Clinical trial NCT01782443
Conditions: Carcinoid Tumor
Keywords: Progressive Metastatic
Sponsor: Dana-Farber Cancer Institute
Start date: 2013-02-13; Completion date: 2021-12-26
Enrollment: 19 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This research study is a Phase II clinical trial, which tests the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific cancer. "Investigational" means that the drug, Ziv-aflibercept, is being studied. It also means that the FDA has not yet approved Ziv-aflibercept for use in patients with your type of cancer.

Every person has molecules in their bloodstream called vascular endothelial growth factors (VEGFs). These molecules help grow and sustain new blood vessels needed by the human body. Cancer tumors hijack this mechanism because they need new blod vessels and oxygen to grow. Ziv-aflibercept is an antibody. Antibodies are proteins that are produced naturally in our bodies and help to recognize foreign substances in our body. Ziv-aflibercept is a "targeted therapy" called a "VEGF Trap", that "traps" (binds) these VEGFs and prevents the cancer from using them to grow.

Though Ziv-aflibercept has not yet been FDA approved for the treatment of carcinoid tumors, it has recently been approved for patients with treatment-resistant colorectal cancer.

In this research study, we will use Ziv-aflibercept in combination with standard octreotide therapy to see if it slows the growth or spread of your carcinoid tumor. Standard octreotide (sandostatin) therapy is currently approved for treating symptoms of carcinoid tumors, such as those caused by carcinoid syndrome. Carcinoid syndrome is caused by hormones and other substances released by carcinoid tumors into the bloodstream. One of these secreted substances is serotonin, one of the body's natural chemical messengers. When excess serotonin secreted by the carcinoid tumors reaches the body's tissues, it is thought to cause diarrhea and redness (flushing) of the face, chest or back. Excess serotonin may also cause changes in the structure of the heart valves, which can impair the heart's function. Octreotide works by binding to receptors found on carcinoid tumors and prevents the release of hormones from the tumor.

Detailed description:
If you are willing to participate in this study you will be asked to undergo some screening tests and procedures to confirm that you are eligible. Many of these tests and procedures are likely to be part of regular cancer care and may be done even if it turns out that you do not take part in the research study. If you have had some of these tests or procedures recently, they may or may not have to be repeated. These tests and procedures include: a medical history, physical examination, CT or MRI, blood tests, serum chromogranin A, urine tests, 24-hour urine collection, pregnancy test and an electrocardiogram. If these tests show that you are eligible to participate in the research study, you will begin the study treatment. If you do not meet the eligibility criteria, you will not be able to participate in this research study.

If you meet the requirements for this study and you agree to continue your participation, you will receive Ziv-aflibercept every two weeks. Each dose of Ziv-aflibercept consists of an approximately 60 minutes infusion (through a needle into a vein). You will also receive an injection of Octreotide LAR (long acting release) monthly as part of your treatment for carcinoid tumor. This injection will be given to you by a nurse in your buttock. You may already be on Octreotide LAR. In that case, you will continue taking it at the same dose and schedule.

You will need to come to the clinic every two weeks while participating in this study. Each cycle is 28 days.

The following tests and procedures will be performed on Days 1 and 15 of each cycle: questions about your health, physical exam (Day 1 of each cycle only), vital signs, blood tests, pregnancy test (Day 1 of each cycle only).

Urine tests will be performed every other cycle.

The following tests and procedures will be done at the end of every third cycle: CT scan or MRI, Serum Chromogranin A, 24-hour urine collection.

After the final dose of the study drug the following tests and procedures will be performed: questions about your general health, physical exam, vital signs, blood tests, pregnancy test, EKG, Serum Chromogranin A, 24-hour urine collection.

Arms: arm 1: Ziv-aflibercept IV every 2 weeks, 4 mg/kg
Interventions: intervention 1: Ziv-aflibercept
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
[cover page generated for ClinicalTrials.gov only. This page was not part of the IRB approved document 
which follows] 
Identifiers: 
NCT01782443   Unique Protocol ID: 12-456 
Brief Title: 
Ziv-Aflibercept for Advanced Progressive Carcinoid Tumors 
Full Title:  
Phase II Study of Ziv-aflibercept in Patients with Advanced, Progressive  
Carcinoid Tumors 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date document downloaded from OnCore portal: 7.22.22 
Document Date: Protocol Version: June 21, 2019 


Ph II Study of Ziv-aflibercept in Carcinoid 
 
 
Jennifer Ang Chan, MD, MPH 
 
 
 
 
 
Phase II Study of Ziv-aflibercept in Patients with Advanced, Progressive 
Carcinoid Tumors. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
Version:  June 21, 2019 
 
 
Principal Investigator: 
 
Jennifer Chan, MD, MPH 
Dana-Farber Cancer Institute 
450 Brookline Avenue   
Boston, MA  02215-5450 
P: 617.632.6315 
F: 617.632.5370 
jang@partners.org 
jang@partners.org 
 
 
 
 
Study Coordinator:   
 
Danielle Stonely  
Dana-Farber Cancer Institute 
617.632. 5728 
DanielleE_Stonely@DFCI.HARVARD.EDU 
 
Research Nurses:    
Christopher Graham, RN 
Dana-Farber Cancer Institute 
617.582.7988 
Christopher_Graham@DFCI.HARVARD.EDU 
 
Victoria Geermon, RN 
Dana-Farber Cancer Institute 
617.632.5594 
VBROCK@partners.org 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
Ziv-aflibercept IV every 2 weeks  
Octreotide LAR (recommended starting dose 20 mg IM every 4 weeks; patients already receiving 
octreotide may continue at their current dose) 
 
 
 
 
 
 
Restaging scans after every every 12 weeks 
)                            
 
 
 
 
CTCAE version 4.0 
 
Enrollment: Patients with advanced carcinoid tumors and 
documented disease progression within 12 months 


CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
TABLE OF CONTENTS 
1. 
OBJECTIVES: ................................................................................................................................................... 6 
1.1 
Study Design ............................................................................................................................................... 6 
1.2 
Primary Objective ...................................................................................................................................... 6 
1.3 
Secondary Objectives ................................................................................................................................. 6 
2. 
BACKGROUND ................................................................................................................................................ 6 
2.1 
Study Agent: Ziv-aflibercept ....................................................................................................................... 6 
2.2 
Neuroendocrine Tumors ............................................................................................................................. 8 
2.5 
Rationale .................................................................................................................................................... 9 
3. 
Participant Selection ........................................................................................................................................ 10 
3.1 
Inclusion Criteria ..................................................................................................................................... 10 
3.2 
Exclusion Criteria: ................................................................................................................................... 12 
4. 
REGISTRATION PROCEDURES ................................................................................................................ 13 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions ..................................................................... 14 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions ................................................................. 14 
5. 
TREATMENT PLAN ...................................................................................................................................... 14 
5.1 
Octreotide Guidelines (naïve patients) ..................................................................................................... 15 
5.2 
Pre-treatment Criteria:............................................................................................................................. 16 
5.3 
Agent Administration .............................................................................................................................. 18 
5.4 
General Concomitant Medication and Supportive Care Guidelines ........................................................ 19 
5.5 
Duration of Therapy ................................................................................................................................. 19 
5.6 
Duration of Follow Up ............................................................................................................................. 20 
5.7 
Criteria for Removal from Study .............................................................................................................. 20 
6. 
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS .................................... 20 
6.1 
Anticipated Toxicities ............................................................................................................................... 20 
6.2 
Toxicity Management: .............................................................................................................................. 22 
6.3 
Hypersensitivity Reaction or Anaphylaxis ................................................................................................ 23 
6.4 
Management of hypertension: .................................................................................................................. 23 
6.5 
Thromboembolic events ............................................................................................................................ 26 
6.6 
Proteinuria: .............................................................................................................................................. 27 
6.7 
Other non-hematological toxicity: ............................................................................................................ 28 
6.8 
Dose Modifications/Delays ....................................................................................................................... 29 
7. 
DRUG FORMULATION AND ADMINISTRATION ................................................................................. 29 
7.1 
Ziv-aflibercept: ......................................................................................................................................... 29 


CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
7.2 
Octreotide................................................................................................................................................. 31 
US brand names: Octreotide acetate; Sandostatin® Sandostatin LAR® Depot....................................................... 31 
8. 
STUDY CALENDAR: ..................................................................................................................................... 34 
9. 
MEASUREMENT OF EFFECT..................................................................................................................... 35 
9.1 
Antitumor Effect– Solid Tumors ............................................................................................................... 35 
10. 
ADVERSE EVENT REPORTING REQUIREMENTS .......................................................................... 41 
10.1 
Definitions ................................................................................................................................................ 41 
10.2 
Procedures for AE and SAE Recording and Reporting ............................................................................ 43 
10.3 
Reporting Requirements ........................................................................................................................... 43 
10.4 
Reporting SAEs: ....................................................................................................................................... 43 
10.5 
Reporting to the Institutional Review Board (IRB)................................................................................... 44 
10.6 
Reporting to Sanofi-aventis: ..................................................................................................................... 45 
10.7 
Reporting to Hospital Risk Management .................................................................................................. 45 
10.8 
Monitoring of Adverse Events and Period of Observation ....................................................................... 45 
11. 
DATA AND SAFETY MONITORING ..................................................................................................... 46 
11.1 
Data Reporting ......................................................................................................................................... 46 
11.2 
Safety Meetings ......................................................................................................................................... 47 
11.3 
Auditing .................................................................................................................................................... 47 
12. 
REGULATORY CONSIDERATIONS ..................................................................................................... 47 
12.1 
Protocol Review and Amendments ........................................................................................................... 47 
12.2 
Informed Consent ..................................................................................................................................... 48 
12.3 
Ethics ........................................................................................................................................................ 48 
12.4 
Study Documentation ................................................................................................................................ 49 
12.5 
Records Retention ..................................................................................................................................... 49 
13. 
STATISTICAL CONSIDERATIONS ....................................................................................................... 49 
13.1 
Study Design/Endpoints ............................................................................................................................ 49 
13.2 
Sample Size/Accrual Rate ......................................................................................................................... 50 
13.3 
Analysis of Secondary Endpoints .............................................................................................................. 50 
13.4 
Reporting and Exclusions ......................................................................................................................... 50 
14. 
PUBLICATION PLAN ............................................................................................................................... 50 
15. 
REFERENCES ............................................................................................................................................ 52 
16. 
APPENDICES ............................................................................................................................................. 54 


12-456 Phase II Ziv-aflibercept/Carcinoid 
Jennifer Ang Chan, MD, MPH 
 
 
 
6
1. OBJECTIVES: 
 
The overall objective of this Phase II study is to assess the potential antitumor activity of Ziv-aflibercept 
in patients with advanced, progressive carcinoid tumors. 
 
 
1.1 
Study Design 
 
This is a single arm, Phase II trial with estimated sample size of 43 patients.  Patients with progressive, 
metastatic carcinoid tumors will receive Ziv-aflibercept (VEGF Trap) administered intravenously every 
two weeks.  All patients will concurrently receive octreotide. Patients will be followed for evidence of 
toxicity and response, with imaging studies performed every 12 weeks.  
 
1.2 
Primary Objective 
 
• 
To evaluate the progression-free survival (PFS) duration of patients with metastatic, unresectable, 
progressive carcinoid tumors treated with Ziv-aflibercept. 
 
 
1.3 
Secondary Objectives 
 
• 
To determine the safety and tolerability of Ziv-aflibercept in patients with advanced carcinoid 
tumors 
 
• 
To evaluate disease response (Partial Response [PR], Complete Response [CR], Stable disease 
[SD]), using RECIST criteria, version 1.1 of patients with advanced carcinoid tumors treated with 
Ziv-aflibercept 
 
• 
To evaluate biochemical response, using levels of chromogranin-A and urinary 5-HIAA 
measured at baseline and following treatment with Ziv-aflibercept 
 
 
2. 
BACKGROUND 
 
2.1 
Study Agent: Ziv-aflibercept 
 
Ziv-aflibercept is also referred to as “VEGF Trap”.  Ziv-aflibercept is a recombinant fusion protein 
consisting of human vascular endothelial growth factor (VEGF) receptor extracellular domains fused to 
the Fc portion of human immunoglobulin G1 (IgG1).   Ziv-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). Ziv-aflibercept drug product is 
formulated as a sterile liquid for intravenous administration. 
 
  
Ziv-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 Ziv-aflibercept to its ligands in vivo is expected to block tumor 
angiogenesis and vascular permeability. 


12-456 Phase II Ziv-aflibercept/Carcinoid 
Jennifer Ang Chan, MD, MPH 
 
 
 
7
 
Ziv-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, Ziv-aflibercept inhibited ascites formation and reduced tumor burden.   
 
Two analytes were assayed in animal models specifically by enzyme linked immunosorbent assay 
(ELISA) methods: free Ziv-aflibercept (compound not complexed to VEGF), and bound Ziv-aflibercept 
(complexed Ziv-aflibercept: VEGF [ratio 1/1]).    
 
Following IV administration in all animal species evaluated, free Ziv-aflibercept was characterized by 
a low clearance (0.5 to 3 mL/hr/kg), a low volume of distribution (69 to 226 mL/kg), and a long apparent 
elimination half life (t1/2) of 48 to 98 hours. 
 
  
Based on the correlation between exposure and activity in non-clinical models, the target 
 pharmacological exposure in humans is proposed to be a safely administered dose of Ziv-aflibercept at 
which an excess of free Ziv-aflibercept is sustained. 
 
The toxicity profile of Ziv-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, Ziv-
aflibercept-induced effects consisted mainly of thickening of the growth plate and osteocartilaginous 
exostoses observed on the axial and appendicular skeleton that correlated with hunched posture at clinical 
examination. In the nasal cavities, degeneration/regeneration of the respiratory and olfactory epithelium, 
and atrophy/loss of nasal septum and/or turbinates was often associated with hemorrhage and suppurative 
exudate. Histopathologic findings in the kidneys (increased glomerular mesangial matrix) were associated 
in a few animals with decreased serum total protein and albumin levels and increased serum 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. Ziv-aflibercept administration also resulted in a decrease in sperm motility 
and increased incidence of abnormal spermatozoa morphology. Most Ziv-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, Ziv-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. 
 
Ziv-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) 
Ziv-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).   
 


12-456 Phase II Ziv-aflibercept/Carcinoid 
Jennifer Ang Chan, MD, MPH 
 
 
 
8
To date, Ziv-aflibercept has been administered to approximately 2000 patients with advanced solid 
malignancies in clinical oncology trials, to 76 healthy subjects, and to 41 ophthalmology patients.  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.  
 
Target pharmacological exposure has been reached at doses ≥2 mg/kg IV given every 2 weeks.  Free 
Ziv-aflibercept levels have remained in excess of bound Ziv-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 Ziv-aflibercept monotherapy and 
with Ziv-aflibercept administered in combination with cytotoxic chemotherapy. 
  
Phase 1 studies, as both single agent and combination chemotherapy, are ongoing. Phase 2 
studies of Ziv-aflibercept, either alone or in combination with standard cytotoxic agents, are ongoingin a 
variety of oncologic indications. Phase 3 combination studies are ongoing in the following 
indications: lung cancer, colorectal cancer, pancreatic cancer, and prostate cancer. On August 3, 2012, the 
U.S. Food and Drug Administration (FDA) approved Ziv-aflibercept in combination with FOLFIRI for 
the treatment of patients with refractory colorectal cancer (following progression or resistance to an 
oxaliplatin based regimen).[20] 
 
 
2.2 
Neuroendocrine Tumors 
 
      NET’s have been reported with increasing frequency from years 1973 and 2004; recent estimates are 
that the incidence of NETs is 5.25 per 100,000 population.1 Moreover, because these tumors may be more 
indolent than other malignancies, the prevalence of patients diagnosed with NETs is estimated to be 
greater than 100,000 in the US.1  The majority of NETs are carcinoid tumors, which most commonly arise 
in the bronchi, small intestine, appendix, or rectum.2 Localized carcinoid tumors are treated with curative 
intent by surgical resection whenever possible.  However, curative surgery is often not possible due to the 
presence of metastatic disease at diagnosis.  The treatment of patients with advanced carcinoid tumors has 
been an area of intense investigation in recent years.2  
 
      The medical treatment of carcinoid tumors includes cytotoxic chemotherapy, biologic agents, and 
somatostatin analogs.  In the past decade, investigators have explored  a number of different cytotoxic 
chemotherapy regimens for this disease, with generally disappointing results.  Agents such as docetaxel, 
irinotecan, cisplatin, and gemcitabine have all failed to demonstrate significant tumor response.3-5 In an 
Eastern Cooperative Oncology Group (ECOG) Phase III study of chemotherapy in carcinoid tumors 
(E1281), patients were randomly assigned to treatment with 5-FU plus doxorubicin or 5-FU plus 
streptozocin.6 The median PFS was 4.5 months for the 5-FU plus doxorubicin arm and 5.3 months for the 
5-FU plus streptozocin arm.  Overall survival durations recorded in this trial were also suboptimal, at 15 
and 24 months respectively.   
 
     In the past year however, the treatment of advanced neuroendocrine tumors has undergone a rapid 
evolution.  Initial phase II studies of sunitinib and everolimus suggested that these biologically targeted 
agents have antitumor activity in patients with advanced neuroendocrine tumors.7-9 In patients with 
pancreatic neuroendocrine tumors, independent placebo-controlled randomized studies of the biologically 
targeted everolimus and sunitinib both revealed clear improvements in progression-free survival.10,11  
Based on the results of these studies, both everolimus and sunitinib were approved by the FDA for the 
treatment of advanced, progressive pancreatic neuroendocrine tumors in May, 2011.  A randomized phase 
III study of Octreotide with or without everolimus in patients with advanced carcinoid tumors 


12-456 Phase II Ziv-aflibercept/Carcinoid 
Jennifer Ang Chan, MD, MPH 
 
 
 
9
(RADIANT 2) demonstrated an improvement in progression-free survival based on local investigator 
review, however did not meet its statistical endpoint which was based on central radiology review (Pavel, 
Hainsworth, Baudin, et al ESMO congress, 2010). 
 
 
 
2.3 VEGF Inhibition in Carcinoid Tumors 
 
While no large randomized studies have been completed, several early phase studies suggest that VEGF 
pathway inhibition is a promising approach in treating patients with advanced carcinoid tumors. Sunitinib, 
Sorafenib, and pazopanib 
have 
been 
evaluated 
in 
advanced carcinoid tumors in 
the phase II setting.7,12,13 
These 
drugs 
have 
been 
associated 
with 
low 
radiographic response rates, 
but a relatively high rate of 
disease 
stabilization 
and 
potentially 
encouraging 
progression-free 
survival 
durations. 
These 
observations 
suggest 
that 
they may have a cytostatic 
effect that is under-appreciated when radiographic response is used as the primary efficacy endpoint. 
 
Bevacizumab has also been evaluated in a randomized phase II study of 44 patients with advanced or 
metastatic carcinoid tumors on a stable dose of octreotide. Patients were randomly assigned to 18 weeks of 
Bevacizumab or pegylated IFNa-2b, followed by treatment with both drugs.14 During the first 18 weeks of 
therapy, four (18 percent) of the Bevacizumab-treated patients experienced radiographic partial responses; 
furthermore, 95 percent of patients treated with octreotide plus Bevacizumab remained progression-free, 
compared with only 68 percent of those receiving octreotide plus IFNa-2b. Based on these results, SWOG 
is leading a large, randomized study of Bevacizumab versus interferon in patients with advanced carcinoid 
tumors (S0518).  
 
2.4 Role of Octreotide in Carcinoid Tumors 
Octreotide is commonly used for the control of symptoms of hormonal hypersecretion in patients with 
advanced carcinoid tumors. Recent evidence also suggests that octreotide may slow tumor growth. In a 
recent study, 85 patients with metastatic midgut neuroendocrine tumors were randomized to receive either 
octreotide or placebo; the median TTP for patients receiving octreotide was 14.3 months as compared to 6 
months for patients receiving placebo.15 Recent studies evaluating novel agents in advanced carcinoid 
tumors have required concurrent octreotide to avoid the potential for confounding.2  
 
2.5 
Rationale 
           
     VEGF Trap (Ziv-aflibercept) is a recombinant protein consisting of the extracellular domains of VEGFR 
1 and 2 fused to the Fc portion of immunoglobulin G1. Ziv-aflibercept compares favorably to other VEGF 
Phase II Studies of VEGF Pathway Inhibitors in Advanced Carcinoid 
Agent 
No. 
Patients 
Tumor 
Response 
Rate (%) 
Median 
TTP or 
PFS 
Reference 
Bevacizumab 
22 
18 
14 mos 
Yao et al.  
2008 
Sunitinib 
41 
2 
10.2 mos 
Kulke et al.  
2008   
Sorafenib 
50 
7 
7.8 mos 
Hobday et al  
2007 
Pazopanib 
22 
0 
12.7 mos 
Phan et al  
2010  


12-456 Phase II Ziv-aflibercept/Carcinoid 
Jennifer Ang Chan, MD, MPH 
 
 
 
10
inhibitors in preclinical studies, showing a high binding affinity for VEGF-A and other VEGF isoforms, as 
well as binding affinity for PlGF, which also contributes to angiogenesis.16 Phase II studies of Ziv-
aflibercept have shown preliminary evidence of activity in patients with advanced glioma, urothelial cancer, 
and treatment resistant lung cancer, utilizing a standard dose of 4 mg/kg administered intravenously every 
2 weeks.17-19  
 
In light of preliminary evidence of activity associated with VEGF inhibitors in carcinoid, as well as the 
significant unmet clinical need in this area, we propose a single-arm phase II study of Ziv-afliberceptin 
patients with advanced carcinoid tumors.  
 
Because prior studies of targeted agents have demonstrated low RECIST-defined tumor response rates 
in advanced carcinoid, we propose using PFS as a primary endpoint. The RADIANT 2 study will be used 
as the primary benchmark to assess median PFS durations that would be expected with an active targeted 
agent or with octreotide alone in this patient population (Pavel, Hainsworth, Baudin, et al ESMO congress, 
2010). Entry criteria for our study will closely parallel those used for the previously reported RADIANT 2 
study: patients will be required to have low or intermediate grade tumors and evidence of disease 
progression within 12 months prior to study enrollment. Concurrent treatment with octreotide will also be 
required.  
 
2.6 
Study design 
Among the first 10 patients with advanced carcinoid tumors treated with Ziv-aflibercept at a 
dose of 4 mg/kg intravenously every 2 weeks, nine developed grade 3 or higher hypertension.  
The protocol has been modified to decrease the starting dose of aflibercept to 2 mg/kg 
intravenously every 2 weeks for any patients enrolling after July 15, 2014.  Any patients enrolled 
prior to July 15, 2014 may continue dosing at their current tolerated dose level.  
 
   
3. 
Participant Selection 
3.1 
Inclusion Criteria 
Participants must meet the following criteria on screening examination to be eligible to participate 
in the study: 
 
3.1.1 
Participants must have histologically confirmed well differentiated or moderately differentiated 
neuroendocrine tumor from either a primary or metastatic site.  Carcinoid tumors of any 
primary site are eligible. 
 
3.1.2 
Participants must have disease that is not amenable to curative resection.   
 
3.1.3 
Participants must have evidence of disease progression within 12 months prior to study entry.   
 
3.1.4 
Participants must have measurable disease.  (RECIST 1.1) 
 
3.1.5 
Prior chemoembolization of local ablative therapies are allowed, provided there is measurable 
disease outside of the area treated, or documented evidence of progression at the site of prior 
treatment.   


12-456 Phase II Ziv-aflibercept/Carcinoid 
Jennifer Ang Chan, MD, MPH 
 
 
 
11
 
3.1.6 
There is no limit to number of prior treatments.  Prior bevacizumab is allowed unless it was 
discontinued due to unacceptable toxicity.  Prior therapy with tyrosine kinase inhibitors (TKI) 
targeting VEGF receptors is allowed. 
 
 
3.1.7 
Treatment with a somatostatin analog (e.g., octreotide acetate) is required for all participants.  
Octreotide naive patients may initiate this during the screening period or at start of study. 
 
 
3.1.8 
Prior treatment including chemoembolization or other ablative therapy, any cytotoxic, biologic 
or other investigational agents must have been completed at least 4 weeks prior to study entry.    
 
 
3.1.9 
Prior palliative radiation must have been completed at least 2 weeks prior to study entry. 
 
 
3.1.10 Age is ≥ 18 years  
 
 
3.1.11 ECOG performance status <1  
 
 
3.1.12 Participants with a history of hypertension must be adequately controlled with antihypertensive 
medication and BP must be less than 140/90 mmHg prior to initiation of Ziv-aflibercept.   
 
 
3.1.13 Therapeutic anticoagulation is allowed.  The participant must be on a stable dose of 
anticoagulant medication (warfarin, or LMWH) prior to study entry. 
 
 
3.1.14 Any major surgery must be completed at least 4 weeks prior to study entry.  Minor surgical 
procedures (except insertion of vascular access device) must have been completed at least 2 
weeks prior to study entry. 
3.1.15 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 3 months after last administration of Ziv-aflibercept. Women of child 
bearing potential must have a negative pregnancy test (urine or blood) within 14 days of 
registration. 
 
3.1.16 Participants must have organ and marrow function as defined below: 
 
 
 
Absolute neutrophil count > 1,500/mcL 
 
Hemoglobin >9g/dL 
 
Platelets > 100,000/mcL 


12-456 Phase II Ziv-aflibercept/Carcinoid 
Jennifer Ang Chan, MD, MPH 
 
 
 
12
 
total bilirubin ≤ 1.5X upper limit of normal 
 
AST (SGOT)/ALT (SGPT) < 2.5 X upper limit of normal or ≤5 X upper limit of 
normal if liver metastases are present. 
 
Alkaline Phosphatase ≤ 5X upper limit of normal 
 
Creatinine ≤ 1.5X upper limit of normal 
 
Urine protein/creatinine ratio of less than 1.   
 
 
 
3.1.17 Participant is able to understand and comply with study requirements and is willing to sign a 
written informed consent document. 
 
 
3.2 
Exclusion Criteria: 
 
Participants who exhibit any of the following conditions at screening will not be eligible to 
participate in the study. 
 
3.2.1 
Poorly differentiated carcinoma, high grade neuroendocrine tumor or small cell carcinomas are 
excluded from this study. 
 
3.2.2 
Prior treatment with Ziv-aflibercept is not allowed. 
 
 
3.2.3 
Pancreatic neuroendocrine tumors (islet cell carcinoma) will be excluded from this study.  All 
non functional and functional islet cell carcinomas such as insulinoma, glucagonoma, 
gastrinoma, VIPoma will be excluded. 
 
 
3.2.4 
No other investigational, biologic or chemotherapy agents, localized ablation or 
chemoembolization for 4 weeks prior to study entry. 
 
 
3.2.5 
Participant has not adequately recovered from toxicity of previous therapy. 
 
 
3.2.6 
Participants with known untreated brain or other central nervous system metastases are 
excluded.   
 
 
3.2.7 
Pregnant or nursing mothers are excluded. 
 
 
3.2.8 
Known allergy to any of the study agents or to compounds of similar chemical or biologic 
composition are excluded (including other somatostatin analogs). 
 
 


12-456 Phase II Ziv-aflibercept/Carcinoid 
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3.2.9 
Participants with a history of congestive heart failure ( NYHA class II, III or IV) are 
excluded 
 
 
3.2.10 No symptomatic peripheral arterial disease 
 
 
3.2.11 No unhealed wounds, ulcers or bone fractures 
 
 
3.2.12 No known HIV positive, or active Hepatitis infection 
 
 
3.2.13 No history of abdominal fistula, GI perforation, intra abdominal abscess, uncontrolled GI 
bleeding, diverticulitis within 6 months of study entry. 
 
 
3.2.14 No history of arterial thrombotic events such as MI (myocardial infarction), unstable angina 
pectoris or any ischemic or hemorrhagic CVA (cerebrovascular accident) within past 6 
months 
 
 
3.2.15 Participants with history of pulmonary embolism, DVT, or vascular access related 
thrombosis will be allowed on study provided they are receiving adequate anticoagulation 
at a stable dose at the time of study entry. 
 
 
3.2.16 No history of prior or synchronous malignancy, except; 
 
 
 
Prior malignancy was treated with curative intent and there is no known active disease 
present for greater than or equal to 3 years prior to study entry 
 
Participants with adequately treated non-melanoma skin cancers, cervical carcinoma in 
situ, or prostatic intraepithelial neoplasia without evidence of prostate cancer are 
eligible. 
 
3.2.17 Any uncontrolled non-malignant illness that in the opinion of the treating investigator may 
increase the risks associated with study participation or may interfere with the conduct of the 
study or interpretation of study results would exclude the participant.   
 
 
3.2.18 Uncontrolled psychiatric illness or social situations that would limit compliance with study 
requirements would exclude the participant. 
 
 
 
 
4. 
REGISTRATION PROCEDURES 
 


12-456 Phase II Ziv-aflibercept/Carcinoid 
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4.1 
General Guidelines for DF/HCC and DF/PCC Institutions 
 
Eligible participants will be registered through the DF/HCC Quality Assurance Office for Clinical Trials 
(QACT) central registration system. Registration must occur prior to the initiation of study related 
treatment.   
 
A designated member of the study team will confirm eligibility criteria and complete the protocol-specific 
eligibility checklist. 
  
Following registration, participants may begin protocol treatment. Issues that would cause treatment 
delays should be discussed with the Principal Investigator, Jennifer Chan, MD, MPH or the DFCI study 
team.  
 
If a participant does not receive protocol therapy following registration, the participant’s protocol status 
must be changed. Notify the QACT Registrar of participant status changes as soon as possible. 
 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions 
 
The QACT registration staff is accessible on Monday through Friday, from 8:00 AM to 5:00 PM 
Eastern Standard Time. In emergency situations when a participant must begin treatment during 
off-hours or holidays, call the QACT registration line at 617-632-3761 and follow the instructions 
for registering participants after hours. 
   
The registration procedures are as follows: 
 
 
1. 
Obtain written informed consent from the participant prior to the performance of any 
study related procedures or assessments. 
 
2. 
Complete the protocol-specific eligibility checklist using the eligibility assessment 
documented in the participant’s medical/research record. To be eligible for registration 
to the study, the participant must meet each inclusion and exclusion criteria listed 
on the eligibility checklist. 
 
 
3. 
Fax the eligibility checklist and all pages of the consent form to the QACT at 617-632-
2295. 
 
 
The QACT Registrar will validate eligibility and register the participant. 
 
4. 
The QACT Registrar will send an email confirmation of the registration and/or 
randomization to the person initiating the registration immediately following the 
registration and/or randomization. 
 
5. 
TREATMENT PLAN  
 
Treatment will be administered on an outpatient basis, however if necessary, treatment may be 
administered while inpatient at Brigham and Women’s Hospital or Massachusetts General Hospital. 


12-456 Phase II Ziv-aflibercept/Carcinoid 
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No investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the participant’s malignancy. 
 
Ziv-aflibercept is commercially available, however, for this study it will be provided free of charge by 
the sponsor Sanofi-Aventis.   
 
Octreotide is commercially available (generic octreotide acetate for subcutaneous injection and 
Sandostatin LAR depot®). It is FDA approved and will not be provided by the study. 
 
All patients will be receiving concurrent octreotide while on this study.  Refer to guidelines below for 
initiating treatment for octreotide naive patients. Octreotide and Ziv-aflibercept do NOT have to 
be administered on the same day.   
 
Table: 2  
 
STUDY AGENT 
 
 
 
Starting Dose 
 
Administration 
 
(28 day cycles) 
(+/-3days is allowed) 
 
Ziv-aflibercept 
Patients enrolled prior to July 15, 
2014: 
4mg/kg 
 
Patients enrolled after July 15, 2014: 
2mg/kg 
 
Intravenously: over 1 hour 
every 2 weeks 
 
Octreotide LAR 
 
(commercially 
available as 
Sandostatin LAR® 
depot) 
 
 
Recommended starting dose 20 mg 
IM:  Every 4 weeks 
 
Refer to section 5.1 
 
 
 
*Patients enrolled prior to July 15, 2014 may continue on their current tolerated dose. 
5.1 
Patient enrollment  
 
To ensure patient safety and to fully assess for adverse events, patients will be enrolled in 
cohorts consisting of 3 patients.  If all 3 patients in each cohort are able to complete one full 
cycle of therapy without unmanageable toxicity, an additional 3 patients will be enrolled to 
another patient cohort.  Enrollment in cohorts of 3 patients and evaluation of adverse events once 
each cohort has completed one cycle of therapy will continue until accrual has been completed. 
 
5.2 
Octreotide Guidelines (naïve patients) 
 
For octreotide naive patients, a suggested test dose of subcutaneous octreotide acetate 150 mcg is 
administered under supervision in clinic and is followed by a minimum of one hour of observation to 


12-456 Phase II Ziv-aflibercept/Carcinoid 
Jennifer Ang Chan, MD, MPH 
 
 
 
16
assess for adverse reaction.  If the test dose is tolerated, the first octreotide LAR depot injection 
(suggested dose 20 mg IM) may be administered anytime following the minimum period of observation. 
 
The dose and frequency of administration of octreotide may vary according to treating 
investigator discretion and symptom management of the study participant.  The suggested 
starting dose and schedule is noted above.  If study participant has been on a stable dose prior to 
study entry, they are to continue with that dose and schedule. Ziv-aflibercept and octreotide do 
not have to be administered on the same day. 
 
 
 
 
5.3 
Pre-treatment Criteria: 
5.3.1 
Screening (within 28 day of day 1 unless otherwise noted) 
• 
CT or MRI scans of chest, abdomen and pelvis with contrast (treating investigators 
discretion).  The same modality must be used throughout the study. 
• 
Informed consent/Confirmation of eligibility 
• 
Medical History, Physical examination, ECOG 
• 
Vital Signs, height and weight 
• 
Pregnancy test within 14 days for all women of childbearing potential (urine or serum) 
• 
EKG 
• 
Screening labs will include CBC with differential, Comprehensive chemistry panel, , U/A, 
UPCR.   
• 
Serum Chromogranin A and 24 hour urine collection for 5HIAA.  
(During the screening period, give patient supplies and instructions for collection of 24 
hour urine for 5HIAA and advise patient to return specimen on C1D1 or before).  If results 
of these are normal at baseline, do not repeat while on study.  If above institutional ULN at 
baseline, perform at the time of tumor restaging.     
• 
May receive test dose of subcutaneous octreotide acetate anytime during screening period 
or on C1D1 if octreotide naive. 
 
5.3.2 
Cycle 1 Day 1:  
If screening labs are done within 14 days of day 1, do not repeat on C1D1, otherwise perform 
the following: 


12-456 Phase II Ziv-aflibercept/Carcinoid 
Jennifer Ang Chan, MD, MPH 
 
 
 
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• 
CBC with differential, comprehensive chemistry panel, U/A and UPCR 
• 
Study Blood samples (Optional) 
• 
Return 24 hour urine collection for 5HIAA  
• 
Physical Exam, ECOG 
• 
Baseline symptom and toxicity assessment 
• 
Pre treatment Vital Signs and weight 
• 
Blood Pressure monitor will be given to patient for use at home. 
• 
Vital Signs 1 hour after first dose of Ziv-aflibercept (just prior to leaving infusion unit) 
 
5.3.3   Cycle 1 Day 3 (+/- 2 days) 
• 
Vital signs 
• 
Physical exam, ECOG 
• 
Toxicity assessment 
 
5.3.4   Day 1 of all subsequent cycles (refer to study calendar, section 8): 
• 
CBC with differential, comprehensive chemistry panel 
• 
Pre-dose study blood sample (optional) 
• 
Physical exam, ECOG 
• 
Toxicity assessment 
• 
Vital signs, weightPregnancy test for sexually active women of childbearing potential 
(urine or serum) 
• 
+/- 3 days for all study assessments and treatment is allowed 
• 
U/A and Urine Protein/creatinine ratio every other cycle 
 
5.1.4:   Day 15 of all cycles: 
• 
CBC with differential, comprehensive chemistry panel 


12-456 Phase II Ziv-aflibercept/Carcinoid 
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• 
Toxicity assessment 
• 
Vital signs, weight 
• 
+/- 3 days for all study assessments and treatment is allowed 
 
5.1.5:  Tumor Assessment/Other: 
• 
Restaging scans will be performed every 12 weeks.   
• 
If baseline levels of serum chromogranin A and/or Urinary 5HIAA levels were greater 
than institutional ULN these tests will be repeated at time of restaging.   
 
5.1.6: Blood Pressure Monitoring at home: 
Hypertension is a common side effect experienced by patients receiving Ziv-aflibercept.  For the 
first 3 cycles, patients will check their blood pressure once daily using a home automated blood 
pressure cuff (provided by study).  After the first 3 cycles, investigator’s discretion may be used to 
determine if blood pressure monitoring at home is still necessary.  Blood pressure will be recorded in 
diary (Appendix C) which will be returned to the study team at each visit for the first three cycles.  
Patients will be advised to contact the study investigator of designee for new or worsening hypertension 
to allow rapid implementation of antihypertensive therapies.   
 
5.4 
Agent Administration  
 
 
5.4.1 
Ziv-aflibercept:     
         
 Ziv-aflibercept is administered intravenously over approximately 1 hour via peripheral vein or central 
venous catheter using an institution approved infusion pump.  The infusion duration should not exceed 2 
hours.   Following the first infusion of Ziv-aflibercept, patient should be observed in clinic for 1 hour post 
infusion.  Vital signs will be observed anytime pre-dose for all infusions and immediately prior to 
discharge from infusion unit following the first infusion only.  
 
 Pre medication is not required prior to the administration of Ziv-aflibercept.   
 
In the event of reaction, subsequent infusions will be up to the discretion of the treating investigator and 
protocol guidelines.  For subsequent infusions, pre-medications may include but are not limited to 
acetaminophen, meperidine, steroids, diphenhydramine, or H2 blockers.  These may be used at the 
investigators discretion as there is no recommended regimen of pre medication established. 
5.4.2 
Octreotide 
Octreotide is administered by injection: as short acting “test dose” (subcutaneous) or long acting LAR 
(intramuscular).    
 


12-456 Phase II Ziv-aflibercept/Carcinoid 
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Octreotide is commercially available as generic octreotide acetate (used in this study for subcutaneous 
administration) or Sandostatin LAR® depot.   
 
 Sandostatin LAR® depot (octreotide acetate for injectable suspension) will be administered 
intramuscular (gluteus muscle) by injection.  It is available in single use kits containing a 5 mL vial of 10 
mg, 20 mg or 30 mg strength, a 2 mL vial of diluent, a 5 mL sterile plastic syringe, two sterile 1½” 19 
gauge needles, and three alcohol wipes.  
 
Sandostatin LAR® depot drug product kit will be brought to room temperature for a 30-60 minute period 
prior to preparation of the drug suspension.  An instruction booklet for the preparation of drug suspension 
for injection is also included with each kit.  Follow package insert and standard institutional practice for 
administration and preparation.  
 
5.5 
General Concomitant Medication and Supportive Care Guidelines 
 
• 
All concomitant medications will be recorded in the medical record. Medication list will be 
reviewed and updated at the time of screening and monitored throughout study.  There are no 
prohibited medications. 
 
• 
The use of antiemetic and other supportive care medications will be at the treating investigators 
discretion 
 
• Pre medication prior to first dose of Ziv-aflibercept is not required or recommended.   
 
• In the event of allergic reaction or anaphylaxis the infusion is to be immediately 
suspended and symptomatic and supportive treatment will be administered according to 
institutional standards.   
 
• Palliative radiation will not be allowed while on study. 
 
• Patients with known history of hypertension will continue on antihypertensive regimens 
as prescribed.  Modify antihypertensive drug therapy based on recommendations in the 
table (section 6.4).  
 
• Transfusions of blood products will be allowed if necessary 
 
• The use of growth factors will not be allowed. 
 
• The use of herbal supplements or high dose vitamins is not recommended as the 
interactions are not known. 
 
 
5.6 
Duration of Therapy 
 
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse events, treatment may continue 
until one of the following criteria applies: 


12-456 Phase II Ziv-aflibercept/Carcinoid 
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• 
Evidence of disease progression per RECIST criteria 1.1 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Unacceptable toxicity or other adverse events 
• 
Participant decides to withdraw consent from the study 
• 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the opinion of the treating investigator. 
• 
Grade 3 or 4 allergic or anaphylactic reaction to Ziv-aflibercept 
• 
Investigator Discretion 
 
 
5.7 
Duration of Follow Up  
 
 
The length of follow-up for the study is two years.  After removal from study, 
participants will be followed during this period for survival approximately every 3 
months until death or until loss to follow-up. Participants removed from study for 
unacceptable adverse events will be followed until resolution or stabilization of the adverse 
event. 
 
 
 
5.8 
Criteria for Removal from Study  
 
Participants will be removed from study when any of the criteria listed in Section 5.5 
applies. The reason for study removal and the date the participant was removed must be 
documented in the study-specific case report form (eCRF). Alternative care options will 
be discussed with the participant. 
 
In the event of unusual or life-threatening complications, participating sub investigators 
must immediately notify Jennifer A. Chan, MD, MPH via email or phone. 
 
6. 
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS  
 
 Common Toxicity Criteria for Adverse events (CTCAE) Version 4.0 will be used for toxicity 
assessment and grading.   
 
All adverse events experienced by participants will be collected from the time of the first dose of 
study treatment, through the study and until the final study visit.  
 
Participants continuing to experience toxicity at the off study visit may be contacted for additional 
assessments until the toxicity has resolved or is deemed irreversible. 
  
 
6.1 
Anticipated Toxicities 
  
A list of the expected or known adverse events and potential risks associated with the study 
agents are listed below.  Assessment of toxicity will be determined by the treating investigator 
or designee, using CTCAE version 4.0.  Recommendations for dose delay or modification are 


12-456 Phase II Ziv-aflibercept/Carcinoid 
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21
noted in the protocol in section 6.3.  The definition of adverse or serious adverse event and 
reporting guidelines are defined in section 10 of this protocol.  
 
ZIV-AFLIBERCEPT:  
 
 
• 
Hematological:  anemia, thrombocytopenia, thrombotic microangiopathy.  When used in 
combination with cytotoxic chemotherapy: neutropenia, febrile neutropenia, neutropenic 
colitis and sepsis 
• 
Cardiac: cardiac failure, hypertension 
• 
Digestive toxicity: abdominal pain, GI hemorrhage, intestinal perforation, intestinal 
obstruction, enteric fistula, peritonitis, pneumatosis intestinalis, nausea, vomiting , diarrhea, 
constipation, mucosal inflammation or ulceration, stomatitis, hepatic enzymes increased 
• 
General disorders: asthenia, fatigue, musculoskeletal pain, injection site reaction 
• 
Immune system disorders: hypersensitivity 
• 
Metabolic disorders: dehydration 
• 
Musculoskeletal: arthralgia, myalgia, osteonecrosis 
• 
Nervous system: headache, dizziness, encephalopathy, RPLS, cerebral ischemia, cerebral 
hemorrhage, cerebral venous thrombosis 
• 
Renal disorders: proteinuria, hematuria, renal failure 
• 
Respiratory disorders: dysphonia, dyspnea, epistaxis, hemoptysis, pulmonary embolism, 
tracheo-esophageal fistula 
• 
Skin disorders: (seen in combination with cytotoxic chemotherapy) palmar/plantar 
erythrodysaesthia syndrome, erythema 
• 
Vascular disorders: hypertension, deep vein thrombosis and phlebitis 
• 
Wound healing impairment. 
 
6.1.1 
OCTREOTIDE LAR:  (refer to package insert Sandostatin LAR® depot) 
 
 
• 
Gallbladder abnormalities, especially stones and/or biliary sludge, frequently develop in 
patients on chronic Octreotide acetate therapy. 


12-456 Phase II Ziv-aflibercept/Carcinoid 
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• 
Sinus bradycardia developed in 25%; conduction abnormalities occurred in 10% and 
arrhythmias developed in 9% of patients during Octreotide acetate therapy. 
• 
Diarrhea, loose stools, nausea and abdominal discomfort. Vomiting, flatulence, abnormal 
stools, abdominal distention, and constipation were each seen in less than 10% of patients. 
• 
In rare instances, gastrointestinal side effects may resemble acute intestinal obstruction, 
with progressive abdominal distention, severe epigastric pain, abdominal tenderness and 
guarding. 
• 
Hypoglycemia and hyperglycemia occurred in 3% and 16% of acromegalic patients, 
respectively, but only in about 1.5% of other patients. Symptoms of hypoglycemia were 
noted in approximately 2% of patients. 
• 
Hypothyroidism:  In acromegalics, biochemical hypothyroidism alone occurred in 12% 
while goiter occurred in 6% during Octreotide acetate therapy. In patients without 
acromegaly, hypothyroidism has only been reported in several isolated patients and goiter has 
not been reported. 
• 
Other adverse events: pain on injection was reported in 7.7%, headache in 6% and dizziness 
in 5%. Pancreatitis was also observed. 
• 
Rare adverse events (relationship to drug not established), each observed in 1%–4% of patients, 
included fatigue, weakness, pruritus, joint pain, backache, urinary tract infection, cold symptoms, 
flu symptoms, injection site hematoma, bruise, edema, flushing, blurred vision, pollakiuria, fat 
malabsorption, hair loss, visual disturbance and depression. 
 
• 
Events reported in less than 1% of patients and for which relationship to drug is not 
established are listed: Gastrointestinal: hepatitis, jaundice, increase in liver enzymes, GI 
bleeding, hemorrhoids, appendicitis, gastric/peptic ulcer, gallbladder polyp; Integumentary: 
rash, cellulitis, petechiae, urticaria, basal cell carcinoma; Musculoskeletal: arthritis, joint 
effusion, muscle pain, Raynaud's phenomenon; Cardiovascular: chest pain, shortness of 
breath, thrombophlebitis, ischemia, congestive heart failure, hypertension, hypertensive 
reaction, palpitations, orthostatic BP decrease, tachycardia; CNS: anxiety, libido decrease, 
syncope, tremor, seizure, vertigo, Bell's Palsy, paranoia, pituitary apoplexy, increased 
intraocular pressure, amnesia, hearing loss, neuritis; Respiratory: pneumonia, pulmonary 
nodule, status asthmaticus; Endocrine: galactorrhea, hypoadrenalism, diabetes insipidus, 
gynecomastia, amenorrhea, polymenorrhea, oligomenorrhea, vaginitis; Urogenital: 
nephrolithiasis, hematuria; Hematologic: anemia, iron deficiency, epistaxis; Miscellaneous: 
otitis, allergic reaction, increased CK, weight loss. 
• 
Anaphylactoid reactions, including anaphylactic shock 
6.2 
Toxicity Management: 
Treatment with Ziv-aflibercept may continue if the following criteria are met. Treatment may be 
delayed for a maximum of four weeks.   


12-456 Phase II Ziv-aflibercept/Carcinoid 
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• 
Absolute neutrophil count > 1,000/mcL 
• 
Platelets > 50,000/mcL 
• 
Creatinine ≤ 1.5X upper limit of normal 
• 
Urine protein: Refer to section 6.6 for specific guidelines. 
• 
BP: Refer to BP management guidelines in section 6.4. 
• 
Resolution of clinically significant non-hematological toxicity to baseline or < 
Grade 1 (clinical significance will be determined by the treating investigator) 
• 
ECOG 2 or less  
 
6.3 
 Hypersensitivity Reaction or Anaphylaxis 
CTCAE version 4.0 
Definitions 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Allergic Reaction 
Transient flushing or 
rash, drug fever 
(<100.4° F); 
intervention not 
indicated 
Intervention or infusion interruption 
indicated; responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, narcotics); 
prophylactic medications indicated for 
≤24 hours 
 
Prolonged (e.g., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization indicated 
for clinical sequelae 
(e.g., renal impairment, 
pulmonary infiltrates) 
Life-threatening 
consequences; urgent 
intervention 
indicated. 
Anaphylaxis 
- 
- 
Symptomatic 
bronchospasm, with or 
without urticaria; 
parenteral intervention 
indicated; allergy-related 
edema/angioedema; 
hypotension 
Life-threatening 
consequences; urgent 
intervention 
indicated. 
Action to be taken 
Continue infusion 
and monitor vital 
signs, administer 
supportive care per 
treating investigators 
discretions. 
 
Immediately interrupt infusion and 
provide supportive care according to 
institutional standards 
Upon recovery may re challenge at 
treating investigators discretion.   
Immediately interrupt 
infusion and provide 
supportive care 
according to institutional 
standards 
Off study 
Immediately interrupt 
infusion and provide 
supportive care 
according to 
institutional standards 
Off study 
6.4 
Management of hypertension: 
 
Hypertension is a common side effect experienced by patients receiving Ziv-aflibercept.   
 


12-456 Phase II Ziv-aflibercept/Carcinoid 
Jennifer Ang Chan, MD, MPH 
 
 
 
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Due to the incidence of hypertension that has been observed in patients with carcinoid tumors 
treated with aflibercept, prophylactic antihypertensive therapy with lisinopril 10 mg daily 
should be considered for patients with no contraindication to use of an ACE inhibitor.  If 
lisinopril is not started prophylactically, initiation of another antihypertensive agent prior to 
treatment with aflibercept can be considered as clinically appropriate.   
 
For patients already on antihypertensive medication, current therapy will be continued.   
 
For all patients, blood pressure will be monitored closely at home and at a clinic visit on C1D3 
(+/- 2 days) so that medications can be titrated as needed to keep systolic BP < 140 and diastolic 
BP < 90. 
 
Blood pressure and dosing of aflibercept will be managed as follows: 
 
 
 
Hypertension 
CTCAE version:4.0 
 
Definition 
 
Recommended management 
 
 
Grade 1 
 
Prehypertension:  
systolic 120-139 mm Hg or diastolic 
80-89 mm Hg 
 
No dose modification or delay 
 
 
 
Grade 2 
 
Stage 1 hypertension: 
systolic: 140-159 mm Hg  
or  
diastolic: 90-99 mm Hg 
• 
Medical intervention 
indicated 
• 
Recurrent or persistent (≥24 
hours) 
• 
Symptomatic increase by >20 
mmHg (diastolic) 
• 
>140/90 mm Hg if previously 
wnl 
• 
Monotherapy indicated 
 
 
No dose modification or delay 
 
• 
Increase current 
antihypertensive medication 
or consider addition of an 
additional agent, such as ACE 
inhibitor, labetalol or 
amlodipine. 
 
Grade 3 
 
Stage 2 hypertension: 
Systolic ≥160 mm Hg or 
Diastolic ≥100 
• 
Medical intervention 
indicated 
• 
More than one 
antihypertensive drug  
• 
or more intensive therapy 
than previously indicated 
 
Delay treatment with Ziv-aflibercept for 
a maximum of 4 weeks. 
 
• Increase current 
antihypertensive medication or 
consider addition of an 
additional agent, such as ACE 
inhibitor, labetalol or 
amlodipine. 
 
 
First occurrence: 
When BP is  controlled to < 140/90, 
resume Ziv-aflibercept at same dose. 
 


12-456 Phase II Ziv-aflibercept/Carcinoid 
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Second occurrence: When BP is  
controlled to < 140/90 resume Ziv-
aflibercept at reduced dose level. 
  
Third occurrence: 
Off study 
 
 
Grade 4 
 
Life threatening consequences (e.g., 
malignant hypertension, transient or 
permanent neurological deficit, 
hypertensive crisis); urgent intervention 
indicated 
 
Ziv-aflibercept: 
Off Study 
 
 
 
 
 
 
* Suggested antihypertensive medications 
 
Agent  
Usual starting 
dose and 
frequency 
Usual dose range 
Combined alpha and beta blockers 
 
 
     Labetalol 
100 mg twice daily 
200 – 800 mg 
 
 
 
Angiotensin converting enzyme 
inhibitors 
 
 
    Lisinopril  
 10 mg once daily 
5- 40 mg 
 
 
 
Dihydropyridine (DHP) Calcium 
Channel Blockers 
 
 
     Amlodipine 
5 mg once daily 
2.5-10 mg 
 
Adapted from Maitland et al, JNCI, 2010 May 5;102(9):596-604. 
 
6.5 
Home Blood Pressure Monitoring 
 
For the first 3 cycles, patients will check their blood pressure daily using a home automated blood 
pressure cuff  (provided by study).  After the first 3 cycles, investigator’s discretion may be used to 
determine if blood pressure monitoring at home is  necessary.   
 
Blood pressure will be recorded in diary  (Appendix C) and returned to the study team at each visit for 
the first three cycles.  Patients will be advised to contact the study investigator or designee for new or 
worsening hypertension to allow rapid implementation of antihypertensive therapies.   
 
 
 


12-456 Phase II Ziv-aflibercept/Carcinoid 
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6.6 
Thromboembolic events 
CTCAE version 4.0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Thromboembolic 
events 
Venous thrombosis 
(e.g., superficial 
thrombosis) 
Venous thrombosis  
(e.g., 
uncomplicated 
DVT), medical 
intervention 
indicated 
Thrombosis  
(e.g., 
uncomplicated 
pulmonary 
embolism 
[venous], non 
embolic cardiac 
mural [arterial] 
thrombosis), 
medical 
intervention 
indicated 
 
Life threatening  
(e.g., pulmonary embolism, CVA, 
arterial insufficiency); hemodynamic 
or neurologic instability; urgent 
intervention indicated 
 
Action to be taken 
 
Continue Ziv-aflibercept at investigator’s 
discretion 
Delay treatment 
with Ziv-
aflibercept for 
maximum of four 
weeks. 
Resume when 
medically stable 
and on stable dose 
of anticoagulation 
at same dose. 
 
Off study 
 


12-456 Phase II Ziv-aflibercept/Carcinoid 
Jennifer Ang Chan, MD, MPH 
 
 
 
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6.7 
Proteinuria: 
 
Toxicity/CTCAE version 
4.0 
Grade 1  
Grade 2 
Grade 3 
Nephrotic Syndrome 
Proteinuria 
 
1+ proteinuria; Urinary 
protein <1g/24 hours  
2+ proteinuria; Urinary 
protein 1-3.4g/24 hours 
Urinary protein >3.5g/24 
hours 
 
 
 
Off study 
 
 
 
 
 
Consider nephrology 
consult 
Actions to be taken 
 
 
Continue Ziv-aflibercept 
• 
UPCR ≤1.9: 
continue Ziv-
aflibercept.  
• 
UPCR > 1.9: 
hold Ziv-
aflibercept 
and collect a 
24 hour urine 
sample for 
urinary 
protein prior 
to next visit.  
Resume Ziv-
aflibercept if 
urinary protein 
is < 2 
gms/24hours 
and UPCR is 
≤1.9 
First occurrence: upon 
recovery resume at current 
dose 
Second occurrence:  upon 
recovery reduce dose of 
Ziv-aflibercept 
Third occurrence: off 
study 
Hold Ziv-aflibercept for a 
maximum of four weeks 
Perform 24 hour urine 
collection for protein 
weekly. 
Resume Ziv-aflibercept at 
reduced dose if resolution 
of urinary protein to 
<2g/24 hours and UPCR 
is ≤1.9 
 
Consider nephrology 
consult 
 
*Urine Protein Creatinine Ratio.  UPCR=Protein/creatinine.  Obtain at least 4 ml of a random urine sample.  Determine urine protein 
concentration (mg/dL) and urine creatinine concentration (mg/dL).  Divide results of protein concentration by creatinine concentration.  


12-456 Phase II Ziv-aflibercept/Carcinoid 
Jennifer Ang Chan, MD, MPH 
 
 
 
28
   
6.8 
Other non-hematological toxicity: 
Toxicity/CTCAE version 
4.0 
 
Grade 1 or 2 
Grade 3 
Grade 4 
Hemorrhage   
(Except intracranial 
hemorrhage) 
 
Mild or moderate; self 
limited; intervention may 
or may not be indicated 
(e.g., cauterization 
Requiring transfusion, 
radiologic, endoscopic or 
operative intervention 
 
 
Life threatening and 
urgent intervention 
indicated 
Actions to be taken 
 
Medically manage and 
continue Ziv-aflibercept at 
investigators discretion 
 
Off Study 
 
Off study 
Other: 
Abdominal fistula or 
wound dehiscence 
Intracranial hemorrhage 
GI perforation  
Reversible Posterior 
Leukoencephalopathy 
syndrome (RPLS) 
Arterial Thrombotic 
Events 
 
Any Grade: Off Study 
 
 
 


12-456 Phase II Ziv-aflibercept/Carcinoid 
Jennifer Ang Chan, MD, MPH 
 
 
 
29
6.9 
Dose Modifications/Delays 
  
Dose modification or delay will be based on clinically significant, study drug related toxicity as 
determined by treating investigator.  Toxicity will be graded according to the Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0. 
 
For hematological toxicity, any dose modification or delay will be based on results obtained on day of 
treatment (e.g., day 1 or 15 of each cycle). 
 
For non-hematological toxicity, any dose modification or delay or will be based on the worst grade of the 
toxicity that occurred at any time, and is thought to be related to Ziv-aflibercept and clinically significant. 
 
Once a dose has been attenuated to dose level -1 (1 mg/kg), there will be no re-escalation allowed.  If 
dose level -1 is not tolerated, the patient will be discontinued from study treatment.  For patients enrolled 
prior to July 15, 2014, reduction to dose level -2 (1 mg/kg) will be allowed.  Treatment with Ziv-
aflibercept may be delayed for a maximum of 4 weeks.   
 
Patients enrolled prior to July 15, 2014: 
 
 
Dose modification 
table:  
 
Starting dose 
 
Dose -1 
 
Dose -2 
Ziv-aflibercept 
4 mg/kg 
2 mg/kg 
1 mg/kg 
 
Patients enrolled after July 15, 2014: 
 
 
Dose modification 
table:  
 
Starting dose 
 
Dose -1 
 
Ziv-aflibercept 
 
 
2mg/kg 
 
1 mg/kg 
 
7. 
DRUG FORMULATION AND ADMINISTRATION  
  
7.1 
Ziv-aflibercept: 
 
7.1.1 
Description 
                
Concentrate for solution for IV infusion: Ziv-aflibercept is supplied for IV administration as a 
sterile, non-pyrogenic, colorless to pale-yellow colored, 25 mg/mL solution, packaged in a type 1, 


12-456 Phase II Ziv-aflibercept/Carcinoid 
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30
clear borosilicate glass vial closed with a flanged cap with tear-off lid and inserted sealing disc, 
Flurotec® (PTFE) coated. The pH of the solution is about 6.2. The aqueous 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. 
 
One Ziv-aflibercept drug product presentationis available: 
200 mg/8 mL in a 10 mL vial 
 
The fill volume has been established to ensure removal of 8 mL, respectively. 
Prior to infusion, the Ziv-aflibercept dosage form must be diluted directly into infusion bags of 
0.9% sodium chloride solution or 5% dextrose to a final volume of 100ml. The concentration of 
the diluted solution can range between 0.6 and 8 mg/mL. The pH of the diluted solution is about 
6.2. 
Ziv-aflibercept does not contain any microbial preservative. Therefore, care must be taken to 
ensure the sterility of the prepared solution. The dilution must be carried out by a healthcare 
professional under aseptic conditions 
 
7.1.2 
Storage and Stability 
Clinical supplies as packaged should be stored under refrigerated conditions (2 to 8°C). 
Stability studies on Ziv-aflibercept concentrate for solution for infusion are ongoing to ensure that 
clinical supplies remain within specifications during the duration of the clinical study. 
 
Based on available stability data, the concentrate for solution for infusion in its original unopened 
container is stable for 36 months under the recommended storage conditions. 
 
7.1.3 
Compatibility 
From a microbiological point of view, the product should be used immediately. If not used 
immediately, in-use storage times and conditions are the responsibility of the user.  
 
Dilution under aseptic conditions should be applied.  Chemical and physical real-time stability of 
dilute Ziv-aflibercept solutions at 0.6 to 8 mg/mL has been demonstrated for up to 24 hours under 
refrigerated conditions (2 to 8°C) or up to 8 hours at ambient temperature (approximately 25°C) 
in polypropylene syringes or in infusion bags made of the following materials: polyvinyl chloride 
(PVC) containing di (2-ethylhexyl) phthalate (DEHP) polyolefin (PVC free DEHP free) 
 
Diluted solutions of Ziv-aflibercept should be administered using infusion tubing made of the 
following materials: 
• 
PVC containing DEHP 
• 
DEHP free PVC containing tris(2-ethylhexyl)trimellitate (TOTM) 
• 
polypropylene 
• 
polyethylene lined PVC 
• 
polyurethane 
 
The infusion sets must contain a 0.2 μm polyethersulfone inline filter. Polyvinylidene fluoride 
(PVDF) filters and Nylon filters should not be used. 
 
Infusions will be administered via the institution approved IV infusion pump using 


12-456 Phase II Ziv-aflibercept/Carcinoid 
Jennifer Ang Chan, MD, MPH 
 
 
 
31
administration sets made of the above materials. 
 
Ziv-aflibercept will be infused over  approximately 1 hour, via peripheral or central venous 
catheter using infusion pump.  The duration of the infusion should not exceed two hours at 
room temperature (approximately 25°C). 
7.1.4 
Handling 
 
Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and safe 
disposal of the chemotherapeutic agent in a self-contained and protective environment. 
7.1.5 
Availability 
• 
Ziv-aflibercept will be provided from the commercial supply, free-of-charge to 
study participants from Sanofi-Aventis. 
 
• 
Octreotide acetate LAR depot and subcutaneous octreotide acetate are 
commercially available and will not be paid for by this study as they are 
considered to be standard of care. 
7.1.6 
Administration 
Ziv-aflibercept will be infused over 1 hour, via peripheral or central venous catheter 
using infusion pump.  The duration of the infusion should not exceed two hours at 
room temperature (approximately 25°C). 
7.1.7 
Ordering 
Ziv-aflibercept will be ordered directly from Sanofi-Aventis by the assigned research 
pharmacist.   
7.1.8 
Accountability 
           The responsible research pharmacist will maintain a record of the inventory and 
disposition of Ziv-aflibercept using the NCI Drug Accountability Record or institutional 
approved drug accountability form.  
 
7.1.9 
Destruction and Return 
 
At the end of the study, any unused supplies of Ziv-aflibercept will be destroyed 
according to institutional policies or returned to Sanofi-Aventis. Destruction will be 
documented in the Drug Accountability Record Form. 
 
7.2 
Octreotide 
 
          US brand names: Octreotide acetate; Sandostatin® Sandostatin LAR® Depot 
           Information available in package insert. 


12-456 Phase II Ziv-aflibercept/Carcinoid 
Jennifer Ang Chan, MD, MPH 
 
 
 
32
 
7.2.1 
 DESCRIPTION 
            Octreotide is the acetate salt of a cyclic octapeptide.  It is a long-acting octapeptide with 
pharmacologic properties mimicking those of the natural hormone somatostatin. Octreotide is 
known chemically as L-Cysteinamide, Dphenylalanyl-L-cysteinyl-L-phenylalanyl-D-tryptophyl-
L-lysyl-L-threonyl-N-[2-hydroxy-1-(hydroxy-methyl) propyl]-, cyclic (2→7)-disulfide; [R-
(R*,R*)]. 
 
Sandostatin LAR® depot (octreotide acetate for injectable suspension) is 
available in a vial containing the sterile drug product, which when mixed with 
diluent, becomes a suspension that is given as a monthly intragluteal injection. 
The octreotide is uniformly distributed within the microspheres which are made of a 
biodegradable glucose star polymer, D,L-lactic and glycolic acids copolymer. 
Sterile mannitol is added to the microspheres to improve suspendability. 
 
Octreotide LAR depot is available as sterile 5 mL vials in 3 strengths delivering 
10 mg, 20 mg or 30 mg octreotide free peptide. 
7.2.2 
Formulation:  
Sandostatin LAR® depot (octreotide acetate for injectable suspension) is available in single use kits 
containing a 5 mL vial of 10 mg, 20 mg or 30 mg strength, a 2 mL vial of diluent, a 5 mL sterile 
plastic syringe, two sterile 1½” 19 gauge needles, and three alcohol wipes. An instruction booklet 
for the preparation of drug suspension for injection is also included with each kit. Please see current 
Prescribing Information packaged with the Sandostatin LAR kit for additional information. 
 
Octreotide exerts pharmacologic actions similar to the natural hormone, somatostatin. It is an 
even more potent inhibitor of growth hormone, glucagon, and insulin than somatostatin. Like 
somatostatin, it also suppresses LH response to GnRH, decreases splanchnic blood flow, and 
inhibits release of serotonin, gastrin, vasoactive intestinal peptide, secretin, motilin, and 
pancreatic polypeptide. 
 
7.2.3 
PHARMACOLOGY 
After a single IM injection of the long-acting depot dosage form octreotide LAR depot in healthy 
volunteer subjects, the serum octreotide concentration reached a transient initial peak of about 
0.03 ng/mL/mg within 1 hour after administration progressively declining over the following 3 to 
5 days to a nadir of < 0.01 ng/mL/mg, then slowly increasing and reaching a plateau about two to 
three weeks post injection. Plateau concentrations were maintained over a period of nearly 2-3 
weeks, showing dose proportional peak concentrations of about 0.07 ng/mL/mg. After about 6 
weeks post injection, octreotide concentration slowly decreased, to < 0.01 ng/mL/mg by weeks 
12 to 13, concomitant with the terminal degradation phase of the polymer matrix of the dosage 
form. The relative bioavailability of the long-acting release octreotide LAR depot compared to 
immediate-release Sandostatin® Injection solution given subcutaneously was 60 - 63%. 
 
In patients with acromegaly, the octreotide concentrations after single doses of 10 mg, 20 mg, and 
30 mg octreotide LAR depot were dose proportional. The transient day 1 peak, amounting to 0.3 
ng/mL, 0.8 ng/mL, and 1.3 ng/mL, respectively, was followed by plateau concentrations of 0.5 


12-456 Phase II Ziv-aflibercept/Carcinoid 
Jennifer Ang Chan, MD, MPH 
 
 
 
33
ng/mL, 1.3 ng/mL, and 2.0 ng/mL, respectively, achieved about 3 weeks post injection. These 
plateau concentrations were maintained for nearly two weeks. Following multiple doses of 
octreotide LAR depot given every 4 weeks, steadystate octreotide serum concentrations were 
achieved after the third injection. Concentrations were dose proportional and higher by a factor of 
approximately 
1.6 to 2.0 compared to the concentrations after a single dose. The steady-state octreotide 
concentrations were 1.2 ng/mL and 2.1 ng/mL, respectively, at trough and 1.6 ng/mL and 2.6 
ng/mL, respectively, at peak with 20 mg and 30 mg octreotide LAR depot given every 4 weeks. 
No accumulation of octreotide beyond that expected from the overlapping release profiles 
occurred over a 
duration of up to 28 monthly injections of octreotide LAR depot. With thelongacting depot 
formulation octreotide LAR depot administered IM every 4 weeks the peak-to-trough variation in 
octreotide concentrations ranged from 44 to 68%, compared to the 163 to 209% variation 
encountered with the daily subcutaneous t.i.d. regimen of Sandostatin® Injection solution. 
 
In patients with carcinoid tumors, the mean octreotide concentrations after 6 doses of 10 mg, 20 
mg, and 30 mg octreotide LAR depot administered by IM injection every four weeks were 1.2 
ng/mL, 2.5 ng/mL, and 4.2 ng/mL, respectively. Concentrations were dose proportional and 
steady-state 
concentrations were reached after two injections of 20 and 30 mg and after three injections of 10 
mg. 
 
Octreotide LAR depot has not been studied in patients with renal impairment. 
 
Octreotide LAR depot has not been studied in patients with hepatic impairment. 
7.2.4 
Storage: 
For prolonged storage, octreotide LAR depot should be stored at refrigerated temperatures 2°C - 
8°C (36°F - 46°F) and protected from light until the time of use. Octreotide LAR depot drug 
product kit should remain at room temperature for 30-60 minutes prior to preparation of the drug 
suspension. 
However, after preparation, the drug suspension must be administered immediately.  
 
 
 
 
 
 
 
 


12-456 Phase II Ziv-aflibercept/Carcinoid 
Jennifer Ang Chan, MD, MPH 
 
 
 
34
 
 
 
 
 
 
 
 
8. 
STUDY CALENDAR: 
 
 
 
 
*Each cycle is 28 days   (+/- 3 days is allowed for all study 
related labs and treatment) 
Screening1 
C1D1
2 
C1D3 
(+/- 2 
days) 
C1D15 
C2 and 
subsequent 
cycles 
Following 
every 2 
cycles 
Following 
every 12 
weeks 
End of 
Study 
D1 
D15 
Medical History 
x 
 
 
 
 
 
 
 
 
Physical Exam and ECOG PS 
x 
x 
x 
 
x 
 
 
 
 
Vital Signs/Height3/Weight  
x 
x 
x 
x 
x 
x 
 
 
x 
EKG 
x 
 
 
 
 
 
 
 
x 
Pregnancy Test4   
x 
 
 
 
x 
 
 
 
 
Hematology5 
x 
x 
 
x 
x 
x 
 
 
x 
Chemistry6 
x 
x 
 
x 
x 
x 
 
 
x 
Urinalysis and Urine Protein/Creatinine ratio (UPCR)7 
x 
 
 
 
 
 
x7 
 
 
Imaging/tumor assessment 8 
x 
 
 
 
 
 
 
x 
 
Chromogranin A /Urinary 5-HIAA (24 hr urine)9 
x 
 
 
 
 
 
 
x 
 
                                                 
1 Screening period is within 28 days of start 
2 Cycle 1 Day 1 labs do not need to be repeated if done within 14 days of start. 
3 Height is only required at screening.  
4 Urine or serum pregnancy test.  For women of childbearing potential only.  Day 1 of each cycle. 
5 CBC with differential 
6 Comp Chemistry Panel: lytes, BUN, creatinine, Calcium, glucose, albumin, ALT, total protein, total bilirubin, AST, alk phos. 
7 U/A and UPCR required every other cycle. 
8  Restaging scans will occur after every 3 cycles of aflibercept, (e.g., within 1 week prior to start of cycles 4, 7, 10, etc).   
9  Assessment of chromogranin A and urinary 5-HIAA will occur after every 3 cycles of aflibercept at the time of restaging scans.  Assessment is 
required only if chromogranin A and urinary 5-HIAA are elevated at baseline. 


12-456 Phase II Ziv-aflibercept/Carcinoid 
Jennifer Ang Chan, MD, MPH 
 
 
 
35
Study Blood Collection10 
 
x 
 
 
 
 
 
 
 
Concomitant Medication Monitoring 
 
      x  
 
x 
Toxicity Assessment/AE monitoring 
 
x 
     x 
 
x 
Ziv-aflibercept  
 
x 
 
x 
x 
x 
 
 
 
Octreotide LAR depot11  
 
x 
 
 
x 
 
 
 
 
Home Blood Pressure Monitoring and Diary 
 
x 
 
x 
x12 
x 
 
 
 
 
 
9. 
MEASUREMENT OF EFFECT  
 
Although response is not the primary endpoint of this trial, participants with measurable disease 
will be assessed by RECIST 1.1 criteria. For the purposes of this study, participants should be 
reevaluated prior to every 4th cycle.  
9.1 
Antitumor Effect– Solid Tumors 
For the purposes of this study, participants should be re-evaluated for response every after 3 
cycles of Ziv-aflibercept (approximately 12 weeks).  
Response and progression will be evaluated in this study using the Response Evaluation 
Criteria in Solid Tumors (RECIST 1.1). 
Definitions 
Evaluable for toxicity. All participants who receive at least one dose of study 
treatment will be evaluable for toxicity from the time of their first treatment. 
Evaluable for objective response. Response rates will be calculated based on an 
intent-to-treat analysis that includes all patients who have received at least one dose 
of study treatment.  Participants will have their response classified according to the 
definitions stated below. 
9.1.1 
Disease Parameters 
Measurable disease. Measurable disease is the presence of at least one (1) lesion 
that can be accurately measured in at least one dimension with longest diameter  >20 
millimeters (mm) using conventional techniques (CT, MRI, x-ray) or  >10 mm with 
spiral CT scan. Measurable lesions must be at least 2 times the slice thickness in mm. 
                                                 
10 Refer to Appendix B for specific collection/storage information 
11 Octreotide schedule may vary according to patient needs or treating investigator discretion.  Patients do not need to receive Octreotide and Ziv-
aflibercept on the same day. 
12 Required through the first three cycles only.  Home blood pressure monitory after the 3rd cycle of aflibercept will be performed at 
investigator discretion. 


12-456 Phase II Ziv-aflibercept/Carcinoid 
Jennifer Ang Chan, MD, MPH 
 
 
 
36
All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
 
 A lesion in a previously irradiated or embolized area is not eligible for 
measurable disease unless there is objective evidence of progression of the lesion 
prior to study enrollment. Lesions in previously irradiated areas must be clearly 
identified as such. 
  
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a 
lymph node must be > 15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline and in follow-up, 
only the short axis will be measured and followed. 
 
Non-measurable disease.  
 
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm 
or pathological lymph nodes with > 10 to < 15mm short axis, are considered non-
measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal masses 
identified by physical exam that are not measurable by reproducible imaging techniques, 
and cystic lesions are all considered non-measurable. 
Target lesions.  
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and 
recorded and measured at baseline. Lesions must be accurately measured in 1 
dimension with a minimum size of 10 mm by CT or MRI (slice thickness no greater 
than 5 mm), 20 mm by chest x-ray. Nodes must have a short axis > 15 mm. The short 
axis should be included in the sum of the lesions in the calculation of response. 
Nodes that shrink to < 10 mm are considered normal. Target lesions should be 
selected on the basis of their size, be representative of all the involved organs, and 
should be lesions that can be followed with reproducible repeated measurements.  
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as CT or 
MRI can be considered target lesions if the soft tissue component meets the definition of 
measurability as defined above. Cystic lesions thought to represent cystic metastases can 
be considered as target lesions. However, if non-cystic lesions are present, these are 
preferred for selection as target lesions. Lesions in previously irradiated areas or areas 
subject to other loco-regional therapy are usually not considered measurable unless there 
has been demonstrated progression of that lesion.  
Non-target lesions.  
All other lesions, including small lesions < 10 mm or pathological lymph nodes 
measuring > 10 mm to < 15 mm in short axis, as well as truly non-measurable 


12-456 Phase II Ziv-aflibercept/Carcinoid 
Jennifer Ang Chan, MD, MPH 
 
 
 
37
lesions, which include leptomeningeal disease, ascites, pleural or pericardial effusion, 
inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses identified by physical exam that are not measurable by reproducible imaging 
techniques.  
9.1.2 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation, using a ruler, calipers, 
or digital measurement tool. 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 anti-tumor 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). For 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. 
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. 
Tumor markers. Tumor biomarkers such as chromogranin A or urinary 5HIAA, 
cannot be the only method used to assess response. If markers are initially above 
the upper normal limit, they must normalize for a subject to be considered in 
complete clinical response.  
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). 


12-456 Phase II Ziv-aflibercept/Carcinoid 
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38
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. 
9.1.3 
 Response Criteria  
9.1.3.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions. Any 
pathological lymph node must have reduction in short axis to < 10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the 
diameters of target lesions, taking as reference the smallest sum on 
study with at least a 5 mm absolute increase in the sum of all lesions. 
The appearance of one or more new lesions* denotes disease 
progression.  
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest 
sum diameters while on study. 
Unknown (UN): Assessment of target lesions cannot be made due to 
insufficient or unevaluable data. In this case, a concise explanation must be 
given. 
Note: If tumor response data is missing for target lesions, the overall 
assessment must be UN unless there is new disease that would result in an 
overall assessment of PD. However, if there is missing or unevaluable data for 
non-target lesions, but data is available for all target lesions, the overall 
response for that time point will be assigned based on the sum LD of all target 
lesions. Additionally, the assessment of CR cannot be made if there is missing 
or unevaluable data for non-target lesions. In this case, the overall assessment 
would be PR. 
*Definition of New Lesion: The finding of a new lesion should be unequivocal (i.e. not 
due to difference in scanning technique, imaging modality, or findings thought to 
represent something other than tumor (ex: new bone lesions may be healing or flare of 
pre-existing lesions). However, a lesion identified on a follow-up scan in an anatomical 
location that was not scanned at baseline is considered new and will indicate PD. If a 
new lesion is equivocal (because of small size, etc.), follow-up evaluation will clarify if 
it truly represents new disease and if PD is confirmed, progression should be declared 
using the date of the initial scan on which the lesion was discovered.  


12-456 Phase II Ziv-aflibercept/Carcinoid 
Jennifer Ang Chan, MD, MPH 
 
 
 
39
9.1.3.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level. All lymph nodes must be non-
pathological in size (< 10 mm short axis).  
Note: If tumor markers are initially above the upper normal limit, they 
must normalize for a subject to be considered in complete clinical 
response. 
Incomplete Response/Stable Disease (SD): Persistence of one or more 
non-target lesions and/or maintenance of tumor marker level above the 
normal limits. 
Progressive Disease (PD): Appearance of one or more new lesions* 
(new lesions must be > slice thickness) and/or unequivocal progression 
of existing non-target lesions. 
Overall level of substantial worsening that merits discontinuation of 
therapy. A useful test that can be applied when assessing non-targets 
for unequivocal progression is to consider if the increase in overall 
disease burden based on the change in non-measurable disease is 
comparable in magnitude to the increase that would be required to 
declare PD for measurable disease. 
Unknown (UN): Assessment of non-target lesions cannot be made due to 
insufficient or unevaluable data. In this case, a concise explanation must be 
given. 
*Definition of New Lesion: The finding of a new lesion should be unequivocal (i.e. not 
due to difference in scanning technique, imaging modality, or findings thought to 
represent something other than tumor (ex: new bone lesions may be healing or flare of 
pre-existing lesions). However, a lesion identified on a follow-up scan in an anatomical 
location that was not scanned at baseline is considered new and will indicate PD. If a 
new lesion is equivocal (because of small size, etc.), follow-up evaluation will clarify if 
it truly represents new disease and if PD is confirmed, progression should be declared 
using the date of the initial scan on which the lesion was discovered.  
9.1.3.3 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 participant's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
For Patients with Measurable Disease (i.e., Target Disease) 


12-456 Phase II Ziv-aflibercept/Carcinoid 
Jennifer Ang Chan, MD, MPH 
 
 
 
40
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response for 
when Confirmation is 
Required: 
CR 
CR 
No 
CR 
>4 wks confirmation 
CR 
Non-CR/Non-PD 
No 
PR 
>4 wks confirmation 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/Not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/Not 
evaluated 
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 
Any 
Any 
Yes 
PD 
* 
In exceptional circumstances, unequivocal progression in non-target lesions may 
be accepted as disease progression. 
 
Note:   Participants 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. 
 
9.1.4 
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 recurrence or PD is objectively documented, taking as reference for PD the 
smallest measurements recorded since the treatment started. 
Duration of overall complete response: 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. 
9.1.5 
Progression-Free Survival 
Progression-Free Survival (PFS) is defined as the duration from date of registration to time of 
objective disease progression per RECIST 1.1 criteria or death.  Patients who come off 
study without documented progression of disease (or clinical progression) will be 


12-456 Phase II Ziv-aflibercept/Carcinoid 
Jennifer Ang Chan, MD, MPH 
 
 
 
41
followed and included in PFS analysis until documented progression, death from any 
cause, or initiation of a new anti cancer therapy.   
9.1.6 
Response Review 
Tumor response will be evaluated at the study required time points by the DFHCC Tumormetrics 
Imaging Core (TIMC). 
 
10. ADVERSE EVENT REPORTING REQUIREMENTS 
10.1 Definitions 
10.1.1 Adverse Event (AE) 
 
An adverse event (AE) is any untoward medical occurrence in a patient administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship 
with the treatment.   
 
Abnormal laboratory values or diagnostic test results constitute adverse events only if 
they are determined to be of clinical significance or require treatment or further 
diagnostic tests.  
10.1.2 Serious adverse event (SAE): 
 
A serious adverse event (SAE) is defined as any adverse event regardless of causality 
that:  
 
• 
Results in death 
 
• 
Is life-threatening. Life-threatening refers to an event in which the study 
participant was at immediate risk of death from the reaction as it occurred, i.e., it 
does not include a reaction which had it occurred in a more severe form may 
have caused death.  
 
• 
Requires or prolongs inpatient hospitalization (e.g., requires greater than 24-hour 
hospitalization or prolonged a hospitalization beyond the expected length of 
stay). Hospitalization admissions and/or surgical operations scheduled to occur 
during the study period, but planned prior to study entry are not considered SAEs 
if the illness or disease existed before the person was enrolled in the trial, 
provided that it did not deteriorate in an unexpected manner during the trial (e.g., 
surgery performed earlier than planned). 
 
• 
Results in persistent or significant disability/incapacity. Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions. 
 
• 
Is a congenital anomaly or birth defect 
 


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• 
Other important medical event, as determined by the primary investigator. These 
events may not result in death or be life-threatening, or require hospitalization 
but may be considered to be SAE as they may require medical or surgical 
intervention to prevent one of the outcomes listed above. Some examples of this 
type of event are: allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency, drug abuse, or 
overdose with an associated serious event, or required intervention to prevent 
impairment/damage. 
 
Events not considered to be SAEs are hospitalizations for: 
 
• 
routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition, or for elective procedures 
 
• 
elective or pre-planned treatment for a pre-existing condition that did not worsen 
 
• 
emergency outpatient treatment for an event not fulfilling the serious criteria 
outlined above and not resulting in inpatient admission 
 
• 
respite or palliative care 
 
10.1.3 Expectedness: 
 
AEs may be 'Expected' or 'Unexpected.'  
10.1.3.1 Expected AE: 
 
Expected adverse events are those that have been previously identified as 
resulting from administration of the agent. For the purposes of this study, an 
adverse event is considered expected when it appears in the known adverse 
event list, the Investigator’s Brochure, the package insert or is included in the 
informed consent document as a potential risk.   
 
Refer to Section 6.1 for a listing of expected adverse events associated with 
the study agents. 
10.1.3.2 Unexpected adverse event 
 
 
For the purposes of this study, an adverse event is considered unexpected when 
it varies in nature, intensity or frequency from information provided in the 
known adverse event list, the Investigator’s Brochure, the package inset, or the 
informed consent document as a potential risk.   
 
10.1.4 Attribution/Causality: 
 


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Causality is a determination of reasonable possibility that the drug may have caused or 
contributed to an AE.  It includes assessing temporal relationships 
dechallenge/rechallenge information, association (or lack of association) with underlying 
diseases and the presence (or absence) or a lack of one or more likely causes. 
 
Attribution is the relationship between an AE or SAE and the study treatment. The 
primary investigator will make final determination of attribution/causality. 
 
The primary investigator, sub-investigator or clinical research team will assign as 
follows: 
 
• 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. 
• Unknown- Based on the evidence available, causality cannot be ascribed. 
10.2 Procedures for AE and SAE Recording and Reporting 
 
Participating investigators and clinical research team will assess the occurrence and attribution 
of AEs and SAEs at all of the required evaluation time points during the study.  
 
All AEs and SAEs whether reported by the participant, discovered during questioning, directly 
observed, or detected by physical examination, laboratory test or other means, will be recorded 
in the participant’s medical record (source document) and on the appropriate study-specific 
case report forms.  
 
The descriptions and grading scales found in the 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 website at: 
 
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
10.3 Reporting Requirements 
 
The study must be conducted in compliance with FDA regulations, Institutional safety reporting 
requirements, and DF/HCC reporting requirements of the principal investigator.  
 
It is the responsibility of each participating investigator to report any serious adverse events to 
the primary study team and to the primary investigator, Jennifer Chan, MD, MPH.  
 
 The study sponsor and/or others will be notified as described below.  
10.4 Reporting SAEs: 
10.4.1 Serious Adverse Event Reporting 
 


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All serious adverse events that occur after the initial dose of study treatment, during 
treatment, or within 30 days of the last dose of treatment must be reported to the DF/HCC 
Principal Investigator via email, phone or facsimile, to Sanofi Group and to the DF/HCC 
OHRS, using the DF/HCC SAE form. This includes events meeting the criteria outlined 
in Section 11.1.2, as well as the following: 
 
• 
Grade 2 (moderate) and Grade 3 (severe) Events – Only events that are 
unexpected and possibly, probably or definitely related/associated with the 
intervention need to be reported to DF/HCC IRB/Sanofi Group  
 
• 
All Grade 4 (life-threatening or disabling) Events – Unless expected AND 
specifically listed in the protocol as not requiring reporting. 
 
• 
All Grade 5 (fatal) Events – When the participant is enrolled and actively 
participating in the trial or when the event occurs within 30 days of the last study 
drug administration or if assessed as related at anytime therafter. 
 
Note: If the participant is in long term follow up, report the death at the time of 
continuing review.  
 
All SAEs must be reported within 24 hours of learning of the occurrence to:  
 
 
PI:  Jennifer Chan, MD, MPH 
jang@partners.org 
Phone: 617-632-5370 
Fax: 617-632-5370 
 
  
 
and 
 
  
 
Sanofi-Aventis  
 
  
 
Sanofi Group Entity Pharmacovigilance Contact 
 
  
 
USPVmailbox@sanofi-aventis.com 
 
  
 
F: 908-203-7783 
 
 
 
 
Follow-up information should be provided as soon as available, and will describe 
whether the event has resolved or continues, if and how the event was treated, and 
whether the participant will continue or discontinue study participation. Results of any 
complementary exams performed to obtain a final diagnosis of an SAE (e.g., hospital 
discharge summary, autopsy results, operative reports) will be made available to Sanofi 
group upon request. 
10.4.2 Non-Serious Adverse Event Reporting  
 
Non-serious adverse events will be reported to the DF/HCC Overall Principal 
Investigator via Case Report Forms (eCRF).   
10.5 Reporting to the Institutional Review Board (IRB) 
 


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In addition to notifying the primary investigator and Sanofi group, all DF/HCC sites will report 
SAEs (as noted above) directly to the DFCI Office for Human Research Studies (OHRS). 
 
10.6 Reporting to Sanofi-aventis 
 
The DF/HCC Overall Principal Investigator will report to Sanofi-Aventis, (regardless of the site 
of occurrence), any AE that is defined as serious and unexpected and is determined to be 
(possible, probable, or definitely) related to the study treatment. 
 
Unexpected or SAEs associated with the use of the study treatment will be reported to Sanofi-
aventis as soon as possible or within 7 calendar days after initial receipt of the information. 
10.7 Reporting to Food and Drug Administration (FDA) 
 
The DF/HCC Overall Principal Investigator, as holder of the IND, will be responsible for all 
communication with the FDA. The DF/HCC Overall Principal Investigator will report to the 
FDA, regardless of the site of occurrence, any adverse event that is serious, unexpected and 
reasonably related (i.e., possible, probable, definite) to the study treatment. 
 
Unexpected fatal or life-threatening experiences associated with the use of the study treatment 
will be reported to FDA as soon as possible but in no event later than 7 calendar days after 
initial receipt of the information. 
 
All other serious unexpected experiences associated with the use of the study treatment will be 
reported to FDA as soon as possible but in no event later than 15 calendar days after initial 
receipt of the information. 
 
Events will be reported to the FDA by telephone (1-800-FDA-1088) or by fax (1-800-FDA-
0178) using Form FDA 3500A (Mandatory Reporting Form for investigational agents) or FDA 
Form 3500 (Voluntary Reporting Form for commercial agents). Forms are available at 
http://www.fda.gov/medwatch/getforms.htm. 
10.8 Reporting to Hospital Risk Management 
 
Participating investigators or research team will report to their local Risk Management office 
any subject safety reports or sentinel events that require reporting according to institutional 
policy. 
10.9 Monitoring of Adverse Events and Period of Observation 
 
All AEs (serious and non serious) and deaths that are encountered from first dose of study 
treatment, throughout the study, and within 30 days of the last study treatment should be: 
• 
followed to their resolution,  
• 
or participating investigator assesses them as stable,  
• 
or participating investigator determines the event to be irreversible,  
• 
or participant is lost to follow-up.  
 


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AEs will be recorded in the participant’s medical record to facilitate source data verification. 
The presence and resolution of AEs and SAEs (with dates if available) should be documented 
on the appropriate case report form (eCRF). 
 
For some SAEs, the study sponsor or designee may follow-up by telephone, fax, and/or 
monitoring visit to obtain additional case details deemed necessary to appropriately evaluate the 
SAE report (e.g., hospital discharge summary, consultant report, or autopsy report).  
 
Participants will be advised to report any serious post-study event(s) that may reasonably be 
related to participation in this study. 
 
 Participating investigators should notify the DF/HCC Overall Principal Investigator and their 
respective IRB of any unanticipated death or adverse event occurring after a participant has 
discontinued or terminated study participation that may reasonably be related to the study.   
 
11. DATA AND SAFETY MONITORING 
11.1 Data Reporting 
11.1.1 Method  
The QACT will collect, manage, and monitor data for this study.  
11.1.2 Data Submission  
The schedule for completion and submission of case report forms (paper or electronic) to 
the QACT is as follows: 
 
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration with QACT 
On Study Form 
Within 14 days of registration 
Baseline Assessment Form 
Within 14 days of registration 
Treatment Form 
Within 10 days of the last day of the cycle 
Adverse Event Report Form 
Within 10 days of the last day of the cycle 
Response Assessment Form 
Within 10 days of the completion of the cycle 
required for response evaluation 
Off Treatment/Off Study Form 
Within 14 days of completing treatment or being 
taken off study for any reason 
Follow up/Survival Form 
Within 14 days of the protocol defined follow up 
visit date or call 


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11.2 Safety Meetings 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor 
toxicity and accrual data from this trial. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. Information that 
raises any questions about participant safety will be addressed with the Principal Investigator 
and study team. 
 
The DSMC will meet quarterly and/or more often if required to review toxicity and accrual 
data.  The first review of the DSMC will occur after the first three patients enrolled have 
completed 1 cycle of therapy.  Information to be provided to the committee may include:  up-
to-date participant accrual; current dose level information; DLT information; all grade 2 or 
higher unexpected adverse events that have been reported; summary of all deaths occurring 
within 30 days for Phase I or II protocols; for gene transfer protocols, summary of all deaths 
while being treated and during active follow-up; any response information; audit results, and a 
summary provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request.  
 
Any significant safety issues or recommendations by the Data Safety Monitoring Committee 
will be submitted to Sanofi group.  
11.3 Auditing  
 
Involvement in this study as a participating investigator implies acceptance of potential audits 
or inspections, including source data verification, by representatives designated by the 
DF/HCC Overall Principal Investigator (or Protocol Chair) or DF/HCC. The purpose of these 
audits or inspections is to examine study-related activities and documents to determine 
whether these activities were conducted and data were recorded, analyzed, and accurately 
reported in accordance with the protocol, institutional policy, Good Clinical Practice (GCP), 
and any applicable regulatory requirements.  
 
Data may be audited by QACT or if deemed necessary by the Overall Principal Investigator.  
 
12. REGULATORY CONSIDERATIONS 
 
12.1 Protocol Review and Amendments 
This protocol, the proposed informed consent and all forms of participant information 
related to the study (e.g., advertisements used to recruit participants) and any other 
necessary documents must be submitted, reviewed and approved by a properly constituted 
IRB governing each study location.  
Any changes made to the protocol must be submitted as amendments and must be approved 
by the IRB prior to implementation. Any changes in study conduct must be reported to the 
IRB. The DF/HCC Overall Principal Investigator (or Protocol Chair) will disseminate 
protocol amendment information to all participating investigators.  


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All decisions of the IRB concerning the conduct of the study must be made in writing. 
 
12.2 Informed Consent 
 
All participants must be provided a consent form describing this study and providing sufficient 
information for participants to make an informed decision about their participation in this 
study.  
 
The formal consent of a participant, using the IRB approved consent form, must be obtained 
before the participant is involved in any study-related procedure.  
 
The consent form must be signed and dated by the participant or the participant’s legally 
authorized representative, and by the person obtaining the consent. The participant must 
be given a copy of the signed and dated consent document. The original signed copy of 
the consent document must be retained in the research file a copy of the signed consent 
document will be scanned into medical record (LMR).  
12.3 Ethics  
This study is to be conducted according to the following considerations, which represent 
good and sound research practice: 
• 
US Code of Federal Regulations (CFR) governing clinical study conduct and ethical 
principles that have their origin in the Declaration of Helsinki 
o Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html  
o Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html  
o Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr56_02.html  
o Title 21 Part 312 – Investigational New Drug Application 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr312_02.html  
• 
State laws 
• 
DF/HCC research policies and procedures        
http://www.dfhcc.harvard.edu/clinical-research-support/clinical-research-unit-
cru/policies-and-procedures/  
It is understood that deviations from the protocol should be avoided, except when 
necessary to eliminate an immediate hazard to a research participant. In such case, the 
deviation must be reported to the IRB according to the local reporting policy.  


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12.4 Study Documentation 
 
The investigator must prepare and maintain adequate and accurate case histories designed to 
record all observations and other data pertinent to the study for each research participant. This 
information enables the study to be fully documented and the study data to be subsequently 
verified. 
 
Original source documents supporting entries in the case report forms include but are not 
limited to hospital records, clinical charts, laboratory and pharmacy records, recorded data from 
automated instruments, microfiches, photographic negatives, microfilm or magnetic media, 
and/or x-rays.  
 
12.5 Records Retention 
 
All study-related documents must be retained for the maximum period required by 
applicable federal regulations and guidelines or institutional policies.  
 
13. STATISTICAL CONSIDERATIONS  
13.1 Study Design/Endpoints  
The primary endpoint of this phase II study is to assess the progression free survival (PFS) of patients 
with advanced carcinoid tumors treated with Ziv-aflibercept. PFS is defined from the date of documented 
progression or death from any cause.  Patients who come off treatment without documented progressive 
disease will be followed and included in PFS analysis until documented progression, death from any 
cause, or the initiation of a new anti cancer therapy.   
 
Recent studies of targeted agents in neuroendocrine tumors suggest that while many of these agents are 
associated with low RECIST-defined response rates, they may be associated with significant progression 
free survival (PFS).  In the registration studies of sunitinib and everolimus in pancreatic neuroendocrine 
patients, PFS durations more than doubled, while overall response rates were only 9% and 4% 
respectively.10,11 
 
In this study of Ziv-aflibercept, we propose using PFS as the primary outcome measure.  The RADIANT 
2 study provides a reasonable estimate of PFS duration in a large cohort of carcinoid tumor patients 
treated with octreotide or octreotide plus an investigational agent (Pavel, Hainsworth, Baudin, et al 
ESMO congress, 2010).  RADIANT 2 randomized 429 patients with a history of symptoms attributed to 
carcinoid syndrome and evidence of radiographic progression within 12 months of enrollment to receive 
everolimus plus octreotide LAR depot, or a placebo plus octreotide LAR depot.  A significant PFS benefit 
in favor of everolimus was demonstrated based on investigator radiology review (12 vs. 8.6 months, p < 
0.01).  However, the primary endpoint of the study was based on adjudicated central review, and while 
this analysis also favored the everolimus arm over placebo, the predefined threshold for statistical 
significance was not met.   
 
Investigator review will be used as the primary endpoint in the current study of Ziv-aflibercept in 
advanced carcinoid  patients. Entry criteria will parallel those of the RADIANT 2 study, and will include 
a requirement for low or intermediate grade histology and for evidence of disease progression within 12 
months of study entry. Concurrent treatment with octreotide will also be required.  We assume that an 


12-456 Phase II Ziv-aflibercept/Carcinoid 
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inactive agent will be associated with PFS of 8 months, and that an agent worthy of further investigation 
will be associated with PFS of 12 months or greater.    
 
13.2 Sample Size/Accrual Rate 
 
A sample size of 43 participants achieves 80% power to detect the difference between null hypothesis 
median PFS of 8 months and the alternative hypothesis median PFS of 12 months at a 0.05 significance 
level (alpha) using a one-sided test. This sample size also allows 90% power to detect the same effect size 
with 10% type one error using a one-sided test. The length of follow up is 2 years. 
 
We expect an accrual rate of 1.5 patients per month. 
 
13.3 Analysis of Secondary Endpoints  
All patients treated with at least one dose of Ziv-aflibercept will be included in this data. 
 
• 
Toxicity data, including laboratory values will be graded using CTCAE version 4.0.   
• 
Response criteria will be assessed using RECIST 1.1 criteria. 
• 
Values of chromogranin A and urinary 5HIAA will be analyzed for actual and/or relative (%) 
change from baseline.  Correlation between changes from baseline may be explored graphically.  
The association of these markers and clinical outcomes of interest (e.g., time to progression) may 
be investigated.  
 
13.4 Reporting and Exclusions 
 
13.4.1 Evaluation of PFS.  Patients who come off treatment without documented progressive disease 
will be followed and included in PFS analysis until documented progression, death from any 
cause, or the initiation of a new anti cancer therapy.   
13.4.2 Evaluation of toxicity. All participants will be evaluable for toxicity after the administration of 
the first dose of Ziv-aflibercept. 
13.4.3 Evaluation of response.  All participants included in the study will be assessed for response to 
treatment.   Each participant 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). By arbitrary convention, category 9 usually 
designates the "unknown" status of any type of data in a clinical database. 
              
14. PUBLICATION PLAN 


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   Upon completion of this study and collection and analysis of all available data the results of this study 
will be submitted for publication within 3 years.  
 


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15. REFERENCES  
 
 
 
1. Yao JC, Hassan M, Phan A, et al: One hundred years after "carcinoid": epidemiology of and 
prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 26:3063-
72, 2008 
 
2. Kulke MH, Siu LL, Tepper JE, et al: Future directions in the treatment of neuroendocrine tumors: 
consensus report of the National Cancer Institute Neuroendocrine Tumor clinical trials planning meeting. 
J Clin Oncol 29:934-43, 2011 
 
3. Kulke MH, Kim H, Clark JW, et al: A Phase II trial of gemcitabine for metastatic neuroendocrine 
tumors. Cancer 101:934-9, 2004 
 
4. Kulke MH, Kim H, Stuart K, et al: A phase II study of docetaxel in patients with metastatic 
carcinoid tumors. Cancer Invest 22:353-9, 2004 
 
5. Kulke MH, Wu B, Ryan DP, et al: A phase II trial of irinotecan and cisplatin in patients with 
metastatic neuroendocrine tumors. Dig Dis Sci 51:1033-8, 2006 
 
6. Sun W, Lipsitz S, Catalano P, et al: Phase II/III study of doxorubicin with fluorouracil compared 
with streptozocin with fluorouracil or dacarbazine in the treatment of advanced carcinoid tumors: Eastern 
Cooperative Oncology Group Study E1281. J Clin Oncol 23:4897-904, 2005 
 
7. Kulke MH, Lenz HJ, Meropol NJ, et al: Activity of sunitinib in patients with advanced 
neuroendocrine tumors. J Clin Oncol 26:3403-10, 2008 
 
8. Yao JC, Phan AT, Chang DZ, et al: Efficacy of RAD001 (everolimus) and octreotide LAR in 
advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study.[erratum appears 
in J Clin Oncol. 2008 Dec 1;26(34)5660.]. Journal of Clinical Oncology 26:4311-8, 2008 
 
9. Yao JC, Lombard-Bohas C, Baudin E, et al: Daily oral everolimus activity in patients with 
metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J 
Clin Oncol 28:69-76, 2010 
 
10. Yao JC, Shah MH, Ito T, et al: Everolimus for advanced pancreatic neuroendocrine tumors. N Engl 
J Med 364:514-23, 2011 
 
11. Raymond E, Dahan L, Raoul JL, et al: Sunitinib malate for the treatment of pancreatic 
neuroendocrine tumors. N Engl J Med 364:501-13, 2011 
 
12. Hobday TJ, Rubin J, Holen K, et al: MC044h, a phase II trial of sorafenib in patients (pts) with 
metastatic neuroendocrine tumors (NET): A Phase II Consortium (P2C) study. Journal of Clinical 
Oncology, 2007 ASCO Annual Meeting Proceedings Part I. 25:Abstract 4505, 2007 
 
13. Phan A, Yao J, Fogelman D, et al: A prospective multi-institutional phase II study of GW786034 
(pazopanib) and depot octreotide (sandostatin LAR) in advanced low-grade neuroendocrine carcinoma. J 
clin Oncol 28:abstr 4001, 2010 
 
14. Yao JC, Phan A, Hoff PM, et al: Targeting vascular endothelial growth factor in advanced 
carcinoid tumor: a random assignment phase II study of depot octreotide with bevacizumab and pegylated 
interferon alpha-2b. J Clin Oncol 26:1316-23, 2008 
 
15. Rinke A, Muller HH, Schade-Brittinger C, et al: Placebo-controlled, double-blind, prospective, 
randomized study on the effect of octreotide LAR in the control of tumor growth in patients with 
metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol 
27:4656-63, 2009 
 
16. Holash J, Davis S, Papadopoulos N: VEGF-trap: a VEGF blocker with potent antitumor effects. 
PNAS 99:11393-11398, 2002 
 
17. Twardowski P, Stadler WM, Frankel P, et al: Phase II study of Ziv-aflibercept (VEGF-Trap) in 
patients with recurrent or metastatic urothelial cancer, a California Cancer Consortium Trial. Urology 
76:923-6, 2010 


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18. Leighl NB, Raez LE, Besse B, et al: A multicenter, phase 2 study of vascular endothelial growth 
factor trap (Ziv-aflibercept) in platinum- and erlotinib-resistant adenocarcinoma of the lung. J Thorac 
Oncol 5:1054-9, 2010 
 
19. de Groot JF, Lamborn KR, Chang SM, et al: Phase II Study of Ziv-aflibercept in Recurrent 
Malignant Glioma: A North American Brain Tumor Consortium Study. J Clin Oncol 29:2689-95, 2011 
20. http://www.fda.gov/Drugs/informatonon Drugs/ApprovedDrugs/ucm3114438.htm 
 
 


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16. APPENDICES  
 
 


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Appendix A: 
 
Urine Protein/Creatinine Ratio 
• 
Obtain at least 4 ml of a random urine sample 
• 
Determine urine protein concentration (mg/dL) and urine creatinine concentration (mg/dL).   
• 
Divide results of protein concentration by creatinine concentration= UPCR 
 
 


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Appendix B:   
CORRELATIVE STUDIES 
Consent for additional study blood samples will be requested in the informed consent 
document, but participation will be optional and eligible patients who do not consent to this 
portion of the study will still be able to proceed with study treatment.  The purpose of 
obtaining these samples is to explore potential biomarkers that correlate with Ziv-aflibercept 
treatment outcomes. Samples will be analyzed after the completion of the clinical portion of 
this study in order to better understand biologic correlates of the clinical activity of Ziv-
aflibercept in this population. The analysis will be performed at a laboratory designated by 
the principal investigator. All samples will be stored and labeled according to directions 
below. All samples will be destroyed after a maximum of 10 years. 
The analysis of results will not be made available to the individual study participant or the 
treating physician; however, group results from this trial may be published when the final 
data is available. 
Study samples will be drawn by an experienced phlebotomist or a research nurse during the 
course of normally scheduled blood draws obtained as part of the treatment study.   Blood 
samples may be drawn either peripherally or via a central line. Each site will be responsible for 
ordering their own laboratory supplies and shipping materials for the specimens.  Shipping costs 
and supplies will be covered by the protocol budget.  Specimens will be stored at each DF/HCC 
site. 
Specific instructions for study blood samples are described below: 
Whole Blood Samples: 
A single tube of whole venous blood will be collected at baseline and will be stored for 
future studies of biomarkers that may prove useful at that time. Venous blood will be 
collected into one 6 ml purple-top EDTA tube. After collection of the sample, the tube 
should be gently inverted to ensure mixing with the anticoagulant.  Whole blood should be 
transferred from EDTA tube into labeled cryotubes and frozen at –20C.  
All cryovials will be labeled as follows:  
1. Protocol Number: 12-456 
2. Unique subject identifier (initials of the patient and subject study #)  
3. Collection date 
4. Tube # (there should be approximately 2 cryovials; please note contents, i.e Whole Blood) 
 


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Plasma Samples: 
Plasma samples will be drawn at the following time points: 
• Prior to initiation of therapy  (may be done on C1D1 prior to administration of study 
drug)  
• Day 1 of each subsequent treatment cycle 
• End of study 
 
Approximately 5-7 ml of blood for plasma-based studies will be collected in EDTA (purple top) 
tubes. Plasma samples should be processed by inverting the tube several times to assure 
complete mixing of anticoagulant (EDTA) and immediately centrifuged in a clinical centrifuge at 
3,000 r.p.m. for 10 minutes at room temperature. Plasma should be aspirated without disturbing 
cells, aliquoted in 3 cryogenic vials, and frozen at –80C.   
 
All cryovials will be labeled as follows:  
1. 
Protocol Number: 12-456 
2. 
Unique subject identifier (initials of patient and study subject #)  
3. 
Collection date 
4. 
Tube # (there should be 3 cryovials)/ please note contents (plasma) 
 
 
 
 


12-456 Phase II Ziv-aflibercept/Carcinoid 
Jennifer Ang Chan, MD, MPH 
 
 
 
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Appendix C:   
12-456 : Home Blood Pressure Monitoring Diary and Instructions 
Name_____________________________   MRN#____________________________ 
Cycle__________       Doctors office phone number:___________________________ 
Instructions:  
1. Blood Pressure readings have two numbers.  The first number is the pressure in your blood vessels during a heart beat 
(systolic), and the second number is the pressure in the vessels when the heart rests in between beats (diastolic).  These 
numbers are written with a slash in between them (for example, 110/85). 
 
2. Record the date, then record your blood pressure ONCE daily using a home blood pressure monitor.  Record your blood 
pressure at approximately the same time of day (while you are relaxed and sitting and after you have rested for at least 5 
minutes).  If you take your blood pressure at other times of the day, please record under “Other readings”. 
 
3. A normal blood pressure is usually considered to be 120/80 mmHg.  If your systolic pressure is greater than 150 or your 
diastolic blood pressure is greater than 90 (150/90 or greater  →, try to relax, wait one hour, and recheck.  If  the second 
reading is greater than or equal to 150/90  please contact your doctor’s office for instructions.   
Date 
AM readings 
PM readings 
 Comments or “other readings” (include time and date) 
 
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**Please bring this form to every clinic visit or appointment. 
 
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Patient’s Signature: _____________________________________________  Date: _________________ 
 
Study Team Signature___________________________________________  Date returned: __________________________ 
 
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