A Randomized Phase II Study of Sequential Biotherapy With Aflibercept and High Dose IL-2 Versus High Dose IL-2 Alone in Patients With Inoperable Stage III or Stage IV Melanoma: Efficacy and Biomarker Study
Phase: PHASE2
Conditions: Metastatic Melanoma, Recurrent Melanoma, Stage III Cutaneous Melanoma AJCC v7, Stage IIIA Cutaneous Melanoma AJCC v7, Stage IIIB Cutaneous Melanoma AJCC v7, Stage IIIC Cutaneous Melanoma AJCC v7, Stage IV Cutaneous Melanoma AJCC v6 and v7
Sponsor: National Cancer Institute (NCI)

 
 
PhII-107, NCI# 8628 
 
 
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SUMMARY OF CHANGES 
 
Date:  
August 21, 2017 
Document: 
NCI Protocol #8628, PhII-107: “A Randomized Phase II Study of Sequential 
Biotherapy with Aflibercept and High Dose IL-2 versus High Dose IL-2 alone in 
Patients with Inoperable Stage III or Stage IV Melanoma: Efficacy and Biomarker 
Study.” 
Note: 
 
The following is a Summary of Changes between the 12.31.15 and 8.21.17 
version of the protocol 
 
Section 
Description of Change (v. 12.31.15 and v. 8.21.17) 
Face page 
Added August 21, 2017 to the list of protocol versions and updated the footer. 
Updated the principal investigator and other participating investigators.   

 
 
PhII-107, NCI# 8628 
 
 
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NCI Protocol #:  
8628 
 
Local Protocol #:  
PhII-107 
 
TITLE: A Randomized Phase II Study of Sequential Biotherapy with Aflibercept and High 
Dose IL-2 versus High Dose IL-2 alone in Patients with Inoperable Stage III or Stage IV 
Melanoma: Efficacy and Biomarker Study   
 
Coordinating Center: 
California Cancer Consortium Data Coordinating Center 
 
City of Hope  
 
1500 E. Duarte Road, Duarte, California 91010 
 
Phone:  626-256-HOPE(4673), extension 65928 
 
Fax:      626-256-8654 
 
 
 
 
Email: cccp@coh.org  
 
*Principal Investigator: 
Ahmad A. Tarhini, MD, PhD 
Cleveland Clinic Taussig Cancer Institute 
Taussig Cancer Center 
500 Euclid Ave CA6-157 
Cleveland, OH 44195 
Phone: 216-636-0200 
Fax:     216-444-9464 
E-mail: tarhina1@ccf.org   
 
Co-Investigators: 
John Kirkwood, MD 
 
University of Pittsburgh Cancer Institute 
 
Hillman Cancer Center Research Pavilion 
 
  
 
 
5117 Centre Ave, Suite 1.32 
 
  
 
 
Pittsburgh, PA 15213 
 
  
 
 
Telephone: 412-623-7707 
 
  
 
 
Fax: 412-623-7704 
 
  
 
 
E-mail: kirkwoodjm@upmc.edu 
 
 
 
 
 
 
Lawrence Flaherty, MD 
 
 
 
 
Professor of Medicine, Medical Director, Clinical Trials Office 
Barbara Ann Karmanos Cancer Institute  
4100 John R  
Detroit, MI 48201 
 
 
 
 
Telephone: 313-576-8725    
 
 
 
 
Fax: 313-576-8726 
Email:  flaherty@karmanos.org 
 
 
 
 
 
 
 
 
    
 
 
 
Kim Margolin, MD 

 
 
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City of Hope National Medical Center 
1500 E. Duarte Rd 
Duarte, CA 91010-3000 
Phone: 626-218-3110 
Fax: 626-301-8233 
E-mail: kmargolin@coh.org 
 
Scott Christensen, M.D. 
UC Davis Cancer Center 
4501 X Street 
Sacramento, CA  95817 
Telephone:  916-734-3772 
Fax:  916-734-7946 
E-mail:  scott.christensen@ucdmc.ucdavis.edu 
 
 
 
 
 
Heinz-Josef Lenz, MD 
 
 
 
 
USC/Norris Comprehensive Cancer Center 
 
 
 
 
1441 Eastlake Avenue 
 
 
 
 
Los Angeles, CA  90033 
 
 
 
 
Phone:  323-865-3955 
 
 
 
 
Fax:  323-865-0061 
 
 
 
 
Email:  lenz@usc.edu 
 
 
 
 
 
Chandra Belani, MD 
 
 
 
 
Penn State Milton S. Hershey Medical Center 
 
 
 
 
500 University Drive, H072 
 
 
 
 
Hershey, PA  17033 
 
 
 
 
Phone:  717-531-1078 
 
 
 
 
Fax:  717-531-0002 
 
 
 
 
Email:  cbelani@psu.edu 
 
Hussein Tawbi, MD, MSc 
UPCI Sarcoma Program Director 
UPCI-CTRC University of Pittsburgh Cancer Institute  
5150 Centre Avenue Pittsburgh, PA 15232 
Telephone: 412-692-2600  
Fax: 412-648-6579 
E-mail: tawbih@upmc.edu  
 
 
  
 
 
Lisa Butterfield, PhD (not a treating physician) 
Director, UPCI Immunologic Monitoring and Cellular Products 
Laboratory 
University of Pittsburgh, Hillman Cancer Center 
Hillman Cancer Center  
5117 Centre Avenue  
Pittsburgh, PA 15213  

 
 
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Telephone: 412-623-1418  
Fax: 412-624-0264  
Email: butterfieldl@upmc.edu   
 
 
 
 
 
 
 
Lionel David Lewis, MD 
Dartmouth Hitchcock Medical Center 
One Medical Center Drive 
Lebanon, NH 03756 
Telephone:  603-650-8685 
Email: lionel.lewis@dartmouth.edu  
 
Theodore F. Logan, MD 
Associate Professor of Clinical Medicine 
Indiana University Health 
535 Barnhill Dr., RT 473 
Indianapolis, IN 46202 
Phone: (317) 948-7576 
Fax: (317)274-8022 
Email: tlogan@iu.edu   
 
Thomas Olencki, D.O. 
Kari Kendra, MD 
Ohio State University 
320 West 10th Avenue 
A433A Starling Loving Hall 
Columbus, Ohio 43210 
Phone: 614-293-4680  
Fax: 614-293-7525  
Email: Thomas.Olencki@osumc.edu 
Email:  Kari.Kendra@osumc.edu  
 
Saby George MD, FACP 
Assistant Professor of Medicine and OncologyRoswell Park 
Cancer Institute 
Elm and Carlton Streets 
Buffalo, NY 14263 
Phone:  (716) 845-8387 
Fax: (716) 845-3519 
Email:  Saby.George@RoswellPark.org  
 
Sunandana Chandra, MD 
Robert H. Lurie Comprehensive Cancer Center  
Northwestern Memorial Hospital  
676 N. St. Clair, Suite 850  
Chicago, IL 60611  
Phone: (312) 695-0990 

 
 
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Email:  sunandana.chandra@northwestern.edu  
 
Igor Puzanov, MD 
Vanderbilt University Medical Center 
2220 Pierce Avenue 
777 Preston Research Building  
Nashville, TN 37232-6307 
Telephone: 615-936-6938 
Fax: 615-936-5850 
Email: igor.puzanov@vanderbilt.edu 
 
David Lawson, MD 
Emory University 
1365C Clifton Road 
Atlanta, GA 30322 
Phone 404-778-1900 
Fax 404-778-5676 
Email: dlawson@emory.edu 
 
Henry Koon, MD 
UH Case Medical Center 
Department of Medicine-Hematology and Oncology 
11100 Euclid Ave 
Cleveland, OH 44106 
Phone: (216) 368-1175 
Email:  Henry.Koon@UHhospitals.org 
 
Patrick James Flynn, M.D. 
Metro-Minnesota Community Clinical Oncology Program 
800 E 28th St, Suite 405 
Minneapolis, MN  55407 
Phone:  612-863-8585 
Fax:  612-863-8586 
Email:  patrick.flynn@usoncology.com 
 
Karl Lewis, MD 
University of Colorado Cancer Center 
1665 Aurora Court 
Aurora, CO 80045 
Phone:  720-848-0584  
Fax: 720 848 0526 
Email:  karl.lewis@ucdenver.edu  
 
Mohammed Milhem, MD 
University of Iowa Hospitals & Clinics 
200 Hawkins Drive, C32 GH 

 
 
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Iowa City, IA 52242 
Phone: 319-356-2324 
Fax: 319-353-8383 
Email:  mohammed-milhem@uiowa.edu  
 
Dr. Marc Ernstoff 
Cleveland Clinic Foundation 
Hematology and Medical Oncology 
9500 Euclid Avenue 
Taussig Cancer Institute Desk R35 
Cleveland, OH 44195 
Phone:  (216) 444-0888 
Email:  ernstom@ccf.org  
 
City of Hope affiliates: 
Stephen Koehler, MD 
City of Hope Medical Group, Inc. 
209 Fair Oaks Avenue 
South Pasadena, CA  91030 
Phone: 626-396-2900 
Fax: 626-396-2912 
Email: Skhehler@cohmg.com 
 
 
Statistician: 
 
 
Paul Frankel, Ph.D. 
City of Hope National Medical Center 
1500 E. Duarte Rd, Duarte, CA 91010-3000 
Phone: 626-359-8111 x65265 
Fax: 626-471-7106 
E-mail: pfrankel@coh.org 
Participating Centers: 
City of Hope National Medical Center, Duarte CA (COH) 
 
 
and affiliates 
 
USC/Norris Comprehensive Cancer Center, Los Angeles (USC) 
 
University of California, Davis Cancer Center, Sacramento (UCD) 
 
 
and affiliates 
 
University of Pittsburgh, Pittsburgh, PA (UOP) 
 
Penn State Milton S. Hershey Medical Center (PSU) 
New York Medical College 
Karmanos Cancer Institute/ Wayne State University (WSU) 
Dartmouth Hitchcock Medical Center 
University of Virginia 
Indiana University Health 
Ohio State University 
Roswell Park Cancer Institute 
Northwestern Memorial Hospital 
Vanderbilt Univeristy 
Emory University 

 
 
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UH Case Medical Center 
University of Iowa Hospitals & Clinics 
Cleveland Clinic Foundation 
 
NCI Supplied Agent: 
Aflibercept (NSC 724770) 
 
Commercial Agent: 
Aldesleukin (Interleukin-2) 
 
Protocol Version Date:  
June 14, 2010 
 
Intial Protocol 
 
 
August 2, 2010  
Response to Consensus Review 
 
 
August 18, 2010  
Response to Follow Up Review 
 
 
December 8, 2010 
Amendment 
 
 
December 20, 2010 Address recommendations, study  
 
 
 
 
 
 
 
 
calendar 
 
 
June 16, 2011 
 
Update investigator on title page 
 
 
July 18, 2011  
 
Update investigator on title page 
 
 
February 8, 2012  
NCI RA CAEPR and risk profile 
 
 
May 11, 2012 
 
Amendment 
 
 
December 17, 2012 Amendment 
 
 
January 15, 2013  
Amendment 
 
 
September 19, 2013 Amendment 
 
 
March 6, 2014 
 
Amendment – disapproved 
 
 
March 18, 2014  
Amendment 
 
 
March 27, 2014   
Amendment 
 
 
April 22, 2014 
 
Amendment 
 
 
May 22, 2014 
 
Amendment 
 
 
January 8, 2015  
Amendment 
 
 
January 23, 2015  
Amendment – disapproved 
 
 
February 3, 2015  
Amendment 
 
 
August 10, 2015  
Amendment 
 
 
December 31, 2015 RRA 
 
 
August 21, 2017  
Amendment 

 
 
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SCHEMA 
This is a randomized phase II study of sequential biotherapy with aflibercept and high dose 
interleukin-2 (IL-2) versus high dose IL-2 alone in patients with advanced inoperable stage III or 
stage IV melanoma.  
 
Arm A: Combination of Aflibercept and IL-2. 
The planned treatment consists of 3 courses of combination aflibercept and high dose IL-2 
followed by maintenance aflibercept monotherapy. Response assessment will occur at the end of 
each course of combination therapy and patients without evidence of disease progression (RECIST 
v.1.1) or limiting toxicities will be offered additional courses of treatment (or maintenance 
aflibercept therapy). 
 
Arm B: High dose IL-2 alone 
The planned treatment consists of 3 courses high dose IL-2. Response assessment will occur at the 
end of each course of therapy and patients without evidence of disease progression (RECIST v.1.1) 
or limiting toxicities will be offered additional courses of treatment of high dose IL-2 for a 
maximum of 3 courses (6 cycles). 
 
Arm A will be conducted in 2 phases: Combination and Aflibercept Monotherapy. The 
combination phase will consist of courses 1, 2 and 3 during which aflibercept will be administered 
at 3mg/kg. For the Aflibercept Monotherapy phase, aflibercept will be administered at 4 mg/kg.  
 
I. 
Combination Phase (Arm A): 
 
 
 
 
 
 
 
 
Course 1 (Arm A) 
 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Aflibercept 
3 mg/kg IV 
X 
 
X 
 
X 
 
X 
 
X 
 
HD IL-2 
600,000 
U/kg/dose IV Q8h 
x 5 days (max 14 
doses) 
 
 
X 
 
X 
 
 
 
 
 
Response 
Assessment 
 
 
 
 
 
 
 
 
 
X 

 
 
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II. 
Aflibercept Monotherapy/Maintenance Phase for Arm A: 
 
Following response assessment after course 3 of combination therapy and after resolution of 
all toxicities to ≤ grade 1 (CTCAE v.4), aflibercept monotherapy will be initiated to be 
administered at 4 mg/kg IV on Day 1of each 14-day cycle. In this case, blood pressure 
monitoring should be done weekly for the first 3 weeks of the maintenance phase to ensure 
tolerance of the higher aflibercept dose. However, if the aflibercept dose had to be reduced 
during the combination phase due to aflibercept-related toxicities, then that reduced dose will 
be used for maintenance therapy. No need for weekly monitoring of blood pressure, if the 
reduced dose has already been demonstrated to be tolerable.   
 
Primary Objective: Test the hypothesis that combination biotherapy with aflibercept and HD IL-
2 will improve the progression-free survival compared to HD IL-2 alone.  
 
Secondary Objectives: (1) Evaluate the response rate (CR+PR) of aflibercept and HD IL-2 as 
assessed by RECIST criteria version 1.1 and compare to HD IL-2 alone.  (2) Evaluate the toxicities 
and tolerance of combination biotherapy with aflibercept and HD IL-2 and maintenance aflibercept 
alone in this patient population and compare to HD-IL2 alone. (3) Test the hypotheses related to 
the laboratory correlative studies. (4) Evaluate the overall survival of patients treated on Arm A 
and B.  
 
The primary endpoint is progression-free survival.  The accrual goal is 105 patients, 70 on Arm A, 
and 35 on Arm B.  
 
Definitions: 
 
1. A cycle of IL-2: eligible patients receive high-dose IL-2 at 600,000 IU/kg IV every 8 hours 
for up to 14 doses. This constitutes one cycle of IL-2. 
2. A cycle of Aflibercept: eligible patients receive aflibercept at 3 mg/kg (combination 
phase) or 4 mg/kg (maintenance phase) IV every 2 weeks. This constitutes one cycle of 
aflibercept. 
Course 2 (Arm A) 
Course 3(Arm A) 
 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Aflibercept 
3 mg/kg IV 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
HD IL-2 
600,000 
U/kg/dose IV 
Q8h x 5 days 
(max 14 
doses) 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
Response 
Assessment 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 

 
 
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3. The combination phase (Arm A): during this phase, IL-2 and aflibercept will be given 
concurrently. It consists of 3 courses of combination therapy.   
a. Each course consists of 2 cycles of IL-2 as follows: high-dose IL-2  at 600,000 
IU/kg is given IV every 8 hours for up to 14 doses (one cycle), followed by a rest 
period of  1-2 weeks and readmission for a second high dose IL-2 cycle for up to 
14 doses (2nd cycle).  
b. In addition, aflibercept will be given concurrently at 3 mg/kg IV every 2 weeks, but 
in course 1 only aflibercept will start 2 weeks prior to IL-2. Therefore, course 1 will 
consist of 5 cycles of aflibercept, while courses 2 and 3 will consist of 4 cycles of 
aflibercept each.  
c. Based on the occurrence of treatment-related toxicities and requirements for dose 
adjustments or delays, a patient may or may not receive the full planned treatment, 
but response assessment will continue to be carried out at the end of each course. 
4. The maintenance phase (Arm A): only aflibercept monotherapy will be given during this 
phase for Arm A patients at 4 mg/kg IV every 2 weeks. Response assessment will be carried 
out every 12 weeks (-/+1 week) for both arms (for arm A patients, approximately every 6 
cycles of aflibercept) for the first 2 years, then every 6 months (-/+ 2 weeks) for years 3-5, 
then yearly (-/+ 4 weeks) afterwards.   
 
For arm B, patients will receive HD IL-2 alone following the institutional standard of care 
guidelines. Patients will receive a maximum of 3 courses (6 cycles; 1 course of IL_2 in arm B 
= 2 cycles of IL-2). Response assessment will be carried out at the end of each course. In the 
absence of disease progression by RECIST v.1.1, patients will be offered additional courses of 
therapy for a maximum of 3 courses (6 cycles). 

 
 
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TABLE OF CONTENTS 
SCHEMA ................................................................................................................................ 7 
1. 
OBJECTIVES ............................................................................................................... 11 
1.1. 
Primary Objectives.................................................................................................... 11 
1.2. 
Secondary Objectives................................................................................................ 12 
2. 
BACKGROUND .......................................................................................................... 12 
2.1. 
Metastatic Melanoma ................................................................................................ 12 
2.2. 
Aflibercept (VEGF Trap, AVE0005) ....................................................................... 12 
2.3. 
High Dose Interleukin-2 ........................................................................................... 19 
2.4. 
Rationale ................................................................................................................... 21 
3. 
PATIENT SELECTION ............................................................................................... 22 
3.1. 
Eligibility Criteria ..................................................................................................... 22 
3.2. 
Exclusion Criteria ..................................................................................................... 25 
3.3. 
Inclusion of Women and Minorities ......................................................................... 26 
4. 
REGISTRATION PROCEDURES .............................................................................. 27 
4.1. 
General Guidelines.................................................................................................... 27 
4.2. 
Registration Process .................................................................................................. 27 
5. 
TREATMENT PLAN ................................................................................................... 28 
5.1. 
Overall Treatment Plan ............................................................................................. 28 
5.2. 
Aflibercept Administration ....................................................................................... 30 
5.3. 
Aldesleukin (Interleukin-2) Administration ............................................................. 32 
5.4. 
General Concomitant Medication and Supportive Care Guidelines ......................... 34 
5.5. 
Duration of Therapy .................................................................................................. 34 
5.6. 
Duration of Follow Up .............................................................................................. 35 
6. 
DOSING DELAYS/DOSE MODIFICATIONS (Aflibercept) ..................................... 35 
6.1. 
Management of Hypertension ................................................................................... 36 
6.2. 
Proteinuria ................................................................................................................. 38 
6.3. 
Other Adverse Events ............................................................................................... 38 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ....................... 39 
7.1. 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) .................... 39 
7.2. 
Adverse Event Characteristics .................................................................................. 49 
7.3. 
Expedited Adverse Event Reporting ......................................................................... 49 
7.4. 
Use the NCI protocol number and the protocol-specific patient ID assigned during 
trial registration on all reports.  Routine Adverse Event Reporting ..................................... 50 
7.5. 
Secondary AML/MDS .............................................................................................. 50 
8. 
PHARMACEUTICAL INFORMATION ..................................................................... 51 
8.1. 
CTEP-Supplied Investigational Agents .................................................................... 51 
8.2. 
Commercial Agents .................................................................................................. 53 
9. 
CORRELATIVE/SPECIAL STUDIES ........................................................................ 54 
9.1. 
Laboratory Correlative Studies ................................................................................. 54 
9.2. 
Anti-VEGF Trap Antibody Testing .......................................................................... 57 
10. 
STUDY CALENDAR .............................................................................................. 60 
11. 
MEASUREMENT OF EFFECT............................................................................... 63 
11.1. Antitumor Effect – Solid Tumors ............................................................................. 63 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS .................................. 67 
12.1. Data Reporting .......................................................................................................... 67 

 
 
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12.2. CTEP Multicenter Guidelines ................................................................................... 68 
12.3. Cooperative Research and Development Agreement (CRADA)/Clinical Trials 
Agreement (CTA) ................................................................................................................. 69 
13. 
STATISTICAL CONSIDERATIONS...................................................................... 71 
13.1. Study Design/Endpoints............................................................................................ 71 
13.2. Sample Size/Accrual Rate ......................................................................................... 71 
13.3. Stratification Factors ................................................................................................. 71 
13.4. Analysis of Secondary Endpoints ............................................................................. 71 
13.5. Reporting and Exclusions ......................................................................................... 73 
14. 
CCCP POLICIES FOR MONITORING CONSORTIUM TRIALS ........................ 73 
15. 
REFERENCES ......................................................................................................... 76 
APPENDIX A – Performance Status Criteria ....................................................................... 78 
APPENDIX B – CTEP Multicenter Guidelines .................................................................... 79 
APPENDIX C – CCCP Registration Procedures for Phase II Trials .................................... 81 
APPENDIX D – CCCP Specimen Submission Forms ......................................................... 82 
APPENDIX E – NYHA functional classification system ..................................................... 83 
APPENDIX F - Labeling Instructions for Serum Samples for Regeneron  (Anti-Aflibercept 
Antibody Testing) ................................................................................................................ 84 
APPENDIX G - COLLECTION OF SERUM SAMPLES for Regeneron (Anti-Aflibercept 
Antibody Testing) ................................................................................................................ 87 
APPENDIX H - Patient Blood Pressure Monitoring Diary (for patients on Arm A receiving 
Aflibercept) .......................................................................................................................... 88 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. 
OBJECTIVES 
1.1. 
Primary Objectives 
• Test the hypothesis that combination biotherapy with aflibercept and HD IL-2 will 

 
 
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improve the progression-free survival compared to HD IL-2 alone.  
 
1.2. 
Secondary Objectives 
• Evaluate the response rate (CR+PR) of aflibercept and HD IL-2 as assessed by 
RECIST criteria version 1.1 and compare to results of HD IL-2 alone.   
 
• Evaluate the toxicities and tolerance of combination biotherapy with aflibercept and 
HD IL-2 and maintenance aflibercept alone in this patient population and compare 
to HD IL-2 alone. 
 
• Test the hypotheses related to the laboratory correlative studies.  
 
• Evaluate the overall survival of patients treated with aflibercept and HD IL-2 and 
HD IL-2 alone. 
 
2. 
BACKGROUND 
2.1. 
Metastatic Melanoma 
Annually, about 8,000 patients are found to have metastatic melanoma presenting as a 
recurrence of an earlier primary melanoma, and this number closely approximates the 
annual number of deaths from this disease [1]. This statistic illustrates the lack of 
progress that has been made in the treatment of stage IV melanoma over the last several 
decades. Therapeutic approaches that have been studied in metastatic melanoma 
include chemotherapy, biochemotherapy, nonspecific immune adjuvants, cancer-
specific vaccines, cytokines, monoclonal antibodies, and specific immunostimulants 
[1]. Chemotherapy with single agent dacarbazine is the only US-FDA approved 
chemotherapy agent for metastatic melanoma. Immunological approaches have yielded 
the only new US-FDA approved agent for metastatic disease in 30 years, high-dose 
bolus interleukin-2 (IL-2), based on prolonged durable responses in some patients with 
metastatic melanoma [2]. Participation in clinical trials is presently the best strategy to 
maximize therapeutic options and to access novel drugs in clinical development. Many 
novel therapeutic approaches are currently undergoing active clinical investigation and 
emerging data are promising from approaches targeting angiogenesis, or targeting 
groups of patients with specific activating mutations that are driving malignant 
proliferation such as the V600E BRAF mutation and mutations and amplifications in 
the receptor tyrosine kinase c-kit.  This is in addition to immunotherapy with anti-
CTLA4 monoclonal antibodies.  Although promising, clinical benefits from current 
investigational agents appear to be of either limited duration and/or confined to small 
groups of patients.  Therefore, there continues to be an urgent need for new therapeutic 
strategies building upon promising clinical activity data and solid preclinical rationale. 
  
2.2. 
Aflibercept (VEGF Trap, AVE0005) 
Aflibercept is a recombinant fusion protein consisting of human vascular endothelial 
growth factor (VEGF) receptor extracellular domains fused to the Fc portion of human 

 
 
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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). Aflibercept drug product 
is formulated as a sterile liquid for intravenous (IV) administration [3]. 
 
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. 
 
Aflibercept has been found to be active with a broad pharmacological index against 
early and advanced stage disease in a variety of preclinical solid tumor models 
including sarcomas, and ovarian, prostate, mammary, colon, and gastric carcinomas 
when used as a single agent or in combination with cytotoxic agents. In mouse models 
of ascites formation with ovarian and renal cell carcinoma, aflibercept inhibited ascites 
formation and reduced tumor burden. 
 
Doses have been administered up to 800 μg/kg subcutaneously (SC) twice weekly, 7 
mg/kg IV every 2 weeks, and 9 mg/kg IV every 3 weeks. The most common adverse 
events reported for aflibercept monotherapy include: hypertension, proteinuria, 
epistaxis, dysphonia, pain (including abdominal pain and back pain), asthenia/fatigue, 
nausea, vomiting, headache, constipation, myalgia, arthralgia, dyspnea, decreased 
appetite, and diarrhea. 
 
Target pharmacological exposure has been reached at doses ≥2 mg/kg IV given every 
2 weeks. Free aflibercept levels have remained in excess of bound aflibercept levels 
throughout the dosing intervals at this, or higher, doses. Objective tumor responses and 
prolonged (>1year) disease stabilization have been reported at dose levels ≥800 μg/kg 
SC and ≥1 mg/kg IV with aflibercept monotherapy and with aflibercept administered 
in combination with cytotoxic chemotherapy. Phase 1 studies, as both single agent and 
combination chemotherapy, are ongoing. Phase 2 studies of aflibercept, either alone or 
in combination with standard cytotoxic agents, are ongoing in a variety of oncologic 
indications. Phase 3 combination studies are ongoing in the following indications: lung 
cancer, colorectal cancer, pancreatic cancer, and prostate cancer [3]. 
 
2.2.1. Animal Toxicology  
 
The toxicity profile of aflibercept was evaluated in monkeys. The main compound-
related microscopic findings were 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 

 
 
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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 
blood urea nitrogen (BUN) and urine protein and/or microalbumin levels. In the 
ovaries, the decreased number of maturing follicles, granulose cells, and/or theca 
cells was associated with an overall inhibition of the female reproductive function. 
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. In 
addition, increased liver enzyme 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 
after treatment cessation. In sexually immature monkeys treated for 3 months, the 
main compound-related findings were comparable to those in sexually mature 
monkeys. 
 
Aflibercept was shown to induce a moderately delay in wound repair and healing 
from 0.3 mg/kg/administration after IV administration in rabbits. When 
administered IV to pregnant rabbits (as a 30 minute infusion once daily, on 
gestation Days 6, 9, 12, 15, and 18 - a total of 5 administrations) aflibercept induced 
minimal to moderate maternal toxicity, abortion, and embryolethality at 60 
mg/kg/administration. External, visceral, and/or skeletal malformations were 
observed in fetuses from pregnant rabbits treated from 3 mg/kg/administration 
(approximately 1.3 times the exposure in patients treated at the recommended 
human dose). 
 
2.2.2. Mechanism of Action 
 
VEGF is a molecule produced by tissues to stimulate angiogenesis. VEGF 
production by tumors is required for vascularization and thus, the survival and 
growth of tumors. VEGF protein that is not internalized through its VEGF receptor 
mediated signaling reaches the circulation where it is cleared rapidly. The VEGF 
Trap, a long-acting inhibitor of VEGF signaling, potently binds and inactivates 
VEGF, thus blocking tumor angiogenesis and growth in both animal models of 
cancer and in humans with a variety of cancers. 
 
2.2.3. Pharmacokinetics 
 
Free aflibercept is cleared by 2 mechanisms in humans: (1) a fast clearance by 
binding systemic VEGF to form bound aflibercept, and (2) a slower pathway where 
the free aflibercept is eliminated by other biological mechanisms, perhaps 
analogous to the clearance of free antibodies (proteins). The results in humans are 

 
 
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similar to observations in animal studies. 
 
The clinical kinetics of aflibercept were characterized by a low volume of 
distribution approaching blood volume and a low clearance decreasing with dose 
in the dose range 0.3 to 
2 mg/kg, then stable at higher doses. 
 
Target pharmacological exposure has been reached at 0.8 mg/kg SC given weekly 
or ≥2 mg/kg IV doses given every 2 weeks. Free aflibercept levels have remained 
in excess of bound aflibercept levels throughout the dosing intervals at these doses. 
 
Following IV administration, the pharmacokinetics of free aflibercept were not 
linear following administration of <2 mg/kg doses, but became linear between the 
2 and 7 mg/kg dose levels. The 
pharmacokinetics of free aflibercept were characterized by high fluctuation and 
essentially no accumulation when given every 2 weeks. The concentrations of 
bound aflibercept increased between the 0.3 and 2 mg/kg dose levels, and then 
plateaued between the 2 and 7 mg/kg dose levels, suggesting that free aflibercept 
was available in sufficient amount to bind all endogenous VEGF in this higher dose 
range. 
 
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. 
 
2.2.3.1. 
Pharmacokinetic/Pharmacodynamic Relationships 
 
Preclinically, circulating levels of VEGF Trap complex appear to be good 
biomarkers of efficacy. VEGF is normally cleared rapidly and does not 
accumulate, but binding to VEGF Trap creates an inactive VEGF:VEGF 
Trap complex with a longer half-life that accumulates to detectable levels. 
Because of the high affinity of VEGF Trap for VEGF, free VEGF Trap is 
rapidly converted to the bound form unless VEGF Trap levels exceed the 
amount of VEGF synthesized over the dosing interval. At high doses of 
VEGF Trap, essentially all VEGF is trapped, VEGF:VEGF Trap complex 
formation is saturated, and free VEGF Trap accumulates. Antitumor 
efficacy in animal xenograft models was observed at VEGF Trap doses that 
resulted in saturation of steady-state VEGF:VEGF Trap complex (bound 
VEGF Trap) plasma levels and an excess of free VEGF Trap over the 

 
 
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16
complex concentrations, as shown in Figure 2 of the Investigator’s 
Brochure [3]. 
 
2.2.4. Clinical Experience 
 
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 and 7 mg/kg IV every 2 weeks, and 9 mg/kg IV every 3 weeks across 
13 Phase 1 clinical trials (11 oncology trials), four Phase 2 single agent, two Phase 
2 combination trials, and four Phase 3 combination trials. Details of Phase 1 trials 
in healthy subjects are presented in Table 36 of IDB. Details of the company 
sponsored clinical oncology trials are presented in Table 37 of IDB; SAEs in these 
trials are summarized in Table 39 of ID, Table 40 of IDB, Table 41 of IDB, and 
Table 42 of ID. 
 
2.2.4.1. 
Efficacy 
 
In the single agent Phase 1 study of SC aflibercept, 2 patients, 1 with heavily 
pretreated bronchoalveolar carcinoma and another with medullary thyroid 
cancer, improved either subjectively and/or radiologically at a dose of 800 
μg/kg with prolonged disease stabilization of over 2 years. 
 
In the Phase 1 studies of IV single agent aflibercept (TED6115 and 
TED6116), 3 patients have had RECIST-defined partial tumor responses: 1 
patient with metastatic malignant thymoma treated at the 3 mg/kg dose 
level, and 2 patients with ovarian cancer treated at the 7 mg/kg dose level. 
Two patients with renal cell cancer, treated at the 1 mg/kg and 2 mg/kg dose 
levels, respectively, have had prolonged (exceeding one year) stable disease 
(SD). 
 
Single agent Phase 2 studies in previously treated patients (2 or more lines 
of chemotherapy treatment) have evaluated aflibercept administered IV 
every 2 weeks in ovarian and lung cancer (ARD6122, ARD6123) with 
response rate as the primary endpoint. In ARD6123, a single agent, single 
arm study of aflibercept at 4 mg/kg in advanced, heavily pretreated non-
squamous nonsmall cell lung cancer (NSCLC), an Investigator-reported 
overall response rate (ORR) of 2% was observed, along with a median 
progression free survival (PFS) of approximately 12 weeks, and stable 
disease (SD) for ≥60 days of approximately 30%. The median overall 
survival (OS) was approximately 6 months. In ARD6122, a randomized, 
double-blind study of aflibercept at 2 mg/kg or 4 mg/kg in advanced ovarian 
cancer, the Investigator-reported ORR was 3.8% in the 2 mg/kg arm and 
7.3% in the 4 mg/kg arm; the median PFS in both arms was approximately 
18 weeks, and SD for ≥60 days of approximately 45% and 37% in the 2 
mg/kg and 4 mg/kg arms, respectively. The median OS was approximately 

 
 
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55 weeks in the 2 mg/kg arm and 50 weeks in the 4 mg/kg arm. 
 
Additionally, single agent Phase 2 studies have explored the efficacy of 
aflibercept in prolonging the time to repeat paracentesis in advanced ovarian 
cancer patients with symptomatic malignant ascites (SMA). Study 
ARD6772 explored 4 mg/kg IV every 2 weeks, and showed at least a 
doubling of the primary endpoint (time to repeat paracentesis compared to 
baseline) for 62% of the patients. Study EFC6125, a randomized, double 
blind study of aflibercept 4 mg/kg IV every 2 weeks versus placebo, in a 
similar patient population, is still ongoing. 
 
In the combination Phase 1 studies, radiological tumor responses per 
RECIST criteria have been observed across different tumor types and 
aflibercept doses. 
 
2.2.4.2. 
Phase II monotherapy study in advanced melanoma 
 
A phase II study of aflibercept in patients with inoperable stage III or IV 
melanoma who had received no prior chemotherapy or hormonal therapy 
has recently completed accrual. A 2-stage design was adopted focusing 
upon response rate (RECIST) and 4-month PFS rate. First stage accrual of 
21 patients was specified, and accrual continued to a total of  41 patients 
due to an adequate 4 month PFSR. Aflibercept was given at 4 mg/kg IV 
every 2 weeks. Response was assessed every 8 weeks. Forty one patients 
(26 male, 15 female), age 23-83 (median 57) have been enrolled. All had 
AJCC stage IV melanoma (2N3, 3M1a, 8M1b, 28M1c). Karnofsky PS: 100 
(19), 90 (14) or 80 (8). Ten patients had primary ocular melanoma, 28 
cutaneous and 3 unknown primary site. A median of 4 cycles have been 
administered (range 1-23). Grade 3/4 toxicities included cerebral ischemia 
(1 patient; 2%), confusion (1; 2%), thrombocytopenia (1; 2%), hypertension 
(8; 20%), hypotension (1; 2%), left ventricular diastolic dysfunction (1; 
2%), fatigue (1; 2%), proteinuria (4; 10%), extraocular muscle paresis (1; 
2%), renal failure (1; 2%), back pain (1; 2%), headache (1; 2%), 
osteonecrosis of mandibular bone in a patient with a history of external 
beam radiation therapy. Overall, one patient (cutaneous, M1c) had a 
confirmed partial response (potential CR; duration of PFS = 293+ days). 
Twenty patients have had stable disease (10 ongoing, 10 have progressed). 
Four patients were taken off study prior to response evaluation for toxicity 
(3) or treatment refusal (1). One patient is currently disease free who was 
not evaluable for response (previous surgery and radiofrequency ablation 
of measurable disease site). Thirteen patients had progression at first 
assessment point. Thus far 16 patients (excluding the non-evaluable NED 
patient) have had at least 4 months of PFS. Eight additional patients are still 
on treatment, but have not reached the 4 month PFS milestone. 
 
These results have lead the investigators to conclude that aflibercept has a 

 
 
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promising clinical activity in metastatic melanoma of cutaneous or ocular 
origin. The final conclusions on the activity of aflibercept as single agent in 
metastatic melanoma require additional follow up (4 months after the last 
patient has started treatment). These data however, provide strong rationale 
for moving forward with further development of aflibercept in combination 
therapy with agents that are known to be active in melanoma [4]. 
 
2.2.5. Safety Considerations 
 
Phase 1, 2, and 3 oncology studies are ongoing, as both single agent and 
combination trials. 
 
In healthy subjects, administration of a single dose, or up to 2 doses of 1, 2, or 4 
mg/kg of aflibercept by IV infusion, or 2 mg/kg by SC route, was considered safe 
and showed an acceptable tolerability. The most frequently reported treatment 
emergent non-serious AEs included headache, dysphonia, epistaxis, acneiform 
dermatitis, 
nasopharyngitis, 
arthralgia, 
diarrhea, 
ALT 
increase, 
and 
nausea/dyspepsia. No serious adverse events (SAEs) were reported in healthy 
subjects. 
 
All grade treatment emergent adverse events (TEAEs) commonly reported across 
single agent oncology trials, regardless of relationship to study drug, include 
hypertension, proteinuria, epistaxis, dysphonia, pain (including abdominal pain, 
musculoskeletal pain, and back pain), asthenia/fatigue, constipation, nausea, 
vomiting, diarrhea, dizziness, headache, cough, dyspnea, decreased appetite, 
peripheral edema, and pyrexia. Serious and less commonly reported events include 
thrombotic microangiopathy, cardiac failure, gastrointestinal hemorrhage, 
intestinal perforation, hemoptysis, tracheoesophageal fistula, enterocutaneous 
fistula, reversible posterior leukoencephalopathy syndrome (RPLS), intracerebral 
hemorrhage, cerebral ischemia, deep vein thrombosis and pulmonary embolism. 
Although these AEs may be drug related, an association with the underlying disease 
and the heavily pretreated patient population studied cannot be ruled out at this 
stage of development. 
 
All grade TEAEs commonly reported across trials exploring aflibercept in 
combination with other anticancer drugs are similar to the single agent drug safety 
profile but also reflect common toxicities associated with the drugs used in these 
combination regimens. Some anticancer drugs being explored in Phase 1 
combination studies include: docetaxel, gemcitabine, erlotinib, irinotecan, 
oxaliplatin, cisplatin, and fluorouracil. Adverse events commonly reported in the 
combination trials include hypertension, proteinuria, epistaxis, dysphonia, pain 
(including abdominal pain, musculoskeletal pain, and back pain), asthenia/fatigue, 
nausea, vomiting, headache, constipation, dyspnea, decreased appetite, diarrhea, 
and also include neuropathy, stomatitis and mucosal inflammation, electrolyte 
changes (including hypomagnesemia), and alopecia. Hematological abnormalities 
commonly reported in the combination trials include neutropenia, anemia, and 

 
 
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thrombocytopenia. 
 
For  more details on AEs associated with Aflibercept, please refer to the current 
version of the IDB [3]. 
 
2.3. 
High Dose Interleukin-2 
IL-2  plays a central role in immune regulation as it affects the survival of key cells of 
the immune system that are responsible for the antitumor cytotoxicity of T-
lymphocytes and natural-killer (NK) cells, and it has a cofactor role in the activation of 
B cells and macrophages [5]. The administration of IL-2 at high bolus IV doses once 
every eight hours was a regimen developed by the National Cancer Institute (NCI) 
based on animal models indicating that antitumor activity with this agent was dose-
dependent [6][6][6][6][6][7].  Initial studies with HDB IL-2 utilized doses of 600,000-
720,000 units/kg every 8 hours from days 1-5 (cycle 1) and days 15-19 (cycle 2) with 
a maximum of 14 doses per cycle or 28 doses per course (1 course = 2 cycles).  
Responding or stable patients were offered a second course of therapy 8-12 weeks later. 
IL-2 was administered either as a single agent or in combination with immunologically 
active cells, so-called adoptive immunotherapy. The latter technique utilized two types 
of immune cells: the lymphokine- activated-killer (LAK) cells and the tumor 
infiltrating lymphocytes (TIL). 
 
Eight clinical trials conducted between 1985 and 1993 and using the HDB IL-2 regimen 
described above, with or without LAK cells, were reviewed in a retrospective analysis. 
These trials had an enrollment of 270 patients with advanced metastatic melanoma [7-
9][7-9][7-9][7-9][7-9][8-10]. In those studies that involved the concurrent 
administration of LAK cells, these cells were obtained using leukapheresis from 
patients during the rebound lymphocytosis that occurs following treatment and 
cessation of bolus IL-2 (days 8 to 12). LAK cells were then cultured in IL-2 for 3 to 4 
days. These generated LAK cells were reinfused with IL-2 during the second cycle of 
IL-2 administration. The retrospective analysis of these trials with a follow-up through 
December 1998 along with a more recent update demonstrated an objective response 
rate of 16% with durable responses in 4% of patients [2, 10][2, 10][2, 10][2, 10][2, 
10][3, 11]. The median response duration was 8.9 months (range 4 to 106+ months). 
Twenty eight percent of the responding patients, including 59% of those patients who 
had achieved a complete response, have remained progression free at a median follow-
up of 62 months. Furthermore, no patient who had responses longer than 30 months 
has relapsed, suggesting the possibility that these patients may be “cured”. The 
frequency of the responses was similar in patients with visceral metastases and/or large 
tumor burdens, but the responses were less in patients with poor performance status or 
those who had received prior systemic therapy. Based on these data, HDB IL-2 received 
approval 
by 
the 
US-FDA 
for 
the 
treatment 
of 
metastatic 
melanoma 
[11][11][11][11][11][12]. In addition to being logistically challenging, randomized 
studies have not shown superiority for IL-2 administered with LAK cells versus therapy 
with HD IL-2 alone [12][12][12][12][12][13]. Furthermore, a randomized phase III 
trial of CD8+ TIL given in combination with rIL-2 in metastatic renal cell carcinoma 
has been negative [13][13][13][13][13][14]. 

 
 
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2.3.1. Baseline Serum VEGF as a Predictor for Non-Response to HD IL-2 
 
Sabatino et al. have reported the results of proteomic analysis of the serum of 
patients (predominantly with metastatic melanoma; N=100, including 48 with 
melanoma and 11 with RCCA) who were treated with high-dose IL-2, using a 
customized, multiplex antibody targeted protein array platform to survey 
expression of soluble factors associated with tumor immunobiology [14].  Soluble 
factors associated with clinical responses were analyzed using a multivariate 
permutation test and survival outcomes were determined using Kaplan-Meier and 
log-rank tests. The customized Pierce SearchLight Proteome ArraysR, (Boston, 
MA) measured 16 proteins per well in standard 96 well plates spotted with different 
monoclonal 
antibodies. 
Sandwich 
ELISA 
was 
utilized 
to 
generate 
chemiluminescence signals for calculation of the levels of each analyte. Sixty 
patients were enrolled in this study. One patient did not complete staging scans and 
could not be included in response determination leaving 59 patients for complete 
analysis. Nineteen patients exhibited an objective response to IL-2 therapy; 18 of 
48 melanoma patients (5 complete and 13 partial) and 1 of 11 RCC patients (1 
partial) responded. 
 
A training set of 10 patients identified 68 of 110 analytes as potentially relevant 
and an independent validation set of 49 patients was then analyzed.  Vascular 
endothelial growth factor (VEGF) and fibronectin were identified as independent 
predictors of non-response to HD IL-2. In particular, high levels of these proteins 
correlated with lack of clinical response and decreased overall survival.  
Combining training and validation analyses identified only VEGF as a predictor of 
response to IL-2 therapy, although fibronectin maintained statistical significance 
after combining the data sets suggesting a potential role as an independent 
predictive biomarker. Patients with serum VEGF levels greater than 125 pg/ml or 
fibronectin levels greater than 8 x 106 pg/ml did not respond to IL-2 therapy and 
elevated levels of these proteins were also associated with a significantly worse 
overall survival. The VEGF family plays a critical role in mediating angiogenesis, 
lymphangiogenesis, and vasculogenesis and has an impact on host innate and 
adaptive immunity [15, 16].  The role of excess VEGF on tumor angiogenesis is 
well documented and recently high circulating serum levels of VEGF were 
associated with poor prognosis in patients with metastatic melanoma [17]. VEGF 
has been shown to block maturation of dendritic cells and inhibit effective priming 
of T cell responses [18, 19]. These data support an important role for VEGF in the 
progression of cancer and evasion of anti-tumor immunity. A therapeutic strategy 
designed to deplete high serum VEGF levels prior to HD IL-2 administration may 
reverse the negative impact of high serum VEGF on dendritic cell maturation and 
T cell priming allowing more effective antitumor T cell cytotoxicity induced by 
HD IL-2.  
 
2.3.2. Studies Testing Bevacizumab in Combination with HD IL-2 
 

 
 
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The safety of the combination of VEGF Trap and High dose IL-2 can be expected 
based on studies involving bevacizumab and IL-2. These include an ongoing phase 
II study of bevacizumab and HD IL-2 in patients with metastatic renal cell 
carcinoma (A Cytokine Working Group Study).  In this study, patients receive 
bevacizumab IV over 30-90 minutes on days -13, 1, 15, 29, 43, 57, and 71 during 
course 1 and on days 1, 15, 29, 43, 57, and 71 during courses 2 and 3. Patients also 
receive high-dose interleukin-2 every 8 hours on days 1-5 and 15-19. Treatment is 
repeated every 84 days for up to 3 courses in the absence of disease progression or 
unacceptable toxicity. Results of the first 15 of a planned 60 patients were reported 
in the ASCO 2007 Annual Meeting (Ernstoff et al.; Abstract 15524) demonstrated 
that HD IL-2 and bevacizumab can be given safely. This study has been updated 
for ASCO 2010 revealing a consistent safety profile (Dandamudi UB, et al. 
Abstract #4530).  Another study presented in ASCO 2007 (Gracia et al.; Abstract 
5103), is a phase II trial of low-dose IL-2 (250,000 U/kg/d SC D1-5 during week 1 
and 125,000 U/kg/d SC D1-5 during weeks 2-6, followed by a 2 week break) and 
bevacizumab (10mg/kg was administered IV every 2 weeks starting on day -14) in 
patients with metastatic renal cell carcinoma. 
 
2.4. 
Rationale 
The VEGF family plays a critical role in mediating angiogenesis, lymphangiogenesis, 
and vasculogenesis and has an impact on host innate and adaptive immunity [15, 16].  
The role of excess VEGF on tumor angiogenesis is well documented and recently high 
circulating serum levels of VEGF were associated with poor prognosis in patients with 
metastatic melanoma [17]. VEGF has been shown to block maturation of dendritic cells 
and inhibit effective priming of T cell responses [18, 19]. These data support an 
important role for VEGF in the progression of cancer and evasion of anti-tumor 
immunity. In addition, recent studies have identified baseline serum VEGF as a marker 
of immune resistance that is predictive for non-response to HD IL-2 [14]. A therapeutic 
strategy designed to deplete high serum VEGF levels prior to HD IL-2 administration 
may reverse the negative impact of high serum VEGF on dendritic cell maturation and 
T cell priming allowing more effective antitumor T cell cytotoxicity induced by HD 
IL-2. in addition, our data with aflibercept as monotherapy has shown promising 
clinical activity in advanced metastatic melanoma with an acceptable safety profile [4].  
 
We hypothesize that sequential biotherapy with aflibercept, as a high-affinity soluble 
VEGF receptor and potent angiogenesis inhibitor, and HD IL-2 will lead to improved 
anti-tumor immunity compared to HD IL-2 alone. This should translate into improved 
anti-tumor clinical efficacy compared to either single agent. 
 
2.4.1. Rationale for the doses selected in the combination and montherapy phases 
 
The study will be conducted in 2 phases for arm A patients: Combination and 
Aflibercept Monotherapy. The combination phase will consist of courses 1, 2 and 
3 during which aflibercept will be administered at 3mg/kg. For the Aflibercept 
Monotherapy Phase aflibercept will be administered at 4 mg/kg. 
 

 
 
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Our primary hypothesis is that the reduction or depletion of high serum VEGF 
levels prior to HD IL-2 administration would reverse immune resistance and the 
negative impact of high serum VEGF on dendritic cell maturation and T cell 
priming allowing more effective antitumor T cell cytotoxicity induced by HD IL-
2. It will ultimately lead to a significant improvement in clinical outcome.  
 
For aflibercept, target pharmacological exposure has been reached at doses ≥2 
mg/kg IV given every 2 weeks. Free aflibercept levels have remained in excess of 
bound aflibercept levels throughout the dosing intervals at this, or higher doses. In 
addition, the concentrations of bound aflibercept were to increase between the 0.3 
and 2 mg/kg dose levels, and then plateau between the 2 and 7 mg/kg dose levels, 
suggesting that free aflibercept was available in sufficient amount to bind all 
endogenous VEGF in this higher dose range. 
 
Our experience with Aflibercept monotherapy at 4 mg/kg in a phase II study 
conducted in melanoma has shown that approximately 16 (out of 41) patients that 
had an aflibercept  dose delay due to toxicity in the first 6 months of therapy. There 
were also 18 patients (of the 41) who had grade 3 or 4 toxicity attributed (possibly, 
probable or definite) to VEGF-trap. All patients who had grade 3-4 had their first 
grade 3-4 within the first 6 months. Therefore, we expect that at 4 mg/kg a 
significant group of patients may have the HD IL-2 treatment delayed in the 
combination phase. 
 
3. 
PATIENT SELECTION 
3.1. 
Eligibility Criteria 
3.1.1. Patients must have histologically or cytologically confirmed metastatic melanoma 
(includes AJCC stage IV or advanced/inoperable stage III. Also includes patients 
with a history of lower stage melanoma and subsequent recurrent metastatic disease 
that is either locally/regionally advanced/inoperable disease or distant metastases).   
 
3.1.2. Patients must have measurable disease, 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 CT scan or clinically (must be measurable with calipers) according 
to RECIST version 1.1 [20].  See Section 10 for the evaluation of measurable 
disease. 
 
3.1.3. Patients must be free of brain metastasis by contrast-enhanced CT/MRI scans 
within 4 weeks prior to enrollment. If known to have prior brain metastases, must 
not have evidence of active brain disease after definitive therapy (surgery, radiation 
therapy or stereotactic radiosurgery) on two successive MRI evaluations at least 3 
months apart (one of which is  4 weeks prior to starting the study drugs). 
 
3.1.4. A patient may be treatment naïve. However, up to two prior regimens for metastatic 
melanoma are allowed. Prior adjuvant IFN-α is allowed. No prior therapy with 
bevacizumab, aflibercept or interleukin-2 (IL-2).  

 
 
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Patients must not have received systemic therapy or radiotherapy within the 
preceding 4 weeks. Patients must have recovered from adverse events due to agents 
administered more than 4 weeks earlier. 
 
Patients must be at least 4 weeks from major surgery and have fully recovered from 
any effects of surgery, and be free of significant detectable infection. 
 
For patients who have received prior anti-CTLA4 monoclonal antibody therapy 
(ipilimumab or tremelimumab), there is a risk of bowel perforation with IL-2 
therapy. Therefore, for these patients if they have a history of colitis or diarrhea 
during anti-CTLA4 monoclonal antibody therapy, they should have a formal 
evaluation by a gastroenterologist and a colonoscopy should be considered to 
demonstrate the absence of active bowel inflammation before initiating IL-2 
therapy on this protocol.    
3.1.5. Age >16 years.   
 
Because VEGF Trap interferes with growth plate maturation in animals, this agent 
may be inappropriate for use in patients <16 years of age. For this reason and 
because no dosing or adverse event data are available on the use of VEGF Trap in 
children, patients <16 years of age are excluded from this study but may be eligible 
for future pediatric single-agent trials, if applicable. 
 
3.1.6. Life expectancy of greater than 3 months in the opinion of the investigator. 
 
3.1.7. ECOG performance status 0 or 1 (Karnofsky >70%; see Appendix A). 
 
3.1.8. Patients must have normal organ and marrow function as defined below: 
 
- 
leukocytes  
 
 
 
 
>3,000/mcL 
- 
absolute neutrophil count  
>1,500/mcL 
- 
platelets 
 
 
 
 
 
>100,000/mcL 
- 
total bilirubin  
 
 
 
within 1.5 x institutional upper limit of 
normal 
- 
AST(SGOT)/ALT(SGPT) 
<2.5 X institutional upper limit of normal 
- 
creatinine  
 
 
 
 
within 1.5 x institutional upper limit of 
normal 
OR 
- 
creatinine clearance  
 
>60 mL/min/1.73 m2 for patients with 
creatinine levels above institutional normal 
 
3.1.9. Urine protein should be screened by urinalysis for Urine Protein Creatinine Ratio 
(UPCR). For UPCR > 1, a 24-hour urine protein should be obtained and the level 
should be <500 mg.  
 
3.1.10. Patients on full-dose anticoagulants (e.g., warfarin) with PT INR >1.5 are eligible 

 
 
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provided that both of the following criteria are met: 
 
a) The patient has an in-range INR (usually between 2 and 3) on a stable 
dose of oral anticoagulant or on a stable dose of low molecular weight 
heparin. 
 
b) The patient has no active bleeding or pathological condition that carries 
a high risk of bleeding (e.g., tumor involving major vessels or known 
varices). 
 
 
3.1.11. Pulmonary:  FEV1 > 2.0 liters or > 75% of predicted for height and age.  (PFTs are 
required for patients over 50 years old or with significant pulmonary or smoking 
history).  
 
3.1.12. Cardiac:  No evidence of congestive heart failure, symptoms of coronary artery 
disease, myocardial infarction less than 6 months prior to entry, serious cardiac 
arrhythmias, or unstable angina.  
 
Patients who are over 40 years old or have had previous myocardial infarction 
greater than 6 months prior to study entry or have significant cardiac family history 
(CAD or serious arrhythmias) will be required to have a negative or low probability 
cardiac stress test (for example, thallium stress test, stress MUGA, stress echo or 
exercise stress test) for cardiac ischemia within 8 weeks prior to registration. 
An echocardiogram should be performed at baseline in all patients. Ejection 
fraction (EF) from baseline echocardiogram must be within the institutional limits 
of normal as determined by the reading cardiologist. If the baseline cardiac stress 
test incorporates an echocardiogram, then this will not need to be done again at 
baseline.  
 
3.1.13. CNS:  No history of cerebrovascular accident or transient ischemic attacks    within 
the past 6 months.  
 
3.1.14. Although clinical data are lacking on the immediate or long-term effects of 
aflibercept on the developing human fetus, the agent is teratogenic and negatively 
affects fetal development in animal models. For this reason and because 
antiangiogenic agents as well as other therapeutic agents used in this trial are known 
to be teratogenic, women of child-bearing potential and men must agree to use 
adequate contraception (hormonal or barrier method of birth control; abstinence) 
prior to study entry, for the duration of study participation, and for at least 6 months 
after completion of study therapy. Should a woman become pregnant or suspect she 
is pregnant while participating in this study, she should inform her treating 
physician immediately. 
 
Women should not be lactating and, if of childbearing age, should have a negative 
pregnancy test (b-HCG test; serum or urine, minimum sensitivity 25 IU/L or 
equivalent units of b-HCG) within two week of registration in the study. 

 
 
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3.1.15. Ability to understand and the willingness to sign a written informed consent 
document. 
 
3.2. 
Exclusion Criteria 
3.2.1. Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for 
nitrosoureas or mitomycin C) prior to entering the study or those who have not 
recovered from adverse events due to agents administered more than 4 weeks 
earlier. 
 
3.2.2. Patients may not be receiving any other investigational agents. 
 
3.2.3. Patients with brain metastases should be excluded from this clinical trial except as 
noted above under section 3.1.3.  
 
3.2.4. Patients with known hypersensitivity to Chinese hamster ovary cell products or 
other recombinant human antibodies, and patients with a history of allergic 
reactions attributed to compounds of similar chemical or biologic composition to 
other agents used in the study. 
 
3.2.5. Serious or non-healing wound, ulcer, or bone fracture. 
 
3.2.6. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal 
abscess within 28 days of treatment. 
 
3.2.7. Patients with the following invasive procedures: 
• major surgical procedure, open biopsy or significant traumatic injury within 28 
days   prior to Day 1 therapy. 
• anticipation of need for major surgical procedures during the course of the study. 
• minor surgical procedures, fine needle aspirations or core biopsies within 7 days 
prior to Day 1 of therapy. Central venous catheter placements are permitted to be 
completed 7 or more days prior to Day 1 of therapy. However, peripherally 
inserted central catheter (PICC or PIC line) may be placed at any time prior to or 
during therapy. 
 
3.2.8. Patients with clinically significant cardiovascular or cerebrovascular disease: 
• history of cerebrovascular accident or transient ischemic attack within past 6 
months 
• uncontrolled hypertension, defined as blood pressure >150/100 mm Hg or systolic 
BP >180 mm Hg if diastolic blood pressure <90 mm Hg, on at least 2 repeated 
determinations on separate days within past 3 months. 
• myocardial infarction, CABG or unstable angina within the past 6 Months. 
• New York Heart Association grade III or greater congestive heart failure 
(Appendix E), serious cardiac arrhythmia requiring medication, unstable angina 
pectoris within past 6 months. 
• clinically significant peripheral vascular disease within past 6 months. 

 
 
PhII-107, NCI# 8628 
 
 
8.21.17v 
26
• Pulmonary embolism, DVT, or other thromboembolic event within past 6 months. 
 
3.2.9. History of tumor-related or other serious hemorrhage, bleeding diathesis, or 
underlying coagulopathy. 
 
3.2.10. PT INR >1.5 unless the patient is on full-dose warfarin. 
 
3.2.11. Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection or psychiatric illness/social situations that would limit compliance with 
study requirements. 
 
3.2.12. HIV-positive patients on combination antiretroviral therapy are ineligible because 
of the potential for pharmacokinetic interactions with VEGF Trap. In addition, 
these patients are at increased risk of lethal infections when treated with marrow-
suppressive therapy.   
 
3.2.13. Patients who have other current malignancies are not eligible. Patients with other 
malignancies are eligible if they have been continuously disease free for > 5 years 
prior to the time of randomization. Patients with prior history at any time of any in 
situ cancer, lobular carcinoma of the breast in situ, cervical cancer in situ, atypical 
melanocytic hyperplasia or melanoma in situ are eligible. Patients with prior history 
of basal or squamous skin cancer are eligible. Patients who have had multiple 
primary melanomas are eligible. 
 
3.2.14. Patients must not have autoimmune disorders or conditions of immunosuppression 
that require current ongoing treatment with systemic corticosteroids (or other 
systemic immunosuppressants), including oral steroids (i.e., prednisone, 
dexamethasone) or continuous use of topical steroid creams or ointments or 
ophthalmologic steroids or steroid inhalers.  
 
If a patient had been taking steroids, at least 2 weeks must have passed since the 
last dose. 
 
3.3. 
Inclusion of Women and Minorities 
Both men and women and members of all races and ethnic groups are eligible for this 
trial.  
 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
6 
+ 
5 
= 
11 
Not Hispanic or Latino 
39 
+ 
55 
= 
94 
Ethnic Category: Total of all 
subjects 
45 
(A1) 
+ 
60 
(B1) 
= 
105 
 
(C1) 
Racial Category 
 

 
 
PhII-107, NCI# 8628 
 
 
8.21.17v 
27
American Indian or Alaskan Native 
0 
+ 
0 
= 
0 
Asian 
2 
+ 
1 
= 
3 
Black or African American 
0 
+      0 
= 
0 
Native Hawaiian or other Pacific 
Islander 
0 
+      0 
= 
0 
White 
43 
+ 
59 
= 
102 
Racial Category: Total of all 
subjects 
45 
(A2) 
+ 
60 
(B2) 
= 
105 
 
(C2) 
 
These numbers are based on the actual historical accrual demographics at City of Hope 
National Medical Center only for patients with melanoma, but these estimates will vary 
with the other CCCP sites (or other consortia sites) accruing from the different 
catchment areas. In addition, the study investigators strongly believe in improving the 
accrual rates of non-white patients and therefore would like to express their strong 
commitment to make an improvement over these historical accrual numbers at COH as 
listed in the accrual targets table. 
 
4. 
REGISTRATION PROCEDURES 
4.1. 
General Guidelines 
Eligible patients will be entered on study centrally at the California Cancer Consortium 
Data Coordinating Center (DCC) at the City of Hope.  All sites should call the DCC at 
(626) 256-4673 extension 65928 to verify slot availabilities.   
 
Following registration, patients should begin protocol treatment within 1 week.  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 DCC should be notified of cancellations 
as soon as possible. 
 
Except in very unusual circumstances, each participating institution will order DCTD-
supplied agents directly from CTEP.  Agents may be ordered by a participating site 
only after the initial IRB approval for the site has been forwarded by the Coordinating 
Center to the CTEP PIO (PIO@ctep.nci.nih.gov) except for Group studies. 
 
4.2. 
Registration Process 
Once the signed informed consent has been obtained, all pretreatment evaluations have 
been performed, and patient’s eligibility has been confirmed by the data coordinating 
center a patient will be entered on study.   
 
To register a patient, the research nurse or data manager must complete the 
eligibility/registration form and contact the Consortium office (Data Coordinating 
Center for the California Cancer Consortium) at the City of Hope (626-256-4673, ext. 
65928), FAX a copy of the completed eligibility checklist, required pre-study tests 
(laboratory and pathology report), signed Informed Consent, signed Patients' Bill of 
Rights and HIPAA authorization form. (FAX Number: 626-256-8654).  See Appendix 

 
 
PhII-107, NCI# 8628 
 
 
8.21.17v 
28
C (“Registration Procedures”) 
 
The research nurse or data manager at the participating site will then call the Data 
Coordinating Center at Tel# 626-256-4673 extension 65928 to confirm receipt of all 
registration documents. To complete the registration process, the data coordinating 
center coordinator will: 
 
• 
Verify the eligibility 
• 
Register the patient on study 
• 
Assign a patient accession number 
• 
Fax or e-mail the patient study number and dose to the participating site 
• 
Call the research nurse or data manager at the participating site and verbally 
confirm registration. 
 
5. 
TREATMENT PLAN 
5.1. 
Overall Treatment Plan 
 
Definitions: 
 
1. A cycle of IL-2: eligible patients receive high-dose IL-2 at 600,000 IU/kg IV 
every 8 hours for up to 14 doses. This constitutes one cycle of IL-2. 
2. A cycle of Aflibercept: eligible patients receive aflibercept at 3 mg/kg 
(combination phase) or 4 mg/kg (maintenance phase) IV every 2 weeks. This 
constitutes one cycle of aflibercept. 
3. The combination phase (Arm A): during this phase, IL-2 and aflibercept will 
be given concurrently. It consists of 3 courses of combination therapy.   
a. Each course consists of 2 cycles of IL-2 as follows: high-dose IL-2  at 
600,000 IU/kg is given IV every 8 hours for up to 14 doses (one cycle), 
followed by a rest period of  1-2 weeks and readmission for a second high 
dose IL-2 cycle for up to 14 doses (2nd cycle).  
b. In addition, aflibercept will be given concurrently at 3 mg/kg IV every 2 
weeks, but in course 1 only aflibercept will start 2 weeks prior to IL-2. 
Therefore, course 1 will consist of 5 cycles of aflibercept, while courses 2 
and 3 will consist of 4 cycles of aflibercept each.  
c. Based on the occurrence of treatment-related toxicities and requirements for 
dose adjustments or delays, a patient may or may not receive the full 
planned treatment, but response assessment will continue to be carried out 
at the end of each course. 
4. The maintenance phase (Arm A): only aflibercept monotherapy will be given during this 
phase at 4 mg/kg IV every 2 weeks. Response assessment will be carried out every 12 
weeks (6 cycles of aflibercept) for the first 2 years, then every 6 months (-/+ 2 weeks) for 
years 3-5, then yearly (-/+ 4 weeks) afterwards.   
 
The planned treatment for Arm A consists of 3 courses of combination aflibercept and 
high dose IL-2 (the combination phase) followed by maintenance aflibercept 

 
 
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8.21.17v 
29
monotherapy (aflibercept monotherapy phase). Arm B is high dose IL-2 alone. 
Response assessment will occur at the end of each course of combination therapy (arm 
A) and patients without evidence of disease progression (RECIST v.1.1) or limiting 
toxicities will be offered additional courses of treatment (or maintenance aflibercept 
therapy). 
 
Management and dose modifications associated with the above adverse events are 
outlined in Section 6. 
 
Arm A:Course 1 (consists of 10 weeks): Aflibercept to be given at 3 mg/kg IV on day 
1 of weeks 1, 3, 5, 7 and 9. HD IL-2 will be given at 600,000 U/kg/dose IV Q8h x 5 
days (max 14 doses) starting on day 1 of weeks 3 and 5. Response assessment will be 
done during week 10. 
 
Arm A: Courses 2 and 3 (consist of 8 weeks each): Patients with evidence of SD, PR 
or CR on response assessment will be offered additional courses of therapy up to a total 
of 3 courses. During courses 2 and 3, aflibercept will be given at 3 mg/kg on day 1 of 
weeks 1, 3, 5 and 7. HD IL-2 will be given at 600,000 U/kg/dose IV Q8h x 5 days (max 
14 doses) starting on day 1 of weeks 1 and 3.  
 
Arm A: Maintenance aflibercept monotherapy: Following response assessment after 
course 3 of combination therapy and after resolution of all toxicities to ≤ grade 1 
(CTCAE v.4), aflibercept monotherapy will be initiated to be administered at 4 mg/kg 
IV on Day 1of each 14-day cycle. Plus or minus 2-day time windows for each treatment 
day are permitted, as are treatment delays of up to 2 weeks in case of unresolved 
toxicity. In this case, blood pressure monitoring should be done weekly for the first 
3 weeks of the maintenance phase to ensure tolerance of the higher aflibercept 
dose. However, if the aflibercept dose had to be reduced during the combination phase 
due to aflibercept-related toxicities, then that reduced dose will be used for maintenance 
therapy. No need for weekly monitoring of blood pressure, if the reduced dose has 
already been demonstrated to be tolerable.   
 
 
Course 1 (Arm A) 
Course 
1 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Aflibercept 
3 mg/kg IV 
X 
 
X 
 
X 
 
X 
 
X 
 
HD IL-2 
600,000 
U/kg/dose IV 
Q8h x 5 days 
 
 
X 
 
X 
 
 
 
 
 

 
 
PhII-107, NCI# 8628 
 
 
8.21.17v 
30
 
 
 
 
 
 
Blood samples for the purpose of measuring serum VEGF levels or other laboratory 
corollary studies will be collected at the multiple time points as noted in section 9.1.1. 
See Section 9.1.1 for handling, processing, and shipping procedures. 
 
For arm B, patients will receive HD IL-2 alone following the institutional standard of 
care guidelines. Patients will receive a maximum of 3 courses (6 cycles; 1 course of 
IL_2 in arm B = 2 cycles of IL-2). Response assessment will be carried out at the end 
of each course. In the absence of disease progression by RECIST v.1.1, patients will 
be offered additional courses of therapy for a maximum of 3 courses (6 cycles). 
 
5.2. 
Aflibercept Administration  
Treatment will be administered on an outpatient basis. Reported adverse events and 
potential risks are described in Section 7. Appropriate dose modifications for 
aflibercept are described in Section 6. 
 
• Patients will receive a dose of aflibercept administered IV on Day 1 of each 14-
day cycle. Plus or minus 2-day time windows for each treatment day are 
permitted, as are treatment delays of up to 2 weeks in case of unresolved 
toxicity. Aflibercept will be administered as an IV infusion over at least 1 hour 
(max 14 doses) 
Response 
Assessment 
 
 
 
 
 
 
 
 
 
X 
Course 2 (Arm A) 
Course 3 (Arm A) 
Courses 2-3 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Aflibercept 
3 mg/kg IV 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
HD IL-2 
600,000 
U/kg/dose 
IV Q8h x 5 
days (max 
14 doses) 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
Response 
Assessment 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 

 
 
PhII-107, NCI# 8628 
 
 
8.21.17v 
31
into a peripheral vein or a central venous catheter via a system that is compatible 
with aflibercept. 
• The dosing solutions will be prepared by diluting aflibercept concentrate (25 
mg/mL) with the appropriate volume of 0.9% NaCl or 5% dextrose to a final 
concentration between 0.6 mg/mL and 8 mg/mL. This will be administered 
intravenously over at least 1 hour into a peripheral vein or central venous 
catheter using an infusion pump. CADD Legacy pump will be used for the 
infusion. See Section 8.1.1 on other suitable delivery devices that are allowed.  
• Doses may be modified for toxicity as described in Section 6. New cycles of 
therapy may not begin until any aflibercept -related adverse events have 
adequately resolved. The Principal Investigator should be contacted for any 
treatment delay of >2 weeks duration. 
 
Special Cautions/Safety Issues 
 
• Infusion and hypersensitivity reactions (e.g., rash, urticaria, fever, rigors, 
hypertension, wheezing, or hypoxia) may occur during or shortly after IV 
administration of protein therapeutics. The most appropriate premedication 
regimen for use with aflibercept has not been determined, and patients should 
not be given prophylactic premedication for acute infusion reactions without 
prior discussion with the NCI Senior Investigator. 
 
If infusion hypersensitivity reactions occur in a given patient, then institutional 
treatment guidelines for similar therapeutic agents should be followed. 
Subsequent doses of aflibercept should not be given without prior consultation 
with the NCI Senior Investigator to discuss appropriate premedication, and 
should be accompanied by an increased level of vigilance in observation and 
monitoring, administration of premedications, etc. However, dose reductions 
will not be made for acute infusion reactions. 
 
If a patient experiences a hypersensitivity or infusion reaction to 
aflibercept, serum should be obtained to evaluate for anti-aflibercept 
antibody formation at the time of the reaction. Please see section 9.2 for 
serum sample collection, preparation and shipping.  
 
• Since aflibercept is a protein, it is possible that patients might experience 
allergic or immunologic reactions to aflibercept administration. If a 
potentially immune-mediated event occurs during infusion of study drug, the 
ongoing infusion will be stopped immediately. Following any potentially 
immunologic toxicity, dosing may not be resumed until the event has been 
reviewed by the investigator and the NCI Senior Investigator, and a plan of 
management has been formulated. 
 
• Hypertension is a known and potentially serious adverse event associated with 
aflibercept treatment. Patients should have their blood pressure monitored 
weekly during the first cycle of therapy and prior to each infusion of aflibercept. 

 
 
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8.21.17v 
32
Aflibercept treatment modifications due to hypertension should follow the 
instructions in Section 6.1. 
 
• Given the potential for hemorrhage or wound healing complications with 
aflibercept, the agent should not be administered ≤ 48 hours following minor 
surgical procedures (e.g., fine needle biopsy/aspiration, placement of a central 
venous access device, or removal/biopsy of a skin lesion), or until evidence of 
wound healing (e.g., scab formation) is observed, whichever is longer. 
 
• Given the potential for osteonecrosis of the jaw with aflibercept in patients who 
have had previous radiation to the head and neck, special attention should be 
given to any complaints of jaw pain, oral pain or sore mouth. 
 
 
• Any patient with an anti- aflibercept (VEGF Trap) antibody level above the 
limit of quantitation who develops a grade ≥2 systemic immunologic adverse 
effect considered at least possibly related to study drug, will be permanently 
discontinued from study drug administration.  
 
• Any patient with an anti- aflibercept (VEGF Trap) antibody level above the 
limit of quantitation who develops one of the following will be permanently 
discontinued from study treatment: 
− 24-hour urine protein total >3.5 grams, or 
− confirmed doubling of the baseline serum creatinine to a level >1.5 x ULN 
while in a well-hydrated state, or 
− confirmed doubling of the baseline BUN to a level >1.5 x ULN while in a 
well-hydrated state 
 
5.3. 
Aldesleukin (Interleukin-2) Administration 
Aldesleukin (Interleukin-2, IL-2) will be administered on an inpatient basis.  Reported 
adverse events and potential risks for aldesleukin are described in Section 7.   
 
• Patients will receive a total of 6 cycles (1 cycle = 5 days) of IL-2 as described 
in section 5.1. A cycle of IL-2 may be delayed for up to 2 weeks in case of 
unresolved toxicity. 
 
• Aldesleukin will be administered at 600,000 IU/kg IV bolus q 8 hours during 
days 1-5 of each cycle (maximum 14 doses per 5 day cycle).  
 
• For arm A (combination arm), dose 1 of aldesleukin on day 1 of each cycle of 
IL-2 will be administered after aflibercept given on that day. 
 
• For arm A (combination arm) an echocardiogram will be performed at baseline 
and following each course of therapy (week 10 of course 1 and week 8 of 
courses 2 and 3). Evidence of cardiac dysfunction compared to baseline 

 
 
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8.21.17v 
33
(decrease in ejection fraction by 25% or more) will lead to treatment 
discontinuation. For arm B, there is no requirement to repeat the 
echocardiogram following each course of IL-2 therapy unless it is clinically 
indicated.  
 
NOTE: Ejection fraction (EF) from baseline echocardiogram done on arm 
A must be within the institutional limits of normal as determined by the 
reading cardiologist. For patients who are required to have a baseline 
cardiac stress test, if the baseline cardiac stress test incorporates an 
echocardiogram, then this will not need to be done again at baseline. For 
subsequent echocardiograms, evidence of cardiac dysfunction compared to 
baseline (decrease in ejection fraction by 25% or more) will lead to 
treatment discontinuation. 
 
• As all institutions participating in this protocol have established and 
experienced high dose interleukin-2 programs, the administration of 
aldesleukin (at the protocol’s specified dose and frequency) and the dose 
delay/discontinuation criteria during a cycle of IL-2 will follow the institutional 
standard of care guidelines. A useful guide is provided by  Schwartzentruber 
DJ.  J Immunother. 2001 Jul-Aug;24(4):287-93[21]. 
 
• For patients receiving high dose IL-2 on Arm A or B and who take anti-
hypertensive medications, it is recommended that the blood pressure 
medications be managed as follows (individual variations are acceptable at 
the discretion of the treating physician when it is felt in the best interest of 
the patient): 
o On the day of admission, the morning blood pressure medications 
should be taken, if the first dose of IL-2 is expected to be given that 
evening and not during the day. Otherwise, if the first dose of IL-2 is 
expected to be given during the day, then the morning blood pressure 
medications should be held. The goal is two-fold: 
▪ Avoid uncontrolled hypertension in patients holding the AM 
antihypertensive medications, if the dose will be delayed till the 
evening.  
▪ Avoid excessive hypotension during IL-2 if the AM dose was 
given and the first dose of IL-2 was given during the day. 
o If the first dose of IL-2 is anticipated to be given in the evening of the 
day of admission, then the blood pressure medications should be held 
for that evening and throughout IL-2 treatment unless otherwise 
specified by the treating physician.  
o Upon completion of IL-2 therapy, the blood pressure medications 
should restarted as soon as the IL-2 induced hypotension (low blood 
pressure) has resolved. Most importantly, the blood pressure 
medications should be restarted before the patient is discharged home, 
unless the patient was found to be hypotensive and the treating physician 
decides to closely monitor the blood pressure before initiating the 

 
 
PhII-107, NCI# 8628 
 
 
8.21.17v 
34
antihypertensive medications.  
 
5.4. 
General Concomitant Medication and Supportive Care Guidelines 
Because there is a potential for interaction of aflibercpt with other concomitantly 
administered drugs, the case report form must capture the concurrent use of all other 
drugs, over-the-counter medications, or alternative therapies. All patient treatments 30 
days prior to registration onto the study, at any time during the study, and up to 60 
days after the end of the study will be considered as concomitant treatments. Any 
treatment administered following the withdrawal from the study that is used to treat 
new or unresolved events related to the study treatment, is also considered as 
concomitant treatment. The type, dose, and route of administration for all concomitant 
treatments must be documented in the case report form (CRF). 
 
Concomitant medications should be kept to a minimum during the study. However, if 
these are considered necessary for the patient’s welfare and are unlikely to interfere 
with the investigational products, they may be given at the discretion of the 
investigator and recorded in the CRF. 
 
The following concomitant treatments are permitted during this study: 
 
• all supportive measures (including hyperalimentation and blood transfusions) 
consistent with optimal patient care. 
 
• medications for chronic pain management, including narcotic analgesics, are 
permitted as clinically indicated. 
 
• therapeutic use of hematopoietic growth factors is permitted at the 
investigator’s discretion and should follow American Society of Clinical 
Oncology guidelines for their use. 
 
5.5. 
Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue for    
per study protocol 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, 
 

 
 
PhII-107, NCI# 8628 
 
 
8.21.17v 
35
 
Arterial thromboembolic events including cerebrovascular accidents, 
myocardial infarctions, transient ischemic attacks, new onset or worsening 
of pre-exiting angina, 
 
 
Evidence of cardiac dysfunction (decrease in ejection fraction by 25% or 
more) compared to baseline noted on study echocardiogram testing, 
  
5.6. 
Duration of Follow Up 
Patients will be followed for 5 years after removal from study or until death, whichever 
occurs first.  Patients removed from study for unacceptable adverse events will be 
followed until resolution or stabilization of the adverse event. The frequency and the  
type of evaluations during this follow up period will follow institutional standard of 
care practices. For patients who wish not to follow with a study investigator, they can 
be followed by their treating physician of choice and also following local standard of 
care practices. Data on disease progression and survival will be collected on all patients 
every 3-4 months.  
 
6. 
DOSING DELAYS/DOSE MODIFICATIONS (Aflibercept) 
NOTE: 
As all institutions participating in this protocol have established and 
experienced high dose interleukin-2 programs, the administration of aldesleukin (at the 
protocol’s specified dose and frequency) and the dose delay/discontinuation criteria during 
a cycle of IL-2 will follow the institutional standard of care guidelines. A useful guide is 
provided by Schwartzentruber DJ.  J Immunother. 2001 Jul-Aug;24(4):287-93[21]. 
 
Aflibercept doses will be modified as shown below. Doses reduced for drug-related toxicity 
should generally not be re-escalated, even if the reduced dose produces minimal or no 
toxicity. 
 
Dose Levels for Dose Reduction 
 
 
 
The lowest dose level will be utilized for patients requiring multiple simultaneous dose 
adjustments. No more than 2 aflibercept dose reductions per patient are permitted. 
Patients requiring more than 2 aflibercept dose reductions will have aflibercept 
permanently discontinued. Unless otherwise indicated, all grades of toxicity refer to NCI 
CTCAE v.4.0 grades.  
 
Dose Level 
Aflibercept 
0 
4 mg/kg 
3 mg/kg 
-1 
3 mg/kg 
2 mg/kg 
-2 
2 mg/kg 
1 mg/kg 

 
 
PhII-107, NCI# 8628 
 
 
8.21.17v 
36
• Frequent blood pressure monitoring is important in patients receiving aflibercept.  
Patients should seek immediate medical advice if their blood pressure (BP) 
exceeds 180 mmHg (systolic) or 105 mmHg (diastolic) at any time and should also 
be encouraged to contact their physician if they are concerned about any symptoms 
that may be associated with high blood pressure (e.g., headache). 
 
• Renal function (creatinine and urinary protein) should be frequently monitored as 
suggested by the pathologic changes noted in animal studies and evidence from 
studies of other antiangiogenic agents. Specific guidelines for management of 
proteinuria are presented in Section 6.2. 
 
In the absence of disease progression or limiting toxicities, patients may continue IL-
2 therapy per study protocol even if aflibercept was permanently discontinued.  
 
6.1. 
Management of Hypertension 
Increases in blood pressure (BP) and cases of hypertension have been associated with 
many drugs acting on the VEGF pathway. The proposed mechanism for this increase 
is through inhibition of VEGF-induced peripheral vasodilation. Hypertension 
following aflibercept treatment has been seen in animal studies as well as clinical trials.  
 
Notes: 
 
• While patients are receiving treatment with aflibercept, the early initiation 
of antihypertensive treatment for grade 1 or 2 hypertension to minimize 
more severe or persistent hypertension is not considered a grade 3 adverse 
event. 
 
• Decisions to hold or decrease the aflibercept dose during treatment must be 
based on BP readings taken in the clinic by a medical professional. 
 
• In case of new-onset or worsening (grade ≥ 2) hypertension, see chart on page 
24. Other preferred treatment options include calcium-channel blockers or 
alpha-1 blockers. Angiotensin converting enzyme inhibitors or angiotensin II 
antagonists may also be appropriate in the absence of significant renal 
dysfunction or suspicion of renovascular disease. Beta blockers and diuretics 
should be used with caution due to their relatively slow onset of action. 
Ultimately, antihypertensive treatment must be individualized based on the 
presence of comorbidity such as diabetes, cardiovascular, or renal disease, 
additionally taking into account the safety and efficacy of any prior 
antihypertensive therapy received. In addition, oral and/or intravenous sodium 
intake should be carefully monitored in these patients. Blood pressure and 
electrolyte monitoring should be performed at least once or twice weekly until 
stable blood pressure control is achieved. Early consultation with a cardiologist 
is strongly encouraged in case of uncontrolled hypertension. 
 

 
 
PhII-107, NCI# 8628 
 
 
8.21.17v 
37
• The following table is a recommendation: 
 
 
Hypertension Monitoring and Management 
Grade 
(CTCAEv4.0) 
Antihypertensive 
Therapy 
Blood Pressure Monitoring 
Aflibercept Dose 
Modification 
Grade 1 
• 
None (Consider initiating 
therapy of choice per MD &/OR 
Increase doses of existing  
medications) 
• Baseline 
• Standard monitoring per 
study protocol 
• In addition, start daily BP 
monitoring at home and 
plan to start treatment for 
grade 2 HTN   
No Change 
Grade 2- Mild 
• Initiate therapy of choice per MD 
&/OR 
• Increase doses of existing  
medications until BP controlled or 
at maximum dose 
• Increased frequency of 
monitoring until stabilized 
No Change 
Persistent Moderate 
Hypertension 
 
(Definition: Patients 
who initiate 
antihypertensive 
therapy or have 
additional 
medications  added to 
existing therapy but 
their BP is not 
controlled to grade 1 
or less) 
• Initiate therapy of choice per MD 
&/OR 
• Increase doses or number of 
medications until BP controlled or 
at maximum dose 
• Increased frequency of 
monitoring until stabilized 
e.g. every 48 hours 
• Supervised by healthcare 
professional 
If partial or no 
control and BP 
still in a moderate 
range for 
24-48 hours, hold 
aflibercept and add 
additional drugs, 
increasing to a 
maximum dose until 
hypertension 
controlled;  
 
Monitor for 
hypotension; 
 
Decrease 
aflibercept by 1 
dose level 
Grade 3- Severe 
• Start immediate therapy with 2 
drug combination including at 
least a DHP- CCB 
• Escalate doses to achieve optimal 
control of BP, up to the maximum 
dose 
• If partial or no BP control, add 
additional drugs up to 4; increase 
to optimal or maximum doses of 
all drugs 
• Increased frequency of 
monitoring until stabilized 
e.g. every 48 hours 
• Supervised by healthcare 
professional 
Hold aflibercept; If 
control of BP in the 
Mild range, restart 
VEGF TRAP at the 
next lower dose 
level 
 
If partial or no 
control, 
discontinue 
therapy per 
investigator 
 
Stop aflibercept if 
hypertension is 
symptomatic, 
hospitalize patient 

 
 
PhII-107, NCI# 8628 
 
 
8.21.17v 
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for 
management of BP 
Grade 4 
Hypertensive Crisis 
• Optimal management with 
intensive support IV in ICU 
• Hospitalize patient for 
management 
Off protocol 
therapy; 
 
Discontinue 
aflibercept; 
 
Monitor closely for 
hypotension 
• 
Abbreviations: dihydropyridine calcium-channel blockers (DHP-CCB), selective beta blockers (BB), 
Angiotensin Converting Enzyme Inhibitors (ACEI), Angiotensin II Receptor Blockers (ARB) 
• 
If patients require a delay of > 2 weeks for management of hypertension, discontinue aflibercept therapy 
• 
If patients require > 2 dose reductions, discontinue aflibercept therapy 
• 
Patients may have up to 2 drugs for management of hypertension prior to any dose reduction in aflibercept 
• 
24-48 hour should elapse between modifications of antihypertensive therapy 
• 
Hypertension should be graded using the NCI CTCAEv4.0 
 
6.2. 
Proteinuria 
A 24-hour urine collection for quantitative protein determination must be obtained for 
a urine protein:creatinine ratio (UPCR) >1. Instructions for dose modifications due to 
proteinuria are summarized below. 
 
Proteinuria 
Action to be Taken 
Grade ≤ 2 
No modification. 
Grade 3 (4+ or >3.5 grams/24 hours) 
• Delay dosing until recovery to urinary protein <2 grams/24 hours. 
• Reduce subsequent doses of aflibercept by 1 dose level if proteinuria 
does not recover to <2 grams/24 hours within 2 weeks. 
• Discontinue patients from aflibercept treatment who experience 
recurrent Grade 3 toxicity after 2 dose reductions. 
Grade 4 
Consult a nephrologist and discontinue patient from aflibercept treatment. 
 
6.3. 
Other Adverse Events 
• No dose modifications should be performed for adverse events (such as alopecia) 
that do not directly affect the patient’s physical health.  
 
• Dose-reduce aflibercept for grade 3 or 4 aflibercept-related adverse events aside 
from hypertension and proteinuria even if therapy is not delayed.  Exception: 
Patients with grade 3 or 4 electrolyte or other laboratory abnormalities that could 
be corrected within 48 hours to grade 2 or less could be retreated with the same 
dose of aflibercept. Re-treatment with aflibercept could be done as soon as these 
abnormalities have been corrected to grade 2 or less.    
 
• Any other drug-related adverse event considered serious or which causes a >2-week 

 
 
PhII-107, NCI# 8628 
 
 
8.21.17v 
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study treatment delay will result in the reduction of subsequent doses by one dose 
level.  If patient cannot restart therapy after 2 weeks delay, contact the Principal 
Investigator for discussion of removing patient from study. 
 
• Other aflibercept dose reductions not described above may be performed at the 
discretion of the investigator after discussion with the NCI Senior Investigator, 
provided that criteria for patient withdrawal from study treatment (described in 
Section 5.5) have not been met. 
 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) 
will determine whether the event requires expedited (via CTEP-AERS) reporting in 
addition to routine reporting. 
 
7.1. 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) 
 
7.1.1. CAEPR for Aflibercept (VEGF-Trap, NSC 724770) 
 
 
 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an 
agent using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Specific Protocol Exceptions to Expedited 
Reporting (SPEER), appears in a separate column and is identified with bold and 
italicized text. This subset of AEs (SPEER) is a list of events that are protocol 
specific exceptions to expedited reporting to NCI via CTEP-AERS (except as 
noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements'  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_even
ts.htm for further clarification. Frequency is provided based on 811 patients. 
Below is the CAEPR for aflibercept (VEGF-Trap). 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted 
in parentheses next to the AE in the SPEER.  If this CAEPR is part of a 
combination protocol using multiple investigational agents and has an AE 
listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
 
Version 2.6, November 24, 20151 

 
 
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8.21.17v 
40
 
 Adverse Events with Possible  
 Relationship to Ziv-aflibercept (VEGF-Trap, AVE 0005) 
 (CTCAE 4.0 Term) 
[n= 811] 
  
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
Likely (>20%) 
Less Likely (<=20%) Rare but Serious (<3%)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 
 Anemia (Gr 2) 
 
 
Febrile neutropenia 
  
 
 
Hemolytic uremic 
syndrome 
  
 
 
Thrombotic 
thrombocytopenic 
purpura 
  
CARDIAC DISORDERS 
  
 
 
Chest pain - cardiac 
  
 
 
Myocardial infarction 
  
 
 
Restrictive 
cardiomyopathy 
  
 
 
Cardiac disorders - 
Other (intracardiac 
thrombus) 
  
GASTROINTESTINAL DISORDERS 
  
Abdominal pain 
 
 
 Abdominal pain (Gr 2) 
 
Anal mucositis 
 
  
 
Constipation 
 
 Constipation (Gr 2) 
 
Diarrhea 
 
 Diarrhea (Gr 2) 
 
 
Gastrointestinal fistula2   
 
 
Gastrointestinal 
perforation3 
  
 
Mucositis oral 
 
  
Nausea 
 
 
 Nausea (Gr 2) 
 
Vomiting 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS   
 
Edema limbs 
 
 Edema limbs (Gr 2) 
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2) 
 
Pain 
 
  
IMMUNE SYSTEM DISORDERS 
  
 
Allergic reaction 
  
  
INFECTIONS AND INFESTATIONS 
  
 
Infection4 
 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  

 
 
PhII-107, NCI# 8628 
 
 
8.21.17v 
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 Adverse Events with Possible  
 Relationship to Ziv-aflibercept (VEGF-Trap, AVE 0005) 
 (CTCAE 4.0 Term) 
[n= 811] 
  
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
Likely (>20%) 
Less Likely (<=20%) Rare but Serious (<3%)  
 
 
Wound complication 
 
  
 
Wound dehiscence 
 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
  
 
Alkaline phosphatase 
increased 
 
  
 
Aspartate 
aminotransferase 
increased 
 
  
Lymphocyte count 
decreased 
 
 
 Lymphocyte count decreased 
(Gr 4) 
 
Neutrophil count 
decreased 
 
 Neutrophil count decreased 
(Gr 4) 
 
Platelet count decreased  
 Platelet count decreased (Gr 4) 
 
Weight loss 
 
  
 
White blood cell 
decreased 
 
 White blood cell decreased (Gr 
2) 
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 2) 
 
Dehydration 
 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
 Arthralgia (Gr 2) 
 
Back pain 
 
  
 
Myalgia 
 
 Myalgia (Gr 2) 
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
  
Headache 
 
 
 Headache (Gr 3) 
 
 
Ischemia 
cerebrovascular 
 Ischemia cerebrovascular (Gr 
2) 
 
 
Reversible posterior 
leukoencephalopathy 
syndrome 
  
 
 
Transient ischemic 
attack 
  
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury 
  

 
 
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8.21.17v 
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 Adverse Events with Possible  
 Relationship to Ziv-aflibercept (VEGF-Trap, AVE 0005) 
 (CTCAE 4.0 Term) 
[n= 811] 
  
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
Likely (>20%) 
Less Likely (<=20%) Rare but Serious (<3%)  
 
 
Proteinuria 
 
 Proteinuria (Gr 3) 
 
 
Renal disorders - Other 
(nephrotic syndrome) 
  
REPRODUCTIVE SYSTEM AND BREAST DISORDERS 
  
 
Genitourinary system 
fistula5 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 3) 
 
Pharyngolaryngeal pain 
 
  
Voice alteration 
 
 
 Voice alteration (Gr 2) 
 
Respiratory, thoracic, and 
mediastinal disorders - 
Other (rhinorrhea) 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
  
 
Palmar-plantar 
erythrodysesthesia 
syndrome 
 
  
 
Rash maculo-papular 
 
  
 
Skin hyperpigmentation  
  
VASCULAR DISORDERS 
  
Hypertension 
 
 
 Hypertension (Gr 3) 
 
Thromboembolic event 
 
 Thromboembolic event (Gr 3) 
 
Vascular disorders - 
Other (hemorrhage)6 
 
 Vascular disorders - Other 
(hemorrhage)6 (Gr 2) 
 
1This table will be updated as the toxicity profile of the agent is revised. Updates will be 
distributed to all Principal Investigators at the time of revision. The current version can be 
obtained by contacting PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, 
the protocol and the agent should be included in the e-mail. 
2Gastrointestinal fistulas may include: Anal fistula, Colonic fistula, Duodenal fistula, Esophageal 
fistula, Gastric fistula, Gastrointestinal fistula, Rectal fistula, and other sites under the 
GASTROINTESTINAL DISORDERS SOC. 
 
3Gastrointestinal perforation imay include: Colonic perforation, Duodenal perforation, 

 
 
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8.21.17v 
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Esophageal perforation, Gastric perforation, Ileal perforation, Jejunal perforation, Rectal 
perforation, and Small intestinal perforation under the GASTROINTESTINAL DISORDERS 
SOC. 
 
4Infection may include any of the 75 infection sites under the INFECTIONS AND 
INFESTATIONS SOC. 
 
5Genitourinary fistulas may include: female genital tract fistula, uterine fistula, and vaginal 
fistula. 
 
6The majority of hemorrhage events were mild.  Major events, defined as symptomatic bleeding 
in a critical area or organ (e.g., eye, GI hemorrhage, GU hemorrhage, respiratory hemorrhage), 
and nervous system [including fatal intracranial hemorrhage and cerebrovascular accident] have 
been reported. 
 
Adverse events reported on Ziv-aflibercept (VEGF-Trap, AVE 0005) trials but for which 
there is insufficient evidence to suggest that there was a reasonable possibility that Ziv-
aflibercept (VEGF-Trap, AVE 0005) caused the event. 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system 
disorders - Other (hemoglobin increased); Hemolysis 
CARDIAC DISORDERS - Acute coronary syndrome; Cardiac disorders - Other (left 
ventricular diastolic dysfunction); Heart failure; Left ventricular systolic dysfunction; 
Pericarditis; Supraventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Tinnitus; Vertigo 
ENDOCRINE DISORDERS - Hyperthyroidism; Hypothyroidism 
EYE DISORDERS - Blurred vision; Extraocular muscle paresis; Eye disorders - Other 
(blindness transient); Eye disorders - Other (diplopia); Vitreous hemorrhage 
GASTROINTESTINAL DISORDERS - Abdominal distension; Colitis; Dental caries; Dry 
mouth; Dyspepsia; Dysphagia; Esophageal pain; Flatulence; Gastritis; Gastrointestinal disorders 
- Other (early satiety); Gastrointestinal disorders - Other (enteric fistula); Gastrointestinal 
disorders - Other (eructation); Gastrointestinal disorders - Other (gastrointestinal necrosis); 
Gastrointestinal disorders - Other (hiatal hernia);Gastrointestinal disorders - Other (intestinal 
ischemia); Gastrointestinal disorders - Other (pneumatosis intestinalis); Gastrointestinal 
disorders - Other (peritonitis); Gingival pain; Hemorrhoids; Ileus; Oral pain; Rectal mucositis; 
Rectal ulcer; Small intestinal mucositis; Small intestinal obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema face; 
Edema trunk; Facial pain; Infusion related reaction; Injection site reaction; Non-cardiac chest 
pain 
HEPATOBILIARY DISORDERS - Cholecystitis 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Biliary anastomotic 
leak; Gastric anastomotic leak; Vascular access complication 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Blood bilirubin 
increased; Creatinine increased; Ejection fraction decreased; GGT increased; Investigations - 
Other (elevated LDH) 
METABOLISM AND NUTRITION DISORDERS - Hypercalcemia; Hyperglycemia; 

 
 
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Hyperkalemia; Hypoalbuminemia; Hypocalcemia; Hypoglycemia; Hypokalemia; 
Hypomagnesemia; Hyponatremia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Avascular 
necrosis; Chest wall pain; Generalized muscle weakness; Head soft tissue necrosis; Joint range 
of motion decreased; Muscle weakness upper limb; Musculoskeletal and connective tissue 
disorder - Other (muscle spasms); Musculoskeletal and connective tissue disorder - Other 
(musculoskeletal stiffness); Musculoskeletal and connective tissue disorder - Other (rotator cuff 
tear); Myositis; Neck pain; Osteonecrosis of jaw; Pain in extremity; Pelvic soft tissue necrosis 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) - Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (tumor 
hemorrhage) 
NERVOUS SYSTEM DISORDERS - Amnesia; Ataxia; Cognitive disturbance; Dysgeusia; 
Encephalopathy; Extrapyramidal disorder; Leukoencephalopathy; Memory impairment; 
Paresthesia; Peripheral sensory neuropathy; Seizure; Syncope; Vagus nerve disorder 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Depression; Insomnia; Psychiatric 
disorders - Other (mental status change); Psychosis 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Irregular menstruation 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Hypoxia; Laryngeal 
mucositis; Nasal congestion; Pharyngeal mucositis; Pleural effusion; Pneumonitis; 
Pneumothorax; Pulmonary fibrosis; Respiratory, thoracic and mediastinal disorders - Other 
(nasal dryness); Respiratory, thoracic and mediastinal disorders - Other (tracheal fistula); 
Respiratory, thoracic and mediastinal disorders - Other (septal perforation); Tracheal mucositis 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin; Hyperhidrosis; Nail loss; 
Rash acneiform; Skin and subcutaneous tissue disorders - Other (hyperemia); Skin ulceration 
VASCULAR DISORDERS - Hematoma; Hypotension; Peripheral ischemia; Phlebitis 
 
 
Note: Ziv-aflibercept (VEGF-Trap, AVE 0005) 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. 
 
 
7.1.2. CAEPR for Interleukin-2 (NSC 373364) 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an agent 
using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Agent Specific Adverse Event List (ASAEL), 
appears in a separate column and is identified with bold and italicized text. This 
subset of AEs (ASAEL) contains events that are considered 'expected' for expedited 
reporting purposes only. Refer to the 'CTEP, NCI Guidelines: Adverse Event 
Reporting 
Requirements'  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_even
ts.htm for further clarification. The CAEPR does not provide frequency data; refer 
to the Investigator's Brochure for this information. Below is the CAEPR for 
interleukin-2. 

 
 
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8.21.17v 
45
 
 
 
Version 1.1, December 14, 2009 
Adverse Events with Possible 
 Relationship to Interleukin-2  
(CTCAE 4.0 Term) 
 
 
 EXPECTED AEs FOR CTEP-
AERS REPORTING  
 
Agent Specific Adverse Event 
List 
(ASAEL) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
Expected 
 
Anemia 
 Anemia 
CARDIAC DISORDERS 
  
 
Conduction disorder 
 Conduction disorder 
 
Left ventricular systolic dysfunction 
 Left ventricular systolic 
dysfunction 
 
Myocardial infarction 
  
 
Myocarditis 
 Myocarditis 
 
Palpitations 
 Palpitations 
 
Sinus tachycardia 
 Sinus tachycardia 
 
Supraventricular tachycardia 
 Supraventricular tachycardia 
 
Ventricular arrhythmia 
 Ventricular arrhythmia 
EAR AND LABYRINTH DISORDERS 
  
 
Hearing impaired 
 Hearing impaired 
EYE DISORDERS 
  
 
Blurred vision 
 Blurred vision 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
  
 
Diarrhea 
 Diarrhea 
 
Dry mouth 
 Dry mouth 
 
Gastrointestinal disorders - Other 
(Perforation, GI – Select) 
  
 
Gastrointestinal disorders - Other (small 
bowel fistula) 
 Gastrointestinal disorders - Other 
(small bowel fistula) 
 
Mucositis oral 
 Mucositis oral 
 
Nausea 
 Nausea 
 
Vomiting 
 Vomiting 
GENERAL DISORDERS AND ADMINISTRATION SITE 
CONDITIONS 
  
 
Chills 
 Chills 
 
Edema limbs 
 Edema limbs 

 
 
PhII-107, NCI# 8628 
 
 
8.21.17v 
46
 
Fatigue 
 Fatigue 
 
Fever 
 Fever 
IMMUNE SYSTEM DISORDERS 
  
 
Allergic reaction 
 Allergic reaction 
 
Autoimmune disorder 
 Autoimmune disorder 
INFECTIONS AND INFESTATIONS 
  
 
Infections and Infestations – Other 
(Infection – Select) 
 Infections and Infestations – Other 
(Infection – Select) 
INVESTIGATIONS 
  
 
Activated partial thromboplastin time 
prolonged 
 Activated partial thromboplastin 
time prolonged 
 
Alanine aminotransferase increased 
 Alanine aminotransferase 
increased 
 
Alkaline phosphatase increased 
 Alkaline phosphatase increased 
 
Aspartate aminotransferase increased 
 Aspartate aminotransferase 
increased 
 
Blood bilirubin increased 
 Blood bilirubin increased 
 
Creatinine increased 
 Creatinine increased 
 
GGT increased 
 GGT increased 
 
INR increased 
 INR increased 
 
Platelet count decreased 
 Platelet count decreased 
 
Weight gain 
 Weight gain 
 
White blood cell decreased 
 White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS 
  
 
Acidosis 
 Acidosis 
 
Anorexia 
  
 
Hyperuricemia 
 Hyperuricemia 
 
Hypocalcemia 
 Hypocalcemia 
 
Hypoglycemia 
 Hypoglycemia 
 
Hypomagnesemia 
  
 
Hyponatremia 
 Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE 
DISORDERS 
  
 
Arthralgia 
 Arthralgia 
 
Myalgia 
 Myalgia 
 
Myositis 
 Myositis 
NERVOUS SYSTEM DISORDERS 
  
 
Depressed level of consciousness 
 Depressed level of consciousness 
 
Dizziness 
  
 
Headache 
 Headache 
 
Memory impairment 
 Memory impairment 
 
Nervous system disorders - Other (sleep  Nervous system disorders - Other 

 
 
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8.21.17v 
47
disturbances) 
(sleep disturbances) 
 
Peripheral sensory neuropathy 
 Peripheral sensory neuropathy 
 
Seizure 
 Seizure 
PSYCHIATRIC DISORDERS 
  
 
Anxiety 
  
 
Confusion 
 Confusion 
 
Personality change 
 Personality change 
 
Psychosis 
 Psychosis 
RENAL AND URINARY DISORDERS 
  
 
Acute kidney injury 
 Acute kidney injury 
RESPIRATORY, THORACIC AND MEDIASTINAL 
DISORDERS 
  
 
Adult respiratory distress syndrome 
 Adult respiratory distress 
syndrome 
 
Allergic rhinitis 
 Allergic rhinitis 
 
Apnea 
  
 
Cough 
  
 
Dyspnea 
 Dyspnea 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 Alopecia 
 
Pruritus 
 Pruritus 
 
Rash maculo-papular 
 Rash maculo-papular 
VASCULAR DISORDERS 
  
 
Capillary leak syndrome 
 Capillary leak syndrome 
 
Hypotension 
 Hypotension 
 
Peripheral ischemia 
  
 
Thromboembolic event 
  
 
Vascular disorders - Other (vasodilation)   
 
1 This table will be updated as the toxicity profile of the agent is revised.  Updates will be 
distributed to all Principal Investigators at the time of revision.  The current version can be obtained 
by contacting PIO@CTEP.NCI.NIH.GOV .  Your name, the name of the investigator, the protocol 
and the agent should be included in the e-mail. 
 
Also reported on interleukin-2 trials but with the relationship to interleukin-2 still 
undetermined: 
 
CARDIAC DISORDERS - Mobitz type I; Pericardial effusion 
EYE DISORDERS - Eye disorders - Other (mydriasis) 
GASTROINTESTINAL DISORDERS - Gastrointestinal disorders – Other (Hemorrhage, GI – 
Select); Pancreatitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - General 
disorders and administration site conditions - Other (phospholipid syndrome); Hypothermia; 
Multi-organ failure 

 
 
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INFECTIONS AND INFESTATIONS – Infections and infestations – Other (Infection 
(documented clinically or microbiologically with Grade 3 or 4 neutrophils [ANC <1.0 x 10e9/L]) 
– Select) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Soft tissue necrosis 
lower limb 
NERVOUS SYSTEM DISORDERS - Encephalopathy; Syncope 
PSYCHIATRIC DISORDERS - Agitation 
RENAL AND URINARY DISORDERS - Renal and urinary disorders - Other (acute tubular 
necrosis) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary 
hemorrhage; Bronchospasm; Hypoxia; Pneumothorax; Pulmonary edema 
VASCULAR DISORDERS – Phlebitis, splenic infarction (in a patient with a history of 
thrombocytosis treated with the combination of IL2 and aflibercept). 
 
Note: Interleukin-2 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. 
 
 
7.1.2.1.Protocol-Specific Expedited Adverse Event Reporting Exclusions for 
Interleukin-2 related Adverse Events 
 
• 
For this protocol only, certain interleukin-2 related AEs/grades are exceptions to 
the Expedited Reporting Guidelines and do not require expedited reporting ( i.e., 
CTEP-AERS).  The following interleukin-2 related AEs must be reported only if 
they exceed the grade listed below through the routine reporting mechanism 
(Section 7.4): 
 
 
Lymphocyte count decreased (Gr 4) 
 
Neutrophil count decreased (Gr 4) 
 
Platelet count decreased (Gr 4) 
 
White blood cell decreased (Gr 2) 
 
Dyspnea (Gr 3) 
 
Fatigue (Gr 3)  
 
Headache (Gr 3) 
 
Nausea (Gr 3) 
 
Vomiting (Gr 2)  
 
Diarrhea (Gr 2)  
 
Anemia (Gr 2)  
 
Abdominal pain (Gr 2) 
 
Fever (Gr 2) 
 
Edema limbs (Gr 2) 
 
 Anorexia (Gr 2) 
 
Arthralgia (Gr 2) 
 
Myalgia (Gr 2) 
 
Cough (Gr 2) 

 
 
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8.21.17v 
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Hypophosphatemia, Gr 3 
 
7.2. 
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 4.0 will be utilized for AE reporting.  All appropriate treatment 
areas should have access to a copy of the CTCAE version 4.0.  A copy of the 
CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov). 
 
• 
‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ (see Section 7.1 above) 
for expedited reporting purposes only.  ‘Expected’ AEs (the ASAEL) are bold and 
italicized in the CAEPR (Section 7.1.1). 
 
• 
Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3. 
Expedited Adverse Event Reporting 
 
7.3.1. Expedited AE reporting for this study must use CTEP-AERS (CTEP- Adverse 
Event 
Reporting 
System), 
accessed 
via 
the 
CTEP 
home 
page 
(http://ctep.cancer.gov).  The reporting procedures to be followed are presented in 
the “CTEP, NCI Guidelines: Adverse Event Reporting Requirements” which can 
be downloaded from the CTEP home page (http://ctep.cancer.gov).  These 
requirements are briefly outlined in the table below (Section 7.3.2). 
 
CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Study Coordinator of the Lead Organization, Principal 
Investigator, and the local treating physician.  CTEP-AERS provides a copy feature 
for other e-mail recipients.  PLEASE INCLUDE CCCP@COH.ORG ON ALL 
CTEP-AERS REPORTS SUBMITTED. 
 
7.3.2. Expedited Reporting Guidelines – CTEP-AERS Reporting Requirements for 
Adverse Events that occur within 30 Days1 of the Last Dose of the Investigational 
Agent on Phase 2 and 3 Trials 
 
Phase 2 and 3 Trials 
 
 
Grade 1 
 
Grade 2 
 
Grade 2 
 
Grade 3 
 
Grade 3 
Grades 
4 & 52 
Grades 
4 & 52 
Unexpected 
and 
Expected 
 
Unex-
pected 
 
 
Expected 
Unexpected 
Expected 
Unex- 
pected  
Expected 
with  
without 
with  
without 

 
 
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8.21.17v 
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Hospitali-
zation 
Hospitali- 
zation 
Hospitali- 
zation 
Hospitali- 
zation 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
10 
Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
10 
Calendar 
Days 
10 
Calendar 
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
10 
Calendar 
Days 
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the last 
dose of treatment with an agent under a CTEP IND require reporting as follows: 
CTEP-AERS 24-hour notification followed by complete report within 5 calendar days for: 
• 
Grade 4 and Grade 5 unexpected events  
 
CTEP-AERS 10 calendar day report: 
• 
Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
• 
Grade 5 expected events 
2 Although an CTEP-AERS 24-hour notification is not required for death clearly related to progressive disease, a full report 
is required as outlined in the table. 
December 15, 2004 
 
Note:  All deaths on study require both routine and expedited reporting regardless of 
causality.  Attribution to treatment or other cause must be provided. 
 
• 
Expedited AE reporting timelines defined: 
➢ “24 hours; 5 calendar days” – The investigator must initially report the AE via 
CTEP-AERS within 24 hours of learning of the event followed by a complete 
CTEP-AERS report within 5 calendar days of the initial 24-hour report. 
➢ “10 calendar days” - A complete CTEP-AERS report on the AE must be 
submitted within 10 calendar days of the investigator learning of the event.  
 
• 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates 
hospitalization (or prolongation of existing hospitalization) must be reported 
regardless of attribution and designation as expected or unexpected with the 
exception of any events identified as protocol-specific expedited adverse event 
reporting exclusions.   
 
• 
Any event that results in persistent or significant disabilities/incapacities, 
congenital anomalies, or birth defects must be reported via CTEP-AERS if the 
event occurs following treatment with an agent under a CTEP IND. 
 
7.4. 
Use the NCI protocol number and the protocol-specific patient ID assigned 
during trial registration on all reports.  Routine Adverse Event Reporting 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
through CTEP-AERS must also be reported in routine study data submissions. 
 
7.5. 
Secondary AML/MDS 
A secondary malignancy is a cancer caused by treatment for a previous malignancy 
(e.g., treatment with radiation or chemotherapy). A secondary malignancy is not 
considered a metastasis of the initial neoplasm. A secondary malignancy is unrelated 
to the first cancer that was treated, and may occur months or even years after initial 

 
 
PhII-107, NCI# 8628 
 
 
8.21.17v 
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treatment. 
 
CTEP has removed the old AML/MDS forms. Effective August 25, 2010, all secondary 
malignancies that occur following treatment with an agent under an NCI IND/IDE must 
be reported via CTEP-AERS. CTCAE v4.0 has three options available to describe 
treatment-related events: 
 
• Leukemia secondary to oncology chemotherapy  
• Myelodysplastic syndrome  
• Treatment related secondary malignancy 
 
8. 
PHARMACEUTICAL INFORMATION 
A list of the adverse events and potential risks associated with the investigational or 
commercial agents administered in this study can be found in Section 7.1. 
 
8.1. 
CTEP-Supplied Investigational Agents 
 
8.1.1. VEGF Trap (NSC 724770) 
 
Other Names: Ziv-aflibercept, AVE0005              M.W.: 115 kDa 
 
Classification: Recombinant humanized fusion protein (Chinese hamster ovary 
source). 
 
Description: The fusion protein VEGF Trap is 2 portions of human VEGF 
receptors 
extracellular domains, VEGFR1 and VEGFR2, fused to the Fc portion of human 
IgG1. 
 
Mode of Action: The cytokine VEGF binds to and activates VEGFR1 and 
VEGFR2 on the vascular endothelium, promoting new vessel formation. VEGF 
Trap is a soluble recombinant decoy receptor that binds and inactivates 
extravacular and hematologic VEGF. It reduces tumor vasculature density, 
available nutrient supply, and tissue matrix components escaping from leaky 
tumor vessels. 
 
How Supplied: VEGF Trap is supplied by sanofi-aventis Pharmaceuticals and 
distributed by the CTEP, DCTD, NCI.  VEGF Trap is a sterile, nonpyrogenic, 
colorless to pale yellow solution in vials of 200 mg (8 mL) at a concentration of 25 
mg/mL. The solution contains the following excipients:  sucrose, sodium chloride, 
sodium citrate dihydrate, citric acid monohydrate, polysorbate 20, sodium 
phosphate dibasic heptahydrate, sodium phosphate monobasic monohydrate, and 
water for injection. The pH of VEGF Trap is 6.2. The product is packaged in a type 
1, clear borosilicate glass vial closed with a flanged cap with tear-off lid and 

 
 
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8.21.17v 
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inserted sealing disc, Flurotec® (PTFE) coated. 
 
Preparation: Do not shake VEGF Trap.  Withdraw the dose from the vial and 
further 
dilute in 0.9% sodium chloride or 5% dextrose to a final concentration between 
0.6 mg/mL and 8 mg/mL. 
 
Storage: Store intact vials in the refrigerator (2° to 8° C). 
 
Stability: Shelf life stability studies of intact vials are ongoing. VEGF Trap’s 
provisional shelf-life is up to 36 months at 2° to 8°C. 
 
Caution: VEGF Trap diluted to a concentration of 0.6 to 8 mg/mL in 
0.9% NaCl or 5% dextrose is stable for 8 hours at 25°C in infusion 
cassettes or IV bags, or up to 24 hours in the refrigerator. 
 
Route of Administration: Intravenous  
 
Method of Administration: Administered VEGF Trap intravenously over 1 hour 
into a peripheral vein or central venous catheter using an infusion pump; do not 
exceed an infusion duration of 2 hours. VEGF Trap may be administered using 
suitable polyvinyl chloride intravenous delivery devices containing DHEP, 
polyethylene lined PVC, DEHP free PVC containing tris(2-ethylhexyl)trimellitate 
TOTM; polypropylene, polyurethane, or polybutadiene. 
polyolefin intravenous delivery devices; and/or polyethersulfone filters. The 
infusion 
set must contain a 0.2 micron polyethersulfone inline filter (for example, a low 
protein binding/low drug binding Supor™ Membrane by Pall, or PES membranes 
by 
Millipore).  Polyvinylidene fluoride (PVDF) filters or Nylon filters should not be 
used. 
 
8.1.2. Agent Ordering 
 
NCI-supplied agents may be requested by the Principal Investigator (or their 
authorized designees) at each participating institution. Pharmaceutical 
Management Branch (PMB) policy requires that the agent be shipped directly to 
the institution where the patient is to be treated. PMB does not permit the transfer 
of agents between institutions (unless prior approval from PMB is obtained). The 
CTEP assigned protocol number must be used for ordering all CTEP-supplied 
investigational agents. The responsible investigator at each participating 
institution 
must be registered with CTEP, DCTD through an annual submission of FDA 
form 1572 (Statement of Investigator), Curriculum Vitae, Supplemental 
Investigator Data Form (IDF), and Financial Disclosure Form (FDF). If there are 
several participating investigators at one institution, CTEP-supplied 

 
 
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investigational agents for the study should be ordered under the name of one lead 
investigator at that institution. 
 
Active CTEP-registered investigators and investigator-designated shipping 
designees and ordering designees can submit agent requests through the PMB 
Online Agent Order Processing (OAOP) application (https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx).  Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account 
(https://eapps-ctep.nci.nih.gov/iam/) and the maintenance of an “active” account 
status and a “current” password.  For questions about drug orders, transfers, 
returns, or accountability, call (240) 276-6575 Monday through Friday between 
8:30 am and 4:30 pm (ET) or email PMBAfterHours@mail.nih.gov anytime. 
 
8.1.3. Agent Accountability 
 
Agent Inventory Records – The investigator, or a responsible party designated by 
the investigator, must maintain a careful record of the inventory and disposition of 
all agents received from DCTD using the NCI Drug Accountability Record Form 
(DARF). See the NCI Investigator’s Handbook for Procedures for Drug 
Accountability and Storage. 
 
8.2. 
Commercial Agents 
 
8.2.1. Interleukin-2 
 
Other Names:  Aldesleukin, IL-2, rlL-2, T-cell growth factor 
 
Classification:  Biological response modifier 
 
Mode of Action:  Endogenous substance secreted by OK-T4 cells and 
lymphocytes. Enhances primary and secondary cytotoxic T-cell responses, causes 
T-cell mitogenesis and proliferation, and enhances non-killer cell activity. 
 
Storage and Stability:  Intact vials are stored in the refrigerator (2-8°C) with 
protection from light. Each vial bears an expiration date. 
 
Reconstituted IL-2 should be further diluted with 5% Dextrose, USP. It is not to be 
mixed with saline-containing solutions. Reconstituted IL-2 may be diluted as 
necessary in volumes of 50 ml to 500 ml with 5% Dextrose, USP plus 0.1% 
Albumin Human, USP. When diluting, the Albumin Human, USP should be added 
to the 5% Dextrose Injection, USP prior to the addition of the IL-2. When diluted 
for IV administration in 5% Dextrose Injection, USP, a plastic bag (e.g., Viaflex, 
manufactured by Travenol Laboratories, Inc.) containing 0.1% Albumin Human. 
IL-2 is chemically stable for 48 hours at refrigerated and room temperatures, 2-
30°C. 

 
 
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Dose Specifics:  Interleukin-2 600,000 MIU/kg/dose or 720,000 MIU/kg/dose over 
15 minute IV infusion every 8 hours on Days 1-5 of each cycle for a maximum of 
14 doses. For the purpose of this study, interleukin-2 will be given at 600,000 
MIU/kg. 
 
Preparation: Aseptically inject 1.2 ml of sterile water for injection into the vial to 
dissolve the lyophilized cake. Since contents of the vial are under vacuum, the 
diluent should be directed against the sides of the vial to avoid excess foaming. 
Remove flip-off plastic cap and swab the target area of the stopper with antiseptic. 
 
Administration:  For sterility considerations, the reconstituted IL-2 should be 
administered immediately or held at 2-8°C for up to 12 hours in 1.2 ml of sterile 
water for injection, and is stable for at least 24 hours at room temperature. 
 
Incompatibilities:  Incompatible with normal saline (results in a precipitate). It 
should not be mixed with anything except D5W and sterile water. 
 
Availability:  IL-2 is a FDA approved therapy for melanoma and is commercially 
available. 
 
Toxicity:  See section 7.1.2. 
 
 
 
For more information please refer to the drug’s package insert. 
 
9. 
CORRELATIVE/SPECIAL STUDIES 
9.1. 
Laboratory Correlative Studies 
All patients participating in the study must undergo correlatives studies.  Laboratory 
correlates will include the following: 
 
• 
Evaluate baseline serum VEGF level as a predictor for response to this combination 
regimen to compare the response rates and survival rates between high (greater 
than 125 pg/ml) and low baseline serum VEGF. 
• 
Measurement of baseline VEGFR2 prior to therapy. 
• 
Measuring VEGF levels prior to and at completion of IL-2 to measure if VEGF 
remained low throughout the 5 days that IL-2 is administrated. 
 
In addition to these studies listed above, other correlatives studies may be done, 
utilizing research samples collected on this study, that will primarily focus on 
biomarkers of prognosis or prediction of therapeutic benefit based on current or future 
scientific evidence.  
 
9.1.1. Collection of Specimens  
Blood specimens will be collected for the purpose of laboratory corollary studies 
as follows: 

 
 
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Table. Blood sample Collection 
Course 1 
Red Top 
Tubes5 
Green Top 
Tubes6 
PAX 
tubes7 
Yellow 
Top 
Tube8 
Baseline1 
3 
10 
1 
1 
Cycle 1 of IL-2, Day 12 
1 
none 
none 
none 
Cycle 1 of IL-2, the day 
after the last dose of IL-2 
1 
none 
none 
none 
Cycle 2 of IL-2, Day 13  
1 
none 
none 
none 
Cycle 2 of IL-2, the day 
after the last dose of IL-2 
3 
10 
1 
none 
Course 2/3 
 
 
 
none 
Week 14 
1 
none 
none 
none 
Cycle 2 of IL-2, the day 
after the last dose of IL-2 
3 
10 
1 
none 
Month 12 
3 
10 
1 
none 
Progression 
3 
10 
1 
none 
1. Baseline: within 72 hours of the first dose of aflibercept (Arm A) or IL-2 (Arm B). 
2. Cycle 1 of IL-2, Day 1: before both the dose aflibercept and the first dose of IL-2 
given on that day. This applies to Arm A only. For Arm B, this time point is not 
required. 
3. Cycle 2 of IL-2, Day 1: before both the dose aflibercept and the first dose of IL-2 
given on that day (Arm A) or the first dose of IL-2 (Arm B). 
4. Course 2/3, week 1, before the first dose of Aflibercept for arm A and the first dose 
of IL-2 for arm B  
5. 10 cc RED top tubes (BDcat #367820 or SST 367988 gel separator/gold top/ tiger 
tubes if the center can centrifuge them) 
6. 10 cc GREEN top tubes (BD cat # 366480) 
7. PAX tube (Fisher #23 021 01) 
8. 10 cc YELLOW top tube. (BD cat # 364606) 
 
Transfer or, if applicable, ship blood samples by overnight courier Monday-
Thursday only to: 
 
Immunologic Monitoring and Cellular Products Laboratory 
University of Pittsburgh Cancer Institute 
UPCI-IMCPL, Suite 1.26 
Study Coordinator 
Hillman Cancer Center 
5117 Centre Avenue 
Pittsburgh, PA 15213 
Tel: (412) 624-0078 
FAX: (412) 623-6625 
 

 
 
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Please submit the Specimen Submission Form (Appendix D) for each sample 
sent.  
 
Notify the IMCPL study coordinator by fax (412-623-6625) when the samples are 
shipped. If you are unable to get through to the laboratory by fax, telephone the 
study coordinator and provide the tracking number. 
 
The IMCPL is the Immunology Core Laboratory for ECOG and has a great deal of 
experience in shipment and handling of blood, tumor and lymph node samples. The 
IMCPL provides contact information and a fax request form to the sites, and when 
a patient is scheduled, a tissue sample kit is shipped (generally via ground) to the 
site, containing all necessary blood tubes, tumor containers (containing sterile 
medium) sample instructions as well as return overnight shipping instructions. 
Upon receipt in the laboratory, the blood and tissue samples are logged in a 
processed according to the protocol-specific SOPs. Samples which are 
compromised (hemolyzed or which arrived more than 48 hours after 
draw/isolation) are discarded (currently less than 2% of >750 samples which arrive 
at the laboratory annually from ECOG sites).  
 
Pathology Specimen Submissions for Banking for Research Studies (at baseline, 
then at disease progression): 
• Primary Melanoma (for patients with known primary cutaneous melanoma) 
Fifteen (15) unstained slides preferably from the thickest portion of the tumor 
for immunostains (please do not deparaffinise slides) OR, if the primary 
pathologist is willing, please request the corresponding block, which will be 
promptly returned upon request.  If the patient has more than one primary 
lesion, please include above slides and/or block for each primary. 
• Resected in-transit or satellite metastases, or cutaneous metastases, or lymph 
node metastases, or lung metastases 
Fifteen to twenty (15-20) unstained slides from the thickest part of the tumor 
or, if the primary pathologist is willing, please request the corresponding block, 
which will be promptly returned upon request.  
NOTE:  
Please provide a surgical pathology report to accompany the slides.  
• Progression/Relapse Biopsy (if performed, for banking for future research)  
Fifteen to twenty (15-20) unstained slides from the thickest part of the tumor 
or, if the primary pathologist is willing, please request the corresponding block, 
which will be promptly returned upon request.  
 
 Please transfer or, if applicable, ship to the IMCPL, as noted above. For shipping, 
regular mail may be used for these tissue samples OR these may be included in the 
same package with the blood samples shipped by overnight courier. Also please 
notify the IMCPL study coordinator as noted above.  
 

 
 
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9.1.2. VEGF and VEGF R2 Testing 
 
  
 
VEGF levels will be tested in serum collected at the following time points: 
• Course 1: 
o Baseline: before the first dose of aflibercept (within 72 hours of the first 
dose of aflibercept) or IL-2 for Arm B patients.  
o Cycle 1 of IL-2, Day 1: before both the dose aflibercept  (Arm A) and the 
first dose of IL-2 given on that day. This applies to arm A only and not 
required for Arm B. 
o Cycle 1 of IL-2, the day after the last dose of IL-2 (Arms A and B). 
o Cycle 2 of IL-2, Day 1: before both the dose aflibercept (Arm A) and the 
first dose of IL-2 given on that day (Arms A and B). 
o Cycle 2 of IL-2, the day after the last dose of IL-2 (Arms A and B). 
• Courses 2 and 3: 
o  Week 1: before the first dose aflibercept for Arm A and the first dose of 
IL-2 for Arm B. 
o Cycle 2 of IL-2, the day after the last dose of IL-2 (Arms A and B) 
• Month 12 
• Progression 
VEGF R2 levels will be tested only at baseline in both arms. 
 
The standardized R&D Systems ELISA kits for measurement of both VEGF and 
VEGF-R2. These will be done at the University of Pittsburgh Cancer Institute 
Immune Monitoring Laboratory (IML).  The IMCPL participates in national quality 
control and comparison surveys and is inspected and accredited by the College of 
American Pathologists (CAP).  It is licensed by DHHS to receive specimens from out-
of-state locations (CLIA ID# 39D0657004).  The IML is also licensed by the state of 
Pennsylvania and is inspected by the Pennsylvania Department of Health.  The CPL 
is registered with FDA (#3004571535) for somatic cell culture and tissue 
processing.  It also has a Master File (BB-MF-12244) for the facility operation with 
FDA. 
 
9.1.3. Banking of Specimens for Future Laboratory Corollary Studies 
 
Specimens will be banked at the IMCPL and additional laboratory corollary studies 
will  be conducted based on the availability of specimens and funding. 
 
9.2. 
    Anti-VEGF Trap Antibody Testing 
 
If a patient experiences a hypersensitivity or infusion reaction to aflibercept, serum 
should be obtained to evaluate for anti-aflibercept antibody formation at the time 
of the reaction. At the time of the reaction, whole blood will be collected in red-top 

 
 
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vacutainer tubes (containing no additives or anti-coagulant) for serum preparation 
using the procedures outlined below. (Schematic diagrams of sample labeling and 
collection procedures are provided in Appendices F and G).   
 
9.2.1. Serum Sample Collection and Preparation 
 
1. Sample collection: Collect 5 mL of blood in one red top tube (B-D Cat #367814 
Hemogard, 5mL plastic tubes with silica clot activator) for each Anti-
Aflibercept Antibody sample.  
2. Immediately mix by inverting tube at least once.  
3. Allow serum to clot for 30 minutes.  
4. Centrifuge at 1200 x g for 15 minutes to separate clot from serum.  
5. Within 30 minutes after centrifugation draw off serum very slowly with transfer 
pipette, approaching no closer than 0.5cm of the buffy coat and taking great 
care not to disturb the buffy coat (any contamination may invalidate the assay).  
6. Labels are provided by Regeneron for each specimen. Complete copy with the 
patient’s subject identification number. Place one label on the cryovial (see 
Appendix F for diagrammatic instructions on label placement) and the second 
copy on the Sample Shipping Log before transferring the patient sample. Note: 
for duplicate samples, repeat the labeling step  
7. Preparation of serum samples for Anti-Aflibercept antibody: Aliquot serum 
specimen equally into TWO plastic cryovials, one for the primary and one for 
the duplicate sample. Do NOT exceed 1.5mL of serum into each cryovial; 
acceptable cryovials are VWR #14224-374 or Corning #430659.  
8. Freeze all cryovials as soon as possible. All specimens must be stored frozen at 
-20° C (or colder) in a freezer that is NOT frost-free, until shipped to the 
laboratory at Regeneron Pharmaceuticals, Inc. Note: The Sample Freezer 
Temperature Log must be completed daily.  
 
9.2.2. Serum Sample Shipping  
 
1. Complete the appropriate information for each blood draw on the Sample 
Shipping Log. Include: subject identification number, and date and time of 
specimen collection, etc. The original Sample Shipping Log should be kept in the 
Sample Shipping Log Binder. The Sample Shipping Log pages have been pre-
numbered. Use one form per shipment. Begin a new form with each new shipment.  
 
2. Include a copy of the Sample Shipping Log with the shipment and send to 
Regeneron Pharmaceuticals, Inc. at the address below:  
 
Sample Management 
Regeneron Pharmaceuticals, Inc. 
767 Old Saw Mill River Road 
Tarrytown, NY 10591 
 

 
 
PhII-107, NCI# 8628 
 
 
8.21.17v 
59
3. The original Sample Shipping Log should be kept in the Sample Shipping Log 
Binder.  
4. Only the primary samples of each patient should be sent with the first 
shipment. This is to ensure that, in case of damage during shipment, there is one 
sample per subject at the site for the backup. Duplicate samples should be 
shipped on alternate shipping dates. Please refer to the Shipping Calendar for 
dates.  
5. Samples should be shipped Monday or Tuesday only.  
6. Sufficient dry ice is to be included for samples to remain frozen for at least 48 
hours (we recommend 14 lbs. of dry ice).  
7. On the date you will be shipping specimens, please notify Sample Management 
at Regeneron Pharmaceuticals, Inc. to expect arrival of the box (914) 345-7644. 
Please also fax a copy of the shipping list and FedEx package tracking number 
to Sample Management at Regeneron Pharmaceuticals, Inc. at (914)-593-1024.  
8. Please note that for all shipments you must access the FedEx Ship Manager at 
www.fedex.com to prepare shipments online. The FedEx Ship Manager provides 
access to Regeneron's Federal Express account for direct billing purposes. 
Prepared shipments that do not utilize the FedEx Ship Manager will NOT 
be reimbursed. Refer to the FedEx shipping requirements in your Sample 
Shipping Log Binder for instructions on shipping the samples.  
 
Note: It is the Investigator’s Responsibility to ensure that all shipments of 
hazardous/dangerous goods comply with current DOT/IATA regulations. 
 
 

 
 
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10. 
STUDY CALENDAR 
These study calendars apply to arm A only. For Arm B (HD IL-2 alone), there are no protocol 
specific requirements. Study investigators should follow the local institutional standard of care 
guidelines for safety monitoring and safety laboratory testing on Arm B. Baseline evaluations are 
to be conducted within 2 weeks prior to administration of protocol therapy on both study arms, 
unless indicated otherwise, elsewhere in the protocol.  Scans and X-rays must be done not more 
than 28 days prior to the start of therapy on both study arms.  In the event that the patient’s 
condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to 
initiation of the next cycle of therapy. 
 
 
Course 1 (Arm A) 
Pre-
Study 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
 4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Aflibercepta 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Interleukin-2a 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
Informed consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
 
X 
    X----------------------------------------------------------------------------X 
 
Physical exam 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Vital signs 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Blood pressureh 
 
X 
 
X 
 
X 
 
X 
   
 
X 
 
 
X 
 
 
X 
 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Performance status 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
CBC w/diff, plts 
Urinalysis and UPCRb 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Serum chemistryc 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
PT/INR 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Echocardiogram 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Cardiac stress test, ECGd 
 
X 
 
 
 
 
 
 
 
 
 
 
PFTse 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Adverse event evaluation 
 
   X ----------------------------------------------------------------------------X 
 
Tumor measurements 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Radiologic evaluationf 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
B-HCGg 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a:   Aflibercept: IV Day 1 14-day cycle. IL-2: 600,000 U/kg/dose IV Q8h x 5 days (max 14 doses) starting on day 1 
of weeks 3 and 5. An IL-2 cycle may be delayed until the resolution of limiting toxicities.  
b:    Spot urine for protein and creatinine must be obtained to calculate urine protein:creatinine ratio (UPCR). A 24-
hour urine collection for quantitative protein determination must be obtained for a UPCR >1. 

 
 
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c:   Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, 
phosphorus, potassium, total protein, SGOT[AST], SGPT[ALT], sodium. 
d:    Patients who are over 40 years old or have had previous myocardial infarction greater than 6 months prior to 
study entry or have significant cardiac family history (CAD or serious arrhythmias) will be required to have a 
negative or low probability cardiac stress test (thallium stress test, stress MUGA or exercise stress test) for cardiac 
ischemia within 8 weeks prior to registration. Patients who are not required to have a cardiac stress test should 
have an electrocardiogram at baseline to be reviewed by the treating physician investigator. Patients who undergo 
echocardiography as part of their cardiac stress test are not required to have a separate baseline echocardiogram. 
e:    Pulmonary function tests (PFTs) are required for patients over 50 years old or with significant pulmonary or 
smoking history.  PFTs may be done up to 4 weeks prior to registration. 
f:     Radiologic evaluation should include MRI or contrast CT of the brain. 
g:    Serum pregnancy test (women of childbearing potential). 
h:    blood pressure will be checked weekly during the first cycle of aflibercept, then every two weeks while on study. 
However, at the initiation of the maintenance phase, if aflibercept is started at a higher dose than in the 
combination phase, blood pressure monitoring should be done weekly for the first 3 weeks of the maintenance 
phase to ensure tolerance of the higher aflibercept dose. This is the minimum blood pressure monitoring required. 
Appendix H includes a patient diary that includes more frequent blood pressure monitoring and can be used at 
the discretion of the treating physician.  
 
 
 
 
Course 2/3 (Arm A) 
Maintenance 
aflibercept 
 
Course 2/3, and  
Maintenance aflibercept 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
 4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
 
Off 
Studye 
Aflibercepta 
  
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Interleukin-2a 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
Concurrent meds 
    X------------------------------------------------------------------------X 
 
 
Physical exam 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X (q 2wks) 
 
X 
 
Vital signs and blood pressure 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X (q 2wks) 
 
X 
 
Weight 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X (q 2wks) 
 
X 
 
Performance status 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X (q 2wks) 
 
X 
 
CBC w/diff, plts 
Urinalysis and UPCRb 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Serum chemistryc 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Echocardiogram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Adverse event evaluation 
   X -------------------------------------------------------------------------X 
X 
 
Tumor measurements 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Radiologic evaluationd 
 
 
 
 
 
 
 
X 
X 
X 
 
a:   Aflibercept: IV Day 1 of a14-day cycle. IL-2: 600,000 U/kg/dose IV Q8h x 5 days (max 14 doses) starting on day 
1 of weeks 3 and 5. An IL-2 cycle may be delayed until the resolution of limiting toxicities. During the maintenance 
aflibercept phase, aflibercept monotherapy will be initiated to be administered IV on Day 1of each 14-day cycle. 
In the absence of limiting toxicities, aflibercept will be given at 4 mg/kg in the maintenance phase. In this case, 
blood pressure monitoring should be done weekly for the first 3 weeks of the maintenance phase to ensure tolerance 
of the higher aflibercept dose. However, if the aflibercept dose had to be reduced during the combination phase due 
to aflibercept-related toxicities, then that reduced dose will be used for maintenance therapy. No need for weekly 
monitoring of blood pressure, if the reduced dose has already been demonstrated to be tolerable.   
b:  Spot urine for protein and creatinine must be obtained to calculate urine protein:creatinine ratio (UPCR). A 24-hour 
urine collection for quantitative protein determination must be obtained for a UPCR >1. During the maintenance 
aflibercept phase, this is to be done every 2 weeks. 
c:   Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, 
phosphorus, potassium, total protein, SGOT[AST], SGPT[ALT], sodium. During the maintenance aflibercept 
phase, this is to be done every 2 weeks. 

 
 
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d: Radiologic evaluation should include MRI or contrast CT of the brain. During the maintenance aflibercept phase 
tumor radiologic evaluation and tumor measurements will take place every  12 weeks (-/+1 week) for the first 2 
years, then every 6 months (-/+ 2 weeks) for years 3-5, then yearly (-/+ 4 weeks) afterwards. 
e: off study evaluation. Patients will be followed for 5 years after removal from study or until death, whichever occurs 
first. The frequency and the type of evaluations during this follow up period will follow institutional standard of 
care practices. For patients who wish not to follow with a study investigator, they can be followed by their treating 
physician of choice and also following local standard of care practices. Data on disease progression and survival 
will be collected on all patients every 3-4 months. 
 
 
For the purposes of this study, patients should be reevaluated for response at the end of course 1 
(10 weeks -/+ 1 week for Arm A and 8 weeks -/+ 1 week for Arm B) and at the end of every 
course thereafter (8 weeks -/+ 1 week).  It will be done every 12 weeks -/+ 1 week during the 
maintenance Aflibercept Monotherapy phase (Arm A) or observation phase (for arm B) for the 
first 2 years, then every 6 months (-/+ 2 weeks) for years 3-5, then yearly (-/+ 4 weeks) 
afterwards. Radiologic evaluation should include MRI or contrast CT of the brain on both study 
arms (A and B). 
Off study evaluation for Arm B: Patients will be followed for 5 years after removal from study or 
until death, whichever occurs first. The frequency and the type of evaluations during this follow 
up period will follow institutional standard of care practices. For patients who wish not to follow 
with a study investigator, they can be followed by their treating physician of choice and also 
following local standard of care practices. Data on disease progression and survival will be 
collected on all patients every 3-4 months.  

 
 
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11. 
MEASUREMENT OF EFFECT 
11.1. Antitumor Effect – Solid Tumors 
For the purposes of this study, patients should be reevaluated for response at the end of 
course 1 (10 weeks -/+ 1 week for Arm A and 8 weeks -/+ 1 week for Arm B) and at 
the end of every course thereafter (8 weeks -/+ 1 week).  It will be done every 12 weeks 
-/+ 1 week during the maintenance Aflibercept Monotherapy phase (Arm A) or 
observation phase (for arm B) for the first 2 years, then every 6 months (-/+ 2 weeks) 
for years 3-5, then yearly (-/+ 4 weeks) afterwards. Radiologic evaluation should 
include MRI or contrast CT of the brain on both study arms (A and B). In addition to a 
baseline scan, confirmatory scans should also be obtained not less than 4 weeks 
following initial documentation of objective response. 
 
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[Eur J Cancer, 2009. 45(2): p. 228-47.].  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 protocol drug administration. 
 
Evaluable for objective response.  Only those patients who have measurable disease 
present at baseline, have received at least course 1 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 course 1 will 
also be considered evaluable.) 
 
NOTE: Since we hypothesize that reducing VEGF will improve response to IL-2, 
a patient must complete course 1 (at least one cycle of VEGF Trap + 2 cycles of 
IL-2) in order to be evaluable for response. 
 
11.1.2. Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >20 mm 
with conventional techniques (CT, MRI, x-ray) or as >10 mm with spiral CT scan.  
All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might 
not be considered measurable.  
 

 
 
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Non-measurable disease.  All other lesions (or sites of disease), including small 
lesions (longest diameter <20 mm with conventional techniques or <10 mm using 
spiral CT scan), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonis, inflammatory breast disease, abdominal masses (not followed by 
CT or MRI), and cystic lesions are all non-measurable. 
 
Target lesions.  All measurable lesions up to a maximum of 5 lesions per organ and 
10 lesions in total, representative of all involved organs, should be identified as 
target lesions and recorded and measured at baseline.  Target lesions should be 
selected on the basis of their size (lesions with the longest diameter) and their 
suitability for accurate repeated measurements (either by imaging techniques or 
clinically).  A sum of the longest diameter (LD) for all target lesions will be 
calculated and reported as the baseline sum LD.  The baseline sum LD will be used 
as reference by which to characterize the objective tumor response. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 10 target lesions should be identified as non-target 
lesions and should also be recorded at baseline.  Measurements of these lesions are 
not required, but the presence or absence of each should be noted throughout 
follow-up.  
 
11.1.3. Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 
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 is preferred to evaluation by clinical examination when 
both methods have been used to assess the antitumor effect of a treatment. 
 
Clinical lesions  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes).  In the case of skin 
lesions, documentation by color photography, including a ruler to estimate the size 
of the lesion, is recommended.  
 
Chest x-ray  Lesions on chest x-ray are acceptable as measurable lesions when they 
are clearly defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI  These techniques should be performed with cuts of 10 
mm or less in slice thickness contiguously.  Spiral CT should be performed using a 
5 mm contiguous reconstruction algorithm.  This applies to tumors of the chest, 
abdomen, and pelvis.  Head and neck tumors and those of extremities usually 
require specific protocols. 

 
 
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Ultrasound (US)  When the primary endpoint of the study is objective response 
evaluation, US should not be used to measure tumor lesions.  It is, however, a 
possible alternative to clinical measurements of superficial palpable lymph nodes, 
subcutaneous lesions, and thyroid nodules.  US might also be useful to confirm the 
complete disappearance of superficial lesions usually assessed by clinical 
examination. 
 
Endoscopy, Laparoscopy  The utilization of these techniques for objective tumor 
evaluation has not yet been fully and widely validated.  Their uses in this specific 
context require sophisticated equipment and a high level of expertise that may only 
be available in some centers.  Therefore, the utilization of such techniques for 
objective tumor response should be restricted to validation purposes in reference 
centers. However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained. 
 
Tumor markers  Tumor markers alone cannot be used to assess response.  If markers 
are initially above the upper normal limit, they must normalize for a patient to be 
considered in complete clinical response.  Specific additional criteria for 
standardized usage of prostate-specific antigen (PSA) and CA-125 response in 
support of clinical trials are being developed. 
 
Cytology, Histology  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in 
tumor types, such as germ cell tumors, where known residual benign tumors can 
remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears 
or worsens during treatment when the measurable tumor has met criteria for 
response or stable disease is mandatory to differentiate between response or stable 
disease (an effusion may be a side effect of the treatment) and progressive disease. 
 
11.1.4. Response Criteria 
 
11.1.4.1. Evaluation of Target Lesions 
 
Complete Response (CR):Disappearance of all target lesions 
 
Partial Response (PR): 
At least a 30% decrease in the sum of the 
longest diameter (LD) of target lesions, 
taking as reference the baseline sum LD 
 
Progressive Disease (PD): 
At least a 20% increase in the sum of the LD 
of target lesions, taking as reference the 
smallest sum LD recorded since the treatment 
started or the appearance of one or more new 

 
 
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lesions 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR 
nor sufficient increase to qualify for PD, 
taking as reference the smallest sum LD since 
the treatment started 
 
11.1.4.2. Evaluation of Non-Target Lesions 
 
Complete Response (CR): 
Disappearance of all non-target lesions and 
normalization of tumor marker level 
 
Note:  If tumor markers are initially above the 
upper normal limit, they must normalize for 
a patient to be considered in complete clinical 
response. 
 
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): 
Appearance of one or more new lesions 
and/or unequivocal progression of existing 
non-target lesions 
 
Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, 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 
Best Response for this 
Category Also Requires: 
CR 
CR 
No 
CR 
>4 wks. confirmation 
CR 
Non-
CR/Non-PD 
No 
PR 
 
>4 wks. confirmation 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
documented at least once 
>4 wks. from baseline 
PD 
Any 
Yes or No 
PD 
 
no prior SD, PR or CR 
Any 
PD* 
Yes or No 
PD 

 
 
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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. 
 
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 progression 
(or death if there is no progression date). Patients with neither a progression date 
nor date of death will be censored as of last contact. 
 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 
7.0 (Adverse Events: List and Reporting Requirements). 
 
12.1. Data Reporting 
 
12.1.1. Method 
 
This study will be monitored by the Clinical Data Update System (CDUS) version 
3.0.  Cumulative CDUS data will be submitted quarterly to CTEP by electronic 
means.  Reports are due January 31, April 30, July 31, and October 31.  Instructions 
for submitting data using the CDUS can be found on the CTEP web site 
(http://ctep.cancer.gov).  Note:  All adverse events that have occurred on the study, 
including those reported through CTEP-AERS, must be reported via CDUS. 
 
12.1.2. Responsibility for Data Submission 

 
 
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Study participants are responsible for submitting CDUS data and/or data forms to 
the 
 
 
Coordinating Center quarterly by  January 31, April 30, July 31, and October 31 to 
allow time for Coordinating Center compilation, Principal Investigator review, and 
timely submission to CTEP (see Section 12.1.1.).  For trials monitored by CTMS, 
the quarterly data submission to CTEP from provided by Theradex should be 
copied to the Coordinating Center. 
 
 
 
The Coordinating Center is responsible for compiling and submitting CDUS data 
to CTEP for all participants and for providing the data to the Principal Investigator 
for review.   
 
12.1.3. Data Collection Forms and Submission Schedule 
 
All data will be collected using COH data collection forms via an electronic data 
capture system.  Any original data collection forms will reside at the originating 
institutions in secure location. 
 
ELIGIBILITY CHECKLIST:  The data manager at the registering site will have 
completed and faxed this form at the time of registration. 
ON-STUDY FORM (FORM OS):  Completed on-study forms due within two 
weeks of registration.  
TREATMENT FORM (FORM RX):  Completed treatment forms are due within 
four weeks of completion of a cycle.  
ADVERSE EVENT COLLECTION:  Completed adverse events collection form 
due within four weeks of completion of a cycle. 
FLOW SHEETS:  Protocol specific flow sheets are to be submitted along with 
each treatment form. 
RESPONSE/OFF-STUDY/FOLLOW-UP:  Form F/U is to be submitted each 
time a patient is evaluated for response and/or new follow-up information is 
obtained.  
SUPPLEMENTAL DATA FORM: The 
timeline 
for 
submission 
of 
the 
supplemental data form will be protocol specific, if applicable. 
 
12.2. CTEP Multicenter Guidelines 
This protocol will adhere to the policies and requirements of the CTEP Multicenter 
Guidelines.  The specific responsibilities of the Principal Investigator and the 
Coordinating Center (Study Coordinator) and the procedures for auditing are presented 
in Appendix B. 
 
• The Principal Investigator/Coordinating Center is responsible for distributing 
all IND Action Letters or Safety Reports received from CTEP to all 
participating institutions for submission to their individual IRBs for action as 
required. 
 

 
 
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• Except in very unusual circumstances, each participating institution will order 
DCTD-supplied agents directly from CTEP.  Agents may be ordered by a 
participating site only after the initial IRB approval for the site has been 
forwarded 
by 
the 
Coordinating 
Center 
to 
the 
CTEP 
PIO 
(PIO@ctep.nci.nih.gov) (except for Group studies). 
 
12.3. Cooperative Research and Development Agreement (CRADA)/Clinical Trials 
Agreement (CTA) 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to 
the NCI under a Collaborative Agreement (CRADA, CTA, CSA) between the 
Pharmaceutical Company(ies) (hereinafter referred to as Collaborator(s)) and the NCI 
Division of Cancer Treatment and Diagnosis.  Therefore, the following 
obligations/guidelines, in addition to the provisions in the Intellectual Property Option 
to Collaborator (http:// ctep.cancer.gov/industry) contained within the terms of award, 
apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor 
can Agent(s) be transferred or licensed to any party not participating in the clinical 
study.  Collaborator(s) data for Agent(s) are confidential and proprietary to 
Collaborator(s) and shall be maintained as such by the investigators.  The protocol 
documents for studies utilizing investigational Agents contain confidential 
information and should not be shared or distributed without the permission of the 
NCI.  If a copy of this protocol is requested by a patient or patient’s family member 
participating on the study, the individual should sign a confidentiality agreement.  
A suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination 
with (an)other investigational Agent(s), each the subject of different collaborative 
agreements , the access to and use of data by each Collaborator shall be as follows 
(data pertaining to such combination use shall hereinafter be referred to as "Multi-
Party Data.): 
 
a. NCI will provide all Collaborators with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with NIH, 
the design of the proposed combination protocol, and the existence of any 
obligations that would tend to restrict NCI's participation in the proposed 
combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the 
clinical trial by any other Collaborator solely to the extent necessary to allow 
said other Collaborator to develop, obtain regulatory approval or commercialize 
its own investigational Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials 
must agree in writing prior to the commencement of the trials that it will use 
the Multi-Party Data solely for development, regulatory approval, and 

 
 
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commercialization of its own investigational Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available exclusively to Collaborator(s), the NCI, and the 
FDA, as appropriate and unless additional disclosure is required by law or court 
order.  Additionally, all Clinical Data and Results and Raw Data will be collected, 
used, and disclosed consistent with all applicable federal statutes and regulations 
for the protection of human subjects including, if applicable, the Standards for 
Privacy of Individually Identifiable Health Information set forth in 45 C.F.R. Part 
164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be 
sent to the NCI, who will then notify the appropriate investigators (Group Chair for 
Cooperative Group studies, or PI for other studies) of Collaborator's wish to contact 
them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance 
with the guidelines and policies of the responsible Data Monitoring Committee 
(DMC), if there is a DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP 
by the Group office for Cooperative Group studies or by the principal investigator 
for non-Cooperative Group studies for immediate delivery to Collaborator(s) for 
advisory review and comment prior to submission for publication.  Collaborator(s) 
will have 30 days from the date of receipt for review.  Collaborator shall have the 
right to request that publication be delayed for up to an additional 30 days in order 
to ensure that Collaborator’s confidential and proprietary data, in addition to 
Collaborator(s)’s intellectual property rights, are protected.  Copies of abstracts 
must be provided to CTEP for forwarding to Collaborator(s) for courtesy review as 
soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings.  
Press releases and other media presentations must also be forwarded to CTEP prior 
to release.  Copies of any manuscript, abstract and/or press release/ media 
presentation should be sent to: 
 
Regulatory Affairs Branch, CTEP, DCTD, NCI 
Executive Plaza North, Suite 7111 
Bethesda, Maryland  20892 
FAX 301-402-1584 
Email: anshers@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborators confidential/ proprietary information. 
 

 
 
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13. 
STATISTICAL CONSIDERATIONS 
13.1. Study Design/Endpoints 
This is a randomized Phase II study of HD-IL2 plus aflibercept vs HD-IL2 alone. The 
randomization is 2:1 in favor of the combination arm, using blocked randomization. 
The randomization is carried out by the central data coordination center. Stratification 
is specified in section 13.3, and does not include stratification by center. The primary 
endpoint is progression-free survival. The accrual goal is 105 (70 patients on the 
combination arm,  35 patients on the single agent HD-IL2 arm) to be accrued over 2 
years, with an additional 6 months of follow-up.  
 
This study design has 89% power to detect a 75% increase in the median PFS (7 vs 4 
months), at the 1-sided 0.10 significance level.  There are no planned interim analysis 
other than toxicity considerations due to the possibility that the aflibercept role may be 
demonstrated in a secondary analysis of the proportion of long-term responders (e.g., 
>2-yrs). 
 
The primary endpoint of progression-free survival will be measured from data of 
randomization until date of progression, death, recurrence or censored at last contact. 
The primary comparison will be based on the log-rank test for comparison of 
progression-free survival, which will be estimated by the Kaplan-Meier method. 
 
Secondary analysis includes overall survival comparison, one-year survival, response 
rate, and toxicity. Response rate will be estimated and a 95% CI provided for each arm, 
and Cox regression will also be conducted for survival and progression-free survival. 
Survival endpoints will be evaluated from data of randomization, although we will also 
report on the as-treated populations for comparison. 
 
 
13.2. Sample Size/Accrual Rate 
We plan 24 months of accrual for 105 patients (approximately 4-5 patients per month) 
and a minimum of 6 months follow-up (no drop outs).   
 
13.3. Stratification Factors 
Randomization will be stratified based on the presence or absence of visceral disease, 
ECOG 0 vs 1, and male vs female. .  
 
13.4. Analysis of Secondary Endpoints 
 
 
Toxicity Monitoring: HD-IL2 plus Aflibercept arm (Arm A): 
 
Toxicity will be primarily be evaluated by examining the number of doses of HD IL-2 
administered during the first cycle of combination  therapy; the percentage of patients 
who receive all 56 doses will also be summarized. The toxicity after the scheduled 10th 
dose of IL-2, the frequency of grade III and IV toxicities, and unusual toxicities will 
also be summarized.  The toxicity profile for the first six patients enrolled on the 

 
 
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combination arm after the first cycle of high dose IL-2 will be reviewed by PI, the 
treating physician or local PI at each of the enrolling institutions, the statistician, and 
the senior investigator at the NCI/CTEP in a conference call. Approval for continuing 
the trial will require a majority consensus to continue in addition to requiring approval 
from the PI and the NCI senior investigator.  
 
For safety reasons, accrual to the study will initially be staggered by at least a week for 
the initial 3 patients. In addition, toxicity profile will be assessed for each of two cohorts 
of 3 patients after the initial 5 weeks of therapy. If no unexpected toxicity or death 
occurs, the next cohort of three patients will be allowed to enter the trial.  The same 
toxicity review will occur for cohort 1 as at the end of cohort 2 (see above). If approval 
is obtained, accrual will be allowed to proceed to the second toxicity analysis point of 
19 patients.   
 
After 19 patients have initiated and completed their first cycle of therapy, an analysis 
of toxicity will be undertaken. Among the initial 15 patients treated with high dose IL-
2 and aflibercept, there is high probability of observing rare toxicities if they exist: 
there is probability of 0.62 of observing at least one event that occurs at a true rate of 
5%; and probability of 0.86 of observing at least one event that occurs at a true rate of 
10%.  This review will also be conducted with same oversight described above at the 
6 patient time point. An additional review will be mandated upon any treatment-related 
death, and every 6 months. 
 
Based on previous experience with high dose IL2 at the University of Pittsburgh, the 
median number of doses per course 1 (first 2 cycles) as monotherapy[22] is 16 (range 
8-26) and in sequential combination with temozolomide[23] is 15 (range 7-23). As a 
result, the median number of doses per course 1 will be considered in addition to 
toxicity reported via CTCAE criteria. 
 
Among all 70 patients treated with combination therapy, there is probability of 0.51 of 
observing at least one event that occurs at a true rate of 1%; and probability of 0.97 of 
observing at least one event that occurs at a true rate of 5%. 
 
 
 
Correlative Endpoints: 
 
If the agent is promising, we expect to have 70 patients to evaluate for correlative 
science on the combination arm. We expect all patients to provide measurements of 
serum VEGF levels and other blood-based biomarkers, with a subset with 
corresponding tissue related correlatives.  Previous data has suggested that high VEGF 
levels predict lower response to IL-2, With a minimum expected balance of 16 
(responders) vs 54 (non-responders), there will be a minimum of 96% power to detect 
a one standard deviation difference  (after aflibercept therapy)  in the VEGF levels in 
responders vs non-responders, with a one-sided type I error of 0.05 (NOTE: we expect 
at least 16 responders out of the 70 patients evaluable for correlative science on the 
combination arm. If more are obtained, the statistical operating characteristics improve 
due to better balance between responders and non-responders). We will also compare 

 
 
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the mean baseline VEGF levels in responders and non-responders and provide a 95% 
confidence interval as part of our exploratory analysis. 
 
Correlative endpoints will also be explored using multivariate Cox regression, 
exploring the impact of both baseline VEGF levels and VEGF levels after aflibercept 
therapy, while adjusting for known patient characteristics that impact survival. 
 
Other correlative endpoints will also be explored, including evaluating the biological 
correlatives in the HD-IL2 alone arm, and while no attempt will be made to adjust for 
multiple comparisons for additional correlative endpoints, any conclusions will be 
stated as exploratory and in the context of a randomized phase II study.   
 
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. 
 
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.  
 
All conclusions will be based on all eligible patients.  Subanalyses may then be 
performed on the basis of a subset of patients, excluding those for whom major 
protocol deviations have been identified (e.g., early death due to other reasons, 
early discontinuation of treatment, major protocol violations, etc.).  However, these 
subanalyses will not serve as the basis for drawing conclusions concerning 
treatment efficacy, and the reasons for excluding patients from the analysis will be 
clearly reported.  The 95% confidence intervals will also be provided for both 
survival and response estimates.  
 
14. 
CCCP POLICIES FOR MONITORING CONSORTIUM TRIALS 
The protocol principal investigator (PI) is responsible for monitoring the conduct and 
progress of this Phase I trial, including the ongoing review of accrual, data and toxicities, 

 
 
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as well as the accumulation of reported adverse events from other trials testing the same 
drug(s).  The participating clinicians and their designees are responsible for timely 
submission of adverse event reports (see Section 7.0) and case report forms.  The Data 
Coordinating Center for the CCCP Consortium is responsible for providing the PI with 
access to the submitted case report form data in summary and detail in a timely fashion.   
Although the PI is responsible for evaluating the cumulative reported adverse events and 
the impact that these have on the continued conduct of the trial, it is the Data Coordinating 
Center of the CCCP that distributes all submitted SAE reports to the appropriate 
individuals, including the local protocol principal investigators, at each of the participating 
institutions.   
 
The Data Coordinating Center posts a summary (accrual, toxicities, and responses) of each 
CCCP initiated trial on the CCCP website.  In this way, each PI has access to up-to-date 
information on the status of his or her trial.  In consultation with the collaborating 
statistician, the PI is responsible for review of: 
 
(a) 
for Phase I trials, all dose limiting toxicities and decisions regarding dose 
escalation, expansion, as well as decisions to terminate escalation, and  
(b) 
for Phase II trials, the toxicities and therapeutic endpoints referred to in the 
statistical plan. 
 
The Data Coordinating Committee meets monthly to review data management and data 
quality issues – completeness of data submissions as well as accuracy in terms of built-in, 
computerized logic checks.  Any issues identified and the corrective plans are presented to 
the Internal Committee and at the next CCCP teleconference meeting for review and 
approval. 
 
Oversight 
Oversight of the conduct of CCCP trials occurs at several levels: 
 
1. 
The Data Coordinating Center for the CCCP flags all trials that are approaching a 
decision in terms of toxicity (for both Phase I and Phase II trials) or responses (for 
Phase II trials).  Decisions are made by the PI with input from the statistician and 
discussion with the principal investigator of the funding mechanism (U01 
Cooperative Agreement or N01 Contract, as appropriate) or his or her designee, and 
are communicated to the participating centers by the CCCP Data Coordinating 
Center. At the monthly teleconferences, the accrual of each open protocol is 
reviewed. 
 
2. 
For CTEP sponsored Phase I trials, data are reported to the NCI-designated clinical 
trials monitoring service (CTMS) which will audit patients’ records on each 
protocol – at each CCCP institution; this audit is initiated by CTEP.  For all other 
CCCP trials, the CCCP will contract with Theradex to audit patient records at each 
CCCP institution. 
 

 
 
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3. 
An independent CCCP DSMC will review CCCP trials every 6 months. This DSMC 
will consist of 3 voting members (2 medical oncologists or hematologists involved 
in Phase I/II cancer clinical trials but not participating in CCCP studies, and a 
statistician) and a non-voting CCCP statistician.   
 
a. DSMC meetings will take place twice a year.  Additional meetings will be 
convened if necessary.  
b. This DSMC will review each CCCP trial in terms of accrual, toxicity/safety, and 
adherence to trial design, audit results, and likelihood of successful completion.   
c. The DSMC will report to the CCCP leadership. 

 
 
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15. 
REFERENCES 
1. 
Tarhini, A.A. and S.S. Agarwala, Cutaneous melanoma: available therapy for metastatic 
disease. Dermatol Ther, 2006. 19(1): p. 19-25. 
2. 
Atkins, M.B., et al., High-dose recombinant interleukin 2 therapy for patients with 
metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin 
Oncol, 1999. 17(7): p. 2105-16. 
3. 
Investigator'sBrochure, [AFLIBERCEPT (VEGF Trap, AVE0005 )] (2009). Regeneron 
Pharmaceuticals,Inc., Tarrytown, NY and Aventis Pharmaceuticals Inc., Bridgewater, 
NJ. Edition 9. May 1,, 2009. 
4. 
Tarhini, A.A. and J.M. Kirkwood. Phase II study of aflibercept (VEGF trap) in recurrent 
inoperable stage III or stage IV melanoma of cutaneous or ocular origin. ASCO Annual 
Meeting; Abs ID 9028  
2009. 
5. 
Smith, K.A., Interleukin-2: inception, impact, and implications. Science, 1988. 
240(4856): p. 1169-76. 
6. 
Rosenberg, S.A., et al., Regression of established pulmonary metastases and 
subcutaneous tumor mediated by the systemic administration of high-dose recombinant 
interleukin 2. J Exp Med, 1985. 161(5): p. 1169-88. 
7. 
Dutcher, J.P., et al., A phase II study of interleukin-2 and lymphokine-activated killer 
cells in patients with metastatic malignant melanoma. J Clin Oncol, 1989. 7(4): p. 477-
85. 
8. 
Parkinson, D.R., et al., Interleukin-2 therapy in patients with metastatic malignant 
melanoma: a phase II study. J Clin Oncol, 1990. 8(10): p. 1650-6. 
9. 
Rosenberg, S.A., et al., Treatment of 283 consecutive patients with metastatic melanoma 
or renal cell cancer using high-dose bolus interleukin 2. Jama, 1994. 271(12): p. 907-13. 
10. 
Atkins, M.B., et al., High-dose recombinant interleukin-2 therapy in patients with 
metastatic melanoma: long-term survival update. Cancer J Sci Am, 2000. 6 Suppl 1: p. 
S11-4. 
11. 
Schwartzentruber, D.J., High-dose interleukin-2 is an intensive treatment regardless of 
the venue of administration. Cancer J, 2001. 7(2): p. 103-4. 
12. 
Rosenberg, S.A., et al., Prospective randomized trial of high-dose interleukin-2 alone or 
in conjunction with lymphokine-activated killer cells for the treatment of patients with 
advanced cancer. J Natl Cancer Inst, 1993. 85(8): p. 622-32. 
13. 
Figlin, R.A., et al., Multicenter, randomized, phase III trial of CD8(+) tumor-infiltrating 
lymphocytes in combination with recombinant interleukin-2 in metastatic renal cell 
carcinoma. J Clin Oncol, 1999. 17(8): p. 2521-9. 
14. 
Sabatino, M., et al., Serum vascular endothelial growth factor and fibronectin predict 
clinical response to high-dose interleukin-2 therapy. J Clin Oncol, 2009. 27(16): p. 2645-
52. 
15. 
Kerbel, R.S., Tumor angiogenesis. N Engl J Med, 2008. 358(19): p. 2039-49. 
16. 
Folkman, J., Tumor angiogenesis: therapeutic implications. N Engl J Med, 1971. 
285(21): p. 1182-6. 
17. 
Tas, F., et al., Circulating serum levels of angiogenic factors and vascular endothelial 
growth factor receptors 1 and 2 in melanoma patients. Melanoma Res, 2006. 16(5): p. 
405-11. 
18. 
Gabrilovich, D.I., et al., Production of vascular endothelial growth factor by human 

 
 
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tumors inhibits the functional maturation of dendritic cells. Nat Med, 1996. 2(10): p. 
1096-103. 
19. 
Ohm, J.E., et al., VEGF inhibits T-cell development and may contribute to tumor-induced 
immune suppression. Blood, 2003. 101(12): p. 4878-86. 
20. 
Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). Eur J Cancer, 2009. 45(2): p. 228-47. 
21. 
Schwartzentruber, D.J., Guidelines for the safe administration of high-dose interleukin-2. 
J Immunother, 2001. 24(4): p. 287-93. 
22. 
Tarhini AA, Kirkwood JM, Gooding WE, Cai C, Agarwala SS, Durable Complete 
Responses With High-Dose Bolus Interleukin-2 in Patients With Metastatic Melanoma 
Who Have Experienced Progression After Biochemotherapy. J Clin Oncol, 2007. 25(25): 
p. 0000-0000. 
23. 
Tarhini, A.A., et al., A phase 2 trial of sequential temozolomide chemotherapy followed 
by high-dose interleukin 2 immunotherapy for metastatic melanoma. Cancer, 2008. 
113(7): p. 1632-40. 
 
 
 
  
 
 
 

 
 
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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 – CTEP Multicenter Guidelines 
 
If an institution wishes to collaborate with other participating institutions in performing a 
CTEP sponsored research protocol, then the following guidelines must be followed. 
 
Responsibility of the Protocol Chair  
• The Protocol Chair will be the single liaison with the CTEP Protocol and Information 
Office (PIO).  The Protocol Chair 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 Protocol Chair.  There 
will be only one version of the protocol, and each participating institution will use that 
document.  The Protocol Chair is responsible for assuring that all participating institutions 
are using the correct version of the protocol. 
• The Protocol Chair is responsible for the overall conduct of the study at all participating 
institutions and for monitoring its progress.  All reporting requirements to CTEP are the 
responsibility of the Protocol Chair.  
• The Protocol Chair is responsible for the timely review of Adverse Events (AE) to assure 
safety of the patients. 
• The Protocol Chair will be responsible for the review of and timely submission of data for 
study analysis. 
 
Responsibilities of the Coordinating Center 
• 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, an OHRP form 310 
(documentation of IRB approval) must be submitted to the CTEP PIO. 
• The Coordinating Center is responsible for central patient registration.  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 the preparation of all submitted data for review 
by the Protocol Chair. 
• The Coordinating Center will maintain documentation of AE reports.  There are two 
options for AE reporting: (1) participating institutions may report directly to CTEP with a 
copy to the Coordinating Center, or (2) participating institutions report to the Coordinating 
Center who in turn report to CTEP.  The Coordinating Center will submit AE reports to 
the Protocol Chair for timely review. 
• Audits may be accomplished in one of two ways:  (1) source documents and research 
records for selected patients are brought from participating sites to the Coordinating Center 
for audit, or (2) selected patient records may be audited on-site at participating sites.  If the 
NCI chooses to have an audit at the Coordinating Center, then the Coordinating Center is 
responsible for having all source documents, research records, all IRB approval documents, 
NCI Drug Accountability Record forms, patient registration lists, response assessments 
scans, x-rays, etc. available for the audit. 
 

 
 
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Inclusion of Multicenter Guidelines in the Protocol 
• The protocol must include the following minimum information:  
➢ The title page must include the name and address of each participating institution and 
the name, telephone number and e-mail address of the responsible investigator at each 
participating institution. 
➢ The Coordinating Center must be designated on the title page. 
➢ Central registration of patients is required.  The procedures for registration must be 
stated in the protocol. 
➢ Data collection forms should be of a common format.  Sample forms should be 
submitted with the protocol.  The frequency and timing of data submission forms to the 
Coordinating Center should be stated. 
➢ Describe how AEs will be reported from the participating institutions, either directly to 
CTEP or through the Coordinating Center. 
➢ Describe how Safety Reports and Action Letters from CTEP will be distributed to 
participating institutions.  
 
Agent Ordering 
• Except in very unusual circumstances, each participating institution will order DCTD-
supplied investigational agents directly from CTEP.  Investigational agents may be ordered 
by a participating site only after the initial IRB approval for the site has been forwarded by 
the Coordinating Center to the CTEP PIO.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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APPENDIX C – CCCP Registration Procedures for Phase II Trials 
 
1. 
Registrations for Phase II protocols must be made through the California Cancer 
Consortium office at the City of Hope between the hours of 8:30 a.m. to 4:30 p.m., Monday 
through Friday (except holidays). 
 
2. 
Patients must be registered within 3 days prior to initiation of protocol therapy. 
 
3. 
A patient failing to meet all protocol requirements may not be registered.  If you have any 
questions regarding eligibility, contact the City of Hope Data Coordinating Center (DCC) 
at (626) 256-HOPE (4673), extension 65928. 
 
4. 
Prestudy laboratory tests, scans and x-rays must be completed prior to registration 
according to study calendar/protocol. 
 
5. 
Patients must sign an informed consent prior to registration. 
 
6. 
Confirm that the patient meets all inclusion and exclusion eligibility criteria for a protocol. 
 
7. 
Complete the Eligibility Checklist.   
 
8. 
Verify that all required prestudy tests were performed. 
 
9. 
Fax the completed Eligibility Checklist, signed and dated informed consent, pathology 
report, and relevant laboratory results to the City of Hope Consortium Coordinator for 
confirmation of eligibility.  The FAX number is (626) 256-8654.  
 
10. 
Call the City of Hope Consortium Coordinator at (626) 256-HOPE (4673), extension 65928 
to confirm the FAX arrival. If the Consortium Coordinator is not in the office, have them 
paged at (626) 423-5365. 
 
11. 
If the patient qualifies, the City of Hope Consortium Coordinator will call the registering 
institution to complete the registration/randomization procedure and assign the patient's 
study ID number.   
 
12. 
Once a patient has been registered, the Data Coordinating Center will provide a 
"Confirmation of Registration" to the center registering the patient.  
 
 
For questions regarding eligibility call City of Hope California Cancer Consortium, Data 
Coordinating Center 
(626) 256-HOPE (4673), extension 65928 
 
 
 
 

 
 
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APPENDIX D – CCCP Specimen Submission Forms 
 
Please contact the Data Coordinating Center at cccp@coh.org for the CCCP Specimen Submission 
Form.  The form will be emailed to the participating institution when the study has been activated.   
 
An additional form called “PhII-107 Research Specimen Submission Form” will also need to be 
completed and will be distributed to activated.  If a copy is needed, please contact the DCC at 
cccp@coh.org.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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APPENDIX E – NYHA functional classification system 
 
 
Class 
Functional Capacity 
Objective Assessment 
I 
Patients with cardiac disease but without resulting limitations of 
physical activity.  Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain. 
No objective evidence of 
cardiovascular disease. 
II 
Patients with cardiac disease resulting in slight limitation of 
physical activity.  They are comfortable at rest.  Ordinary physical 
activity results in fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
minimal cardiovascular 
disease. 
III 
Patients with cardiac disease resulting in marked limitation of 
physical activity.  They are comfortable at rest.  Less than 
ordinary activity causes fatigue, palpitation, dyspnea, or anginal 
pain. 
Objective evidence of 
moderately severe 
cardiovascular disease. 
IV 
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort.  Symptoms of heart failure 
or the anginal syndrome may be present even at rest.  If any 
physical activity is undertaken, discomfort is increased. 
Objective evidence of 
severe cardiovascular 
disease. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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APPENDIX F - Labeling Instructions for Serum Samples for Regeneron  (Anti-
Aflibercept Antibody Testing) 
 
 
1. Verify that the number directly under the Barcode on the label to be affixed to the vial 
matches the corresponding label to be affixed to the shipping paperwork. 
 
2. Complete the information required on the visit-specific label: Subject ID.  Please note 
that you will need to complete the following additional fields if you are using an 
Unscheduled Visit Label: Visit #, Date, Time, and Sample Type (serum or plasma). 
 
 
 
Visit-Specific Specimen Label 
                       Unscheduled Visit Specimen Label 
 
 
 
 
                                         
                                                                                 Barcode 
 
                                                                      Complete these fields 
 
 
 
 
 
 
 
 
3. Remove label from backing, turn label sideways (to the left), and apply the bottom of 
the label to the cryovial first.  Make sure that the label does not cover the threading on 
the top of the cryovial.  Wrap remaining portion of label in a clockwise direction around 
cryovial and be sure that the label’s bar code runs vertically along the cryovial.  Please 
refer to the picture of correctly labeled cryovial on next page. 
 
REGENERON 
Pharmaceuticals, Inc 
                                   
SAG 
VEGFT-RA-0402-
00100004 
        
 
 
Subject ID  _ _ _ _ _ _ 
 
__ 
 
Visit 1, Timepoint: 
2hr
REGENERON 
Pharmaceuticals, Inc 
                                   
SAG 
VEGFT-RA-0402-
00100004 
        
 
 
Subject ID  _ _ _ _ _ _ 
 
__ 
 
Visit # 

 
 
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                                                    1.8 mL cryovial 
 
                                                                           Top 
 
 
 
 
                                                                                                             
 
 
 
 
                                                                                          Bottom 
                                                                   
       
 
 
 
 
 
Correctly Labeled Cryovial with Barcode in Vertical Direction 
 
 
                                                  Top 
 
 
 
 
 
 
                                                                                                      Barcode 
 
 
 
 
                                              Bottom 
 
 
Please note that the label must appear this way to be read by the label scanner. 
 
 
REGENERON 
Pharmaceuticals, Inc 
                                   
SAG 
IL1T-RA-0402-
00100004 
        
 
Subject ID   _ _ _ _ _ 
 
Subject Initials __ __  
Visit 1, Timepoint: 
2hr 
REGENERON 
Pharmaceuticals, Inc                       
SAG 
IL1T-RA-0402-00100004 
        

 
 
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WHAT TO DO IN CASE OF MISTAKES 
 
If you accidentally used the wrong label for a cryovial, please: 
 
• Remove the incorrect label and re-label the cryovial with the correct label.  If you 
do not have an extra label for a particular visit, you should use an Unscheduled 
Visit Label and complete the required information.  Please save the incorrect label 
and attach it to the shipping list with a written explanation of the error.  
 
 
If you made a mistake on the label, such as writing the wrong subject initials or date, please: 
 
• Cross out the wrong information and write the correct information on the label.  
Make sure that you initial and date the cross-out.  If you cannot correct the label in 
a legible fashion, use an Unscheduled Visit Label (see top of Page 1).  

 
 
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APPENDIX G - COLLECTION OF SERUM SAMPLES for Regeneron (Anti-Aflibercept Antibody Testing) 
 
SERUM Samples for Regeneron  
 
 
Anti-VEGF Trap Antibody Samples  
 
 
 
 
 
 
                                 
     5 mL plain red top tube                                                  2 cryovials with 0.8 mL serum each 
 
Note:  1. Collect one red top tube for each sample. 
2. Only one cryovial per subject per time point should be sent with the initial scheduled shipment. 
3.  Refer to SERUM Sample Collection and Preparation instructions for additional details.
1.  Immediately invert tube 4 times then 
allow 30 min. for serum to clot.  Centrifuge 
at 2000 x g for 15 min. at room temp. within 
1 hour of collection 
2.  Within 30 min. draw 
off serum very slowly 
with transfer pipette 
3. Pipette 0.8 mL of serum into 
each of 2 separate labeled plastic 
cryovials and store frozen at -
20°C 
ANTIBODY 
PRIMARY
ANTIBODY 
DUP 
Duplicate 
Samples 
Storage 
box 
(Freezer) 
Primary 
Samples 
Storage 
box 
(Freezer) 

 
 
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APPENDIX H - Patient Blood Pressure Monitoring Diary (for patients on 
Arm A receiving Aflibercept) 
 
NOTE: This optional diary is strongly recommended to be used as more frequent blood pressure 
monitoring than what is required in the protocol and can be used at the discretion of the treating 
physician. 
 
Diary Card 
Blood Pressure Monitoring 
 
Dates: ____/____/____ to ____/____/____ 
 
Patient Number: 
       Patient Initials: 
 
 
Hypertension is a known and potentially serious adverse event associated with aflibercept treatment. It is 
recommended that you have your blood pressure monitored as follows: 
• 
At least twice weekly during the first 5 cycles of aflibercept therapy (Course 1 of protocol therapy) and prior 
to each infusion of aflibercept.  
• 
At least once weekly during each subsequent cycle of aflibercept therapy. 
• 
If the blood pressure is not well controlled, then it should monitored more frequently. 
 
Blood pressure is typically recorded as two numbers, written as a ratio. The top number (systolic), which is also the 
higher of the two numbers, measures the pressure in the arteries when the heart beats (when the heart muscle contracts). 
The bottom number (diastolic), which is also the lower of the two numbers, measures the pressure in the arteries 
between heartbeats (when the heart muscle is resting between beats and refilling with blood). 
 
You should contact your physician’s office if your blood pressure exceeds 140 mmHg (systolic) or 90 mmHg 
(diastolic) at any time and are encouraged to contact your physician if you are concerned about any symptoms that 
may be associated with high blood pressure (e.g., headache).  
 
You should seek immediate medical advice if your blood pressure exceeds 180 mmHg (systolic) or 105 mmHg 
(diastolic) at any time and are encouraged to contact you physician if they are concerned about any symptoms that 
may be associated with high blood pressure (e.g., headache).  
  
While you are receiving treatment with aflibercept, the early initiation of antihypertensive treatment to 
minimize more severe or persistent hypertension is considered an important precautionary measure to avoid 
potentially serious complications. 
 
When you are receiving IL2 on Arm A, the blood pressure medications should be managed 
as follows: 
• 
On the day of admission, the morning blood pressure medications should be taken, anticipating 
that the first dose of IL2 is given that evening. Otherwise, if the first dose of IL2 is expected to be 
given during the day, then the morning blood pressure medications should be held. 
• 
If the first dose of IL2 is anticipated to be given in the evening of the day of admission, then the 
blood pressure medications should be held for that evening and throughout IL2 treatment unless 
otherwise specified by the treating physician  

 
 
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• 
Upon completion of IL2 therapy, the blood pressure medications should restarted as soon as the 
IL2 induced hypotension (low blood pressure) has resolved. Most importantly, the blood pressure 
medications should be restarted before the patient is discharged home.  
• 
Following home discharge from inpatient IL2 therapy, you should have the blood pressure 
monitored at least twice weekly and contact your physician’s office if your blood pressure exceeds 
140 mmHg (systolic) or 90 mmHg (diastolic) as noted above. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient sequence number:                                                           

 
 
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Blood 
Pressure 
No. 
 
 
 
Date 
 
 
TIME 
Record Time of Blood Pressure 
(Circle AM or PM) 
 
 
    BP           TIME      circle AM/PM 
Use the space below to make 
notes about things you would 
like to tell the doctor (include 
any unusual symptoms you 
experience, other medicine you 
have taken and anything else 
you think may be of interest. 
Month 
Day 
Year 
1 
 
 
 
 
 
 
 
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AM  PM 
 
2 
 
 
 
 
 
 
 
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AM  PM 
 
3 
 
 
 
 
 
 
 
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AM  PM 
 
4 
 
 
 
 
 
 
 
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AM  PM 
 
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AM  PM