of M RI 
sca n 
•  F D G -P E T -(fl u or o de o x y gl uc ose- p ositr o n e missi o n t o m o gra p h y) t y pe of PE T sca n  
 
All  of  t he  a b o ve  me nti o ne d  st u dies  are  sta n dar d  of  care  e xce pt  f or  bl o o d  sa m ples  f or 
p har mac o d y na mic bl o o d tests, re peat t u m or bi o psies, bl o o d f or  gl uc ose a n d  ge ne a nal ysis,  
E C G , F D G -P E T  a n d D C E -M RI . 
 
Pre g n a nc y Pre ve nti o n:  
We  d o  n ot  k n o w  t he  effect  of  t he 
Afli berce pt  i n  pre g na nt  w o me n,  or  t he  i m pact  of 
Afli berce pt prese nce i n breast mil k or its effects o n t he breast -fe d c hil d.  Pre vi o us st u dies 
ha ve s h o w n male a n d fe male  fertilit y are li kel y t o be c o m pr o mise d d uri n g treat me n t wit h 
Afli berce pt.   T heref ore, b ot h me n a n d w o me n m ust n ot atte m pt pre g na nc y a n d w o me n m ust 
n ot be pre g na nt or breast -fee di n g w hile partici pati n g i n t his st u d y. Y o u m ust a gree t o use 
a n  a de q uate  f or m  of  birt h  c o ntr ol  d uri n g  st u d y  partici pati o n  a n d  f or a  6-m o nt h  peri o d 
f oll o wi n g  y o ur treat me nt  Afli berce pt.    W hile  a  n u m ber  of  met h o ds  of  birt h  c o ntr ol  are 
acce pta ble f or t he p ur p oses of pre ve nti n g c o ntrace pti o n w hile y o u are o n t his st u d y, please 
re me m ber t hat o nl y birt h c o ntr ol met h o ds t hat use c o n d o ms pr o vi de a de q uate pr otecti o n 
a gai nst se x uall y tra ns mitte d diseases .   
 
If y o u or y o ur part ner bec o me pre g na nt w hile ta ki n g t he st u d y dr u g, it is i m p orta nt t hat y o u 
n otif y  y o ur  st u d y  n urse/ p h ysicia n  i m me diatel y.    If  y o u  are  a  w o ma n  of  c hil d -beari n g 
p ote ntial, y o u will ha ve a pre g na nc y test d o ne bef ore y o u be gi n t he st u d y t o ma ke s ure t hat 
y o u are n ot pre g na nt.   Pre g na nc y tests will be perf or me d if y o u or y o ur d oct or s us pect y o u 
ma y be pre g na nt. If y o u bec o me pre g na nt, y o u will be re q uire d t o st o p t he st u d y treat me nt 
at  w hic h  ti me  ot her  treat me nt  o pti o ns  will  be  disc usse d  wit h  y o u.  If  y o u  re q uire  m ore 
i nf or mati o n a b o ut pre ve nti n g pre g na nc y, as k y o ur st u d y d oct or. 
 
M y i nitials bel o w  i n dicate t hat I ha ve rea d a n d u n dersta n d t he repr o d ucti ve ris k secti o n  a n d 
a gree t o use a de q uate birt h c o ntr ol t o pre ve nt pre g na nc y as state d a b o ve :   
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ (I nitials)  
  
  
  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ ( Date) 
 
 
D uri n g T he S t u dy 
If t he e xa ms, tests a n d pr oce d ures s h o w t hat y o u ca n be i n t he st u d y, a n d y o u c h o ose t o 
partici pate, t he n y o u will ha ve treat me nt c ycles w hic h last 2 8  da ys. T he f oll o wi n g tests a n d 
pr oce d ures will occ ur:  
 
Da y 1 a n d 1 5 of eac h c ycle 
•  P h ysical  e xa m ,  wei g ht  a n d  perf or ma nce  stat us- i ncl u di n g  h o w  well  y o u  perf or m 
e ver y da y tas ks  


C O N S E N T  
Bi o m e di c al/ C a n c er  
O S U 1 1 1 8 2  
 
 
I R B Pr ot o c ol N u m b er: 
2 0 1 2 C 0 0 5 5  
I R B A p pr o v al d at e:  
0 1/ 0 6/ 2 0 1 7  
V er si o n:  2 7 D e c. 2 0 1 6  
 
 
P a g e 4  of 2 1  
F or m d at e:  0 2/ 1 0/ 1 2   
 
•  Vital Si g ns:  Bl o o d press ure, p ulse rate, res pirat or y rate, te m perat ure 
•  Bl o o d tests: c o m plete bl o o d c o u nt i ncl u di n g bl o o d cl otti n g tests, bl o o d c he mistries 
t o c hec k t he le vels of vari o us electr ol ytes a n d c he micals i n y o ur bl o o d, bl o o d test 
t hat tells h o w y o ur li ver is w or ki n g. 
•  Y o u will be  as ke d a b o ut a n y si d e effects t hat y o u ma y ha ve e x perie nce d w hile o n 
treat me nt 
•  Re vie w t he c urre nt me dicati o n s y o u are ta ki n g  
•  Afli berce pt  a n d 
m o difie d 
F O L F O X 6  ( m F O L F O X 6)  will  be  a d mi nistere d 
i ntra ve n o usl y (t hr o u g h  a  nee dle  i n  y o ur  vei n), f oll o we d  b y  c o nti n u o us  i nf usi o n 
(t hr o u g h a nee dle i n y o ur vei n) 5- F U o ver 4 6 h o urs. 
•  C E A Bl o o d Test ( T u m or Test Mar ker ) -T his test w ill o nl y be perf or me d o n Da y 1 
of eac h c ycle.  
 
 
U nless y o u ha ve o ne, a  p orta ble bl o o d press ure de vice will be gi ve n t o y o u t o c hec k 
  
y o ur bl o o d  press ure  at h o me a n d  re p ort  t he  l o wer  n u m ber  bac k  t o  t he  st u d y 
  
c o or di nat or b y p h o ne o n t he f oll o wi n g da ys: 
  
C ycle 1 Da y 8, C ycle 1 Da y 2 2 a n d C ycle 2 Da y 8. 
 
 
E ver y 8 w ee ks  
Y o u will ha ve a C T sca n t o meas ure y o ur t u m ors pri or t o starti n g  t he ne xt c ycle.   
 
C orrelati ve St u dies  
After wee k 8 (c ycle 2), y o u will ha ve a F D G -P E T  a n d D C E -M RI sca n d o ne. 
 
B l o o d sa m ples f or p har mac o d y na mic tests will be d o ne at  da y 1 of wee ks 1, 3 , 9 1 3 a n d 4 
wee ks after y o u g o off st u d y. 
 
O pti o nal Tests  
 
At 8 wee ks after starti n g treat me nt , y o u will ha ve t he o pti o n t o u n der g o a t u m or bi o ps y t o 
assess f or c ha n ges i n y o ur t u m or. T his is a n o pti o nal  bi o ps y. Y o u ma y o pt t o n ot ha ve t he 
e xtra bi o ps y d o ne.  N o matter w hat decisi o n y o u ma ke, t here will be n o pe nalt y t o y o u a n d 
y o u will n ot l ose a n y of y o ur us ual be nefits.   
Y E S C hec k  t his b o x if y o u w o ul d li ke t o ha ve t he bi o ps y d o ne. 
         
N O    C hec k  if y o u w o ul d n ot li ke t o ha ve t he bi o ps y d o ne. 
      
F ut ure Rese arc h wit h y o ur Tiss ue a n d Bl o o d S a m ples  
T he researc hers w o ul d li ke t o kee p a n y of t he  e xtra tiss ue a n d bl o o d t hat was left o ver f or 
f ut ure researc h. If y o u a gree, t his tiss ue will be ke pt a n d ma y be use d i n researc h t o lear n 


C O N S E N T  
Bi o m e di c al/ C a n c er  
O S U 1 1 1 8 2  
 
 
I R B Pr ot o c ol N u m b er: 
2 0 1 2 C 0 0 5 5  
I R B A p pr o v al d at e:  
0 1/ 0 6/ 2 0 1 7  
V er si o n:  2 7 D e c. 2 0 1 6  
 
 
P a g e 5  of 2 1  
F or m d at e:  0 2/ 1 0/ 1 2   
 
m ore a b o ut ca ncer a n d ot her diseases. A n y f ut ure researc h t hat ma y be do ne wit h y o ur tiss ue 
or bl o o d is n ot desi g ne d s pecificall y t o hel p y o u. Y o ur tiss ue will be use d o nl y f or researc h 
a n d will n ot be s ol d.  
 
S o meti mes tiss ue is use d f or ge netic researc h (a b o ut diseases t hat are passe d o n i n fa milies). 
E ve n if y o ur tiss ue is  use d f or t his ki n d of researc h, t he res ults will n ot be p ut i n y o ur healt h 
rec or ds. N o matter w hat decisi o n y o u ma ke, t here will be n o pe nalt y t o y o u a n d y o u will 
n ot l ose a n y of y o ur us ual be nefits.   
Y E S  C hec k t his b o x if we ma y kee p/ use y o ur tiss ue a n d bl o o d f or f ut ure u n k n o w n       
use i n researc h t o lear n a b o ut, pre ve nts, treat, or c ure ca ncer or ot her healt h pr o ble ms. 
N O    C hec k  t his b o x if y o u w o ul d n ot li ke y o ur sa m ples ke pt/ use d f or f ut ure u n k n o w n   
researc h. 
 
W he n y o u are fi nis he d wit h  t he st u d y tre at me nt: 
W he n y o u ha ve c o m plete d y o ur treat me nt o n t his re gi me n y o u will be as ke d t o c o me bac k 
a n d c o m plete a n E n d of St u d y visit ( E O S). T his visit will c o nsist of t he f oll o wi n g tests a n d 
pr oce d ures: 
•  
P h ysical e xa m - i ncl u di n g h o w well y o u perf or m e ver y da y tas ks. 
•  
Vital Si g ns: B l o o d press ure, p ulse rate, res pirat or y rate, te m perat ure) i ncl u di n g  
  
wei g ht  
•  
Bl o o d  tests:  c o m plete  bl o o d  c o u nt  i ncl u di n g  bl o o d  cl otti n g  tests,  bl o o d 
 
c he mistries  t o  c hec k  t he  le vels  of  vari o us  electr ol ytes  a n d  c he micals  i n  y o ur 
  
bl o o d, bl o o d test t hat tells h o w y o ur li ver is w or ki n g. 
•  
C E A  Bl o o d Test -(t u m or mar ker test) 
•  
T u m or meas ure me nt  ( C T sca n) 
•  
Y o u will be as ke d a b o ut a n y si de effects  t hat y o u ma y ha ve e x perie nce d w hile 
 
o n treat me nt.  
 
4.   H o w l o n g will I be i n t he st u d y ? 
If y o u are res p o n di n g t o t hera p y or if y o ur disease is sta ble ( n ot getti n g w orse), y o u will 
c o nti n ue t o be treate d u ntil  o ne of t he f oll o wi n g occ urs:  y o ur disease gets w orse, y o u ha ve  
a se vere si de effect  t hat w o ul d re q uire y o u t o c o me off st u d y, y o u ref use t o c o nti n ue wit h 
st u d y, t he st u d y d oct or deci des it is i n y o ur best i nterest f or y o u t o st o p t he st u d y, t he st u d y 
e n ds, or y o u are re m o ve d fr o m t he st u d y t o u n der g o s ur gical re m o val of y o ur ca ncer. . 
 
Y o u will be f oll o we d f or s ur vi val after bei n g re m o ve d fr o m t he st u d y as l o n g as y o u li ve . 
If y o u are re m o ve d fr o m t he st u d y f or a se vere si de effect,  y o u will be f oll o we d u ntil  t his 
gets better. . 
 


C O N S E N T  
Bi o m e di c al/ C a n c er  
O S U 1 1 1 8 2  
 
 
I R B Pr ot o c ol N u m b er: 
2 0 1 2 C 0 0 5 5  
I R B A p pr o v al d at e:  
0 1/ 0 6/ 2 0 1 7  
V er si o n:  2 7 D e c. 2 0 1 6  
 
 
P a g e 6  of 2 1  
F or m d at e:  0 2/ 1 0/ 1 2   
 
5.  C a n I st o p bei n g i n t he st u d y ? 
Y o u ma y lea ve t he st u d y at a n y ti me.  If y o u deci de t o st o p partici pati n g i n t he st u d y, t here 
will be n o pe nalt y t o y o u, a n d y o u will n ot l ose a n y be nefits t o w hic h y o u are ot her wise 
e ntitle d. Y o u ca n re q uest t he destr ucti o n of all y o ur sa m ples if y o u wit h dra w fr o m t he st u d y.  
Y o ur decisi o n will n ot affect y o ur f ut ure relati o ns hi p wit h T he O hi o State U ni versit y.   
 
Tell y o ur st u d y d oct or if y o u are t hi n ki n g a b o ut st o p pi n g or deci de t o st o p.  He or s he will 
tell y o u h o w t o st o p safel y. 
 
6.    W h at ris ks, si de effects or disc o mf orts c a n I e x pect fr o m bei n g i n t he st u d y ? 
Y o u ma y ha ve si de effects w hile o n t he st u d y.  E ver y o ne ta ki n g part i n t he st u d y will be 
watc he d caref ull y f or a n y si de effects.  H o we ver, researc hers d o n’t k n o w all t he si de effects 
t hat ma y ha p pe n. Si de effects ma y be mil d or ver y seri o us. Y o ur healt h care tea m ma y gi ve 
y o u me dici nes t o hel p lesse n si de effects. Ma n y si de effects g o a wa y s o o n after y o u st o p 
ta ki n g t he treat me nt. I n s o me cases, si de effects ca n be seri o us, l o n g lasti n g, or ma y ne ver 
g o a wa y. T here als o is a ris k of deat h.  
 
Y o u s h o ul d tal k t o y o ur st u d y d oct or a b o ut a n y si de effects t hat y o u ha ve w hile ta ki n g part 
i n t he st u d y. 
 
RI S K S O F A F LI B E R C E P T  
Li kel y: occ urs i n m ore t h a n > 1 0 % of pe o ple recei vi n g Afli berce pt : 
•  A ne mia  (l o w re d bl o o d cell c o u nt) 
•  N a usea 
•  V o miti n g  
•  D iarr hea 
•  Ast he nia (feeli n g wea k) 
•  Fati g ue (tire d ness) 
•  A rt hral gia (j oi nt pai ns) 
•  M yal gia ( m uscle pai ns) 
•  H ea dac he 
•  D izzi ness 
•  P r otei n uria (i ncl u di n g ne p hr otic s y n dr o me) ( ki d ne y da ma ge ca usi n g pr otei n i n t he 
uri ne) 
•  E pista xis  ( N ose blee ds) 
•  H y perte nsi o n- ( hi g h bl o o d press ure) (i ncl u di n g mali g na nt h y perte nsi o n- Mali g na nt 
h y perte nsi o n is ver y hi g h bl o o d press ure  t hat c o mes o n s u d de nl y a n d q uic kl y. T he 
l o wer  ( diast olic)  bl o o d press ure  rea di n g,  w hic h  is  n or mall y  ar o u n d  8 0  m m H g,  is 
ofte n a b o ve 1 3 0 m m H g.  
 
Less Li kel y: occ urs i n  1- 1 0 % of pe o ple recei vi n g Afil berce pt : 
•  T hr o m b oc yt o pe nia (l o w platelet c o u nt t hat ma y lea d t o a n i ncrease i n br uisi n g or 
blee di n g) 


C O N S E N T  
Bi o m e di c al/ C a n c er  
O S U 1 1 1 8 2  
 
 
I R B Pr ot o c ol N u m b er: 
2 0 1 2 C 0 0 5 5  
I R B A p pr o v al d at e:  
0 1/ 0 6/ 2 0 1 7  
V er si o n:  2 7 D e c. 2 0 1 6  
 
 
P a g e 7  of 2 1  
F or m d at e:  0 2/ 1 0/ 1 2   
 
•  H y p o natre mia (l o w s o di u m le vels i n bl o o d , if se vere t hese l o w le vels ca n lea d t o 
a b n or mal f u ncti o n of ner ves, m uscles or brai n) 
•  H y p o ma g nese mia (l o w ma g nesi u m le vels i n bl o o d , if se vere t hese l o w le vels ca n 
lea d t o a b n or mal f u ncti o n of ner ves, m uscles or brai n) 
•  H y p o kale mi a (l o w p otassi u m le vels i n bl o o d , if se vere t hese l o w le vels ca n lea d t o 
a b n or mal f u ncti o n of ner ves, m uscles or brai n) 
 
R are : occ urs i n less t h a n 1 %  of pe o ple recei vi n g Afil berce pt : 
•  T hr o m b otic micr oa n gi o pat h y ( brea k d o w n of re d bl o o d cells i n t he arteries) 
•  Ne utr o pe nia i ncl u di n g ne utr o pe nia wit h fe ver (l o w w hite bl o o d c o u nt) 
•  Ne utr o pe nic c olitis (irritati o n of t he c ol o n wit h l o w bl o o d c o u nts) 
•  S e psis (se vere i nfecti o n of t he bl o o dstrea m ) 
•  C ar diac fail ure  ( heart fail ure) 
•  Bell y  pai n 
•  G astr oi ntesti nal he m orr ha ge  ( blee di n g fr o m t he st o mac h or b o wel) 
•  Intesti nal perf orati o n  (a h ole i n t he b o wel) 
•  Intesti nal o bstr ucti o n  ( bl oc ka ge of t he b o wel) 
•  E nteric fist ula  (lea ka ge of b o wel fl ui d i nt o ot her or ga ns) 
•  P erit o nitis (irritati o n of t he li ni n g of t he a b d o me n) 
•  P ne u mat osis i ntesti nalis  (air acc u m ulati o n i n t he i ntesti nes) 
•  M uc osal  i nfla m mati o n  or  ulcerati o n  (irritati o n  of  t he  li ni n g  of  t he  di gesti ve  tract 
a n y w here fr o m m o ut h t o rect u m) 
•  S t o matitis ( m o ut h s ores) 
•  H e patic e nz y mes i ncrease d  (li ver i nfla m mati o n) 
•  M usc ul os keletal pai n   
•  Injecti o n  site reacti o n 
•  H y perse nsiti vit y (aller gic reacti o n) 
•  De h y drati o n 
•  O ste o necr osis ( b o ne da ma ge) 
•  
P osteri or Re versi ble E nce p hal o pat h y S y n dr o me (irritati o n of t he brai n), (i ncl u di n g 
re versi ble p osteri or le u k oe nce p hal o pat h y s y n dr o me, is a s y n dr o me t hat ca n ca use: 
hea dac he , c o nf usi o n, seiz ures a n d vis ual  l oss.  It  ma y  occ ur  d ue  t o  a  n u m ber  of 
ca uses, o ne bei n g  mali g na nt h y perte nsi o n  
•  C ere bral isc he mia  ( decrease d bl o o d g oi n g t o t he brai n) 
•  Cere bral he m orr ha ge ( blee di n g i n t he brai n) 
•  Cere bral ve n o us t hr o m b osis ( bl o o d cl ot i n t he brai n) 
•  H e mat uria ( bl o o d i n t he uri ne) 
•  R e nal fail ure  ( ki d ne y fail ure) 
•  D ys p h o nia (altere d v oice) 
•  D ys p nea (s h ort ness of breat h) 
•  He m o pt ysis (c o u g hi n g bl o o d) 
•  P ul m o nar y e m b olis m ( bl o o d cl ot i n t he l u n gs) 
•  T rac he o-es o p ha geal fist ula  (a h ole bet wee n t he s wall o wi n g t u be a n d breat hi n g t u be) 


C O N S E N T  
Bi o m e di c al/ C a n c er  
O S U 1 1 1 8 2  
 
 
I R B Pr ot o c ol N u m b er: 
2 0 1 2 C 0 0 5 5  
I R B A p pr o v al d at e:  
0 1/ 0 6/ 2 0 1 7  
V er si o n:  2 7 D e c. 2 0 1 6  
 
 
P a g e 8  of 2 1  
F or m d at e:  0 2/ 1 0/ 1 2   
 
•  P al mar-pla ntar  er yt hr o d ysaest hia  s y n dr o me  (s ore  a n d  re d  s ki n  of  t he  pal ms  a n d 
s oles) 
•  Er yt he ma (re d s ki n) 
•  Dee p vei n t hr o m b osis, ( Bl o o d cl ots) 
•  P hle bitis  (irritati o n of t he vei ns) 
•  A n xiet y 
•  Fe male ge nital tract fist ula (a h ole bet wee n t he ge nital tract a n d a n ot her or ga n or 
s ki n) 
•  P yre xia (fe ver)  
•  H y pertri gl yceri de mia ( hi g h bl o o d le vels of fat)  
•  H y perc h olester ole mia ( hi g h bl o o d le vels of c h olester ol) 
 
  
Pe o ple w h o  start 
Afli berce pt  after  a  rece nt  s ur ger y  or  w h o  u n der g o  s ur ger y 
 
after  recei vi n g Afli berce pt  are  at a n i ncrease d  ris k  of  brea kd o w n  of  t he  w o u n d 
  
( w o u n d de hisce nce) a n d of ha vi n g w o u n d heali n g pr o ble ms.  
 
 
Ris ks of m o difie d F O L F O X 6 ( m F O L F O X 6)  ( 5- F U, Le uc o v ori n a n d O x ali pl ati n)  
 
Ris ks of Le uc o v ori n  
T he  f oll o wi n g  ris ks  ha ve  bee n  re p orte d  w he n  le uc o v ori n  was  gi ve n  ( occ urs  i n  2 0 %  of 
pe o ple recei vi n g le uc o v ori n) : aller gic reacti o ns ( w hic h ma y be se vere a n d life t hreate ni n g), 
s h oc k (l o w bl o o d press ure), na usea, diarr hea, t hr o m b oc yt osis ( hi g h platelet c o u nt), ras h, 
hi ves, pr urit us (itc hi n g), hea dac he, a n d w heezi n g. 
 
Ris ks of 5 -F U  
 
Li kel y: ( occ urs i n 2 0 % or m ore of pe o ple recei vi n g 5- F U ) 
•  L oss of a p petite  
•  A n i nfla m mati o n of t he m uc o us li ni n g  of a n y of t he str uct ures i n t he m o ut h , w hic h 
ma y i n v ol ve t he c hee ks, g u ms , t o n g ue, li ps, t hr oat, a n d r o of or fl o or of t he m o ut h 
a n d s welli n g of t he es o p ha g us w hic h ma y lea d t o t he m uc o us li ni n g f or mi n g p us 
a n d/ or d yi n g a n d se parati n g fr o m t he str uct ure i n t he m o ut h ( m o ut h ulcers). 
•  diarr hea  
•  Na usea, a n d v o miti n g 
•  Hair  l oss  a n d  der matitis  (i nfla m mati o n  of  t he  s ki n)  ma y  be  see n  i n  a  s u bsta ntial 
n u m ber of cases. T he der matitis m ost ofte n see n is a ras h us uall y a p peari n g o n t he 
e xtre mities  
•  Le u k o pe nia (l o w w hite bl o o d cell c o u nt, w hic h ca n  i ncrease y o ur ris k of i nfecti o n) 
us uall y  f oll o ws  e ver y  c o urse  of  t hera p y  wit h  5 -F U.  T he  l o west  w hite  bl o o d  cell 
c o u nts are c o m m o nl y o bser ve d bet wee n t he 9 t h a n d 1 4 t h da ys after t he first c o urse 
of treat me nt.  B y t he 3 0 t h da y, t he c o u nt has us uall y ret ur ne d t o n or mal.  
•  L o w bl o o d cells w hic h ca n i ncrease y o ur ris k of i nfecti o n, ca use fati g ue or s h ort ness 
of breat h, a n d i ncrease y o ur ris k of blee di n g 


C O N S E N T  
Bi o m e di c al/ C a n c er  
O S U 1 1 1 8 2  
 
 
I R B Pr ot o c ol N u m b er: 
2 0 1 2 C 0 0 5 5  
I R B A p pr o v al d at e:  
0 1/ 0 6/ 2 0 1 7  
V er si o n:  2 7 D e c. 2 0 1 6  
 
 
P a g e 9  of 2 1  
F or m d at e:  0 2/ 1 0/ 1 2   
 
•  L o w he m o gl o bi n le vels w hic h ca n ca use fati g ue a n d/ or s h ort ness of breat h 
 
Less Li kel y: ( occ urs i n 3 - 1 9 % of pe ople recei vi n g  5-F U ) 
•  W he n  gi ve n  5 -F U,  s u bjects  ha ve  re p orte d  s o met hi n g  k n o w n  as Ha n d-f o ot 
s y n dr o me. T his ca uses a ti n gli n g se nsati o n i n t he ha n ds a n d feet w hic h ma y t ur n 
i nt o pai n w he n h ol di n g o bjects or wal ki n g o ver t he ne xt fe w da ys. T he pal ms a n d 
s oles ma y bec o me s w olle n o n b ot h si des wit h re d ness of t he s ki n a n d se nsiti vit y of 
t he  fi n gers  or  t oes,  p ossi bl y  i ncl u di n g  peeli n g  of  t he  s ki n.  T hese  s y m pt o ms  ma y 
res ol ve o ver 5 t o 7 da ys w he n y o u st o p t he dr u g. Y o u m ust c o ntact t he st u d y staff 
i m me diatel y if y o u e x perie nce a n y of t hese s y m pt o ms.  
•  Nail c ha n ges (i ncl u di n g l oss of nails) 
•  Dr y s ki n  
•  Crac ki n g s ki n 
•  Vei n c ol ori n g 
•  Li g ht se nsiti vit y ; i ncrease d se nsiti vit y t o t he s u n 
 
Rare b ut Seri o us:  ( occ urs i n less t ha n 3 % of pe o ple recei vi n g 5- F U ) 
•  T ear d uct narr o wi n g  (t his ma y ca use i ncrease d teari n g of t he e yes) 
•  Vis ual c ha n ges  
•  I ncrease d tears 
•  E ye t witc hi n g  
•  Hea dac he  
•  Dis orie ntati o n  
•  C o nf usi o n 
•  E u p h oria (a n e xa g gerate d feeli n g of ha p pi ness, c o nfi de nce, or well- bei n g)  
•  D ecrease  i n  bl o o d  fl o w  w hic h  ca n  ca use  dizzi ness, bl urre d  visi o n,  c o nf usi o n, 
fai nti n g, li g ht-hea de d ness, slee pi ness a n d wea k ness  
•  A n gi na (a n attac k of pai nf ul s pas ms t hat ca use y o u t o feel li ke y o u are c h o ki n g or 
s uff ocati n g, a n d ca n lea d t o a heart attac k)  
•  A c ute cere bellar s y n dr o me, w hic h ca n ca use i na bilit y t o wal k wit h o ut assista nce a n d 
diffic ult y s pea ki n g, w hic h ma y be per ma ne nt. 
•  Bl o o d cl ots 
•  N ose blee ds  
•  I ncrease d se nsiti vit y t o li g ht 
 
Ris ks of O x ali pl ati n  
 
Li kel y:  ( occ urs i n m ore t ha n 2 0 % of pe o ple recei vi n g O xali plati n)  
•  Lac k of e n o u g h re d bl o o d cells  (a ne mia, w hic h ma y ma ke y o u s h ort of breat h, wea k, 
fati g ue d or tire d) 
•  Diarr hea  
•  Na usea or t he ur ge t o v o mit 
•  V o miti n g  


C O N S E N T  
Bi o m e di c al/ C a n c er  
O S U 1 1 1 8 2  
 
 
I R B Pr ot o c ol N u m b er: 
2 0 1 2 C 0 0 5 5  
I R B A p pr o v al d at e:  
0 1/ 0 6/ 2 0 1 7  
V er si o n:  2 7 D e c. 2 0 1 6  
 
 
P a g e 1 0  of 2 1  
F or m d at e:  0 2/ 1 0/ 1 2   
 
•  Fati g ue or tire d ness  
•  I ncrease d bl o o d le vel of t he li ver e nz y mes ( A L T/ S G P T a n d A S T/ S G O T) w hic h ma y 
i n dicate t hat y o ur li ver is n ot w or ki n g pr o perl y 
•  Decrease d n u m ber of a t y pe of bl o o d cell t hat hel ps t o cl ot bl o o d ( platelet) w hic h 
ma y res ult i n eas y br uisi n g or blee di n g 
•  I nfla m mati o n (s welli n g a n d re d ness) or de ge nerati o n of t he peri p heral ner ves (t h ose 
ner ves o utsi de of t he brai n a n d s pi nal c or d) ca usi n g n u m b ness, ti n gli n g, or b ur ni n g 
 
Less Li kel y:  ( occ urs i n 3 - 2 0 % of pe o ple  recei vi n g O xali plati n) 
•  A b n or mal bl o o d cl otti n g a n d/ or blee di n g 
•  Fe ver  ass ociate d  wit h da n ger o usl y  l o w  le vels  of  a  t y pe  of  w hite  bl o o d  cell 
( ne utr o p hils) 
•  Destr ucti o n of re d bl o o d cells 
•  A b n or mall y fast or sl o w, re g ular or irre g ular heart beat i n v ol vi n g t he u p per c ha m bers 
of t he heart (atria)  
•  Peri o d of ver y ra pi d a n d re g ular heart beats t hat be gi ns a n d e n ds s u d de nl y 
•  Irre g ular heart beat res ulti n g fr o m a n a b n or malit y i n o ne of t he l o wer c ha m bers of 
t he heart ( ve ntricle) a n d res ults i n u nc o or di nate d m uscle m o ve me nt of t he ve ntricles, 
ma ki n g t he m tre m ble rat her t ha n c o ntract pr o perl y. T his ca n be lif e-t hreate ni n g a n d 
nee ds i m me diate atte nti o n.  
•  Ra pi d heart beat i n or a b o ve o ne of t he l o wer c ha m bers ( ve ntricles) of t he heart, wit h 
a re g ular r h yt h m.  T his ca n als o be life- t hreate ni n g a n d nee ds i m me diate atte nti o n. 
•  Heari n g l oss t hat is us uall y te m p orar y a n d s h o ul d res ol ve o nce st u d y treat me nt has 
e n de d. H o we ver, t here is a p ossi bilit y t hat it ma y be per ma ne nt. 
•  I nfla m mati o n (s welli n g a n d re d ness) t o t he mi d dle ear 
•  I nfla m mati o n (s welli n g a n d re d ness) of t he c o nj u ncti va (t he o uter m ost la yer of t he 
e ye a n d t he i n ner s urface of t he e yeli ds).  T his is c o m m o nl y calle d “ pi n k e ye.” 
•  Dr y e yes 
•  A sit uati o n i n w hic h o ne has te m p orar y bli n d ness of o ne e ye, d ue t o a bl oc ka ge ( or 
decrease d bl o o d fl o w) i n t he bl o o d vessels lea di n g t o t hat e ye 
•  Te m p orar y visi o n pr o ble ms ca use d b y c ol d te m perat ures 
•  Pr o ble ms wit h t he e yeli d(s)  
•  S welli n g ar o u n d t he ner ve i n t he bac k of t he e ye w hic h is res p o nsi ble f or visi o n 
•  Bell y pai n  
•  Fl ui d c ollecti o n i n t he a b d o me n 
•  I nfla m mati o n (s welli n g a n d re d ness) of t he lar ge b o wel (c ol o n) 
•  C o nsti pati o n 
•  Dr y m o u t h 
•  Heart b ur n  
•  Diffic ult y s wall o wi n g  
•  I nfla m mati o n (s welli n g a n d re d ness) of t he s mall a n d lar ge b o wel 
•  I nfla m mati o n (s welli n g a n d re d ness) of t he es o p ha g us ( g ullet or t he t u be t he g oes 
fr o m t he m o ut h t o t he st o mac h, t hr o u g h w hic h f o o d passes) 


C O N S E N T  
Bi o m e di c al/ C a n c er  
O S U 1 1 1 8 2  
 
 
I R B Pr ot o c ol N u m b er: 
2 0 1 2 C 0 0 5 5  
I R B A p pr o v al d at e:  
0 1/ 0 6/ 2 0 1 7  
V er si o n:  2 7 D e c. 2 0 1 6  
 
 
P a g e 1 1  of 2 1  
F or m d at e:  0 2/ 1 0/ 1 2   
 
•  E xcess passi n g of gas 
•  I nfla m mati o n (s welli n g a n d re d ness) of t he st o mac h li ni n g 
•  Blee di n g i n s o me or ga n(s) of t he di gesti ve tract  
•  Deat h of tiss ue s o me w here i n t he di gesti ve tract (st o mac h or i ntesti nes). S ur ger y 
ma y be re q uire d t o re m o ve t he dea d tiss ue. 
•  S ore ( ulcer) s o me w here i n t he di gesti ve tract 
•  Partial or c o m plete bl oc ka ge of t he s mall a n d/ or lar ge b o wel, calle d ile us. Ile us is a 
f u ncti o nal rat her t ha n a n act ual bl oc ka ge of t he b o wel, b ut ma y re q uire s ur ger y t o 
re pair. 
•  Irritati o n or s ores i n t he li ni n g of t he m o ut h 
•  I nfla m mati o n (s welli n g a n d re d ness) of t he pa ncreas 
•  Bl oc ka ge of t he s mall b o wel 
•  C hills  
•  S welli n g of t he face 
•  S welli n g of t he e xtre mities (ar ms a n d/ or le gs)  
•  Fe ver  
•  Li m p or diffic ult y wal ki n g  
•  A c o n diti o n i n w hic h b ot h t he li ver a n d ki d ne ys fail 
•  I nfla m mati o n (s welli n g a n d re d ness) or da ma ge t o t he tiss ue s urr o u n di n g w here a 
dr u g was i njecte d (a d mi nistere d) 
•  C hest pai n  t hat is n ot heart-relate d 
•  Li ver fail ure  
•  I ncrease i n t he size of t he li ver 
•  A c o n diti o n i n w hic h t here is bl oc ka ge of t he vei ns of t he li ver. T his ca n lea d t o li ver 
da ma ge.  
•  Aller gic reacti o n b y y o ur b o d y t o t he dr u g pr o d uct t hat ca n occ ur i m me diatel y or 
ma y  be  dela ye d.  T he  reacti o n  ma y  i ncl u de  hi ves,  l o w  bl o o d  press ure,  w heezi n g, 
s welli n g of t he t hr oat, a n d diffic ult y breat hi n g. 
•  I nfecti o n 
•  Test t hat s h o ws  a pr o ble m i n bl o o d cl otti n g 
•  I ncrease d bl o o d le vel of a li ver or b o ne e nz y me (al kali ne p h os p hatase) 
•  I ncrease d bl o o d le vel of a li ver pi g me nt ( bilir u bi n) ofte n a si g n of li ver pr o ble ms 
•  I ncrease d bl o o d le vel of creati ni ne (a s u bsta nce n or mall y eli mi nate d b y t he ki d ne ys 
i nt o t he uri ne) 
•  I ncrease d bl o o d le vel of a li ver e nz y me ( G G T) 
•  I ncrease d I N R ( meas ure of t he a bilit y of t he bl o o d t o cl ot pr o perl y) w hic h i ncreases 
t he ris k of blee di n g 
•  Decrease d n u m ber of a t y pe of w hite bl o o d cells (l y m p h oc yte), w hic h ma y ma ke  
y o u m ore v ul nera ble t o i nfecti o n w hic h c o ul d be seri o us e ve n life t hreate ni n g 
•  Decrease i n t he n u m ber of a t y pe of w hite bl o o d cell ( ne utr o p hil/ gra n ul oc yte) w hic h 
ca n i ncrease t he ris k of seri o us i nfecti o n  
•  Wei g ht gai n 
•  Wei g ht l oss 


C O N S E N T  
Bi o m e di c al/ C a n c er  
O S U 1 1 1 8 2  
 
 
I R B Pr ot o c ol N u m b er: 
2 0 1 2 C 0 0 5 5  
I R B A p pr o v al d at e:  
0 1/ 0 6/ 2 0 1 7  
V er si o n:  2 7 D e c. 2 0 1 6  
 
 
P a g e 1 2  of 2 1  
F or m d at e:  0 2/ 1 0/ 1 2   
 
•  Decrease i n t he t otal n u m b er of w hite bl o o d cells (le u k oc ytes) w hic h ca n i ncrease 
y o ur ris k of i nfecti o n 
•  M ore aci d t ha n n or mal i n t he bl o o d, w hic h ma y i n dicate t hat y o ur ki d ne ys are n ot 
w or ki n g pr o perl y 
•  L oss of a p petite 
•  De h y drati o n ( w he n y o ur b o d y d oes n ot ha ve as m uc h water a n d fl ui d as it s h o ul d) 
•  I ncrease d bl o o d s u gar le vel, w hic h ca n ca use y o u t o be t hirst y, or ha ve hea dac hes 
or bl urre d visi o n 
•  I ncrease d bl o o d le vel of uric aci d, a waste material fr o m f o o d di gesti o n, w hic h ma y 
i n dicate t hat y o ur ki d ne ys are n ot w or ki n g pr o perl y 
•  De crease d le vels of a bl o o d pr otei n calle d al b u mi n , w hic h ma y i n dicate t hat y o ur 
li ver is n ot w or ki n g pr o perl y 
•  Decrease d  bl o o d  le vel  of  calci u m , w hic h  ca n  ca use  a  ti n gli n g  se nsati o n  i n  t he 
e xtre mities of t he ha n ds a n d feet  
•  Decrease d bl o o d s u gar le vel , w hic h ma y ca use y o u t o l ose y o ur a p petite 
•  Decrease d bl o o d le vel of p otassi u m , w hic h ca n ca use wea k ness, na usea, v o miti n g, 
a n d a b d o mi nal pai n or c o nsti pati o n 
•  Decrease d  bl o o d  le vel  of  ma g nesi u m,  w hic h  c o ul d  ca use  m uscle  wea k ness, 
c o nf usi o n a n d decrease d refle xes.  
•  Decrease d bl o o d le vel of s o di u m, w hic h ca n ca use na usea, hea dac he, or c o nf usi o n 
•  Decrease d bl o o d le vel of p h os p hate , w hic h i n s o me cases ca n ca use y o u t o bec o me 
mil dl y s h ort of breat h  
•  J oi nt pai n 
•  Bac k pai n  
•  B o ne pai n 
•  M uscle pai n  
•  Diffic ult y or li mitati o n i n a bilit y t o o pe n m o ut h 
•  L oss of m uscle c o or di nati o n; a w k war d, u nc o or di nate d wal ki n g; u nstea di ness w he n 
wal ki n g 
•  Slee pi ness  
•  Dizzi ness  ( or  se nsati o n  of  li g ht hea de d ness,  u nstea di ness,  gi d di ness,  s pi n ni n g  or 
r oc ki n g) 
•  Taste c ha n ges  
•  S peec h pr o ble ms 
•  Restless, re peti ti ve, or i n v ol u ntar y m o ve me nts a n d ra pi d s peec h 
•  Hea dac he or hea d pai n  
•  Blee di n g i n t he brai n 
•  Decrease d bl o o d fl o w t o t he brai n w hic h ma y lea d t o str o ke 
•  A malf u ncti o n of t he ner ves wit hi n t he hea d a n d nec k , w hic h ca n ca use i ncrease d 
se nsiti vit y or pai n 
•  Paral ysis of facial m uscles d ue t o pr o ble ms wit h t he ner ves t hat s u p pl y t he m 
•  Wea k ness  or  paral ysis  (l oss  of  m uscle  f u ncti o n)  ca use d  b y  da ma ge  t o  peri p heral 
ner ves (t h ose o utsi de of t he brai n a n d s pi nal c or d) 


C O N S E N T  
Bi o m e di c al/ C a n c er  
O S U 1 1 1 8 2  
 
 
I R B Pr ot o c ol N u m b er: 
2 0 1 2 C 0 0 5 5  
I R B A p pr o v al d at e:  
0 1/ 0 6/ 2 0 1 7  
V er si o n:  2 7 D e c. 2 0 1 6  
 
 
P a g e 1 3  of 2 1  
F or m d at e:  0 2/ 1 0/ 1 2   
 
•  C o n v ulsi o n or seiz ure  
•  A n xiet y, feeli n gs of drea d or da n ger 
•  C o nf usi o n 
•  Feeli n gs of sa d ness, w ort hless ness, t h o u g hts of s uici de or deat h ( de pressi o n) 
•  Diffic ult y slee pi n g or falli n g aslee p  
•  Bl o o d i n t he uri ne 
•  Blee di n g i n t he ki d ne y 
•  Nee d t o uri nate ofte n  
•  Diffic ult y e m pt yi n g t he bla d der 
•  Prese nce of bl o o d i n a fall o pia n t u be (t he t u be bet wee n t he o var y a n d uter us [ w o m b])  
•  Blee di n g i n t he o var y  
•  Blee di n g i n t he pr ostate 
•  Blee di n g i n t he s per mic c or d (a str uct ure rese m bli n g a c or d t hat s us pe n ds t he testes 
wit hi n t he scr ot u m a n d c o ntai ns t he vas defere ns [t he t u be t h at carries s per m] a n d 
ot her vessels a n d ner ves)  
•  Blee di n g i n t he testis  
•  Blee di n g i n t he uter us ( w o m b) 
•  Blee di n g i n t he va gi na 
•  St uff y or r u n n y n ose, s neezi n g 
•  Blee di n g fr o m t he l u n gs 
•  S u d de n  n arr o wi n g of  t he  s mall  air wa ys  of  t he  l u n g t hat  ca n  ca use  w heezi n g  a n d 
s h ort ness of breat h 
•  C o u g h  
•  S h ort ness of breat h 
•  Hicc u ps 
•  I nfla m mati o n (s welli n g a n d re d ness) of t he l u n gs t hat ma y ca use diffic ult y breat hi n g 
a n d ca n be life- t hreate ni n g 
•  Scarri n g of t he l u n gs t hat ca n ca use s h ort ness of breat h a n d i nterfere wit h breat hi n g  
•  Pr o ble m of t he si n uses 
•  V oice c ha n ges  
•  Hair l oss  
•  Dr y s ki n 
•  E xcess s weati n g  
•  Itc hi n g  
•  S ki n ras h wit h t he prese nce of mac ules (flat disc ol ore d area) a n d pa p ules (raise d 
b u m p) 
•  Hi ves  
•  S u d de n re d de ni n g of t he face a n d/ or nec k 
•  H ot flas hes  
•  Hi g h bl o o d press ure 
•  L o w bl o o d press ure 
•  I nfla m mati o n (s welli n g a n d irritati o n) of a vei n, bl o o d cl ot 
•  F or mati o n of a bl o o d cl ot t hat pl u gs t he bl o o d vessel; t he bl o o d cl ot(s) ma y brea k 


C O N S E N T  
Bi o m e di c al/ C a n c er  
O S U 1 1 1 8 2  
 
 
I R B Pr ot o c ol N u m b er: 
2 0 1 2 C 0 0 5 5  
I R B A p pr o v al d at e:  
0 1/ 0 6/ 2 0 1 7  
V er si o n:  2 7 D e c. 2 0 1 6  
 
 
P a g e 1 4  of 2 1  
F or m d at e:  0 2/ 1 0/ 1 2   
 
l o ose a n d ca n be carrie d b y t he bl o o d strea m t o pl u g a n ot her  place, s uc h as t he l u n g  
•  Blee di n g wit h a decrease d n u m ber of bl o o d cells t hat hel p t o cl ot bl o o d ( platelets) 
 
Rarel y:  ( occ urs i n less t ha n 3 % of pe o ple recei vi n g O xali plati n) 
•  F or mati o n of bl o o d cl ots i n s mall bl o o d vessels ar o u n d t he b o d y t hat lea ds t o a l o w 
platelet (a t y pe of bl o o d cell t h at hel ps t o cl ot bl o o d) c o u nt 
•  Gas i n t he i ntesti nal ( b o wel) wall w hic h ca n res ult i n a bl o o d cl ot, or deat h of t he 
cells i n t he wall. 
•  I nfla m mati o n  (s welli n g  a n d  re d ness)  of  t he  gall  bla d der  p ossi bl y  ass ociate d  wit h 
gall st o nes  
•  S u d de n decrease of  ki d ne y f u ncti o n 
•  Se vere, p ote ntiall y life -t hreate ni n g da ma ge t o t he l u n gs w hic h ca n lea d t o fl ui d i n 
t he l u n gs 
•  S welli n g a n d re d ness of t he s ki n o n t he pal ms of t he ha n ds a n d s oles of t he feet  
 
T he  ner ves  t hat  affect  y o ur  t hr oat  ma y  be  affecte d  a n d  ca use  a  stra n ge  se nsati o n  w he n 
s wall o wi n g c ol d li q ui ds. Y o u s h o ul d a v oi d c ol d be vera ges w hile y o u are partici pati n g i n 
t his st u d y. Y o u ma y als o n otice a ti n gli n g a n d n u m b ness or pai n i n y o ur ha n ds a n d feet t hat 
w orse n o n e x p os ure t o c ol d. E xtra la yers of cl ot hi n g ( gl o ves, mitte ns a n d war m s oc ks) ma y 
hel p t hese s y m pt o ms bec o me less se vere.  
 
If y o u s h o ul d de vel o p t hr oat ti g ht ness, s h ort ness of breat h, or a c h o ki n g se nsati o n, c o ntact 
y o ur d oct or i m me diate l y. Scarri n g of t he l u n g, w hic h ma y be fatal, was o bser ve d i n less 
t ha n 1 % of o ver 4, 0 0 0 patie nts treate d wit h o xali plati n o n cli nical researc h st u dies. 
 
I nfla m mati o n of t he ner ves ca n bec o me w orse d uri n g t he ti me y o u are recei vi n g treat me nt, 
a n d  t he  ris k  of  de vel o pi n g  it  i ncreases  wit h  t he  a m o u nt  of  o xali plati n  y o u  recei ve.  T his 
i nfla m mati o n us uall y g oes a wa y o ver ti me . 
 
I n s o me cases, t he c o m bi nati o n of o xali plati n a n d 5-F U ca n ca use a se vere i nfecti o n ofte n 
ass ociate d wit h diarr hea. T his i nfecti o n is ser i o us a n d ca n be life t hreate ni n g. C o ntact y o ur 
p h ysicia n i m me diatel y if y o u are e x perie nci n g se vere diarr hea, fe ver, as well as n u m b ness 
or ti n gli n g i n y o ur ha n ds, feet or t hr oat, or wea k ness. 
 
A fe w patie nts treate d wit h o xali plati n ha ve de vel o pe d a c o n diti o n k n o w n as “ T u m or L ysis 
S y n dr o me.” T u m or L ysis S y n dr o me is a c o m plicati o n t hat ca n occ ur w he n ca ncer cells are 
destr o ye d  b y  treat me nt.  T he  destr ucti o n  of  cells  ma y  da ma ge  t he  ki d ne ys  a n d  c ha n ge 
calci u m  le vels  i n  t he  b o d y.  T his  c o m plicati o n  ma y  lea d  t o  t he  nee d  f or  ki d ne y  dial ysis 
us uall y  o n  a  te m p orar y  basis.  Y o u  ma y  als o  de vel o p  a  c o n diti o n  ass ociate d  wit h  t he 
d ysf u ncti o n of y o ur ki d ne ys calle d He m ol ytic Ure mic S y n dr o me. T his s y n dr o me ca n be 
seri o us a n d ma y lea d t o seiz ures, pr o ble ms wit h t he ce ntral ner v o us s yste m, or c o ma.  
 
Plati n u m dr u gs li ke o xali plati n ha ve bee n k n o w n t o ca use le u ke mia i n a s mall n u m ber of 
patie nts. It is n ot k n o w n w het her ris k of f ut ure de vel o p me nt of le u ke mia is a si de effect of 
o xali plati n. O ne case of le u ke mia a n d o ne case of m yel o d ys plastic s y n dr o me, a c o n diti o n 


C O N S E N T  
Bi o m e di c al/ C a n c er  
O S U 1 1 1 8 2  
 
 
I R B Pr ot o c ol N u m b er: 
2 0 1 2 C 0 0 5 5  
I R B A p pr o v al d at e:  
0 1/ 0 6/ 2 0 1 7  
V er si o n:  2 7 D e c. 2 0 1 6  
 
 
P a g e 1 5  of 2 1  
F or m d at e:  0 2/ 1 0/ 1 2   
 
w hic h c o ul d lea d t o le u ke mia, ha ve bee n see n f oll o wi n g o xali plati n c he m ot hera p y, alt h o u g h 
it is n ot certai n t hat o xali plati n ca use d t hese bl o o d dis or ders.  
 
It is p ossi ble t hat n ot all si de effects of t his c o m bi nati o n ma y be k n o w n. Y o u ma y e x perie nce 
si de effects ot her t ha n t h ose liste d pre vi o usl y. 
 
Ris ks ass oci ate d wit h st u d y pr oce d ures/tests  
 
Bl o o d C ollecti o n  
D uri n g y o ur partici pati o n i n t his st u d y, y o u will ha ve bl o o d dra ws. P ossi ble ris ks ass ociate d 
i ncl u de pai n, blee di n g, br uisi n g, i nfecti o n, or i nfla m mati o n at t he site w here t he bl o o d is 
ta ke n. 
 
M RI Sca n  
W he n ha vi n g a n M RI ( ma g netic res o na nce i ma gi n g) sca n, y o u will lie still o n a ta ble t hat 
sli des  i nt o  a  t u n nel  sli g htl y  wi der  t ha n  y o ur  b o d y.  Pe o ple  w h o  feel  u nc o mf orta ble  i n 
c o nfi ne d s paces (cla ustr o p h o bia) ma y feel u nc o mf orta ble i n t he narr o w c yli n der. If y o u feel 
u nc o mf orta ble  i n c o nfi ne d  s paces,  please tell  y o ur  st u d y  d oct or.  Y o ur  st u d y  d oct or ma y 
gi ve y o u a me dicati o n t o ma ke y o u feel m ore c o mf orta ble i n a c o nfi ne d s pace. M RIs use 
p o werf ul ma g nets t o ma ke i ma ges. T heref ore, pers o ns wit h certai n metal i m pla nts, s uc h as 
pace ma kers, s h o ul d n ot ha ve a n M RI. If y o u ha ve a n i m pla nt or a n y metal i n y o ur b o d y, 
please c hec k wit h y o ur st u d y d oct or t o fi n d o ut w het her or n ot y o u ca n ha ve a n M R I. F or 
pe o ple wit h o ut metal i m pla nts, t here are n o k n o w n healt h ris ks ass ociate d wit h e x p os ure t o 
t he ma g net.  
 
T he c o ntrast s ol uti o n t hat ma y be gi ve n f or a n M RI sca n ma y ca use a metallic taste or war m 
feeli n g i n y o ur m o ut h. Rarel y, it ca uses, na usea, v o miti n g, a n d/ or a n aller gic reacti o n t hat 
ca n i n v ol ve itc hi n g, ras h, or i n se vere cases, diffic ult y breat hi n g a n d da n ger o us l o weri n g of 
bl o o d press ure. 
 
T he ne p hr o ge nic s yste mic fi br osis ( N S F) ass ociate d wit h ga d oli ni u m -base d c o ntrast me dia, 
as  well  as  t he  car diac  d ose  use d  d uri n g t he car diac  ma g netic  res o na nce  i ma gi n g  ( C M R) 
pr oce d ure:  
•  A rare, seri o us c o n diti o n calle d ne pr o ge nic s yste mic fi br osis ( N S F) has bee n li n ke d 
t o  ga d oli ni u m-base d  c o ntrast  a ge nts  use d  t o  i m pr o ve  M RI  i ma ges.  Ne p hr o ge nic 
s yste mic fi br osis has occ urre d i n patie nts i n t he peri o d j ust bef ore or j ust after li ver 
tra ns pla ntati o n. 
•  N S F ma y res ult i n a fatal or de bilitati n g c o n diti o n t hat affects t he s ki n, m uscles, a n d 
i nter nal  or ga ns.  T he  m ost  c o m m o n  seri o us  si de  effect  fr o m  ga d oli ni u m-base d 
c ontrast a ge nts is a n aller gic reacti o n t hat is us uall y mil d b ut is occasi o nall y se vere 
a n d e ve n res ults i n fatalities. S o me patie nts ha ve de vel o pe d s ki n c o n diti o ns s uc h as 
ras h, s weati n g, itc hi n g, hi ves a n d facial s welli n g. Y o u will be scree ne d t hr o u g h y o ur 
me dical hist or y a n d/ or la b tests f or t hese c o n diti o ns. 


C O N S E N T  
Bi o m e di c al/ C a n c er  
O S U 1 1 1 8 2  
 
 
I R B Pr ot o c ol N u m b er: 
2 0 1 2 C 0 0 5 5  
I R B A p pr o v al d at e:  
0 1/ 0 6/ 2 0 1 7  
V er si o n:  2 7 D e c. 2 0 1 6  
 
 
P a g e 1 6  of 2 1  
F or m d at e:  0 2/ 1 0/ 1 2   
 
•  A bl o o d test will be d o ne o n t he da y of y o ur M RI sca n bef ore t he a d mi nistrati o n of 
ga d oli ni u m. If y o ur test res ults are si g nifica ntl y a b n or mal, y o u will n ot be a ble t o 
ha ve t he ga d oli ni u m- base d, c o ntr ast-e n ha nce d M RI sca n.  
•  Alt h o u g h t he c o ntrast d ose is t wice t hat rec o m me n de d b y F D A g ui deli nes, it is t he 
sta n dar d car diac d ose.    
 
P E T Sca n  
D uri n g t he P E T  sca n y o u will be as ke d t o lie ver y still o n a c o mf orta ble ta ble t hat m o ves 
t hr o u g h a ri n g-li ke sca n ner.  Y o u s h o ul d n ot feel a n yt hi n g d uri n g t he sca n w hic h ca n last 
bet wee n 4 5- 6 0 mi n utes.  A s pecial s u gar pl us a ra di oacti ve tracer is i njecte d i nt o y o ur vei n 
bef ore t he sca n.  Acti ve cells, li ke ca ncer cells, use s u gar f or e ner g y a n d t he sca n will pic k 
u p t he tracer a n d s h o w a n y c ollecti o n of a b n or mal cells. T he ris k of si de effects after t he 
P E T sca n  is  ver y  l o w,  b ut  t here  ma y  be  a  ris k  of  ha vi n g  a n  aller gic  reacti o n  t o  t he 
a d mi nistere d ra diati o n -la bele d s u gar.  H o we ver, t his reacti o n has o nl y bee n rarel y o bser ve d. 
 
T he P E T/ C T sca n will als o e x p ose y o u t o l o w d oses of ra diati o n. T o gi ve y o u a n i dea a b o ut 
h o w m uc h r a diati o n y o u will get, we will ma ke a c o m paris o n wit h a n e ver y -da y sit uati o n. 
E ver y o ne  recei ves  a  s mall  a m o u nt  of  u na v oi da ble  ra diati o n  eac h  year .  S o me  of  t his 
ra diati o n c o mes fr o m s pace a n d s o me fr o m nat urall y-occ urri n g ra di oacti ve f or ms of water 
a n d mi nerals. T w o P E T/ C T sca ns will gi ve y o ur b o d y t he e q ui vale nt of a b o ut 2 0 e xtra years' 
w ort h  of  t his  nat ural  ra diati o n.  T he  ra diati o n  d ose  we  ha ve  di sc usse d  is  w hat  y o u  will 
recei ve fr o m t his st u d y o nl y, a n d d oes n ot i ncl u de a n y e x p os ure y o u ma y ha ve recei ve d or 
will recei ve fr o m ot her tests.  
 
C T Sca n  
T here is a sli g ht ris k of de vel o pi n g a n aller gic reacti o n t o t he i o di ne c o ntrast material  (is a 
f or m of i ntra ve n o us c o ntract , w hic h e n ha nces t he visi bilit y of vasc ular str uct ures a n d or ga ns 
d uri n g  ra di o gra p hic  pr oce d ures) .  T he  reacti o n  ca n  be  mil d  (itc hi n g,  ras h)  or  se vere 
( diffic ult y  breat hi n g  or  s u d de n  s h oc k).  Deat h  res ulti n g  fr o m  a n  aller gic reacti o n  is  rare. 
M ost reacti o ns ca n be c o ntr olle d usi n g dr u gs. Be s ure t o tell y o ur st u d y d oct or if y o u ha ve 
aller gies of a n y ki n d (s uc h as ha y fe ver, i o di ne aller g y, ecze ma, hi ves, or f o o d aller gies). 
T he  c o ntrast  materials  use d  d uri n g  C T  sca n ni n g  ca n  ca use  water  l oss  or  da ma ge  t o  t he 
ki d ne ys t hat ma y lea d t o ki d ne y fail ure. T his is a c o ncer n if y o u ha ve p o or ki d ne y f u ncti o n, 
de h y drati o n or dia betes, es peciall y if y o u ta ke Metf or mi n
® ( Gl uc o p ha ge) t o c o ntr ol y o ur 
dia betes.  
 
Y o u will be e x p ose d t o a li mite d a n d me dicall y acce pta ble d ose of ra diati o n d uri n g t his 
pr oce d ure. T here is al wa ys a sli g ht ris k fr o m bei n g e x p ose d t o a n y ra diati o n, i ncl u di n g t he 
l o w le vels of x-ra ys use d f or a C T sca n.  
 
Y o u  ma y  als o  e x perie nce  disc o mf ort  relate d  t o  l yi n g  still  i n  a n  e ncl ose d  s pace  f or  a 
pr ol o n ge d peri o d of ti me. 
 
Electr ocar di o gra m  


C O N S E N T  
Bi o m e di c al/ C a n c er  
O S U 1 1 1 8 2  
 
 
I R B Pr ot o c ol N u m b er: 
2 0 1 2 C 0 0 5 5  
I R B A p pr o v al d at e:  
0 1/ 0 6/ 2 0 1 7  
V er si o n:  2 7 D e c. 2 0 1 6  
 
 
P a g e 1 7  of 2 1  
F or m d at e:  0 2/ 1 0/ 1 2   
 
A n  electr ocar di o gra m  ge nerall y  has  n o  ris ks.  Beca use  t his  pr oce d ure  o nl y  rec or ds  t he 
electr o nic acti vit y of t he heart a n d d oes n ot se n d o ut electricit y, t here is n o ris k of s h oc k. 
Occasi o na ll y,  t here  ma y  be  s o me  mi n or  s ki n  irritati o n  or  sli g ht  disc o mf ort  fr o m  E C G 
electr o des ( dis p osa ble a d hesi ve ta bs place d o n t o p of t he s ki n i n t he c hest area a n d t he n 
re m o ve d fr o m t he s ki n at t he e n d of t he pr oce d ure).  
 
Ris k of T u m or Bi o ps y  
A t u m or bi o ps y pr oce d ure ma y ca use pai n, blee di n g, a n d p ossi bl y i nfecti o n a n d disc o mf ort 
at t he site of t he bi o ps y. 
 
7.    W h at be nefits c a n I e x pect fr o m bei n g i n t he st u d y ? 
Ta ki n g part i n t his st u d y ma y or ma y n ot ma ke y o ur healt h better. W hile researc hers h o pe 
t hat t he c o m bi nati o n of Afli berce pt  wit h m o difie d F O L F O X 6 ( m F O L F O X 6)  will be m ore 
usef ul a gai nst y o ur t y pe of ca ncer c o m pare d t o t he us ual treat me nt, t here is n o pr o of  of t his 
yet. We d o k n o w t hat t he i nf or mati o n fr o m t his st u d y will hel p researc hers lear n m ore a b o ut 
t his dr u g c o m bi nati o n as a treat me nt f or ca ncer. T his i nf or mati o n c o ul d hel p f ut ure ca ncer 
patie nts  
 
 8.   W h at ot her c h oices d o I h a ve if I d o n ot t a ke p art i n t he st u d y ? 
Y o u  ma y  c h o ose  n ot  t o  partici pate  wit h o ut  pe nalt y  or  l oss  of  be nefits  t o  w hic h  y o u  are 
ot her wise e ntitle d.  
 
Y o ur ot her c h oices ma y i ncl u de: 
• 
Getti n g treat me nt or care wit h o ut bei n g i n a st u d y  
•  
Ta ki n g part i n a n ot her st u d y 
•  
Getti n g n o treat me nt 
• 
Getti n g c o mf ort care, als o calle d palliati ve care.  
 
Y o u  ma y tal k t o his or her d oct or a b o ut t hese a n d ot her o pti o ns. 
 
9.    Will m y st u d y -rel ate d i nf or m ati o n be ke pt c o nfi de nti al ? 
Eff orts will be ma de t o kee p y o ur st u d y-relate d i nf or mati o n c o nfi de ntial.  H o we ver, t here 
ma y  be  circ u msta nces  w here  t his  i nf or mati o n  m ust  be release d.    F or  e xa m ple,  pers o nal 
i nf or mati o n re gar di n g y o ur partici pati o n i n t his st u d y ma y be discl ose d if re q uire d b y state 
la w.   
 
Als o, y o ur rec or ds ma y be re vie we d b y t he f oll o wi n g gr o u ps (as a p plica ble t o t he researc h): 
•  
Office f or H u ma n  Researc h  Pr otecti o ns  or  ot her  fe deral,  state,  or  i nter nati o nal 
re g ulat or y a ge ncies; 
•  
U. S.  F o o d a n d Dr u g A d mi nistrati o n; 
•  
T he  O hi o  State  U ni versi t y  I nstit uti o nal  Re vie w  B oar d  or Office  of Res p o nsi ble 
Researc h Practices;  
•  
Sa n ofi- A ve ntis, t he st u d y’s f u n di n g or ga nizati o n a n d t heir age nts or st u d y m o nit ors;  
•  
Y o ur i ns ura nce c o m pa n y (if c ha r ges are bille d t o i ns ura nce). 
 


C O N S E N T  
Bi o m e di c al/ C a n c er  
O S U 1 1 1 8 2  
 
 
I R B Pr ot o c ol N u m b er: 
2 0 1 2 C 0 0 5 5  
I R B A p pr o v al d at e:  
0 1/ 0 6/ 2 0 1 7  
V er si o n:  2 7 D e c. 2 0 1 6  
 
 
P a g e 1 8  of 2 1  
F or m d at e:  0 2/ 1 0/ 1 2   
 
If t his st u d y is relate d t o y o ur me dical care, y o ur st u d y -relate d i nf or mati o n ma y be placed 
i n  y o ur  per ma ne nt  h os pital,  cli nic,  or  p h ysicia n’s  office  rec or ds.  A ut h orize d  O hi o  State 
U ni versit y  staff  n ot  i n v ol ve d  i n  t he  st u d y  ma y  be a ware  t hat  y o u  are  partici pati n g  i n  a 
researc h st u d y a n d ha ve access t o y o ur i nf or mati o n.  
T here is a s mall ris k of healt h i ns ura nce discri mi nati o n base d o n ge netic testi n g; h o we ver, 
per t he Ge netic I nf or mati o n N o n discri mi nati o n Act of 2 0 0 8 ( GI N A), gr o u p a n d i n di vi d ual 
healt h i ns urers ma y n ot use y o ur ge netic i nf or mati o n t o set i ns ura nce eli gi bilit y, 
pre mi u ms, or c o ntri b uti o n a m o u nts, n or ca n t he y re q uest or re q uire t hat y o u ta ke a ge netic 
test.  I n a d diti o n, e m pl o yers wit h 1 5 or m ore e m pl o yees ma y n ot use y o ur ge netic 
i nf or mati o n t o ma ke decisi o ns re gar di n g hiri n g, firi n g, j o b assess me nts, or pr o m otsi o ns, 
n or ca n t he y re q uest, re q uire, or p urc hase y o ur ge netic i nf or mati o n.  I n O hi o, t here is a 
si milar state la w t hat als o pr o vi des s o me pr otecti o n f or pri vate healt h i ns ura nce pla ns.  
GI N A d oes n ot pr otect y o u a gai nst ge netic discri mi nati o n b y c o m pa nies t hat sell life, 
disa bilit y, or l o n g- ter m care i ns ura nce.   
A descri pti o n  of  t his  cli nical  trial  will  be  a vaila ble  o n htt p:// w w w. Cli nical Trials. g o v ,  as 
re q uire d b y U. S. la w.  T his we bsite will n ot i ncl u de i nf or mati o n t hat ca n i de ntif y y o u.  At 
m ost, t he we bsite will i ncl u de a s u m mar y of t he res ults.  Y o u ca n searc h t he we bsite at a n y 
ti me.  
 
Y o u ma y als o be as ke d t o si g n a se parate H ealt h Ins ura nce P orta bilit y a n d Acc o u nta bilit y 
A ct ( HI P A A) researc h a ut h orizati o n f or m if t he st u d y i n v ol ves t he use of y o ur pr otecte d 
healt h i nf or mati o n . 
 
 
1 0. W h at are t he c osts of t a ki n g p art i n t his st u d y ? 
Y o u will n ot be c har ge d f or t he st u d y treat me nts or a d diti o nal tests re q uire d f or t his st u d y 
t hat  are  n ot  re q uire d  f or  t he  care  a n d  ma na ge me nt  of  y o ur  ca ncer.  T he  st u d y  dr u g 
Afli berce pt is bei n g pr o vi de d t o y o u at n o c ost. 
 
T he f oll o wi n g pr oce d ures/tests are c o nsi dere d t o be researc h a n d will n ot be bille d t o y o u 
or y o ur i ns ura nce c o m pa n y:  
 
•  Arc hi ve d Tiss ue Sa m ple at scree ni n g  
•  Ser u m/ Plas ma P D Researc h  at scree ni n g a n d da y 1 of wee ks 3, 9 a n d 1 3 
•  F D G -P E T  sca n at scree ni n g a n d at wee k 8  
•  D C E -M RI  at scree ni n g a n d at wee k 8 
•  Gl uc ose bl o o d test at scree ni n g a n d e ver y ot her wee k w hile recei vi n g treat me nt 
•  E C G  at scree ni n g 
•  T u m or Bi o ps y (if perf or me d) at scree ni n g a n d wee k 8  
 
Y o u a n d/ or y o ur healt h pla n/i ns ura nce c o m pa n y will nee d t o pa y f or s o me or all of t he c osts 
of t reati n g y o ur ca ncer i n t his st u d y. S o me healt h pla ns will n ot pa y t hese c osts f or pe o ple 


C O N S E N T  
Bi o m e di c al/ C a n c er  
O S U 1 1 1 8 2  
 
 
I R B Pr ot o c ol N u m b er: 
2 0 1 2 C 0 0 5 5  
I R B A p pr o v al d at e:  
0 1/ 0 6/ 2 0 1 7  
V er si o n:  2 7 D e c. 2 0 1 6  
 
 
P a g e 1 9  of 2 1  
F or m d at e:  0 2/ 1 0/ 1 2   
 
ta ki n g part i n st u dies. C hec k wit h y o ur healt h pla n or i ns ura nce c o m pa n y t o fi n d o ut w hat 
t he y will pa y f or. Ta ki n g part i n t his st u d y ma y or ma y n ot c ost y o ur i ns ura nce c o m pa n y 
m ore t ha n t he c ost of getti n g re g ular ca ncer treat me nt. Y o u will be bille d f or a n y de d ucti bles  
c o-i ns ura nce a n d or c o -pa y me nts re q uire d b y y o ur i ns ura nce c o m pa n y or t hir d -part y pa yer.  
 
1 1. Will I be p ai d f or t a ki n g p art i n t his st u d y ? 
Y o u will n ot be pai d f or partici pati n g i n t his cli nical trial.  
 
1 2. W h at h a p pe ns if I a m i nj ure d bec a use I t o o k p art i n t his st u d y ? 
 
O HI O  S T A T E U NI V E R SI T Y LI A BI LI T Y  
If y o u are i nj ure d as a res ult of y o ur partici pati o n i n t his st u d y, y o u ma y o btai n i m me diate 
care at  T he O hi o State U ni versit y Me dical Ce nter.   T he c ost of t his treat me nt will be 
c har ge d t o y o u or y o ur i ns ura nce c o m pa n y.  Y o ur healt h i ns ura nce c o m pa n y ma y or ma y 
n ot pa y f or treat me nt of i nj uries as a res ult of y o ur partici pati o n i n t his st u d y.  T he O hi o 
State U ni versit y has n o f u n di n g set asi de f or t he pa y me nt of healt h care e x pe nses res ulti n g 
fr o m i nj ur y f or t his st u d y. 
 
S P O N S O R LI A BI LI T Y  
If t he i nj ur y was ca use d b y a defect i n t he st u d y dr u g Afli berce pt, t he n sa n ofi -a ve ntis, t he 
pr o vi der of t he st u d y dr u g, will pa y t he reas o na ble c osts f or necessar y me dical treat me nt 
t hat are n ot c o vere d b y y o ur me dical i ns ura nce pr o vi de d y o u ha ve f oll o we d t he directi o ns 
of t he st u d y d oct or.   T his c o m mit me nt f or free me dical treat me nt d oes n ot i ncl u de treat me nt 
f or a n y ot her c o m plicati o ns or ill ness t hat y o u ma y e x perie nce d uri n g t his st u d y, w hic h d o 
n ot res ult fr o m y o ur partici pati o n i n t he st u d y. 
 
B y si g ni n g t his c o nse nt f or m, y o u will n ot be wai vi n g a n y of t he le gal ri g hts w hic h y o u 
ot her wise w o ul d ha ve as a s u bject i n a researc h st u d y. 
 
1 3 . W h at are m y ri g hts if I t a ke p art i n t his st u d y ? 
If  y o u  c h o ose  t o  partici pate i n  t he  st u d y,  y o u ma y  disc o nti n ue  partici pati o n  at  a n y  ti me 
wit h o ut pe nalt y or l oss  of be nefits.  B y  si g ni n g t his f or m, y o u d o n ot gi ve u p a n y pers o nal 
le gal ri g hts y o u ma y ha ve as a partici pa nt i n t his st u d y. 
 
Y o u  will  be  pr o vi de d  wit h  a n y  ne w  i nf or mati o n  t hat  de vel o ps  d uri n g  t he  c o urse  of  t he 
researc h t hat ma y affect y o ur decisi o n w het her or n ot t o c o nti n ue partici pati o n i n t he st u d y. 
 
Y o u ma y ref use t o  partici pate i n t his st u d y  wit h o ut pe nalt y or l oss of be nefits t o w hic h y o u 
are ot her wise e ntitle d.  
 
A n  I nstit uti o nal Re vie w B oar d res p o nsi ble f or h u ma n s u bjects researc h at T he O hi o State 
U ni versit y  re vie we d  t his  researc h  pr oject  a n d  f o u n d  it  t o  be  acce pta ble,  acc or di n g  t o 
a p plica ble state a n d fe deral re g ulati o ns a n d U ni versit y p olicies desi g ne d t o pr otect  t he ri g hts 
a n d welfare of partici pa nts i n researc h.  
 


C O N S E N T  
Bi o m e di c al/ C a n c er  
O S U 1 1 1 8 2  
 
 
I R B Pr ot o c ol N u m b er: 
2 0 1 2 C 0 0 5 5  
I R B A p pr o v al d at e:  
0 1/ 0 6/ 2 0 1 7  
V er si o n:  2 7 D e c. 2 0 1 6  
 
 
P a g e 2 0  of 2 1  
F or m d at e:  0 2/ 1 0/ 1 2   
 
1 4 . W h o c a n a ns wer m y q uesti o ns a b o ut t he st u d y ? 
 
F or q uesti o ns , c o ncer ns, or c o m plai nts a b o ut t he st u d y  y o u ma y c o ntact  Dr . J o h n H a ys  at 
6 1 4- 6 8 5- 6 7 0 0. 
 
F or q uesti o ns a b o ut y o ur ri g hts as a partici pa nt  i n t his st u d y or t o disc uss ot her st u d y -relate d 
c o ncer ns or c o m plai nts wit h s o me o ne w h o is n ot part of t he researc h tea m , y o u ma y c o ntact  
Ms. Sa n dra Mea d o ws i n t he Office of Res p o nsi ble Researc h Practices at 1- 8 0 0- 6 7 8- 6 2 5 1. 
 
If y o u are i nj ure d as a res ult  of partici pati n g i n t his st u d y or f or q uesti o ns a b o ut a st u d y -
relate d i nj ur y, y o u ma y c o ntact Dr . J o h n H a ys at 6 1 4- 6 8 5- 6 7 0 0. 
 
 
 
 
 
 
 
Si g ni n g t he c o nse nt f or m  
 
I ha ve rea d ( or s o me o ne has rea d t o me) t his f or m a n d I a m a ware t hat I a m b ei n g as ke d t o 
partici pate i n a researc h st u d y.  I ha ve ha d t he o p p ort u nit y t o as k q uesti o ns a n d ha ve ha d t he m 
a ns were d t o m y satisfacti o n.  I v ol u ntaril y a gree t o partici pate i n t his st u d y.  
 
I a m n ot gi vi n g u p a n y le gal ri g hts b y si g ni n g t his f or m.  I will be gi ve n a c o p y of t his f or m. 
 
 
 
 
 
Pri nte d n a me of s u bject  
 
Si g n at ure of s u bject  
 
 
 
 
 
A M/ P M  
 
 
D ate a n d ti me  
 
 
 
 
 
 
 
 
 
Pri nte d  n a me  of  pers o n  a ut h ori ze d  t o  c o nse nt  f or su bject  
( w he n a p plic a ble) 
 
Si g n at ure of p e rs o n a ut h ori ze d t o c o nse nt f or s u bject   
( w he n a p plic a ble) 
 
 
 
 
 
A M/ P M  
Rel ati o ns hi p  t o t h e s u bject 
 
D ate a n d ti me  
 
 
I n vesti g at or/ Rese arc h St aff 
 
I ha ve e x plai ne d t he researc h t o t he partici pa nt or his/ her re prese ntati ve bef ore re q uesti n g t he 
si g nat ure(s) a b o ve.  T here are n o  bla n ks i n t his d oc u me nt.  A c o p y of t his f or m has bee n gi ve n 
t o t he partici pa nt or his/ her re prese ntati ve. 


C O N S E N T  
Bi o m e di c al/ C a n c er  
O S U 1 1 1 8 2  
 
 
I R B Pr ot o c ol N u m b er: 
2 0 1 2 C 0 0 5 5  
I R B A p pr o v al d at e:  
0 1/ 0 6/ 2 0 1 7  
V er si o n:  2 7 D e c. 2 0 1 6  
 
 
P a g e 2 1  of 2 1  
F or m d at e:  0 2/ 1 0/ 1 2   
 
 
 
 
 
 
Pri nte d n a me of pers o n o bt ai ni n g c o nse nt  
 
Si g n at ure of p ers o n o bt ai ni n g c o nse nt  
 
 
 
 
 
A M/ P M  
 
 
D ate a n d ti me  
 
 
Wit ness(es)  - M ay be left bl a nk if n ot re q uire d by t he I R B  
 
 
 
 
 
Pri nte d n a me of w it ness 
 
Si g n at ure of wit ness  
 
 
 
 
 
A M/ P M  
 
 
D ate a n d ti me  
 
 
 
 
 
Pri nte d n a me of w it ness 
 
Si g n at ure of wit ness  
 
 
 
 
 
 
A M/ P M  
 
 
D ate a n d ti me