Conditions: Gastrinoma Glucagonoma Insulinoma Pancreatic Polypeptide Tumor Recurrent Islet Cell Carcinoma Recurrent Pancreatic Cancer Somatostatinoma Stage III Pancreatic Cancer Stage IV Pancreatic Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 20
Healthy volunteers: no

Brief summary:
The purpose of this research is to evaluate the effectiveness and safety of a combination of capecitabine, temozolomide and bevacizumab in the treatment of advanced pancreatic neuroendocrine tumors.

Detailed description:
PRIMARY OBJECTIVES:

* Estimate if the combination of capecitabine and temozolomide with bevacizumab for metastatic or unresectable neuroendocrine tumors will improve response rate (RR) by 62% over historical controls (null RR of 40% to true RR 65%).
* Assess the toxicities using Common Terminology Criteria for Adverse Events (CTCAE) v4.0.

SECONDARY OBJECTIVES:

* Evaluate progression-free survival (PFS) and overall survival (OS) using Kaplan-Meier analysis.
* Assess O6-methyl guanine-deoxyribonucleic acid (DNA) methyltransferase (MGMT) at baseline by central pathology (path) review.
* Assess serum hormone marker levels.
* Evaluate computed tomography (CT) Perfusion as a tool to predict early therapeutic response. (Optional)
* Bank serum for future correlative analyses.

OUTLINE:

Patients receive bevacizumab intravenously (IV) over 30 to 90 minutes on days 1 and 15, capecitabine orally (PO) twice daily (BID) on days 1 to 14, and temozolomide PO once daily (QD) on days 10 to 14. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity, with assessment for treatment effect every 3 cycles.

After completion of study treatment, patients are followed up patients are followed long-term for survival.

Arms:
arm 1: Cycles repeat every 28 days until disease progression, unacceptable toxicity, or withdrawal.

Interventions: intervention 1: Capecitabine intervention 2: Temozolomide intervention 3: Bevacizumab
Intervention descriptions: intervention 1: Capecitabine by mouth twice daily on Days 1 to 14 intervention 2: Temozolomide by mouth daily on Days 10 to 14 intervention 3: Bevacizumab IV over 30 to 90 minutes on Days 1 \& 15

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
1 
 A Phase II Study of Capecitabine, Temozolomide and Bevacizumab for Metastatic 
or Unresectable Pancreatic Neuroendocrine Tumors 
 
 
NCT01525082 
Version 12.0 / 07.25.14 
 
 
 
Coordinating Center: 
 
Stanford Cancer Institute  
 
 
 
 
 
 
875 Blake Wilbur Drive 
 
 
 
 
 
Stanford, CA 94035 
 
Principal Investigator: 
 
Pamela L. Kunz, MD 
 
 
 
 
 
Stanford University School of Medicine 
 
 
Department of Medicine / Division of Oncology 
 
 
 
 
 
875 Blake Wilbur Drive 
 
 
 
 
 
Stanford, CA 94305-5826 
Phone: xxx-xxx-xxxx 
 
 
 
 
 
Fax: xxx-xxx-xxxx 
 
 
 
 
 
pkunz@stanford.edu 
 
Co-Investigators: 
 
 
George A. Fisher, MD, PhD 
 
 
Stanford University School of Medicine 
 
 
Department of Medicine / Division of Oncology 
 
 
 
 
 
875 Blake Wilbur Drive 
 
 
 
 
 
Stanford, CA 94305-5826 
 
 
 
 
 
 
 
James M. Ford, MD 
 
 
Stanford University School of Medicine 
 
 
Department of Medicine / Division of Oncology 
 
 
269 Campus Drive West 
 
 
CCSR-South,  
 
 
 
Stanford, CA 94305-5152 
 
 
 
 
 
 
 
 
 
 
Jonathan Strosberg, MD 
H. Lee Moffitt Cancer Center  
12902 Magnolia Drive  
Tampa, FL 33612 
 
 
 
Aya Kamaya, MD 
Stanford University School of Medicine 
Department of Radiology 


 
 
 
 
2 
300, Pasteur Drive;  
Stanford, CA 94305-5105 
 
Statistician: 
 
Alex McMillan, PhD 
 
 
Stanford University School of Medicine 
Biostatistics, Health Research and Policy 
259 Campus Drive,  
Stanford, CA 94305-5405 
 
Pharmacists: 
 
Martha Hamilton, Pharm D 
 
 
Stanford University School of Medicine 
 
 
300 Pasteur Drive, Rm H0301 
 
 
Stanford, CA, 94305 
 
 
Phone: (xxx)-xxx-xxxxx 
 
 
Fax: (xxx)-xxx-xxxx 
 
 
 
 
 
Research Pharmacist 
H. Lee Moffitt Cancer Center 
researchpharmacy@moffitt.org  
 
Research Coordinators: 
 
Prachi Nandoskar  
 
 
Stanford Cancer Center 
 
 
875 Blake Wilbur Drive 
 
 
Stanford, CA 94305 
 
 
 
 
 
 
 
Research Coordinator 
H. Lee Moffitt Cancer Center  
Tampa, FL 33612 
 
 
 
 
Protocol Version/Date: 
 
Version 12.0 / 07.25.14 
 
Revision history: 
 
 
Version 10.0 / 09.07.12 
Version 9.0 / 10.20.11 
                                                      Version 8.0 / 10.06.11 
Version 8.0 / 9.29.11 
Version 7.0 / 9.25.11 
Version 6.0 / 9.6.11 
Version 5.0 / 8.7.11 
Version 4.0 / 7.27.11 


 
 
 
 
3 
Version 3.0 / 6.13.11 
Version 2.0 / 5.10.11 
Version 2.0 / 4.7.11 


 
 
 
 
4 
Protocol Synopsis 
 
A Phase II Study of Capecitabine, Temozolomide and Bevacizumab for 
Metastatic or Unresectable Pancreatic Neuroendocrine Tumors 
 
 
Principal Investigator: 
Pamela L. Kunz, MD 
 
 
 
 
Assistant Professor of Medicine 
 
Stanford University Cancer Center 
 
 
 
 
875 Blake Wilbur Drive 
 
 
 
 
Stanford, CA 94305-5826 
 
 
 
 
Phone:  
 
 
 
 
Fax:  
 
 
 
 
pkunz@stanford.edu 
 
 
Study Centers: Stanford University School of Medicine (coordinating institution), , H. 
Lee Moffitt Cancer Center (subsite) 
 
Number of subjects planned: 30 (20 at Stanford and 10 at Moffitt) 
 
Planned accrual:  
• 2-4 patients per month per site with enrollment complete in 18 months. 
• Time on study per patient estimated at 6-9 months. 
• Median follow-up at time of study completion estimated at 12 months. 
Objectives 
1. Primary Objective 
a. To estimate the Radiographic Response Rate (RR), as defined by revised 
RECIST 1.1, under the combination of capecitabine and temozolomide with 
bevacizumab in patients with metastatic or unresectable pancreatic 
neuroendocrine tumors in comparison with the historical control rate. 
b. To assess the toxicities using CTCAE v4.0. 
 
2. Secondary Objectives 
a. To evaluate progression-free survival (PFS) and overall survival (OS) using 
Kaplan-Meier analysis 
b. To assess MGMT by central path review 
c. To assess serum hormone marker levels 
d. To evaluate CT Perfusion as a tool to predict early therapeutic response 
(OPTIONAL) 
e. To bank serum for future correlative analyses 


 
 
 
 
5 
Study Design 
We propose a multi-institution, phase II, single-arm, non-randomized study investigating 
bevacizumab in combination with capecitabine and temozolomide for unresectable or 
metastatic pancreatic neuroendocrine tumors.  Treatment will be given every 28 days as 
per the schema outlined below.  Patients will receive CT scans at baseline and after every 
3 cycles (approximately 3 months) and be evaluated by RECIST criteria.  We estimate 
that most patients will complete 6-9 cycles of treatment.  Dose reductions are allowed 
after cycle 1. If, after 3 cycles, patients develop significant toxicities attributed to either 
temozolomide (including nausea, cytopenias, etc) or capecitabine (including diarrhea, 
hand-foot skin syndrome, etc) patients may discontinue these agents and continue 
receiving bevacizumab as a single agent.  We will continue treatment indefinitely until one 
of the following occurs: patient withdraws consent and decides to discontinue study 
treatment, development of unacceptable toxicities, or evidence for progression of 
disease. If a patient is on single-agent bevacizumab at the time of disease progression, 
temozolomide and capecitabine may be restarted at the discretion of the investigator.  
 
 
Target Subject Population 
Patients with unresectable or metastatic pancreatic neuroendocrine tumors will be eligible 
for enrollment in this study. Patients must have measurable disease at the time of 
enrollment. No prior bevacizumab, fluoropyrimidine (capecitabine or 5FU) or 
temozolomide will be allowed. Prior sunitinib and everolimus will be allowed.  Tumor 
tissue for MGMT analysis will be requested for centralized path review at Stanford 
(archival tissue is acceptable). 
 
Investigational Products, Dosage and Mode of Administration 
Bevacizumab:  
10 mg/kg IV days 1 and 15 (28-day cycle) 
Capecitabine: 
750 mg/m2 PO BID days 1-14 
Temozolomide: 
200 mg/m2 PO QHS days 10-14 
 
Comparator, Dosage and Mode of Administration 
None.  
 
Bevacizumab 10 mg/kg IV day 1 and 15 
Capecitabine 750 mg/m2 po BID days 1-14 
Temozolomide 200 mg/m2 po QHS days 10-14 
Repeat Q28 days with imaging Q3 cycles 
R
E
G
I
S
T
E
R 
Screening 
evaluation 
Continue until 
disease 
progression 


 
 
 
 
6 
Duration of Treatment 
Each cycle lasts 28 days.  Patients will continue on treatment until one of the following 
occurs: 
1. 
Patient chooses to withdraw from study 
2. 
Unacceptable toxicity occurs 
3. 
Evidence of progressive disease by RECIST criteria  
4. 
At the discretion of the investigator 
 
Safety 
Safety assessments will consist of routine and frequent monitoring and recording of all 
adverse events and serious adverse events, regular monitoring of hematology and serum 
chemistry, coagulation tests, urinalysis, regular measurement of vital signs, weight, WHO 
Performance Status and the performance of physical examination.  The toxicities 
experienced by each patient on the study, and the study’s overall progress, will be 
reviewed weekly at the Stanford University GI Oncology Research Meeting. Dose 
adjustments will be made at the discretion of the investigators as per protocol. 
 
Statistical Methods 
A sample size of 30 patients would give 80% power to reject the null RR of 40% if the true 
response rate (RR) is 65% or higher. The null hypothesis is based on a prospective phase 
II study conducted by Kulke, et al evaluating the efficacy of temozolomide and 
thalidomide1.  In this study, 29 patients with mixed metastatic NETs were treated with 
temozolomide 150 mg/m2 for 7 days every other week and thalidomide at doses of 50-
400 mg daily.  The overall radiographic response was 25% (45% in patients with 
pancreatic NETs).  The alternative hypothesis is based on the more recent retrospective 
study in patients with pancreatic NETs reported by Strosberg, et al in which 30 patients 
were treated with capecitabine (750mg/m2 twice daily, days 1-14) and temozolomide (200 
mg/m2 once daily, days 10-14) every 28 days; the RR was 70%.2  RR is defined as the 
proportion of patients with complete response + partial response (CR+PR) based on a 
patient’s best response. Progression-free survival (PFS) and overall survival (OS) will be 
evaluated using Kaplan-Meier analysis.  For PFS analyses, patients will be censored at 
time last known alive if no progression has occurred. 
 
 


 
 
 
 
7 
Table of Contents 
List of abbreviations and definition of terms ......................................................................... 10 
1.0 
Background .............................................................................................................................. 12 
1.1 
Disease Background .................................................................................................................... 12 
1.2 
Bevacizumab Clinical Experience .......................................................................................... 12 
1.2.1 
Safety Profile ................................................................................................................................................. 13 
1.3 
Temozolomide Clinical Experience........................................................................................ 19 
1.3.1 
Clinical Pharmacokinetics of Temozolomide................................................................................... 19 
1.3.2  
Adverse Reactions: ................................................................................................................................ 22 
1.3.3 
MGMT Methylation Status ....................................................................................................................... 23 
1.4 
Capecitabine Clinical Experience ........................................................................................... 23 
1.4.1 Capecitabine Safety Profile .......................................................................................................................... 23 
1.5 
Study Rationale .............................................................................................................................. 24 
1.6 
Correlative Studies Background ............................................................................................. 24 
2.0 
Objectives .................................................................................................................................. 27 
3.0 
Study Design ............................................................................................................................ 27 
3.1 
Description of the Study ............................................................................................................. 27 
3.2 
Rationale for Study Design........................................................................................................ 28 
3.3 
Outcome Measures ....................................................................................................................... 28 
3.3.1 
Primary ............................................................................................................................................................ 28 
3.3.2  Secondary ........................................................................................................................................................... 28 
3.3.3 
Safety Outcome Measures ........................................................................................................................ 28 
4.0 
Safety Plan ................................................................................................................................ 29 
4.1 
Bevacizumab-specific .................................................................................................................. 29 
4.2 
Other Study Drug(s)-Specific ................................................................................................... 30 
5.0 
Study Subjects ......................................................................................................................... 30 
5.1 
Inclusion Criteria ............................................................................................................................ 30 
5.2 
Exclusion Criteria .......................................................................................................................... 31 
6.0 
Study Medications .................................................................................................................. 33 
6.1  
Bevacizumab administration, storage, and toxicity management ........................... 33 
6.1.1 
Bevacizumab Administration ................................................................................................................. 33 
6.1.2 
Bevacizumab Storage ................................................................................................................................ 34 
6.1.3 
Bevacizumab Dose Modification and Toxicity Management ..................................................... 34 
6.2 
Temozolomide administration, storage, and toxicity management ........................ 39 
6.2.1 
Temozolomide Administration: ............................................................................................................ 39 
6.2.2 Temozolomide Storage: ................................................................................................................................. 40 
6.2.3  
Temozolomide Dose Modifications: ............................................................................................... 40 
For non-hematologic toxicities, dose reductions of temozolomide will be at the 
discretion of the investigator.  Dose-reductions should follow the Temozolomide Dose 
Level Table above.  A maximum of 2 dose reductions can be performed. ......................... 42 
6.3 
Capecitabine administration, storage, and toxicity management ............................ 42 
6.3.1 Capecitabine Administration ...................................................................................................................... 42 
6.3.2 Capecitabine Dose Modification and Toxicity Management .......................................................... 43 
6.4 
General Dose Modifications ...................................................................................................... 45 
6.5 
Concomitant and Supportive Medications ......................................................................... 45 
6.5.1 Concomitant medications ............................................................................................................................. 45 


 
 
 
 
8 
6.5.2 
Pre-medications ........................................................................................................................................... 46 
6.5.3  
Supportive Care Guidelines ............................................................................................................... 46 
7.0 
Clinical and Laboratory Evaluations ............................................................................... 46 
7.1 
Pre-Treatment Evaluations ........................................................................................................ 47 
7.2 
Evaluations During Treatment ................................................................................................. 48 
7.3 
Post-Treatment Evaluations ...................................................................................................... 48 
7.4 
Correlative Tissue/Blood Studies ........................................................................................... 48 
8.0 
Subject Discontinuation ....................................................................................................... 51 
9.0 
Study Follow Up ...................................................................................................................... 52 
10.0 Statistical Methods ................................................................................................................ 52 
10.1 
Determination of Sample size .................................................................................................. 52 
10.2 
Planned Efficacy Evaluations ................................................................................................... 53 
11.0 Safety Reporting of Adverse Events ................................................................................. 57 
    11.1  Genentech-specific Safety Reporting (for both capecitabine and 
bevacizumab) ....................................................................................................................................... 57 
Assessment of Safety ................................................................................................................................. 57 
Specification of Safety Variables ........................................................................................................................... 57 
Adverse Events............................................................................................................................................................. 57 
Serious Adverse Events ............................................................................................................................................ 58 
Methods and Timing for Assessing AND Recording Safety variables .................................. 58 
Adverse Event Reporting Period .......................................................................................................................... 58 
Assessment of Adverse Events .............................................................................................................................. 58 
Procedures for Eliciting, Recording, and Reporting Adverse Events ................................... 59 
Eliciting Adverse Events........................................................................................................................................... 59 
Specific Instructions for Recording Adverse Events .................................................................................... 59 
MedWatch 3500A Reporting Guidelines ........................................................................................................... 61 
Additional Reporting Requirements for IND Holders ................................................................................. 62 
IND Annual Reports ................................................................................................................................................... 63 
Study Close-Out ............................................................................................................................................ 64 
11.2  Merck Safety Reporting................................................................................................................... 64 
12.0 Retention of Records............................................................................................................. 64 
13.0 Data and Safety Monitoring Plan ...................................................................................... 65 
14.0 Ethical and Regulatory Considerations .......................................................................... 66 
SAFETY REPORTING FAX COVER SHEET ..................................................................................... 74 
 
 
APPENDICES:  
Appendix A: NCI Common Toxicity Criteria, v4.0 (website provided) 
Appendix B: FDA MedWatch 3500a Form (website provided) 
Appendix C: NYHA Guidelines (included) 
Appendix D: Genentech Safety Reporting Cover Sheet (included) 
 
 


 
 
 
 
9 
ATTACHMENTS: 
Attachment 1:  Informed Consent Form (separate attachment) 
 
 
 


 
 
 
 
10 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ADL 
Activities of daily living 
AE 
Adverse event 
ALT/SGPT 
Alanine transaminase/Serum glutamate pyruvate transaminase 
ANC 
Absolute neutrophil count 
AST/SGOT 
Aspartate transaminase/Serum glutamic oxaloacetic transaminase 
BID 
Twice daily 
BSA 
Body surface area 
CBC 
Complete Blood Count 
CI 
Confidence interval 
Cmax 
Maximum concentration of drug 
CNS 
Central Nervous System 
CRC 
Colorectal cancer 
CRF 
Case Report/Record Form 
CR 
Complete response  
CrCl 
Creatinine Clearance 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DSMC 
Data and Safety Monitoring Committee 
ECG 
Electrocardiogram 
EGFR 
Epidermal growth factor receptor 
5-FU 
5-Fluorouracil 
G-CSF 
Granulocyte colony-stimulating factor (filgrastim) 
GI 
Gastrointestinal 
Hgb 
Hemoglobin 
HIV 
Human Immunodeficiency Virus 
HPF 
High-power field 
HTN 
Hypertension 
IRB 
Institutional Review Board 
IV 
Intravenous(ly) 
LLN 
Lower limit of normal 
MGMT 
O6-alkyl guanine-DNA alkyltransferase 
NSCLC 
Non-small cell lung cancer 
OS 
Overall survival  
PLT 
Platelet 
PO 
Per os/by mouth/orally 


 
 
 
 
11 
PD 
Progressive disease  
PFS 
Progression free survival  
PR 
Partial response  
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QD 
Once daily 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RR 
Radiographic Response Rate 
SAE 
Serious adverse event 
SD 
Stable disease  
TTP 
Time to progression  
ULN 
Upper Limit of Normal 
UNK 
Unknown 
VEGF 
Vascular Endothelial Growth Factor 
VEGF-R 
Vascular Endothelial Growth Factor Receptor 
WBC 
White Blood Cell 
WHO 
World Health Organization 


 
 
 
 
12 
1.0 
Background 
1.1 
Disease Background 
Neuroendocrine tumors (NETs) are a diverse group of malignancies that range from the 
well-differentiated carcinoid tumor to the poorly or undifferentiated neuroendocrine 
carcinoma.  While localized disease may potentially be cured with surgical resection, 
systemic therapies for metastatic or unresectable disease have largely been ineffective.   
 
Until recently there has been a paucity of randomized clinical trials using systemic 
therapies in this disease.  However, two recent practice-changing studies have 
validated the use of new medications for this disease.  The RADIANT-3 study3, 
published in 2011, is a randomized Phase III study evaluating the efficacy of everolimus 
in advanced pancreatic NETs.  A second randomized study evaluated the efficacy of 
sunitinib in advanced pancreatic NETs4.  Both studies showed improvements in PFS 
favoring the treatment arms but did not show significant RRs.  Yet, there is still a subset 
of patients in need of more dramatic response rates rather than just prolonged PFS.  
Recent reports of temozolomide and capecitabine in this disease have been 
encouraging.  Temozolomide is an alkylating agent and shares an active metabolite with 
dacarbazine.  In contrast to dacarbazine, temozolomide can penetrate the blood-brain 
barrier, is given orally, and has a more favorable side effect profile.  Temozolomide has 
demonstrated modest single-agent efficacy for advanced NETs5 but even more 
encouraging results when combined with capecitabine with reported response rates of 
70% for pancreatic NETs6.  MGMT deficiency is thought to be predictive of response to 
temozolomide and is more often associated with pancreatic NETs7. 
 
Additionally, NETs are highly vascular and have been shown to express high levels of 
vascular endothelial growth factor (VEGF).  One of the first studies to incorporate an 
antiangiogenic strategy in this disease was a Phase II study using temozolomide and 
thalidomide in metastatic NETs that reported radiographic response rates of 25% (45% 
among pancreatic NETs, 33% among pheochromocytomas and 7% among carcinoid 
tumors.1 A Phase II study using temozolomide and bevacizumab for metastatic 
carcinoid and pancreatic NETs also showed activity, with partial responses in 14% of all 
patients and stable disease in 79%8.  Other data suggest that single-agent 
administration of bevacizumab for advanced carcinoid tumors results in inhibition of 
tumor blood flow and increases progression-free survival9.   
 
These prior studies have demonstrated encouraging results and acceptable toxicity 
profiles.  We propose a multi-institution, phase II, single-arm, non-randomized study 
investigating bevacizumab in combination with temozolomide and capecitabine for 
patients with unresectable or metastatic neuroendocrine tumors. 
 
1.2 
Bevacizumab Clinical Experience   
Bevacizumab has been studied in a multitude of Phase I, II, and III clinical trials in more 
than 5000 patients and in multiple tumor types. In addition, data are available from 3,863 
patients enrolled in two postmarketing studies in metastatic colorectal cancer (CRC).  


 
 
 
 
13 
Approximately 130,000 patients have been exposed to bevacizumab as a marketed 
product or in clinical trials.  The following discussion summarizes bevacizumab’s safety 
profile and presents some of the efficacy results pertinent to this particular trial. Please 
refer to the bevacizumab Investigator Brochure for descriptions of all completed Phase I, 
II, and III trials reported to date. 
In a large phase III study (AVF2107g) in patients with metastatic colorectal cancer, the 
addition of bevacizumab, a monoclonal antibody directed against vascular endothelial 
growth factor (VEGF), to irinotecan/5-fluorouracil/leucovorin (IFL) chemotherapy resulted 
in a clinically and statistically significant increase in duration of survival, with a hazard 
ratio of death of 0.67 (median survival 15.6 vs. 20.3 months; p < 0.001).  Similar increases 
were seen in progression-free survival (6.2 vs. 10.6 months; p < 0.001), overall response 
rate (35% vs. 45%; p < 0.01) and duration of response (7.1 vs. 10.4 months; p < 0.01) for 
the combination arm versus the chemotherapy only arm (bevacizumab Investigator 
Brochure, October 2005). 
Based on the survival advantage demonstrated in Study AVF2107g, bevacizumab was 
designated for priority review and was approved on 26 February 2004 in the United States 
for first-line treatment in combination with IV 5-FU−based chemotherapy for subjects with 
metastatic colorectal cancer.  
Additional data from Phase III trials in metastatic CRC (E3200), non−small cell lung 
cancer (NSCLC; E4599), and metastatic breast cancer (E2100) have also demonstrated 
clinical benefit from bevacizumab when added to chemotherapy.  In Study E3200, the 
addition of bevacizumab to FOLFOX chemotherapy resulted in improved overall survival 
compared with FOLFOX alone (13.0 vs. 10.8 months, respectively, HR = 0.75; p  0.01) 
in a population of previously treated CRC patients.   
There was also improved overall survival in first-line NSCLC patients (E4599) treated 
with carboplatin/paclitaxel + bevacizumab compared with chemotherapy alone (12.3 vs. 
10.3 months, respectively; HR = 0.80; p = 0.003).  The results from this trial were the 
basis for FDA approval of bevacizumab for use in combination with 
carboplatin + paclitaxel as first-line treatment of patients with unresectable, locally 
advanced, recurrent or metastatic, non-squamous NSCLC in October 2006.  Finally, 
patients with untreated metastatic breast cancer (E2100) who received bevacizumab in 
combination with weekly paclitaxel had a marked improvement in PFS compared with 
chemotherapy alone (13.3 vs. 6.7 months, respectively; HR = 0.48; p  0.0001) (see the 
Bevacizumab Investigator Brochure for additional details). 
1.2.1 Safety Profile 
In the initial Phase I and II clinical trials, four potential bevacizumab-associated safety 
signals were identified: hypertension, proteinuria, thromboembolic events, and 
hemorrhage.  Additional completed Phase II and Phase III studies of bevacizumab as well 
as spontaneous reports have further defined the safety profile of this agent. 
Bevacizumab-associated adverse events identified in phase III trials include congestive 
heart failure (CHF) primarily in metastatic breast cancer, gastrointestinal perforations, 
wound healing complications, and arterial thromboembolic events (ATE). These and other 


 
 
 
 
14 
safety signals are described in further detail as follows and in the bevacizumab 
Investigator Brochure. 
Hypertension: An increased incidence of hypertension has been observed in patients 
treated with bevacizumab.  Grade 4 and 5 hypertensive events are rare. Clinical sequelae 
of hypertension are rare but have included hypertensive crisis, hypertensive 
encephalopathy, and reversible posterior leukoencephalopathy syndrome (RPLS) 
(Ozcan et al., 2006; Glusker et al., 2006).  
There is no information on the effect of bevacizumab in patients with uncontrolled 
hypertension at the time of initiating bevacizumab therapy.  Therefore, caution should 
be exercised before initiating bevacizumab therapy in these patients.  Monitoring of 
blood pressure is recommended during bevacizumab therapy.  Optimal control of blood 
pressure according to standard public health guidelines is recommended for patients on 
treatment with or without bevacizumab.   
Temporary interruption of bevacizumab therapy is recommended in patients with 
hypertension requiring medical therapy until adequate control is achieved.  
If hypertension cannot be controlled with medical therapy, bevacizumab therapy should 
be permanently discontinued.  Bevacizumab should be permanently discontinued in 
patients who develop hypertensive crisis or hypertensive encephalopathy. 
Proteinuria:  An increased incidence of proteinuria has been observed in patients treated 
with bevacizumab compared with control arm patients.  In the bevacizumab-containing 
treatment arms of clinical trials (across all indications), the incidence of proteinuria 
(reported as an adverse event) was up to 38% (metastatic CRC Study AVF2192g). The 
severity of proteinuria has ranged from asymptomatic and transient events detected on 
routine dipstick urinalysis to nephrotic syndrome; the majority of proteinuria events have 
been grade 1. NCI-CTC Grade 3 proteinuria was reported in up to 3% of bevacizumab-
treated patients, and Grade 4 in up to 1.4% of bevacizumab-treated patients.  The 
proteinuria seen in bevacizumab clinical trials was not associated with renal impairment 
and rarely required permanent discontinuation of bevacizumab therapy.  Bevacizumab 
should be discontinued in patients who develop Grade 4 proteinuria (nephrotic 
syndrome). 
Patients with a history of hypertension may be at increased risk for the development of 
proteinuria when treated with bevacizumab.  There is evidence from the dose-finding, 
Phase II trials (AVF0780g, AVF0809s, and AVF0757g) suggesting that Grade 1 
proteinuria may be related to bevacizumab dose. 
Proteinuria will be monitored by urine or urinalysis at least every 4 weeks.   
Thromboembolic Events: Both venous and arterial thromboembolic (TE) events, 
ranging in severity from catheter-associated phlebitis to fatal, have been reported in 
patients treated with bevacizumab in the colorectal cancer trials and, to a lesser extent, 
in patients treated with bevacizumab in NSCLC and breast cancer trials.  
Venous thromboembolism (including deep venous thrombosis, pulmonary 
embolism, and thrombophlebitis:  In the phase III pivotal trial in metastatic CRC, there 


 
 
 
 
15 
was a slightly higher rate of venous TE events in patients treated with bevacizumab plus 
chemotherapy compared with chemotherapy alone (19% vs. 16%).  
In Study AVF2107g, a Phase III, pivotal trial in metastatic CRC, VTE events, including 
deep venous thrombosis, pulmonary embolism, and thrombophlebitis, occurred in 
15.2% of patients receiving chemotherapy alone and 16.6% of patients receiving 
chemotherapy + bevacizumab.  
The incidence of NCI-CTC Grade  3 venous VTE events in one NSCLC trial (E4599) 
was higher in the bevacizumab-containing arm compared to the chemotherapy control 
arm (5.6% vs. 3.2%).  One event (0.2%) was fatal in the bevacizumab-containing arm; 
not fatal events were reported in the carboplatin/paclitaxel arm (see Bevacizumab 
Investigator Brochure).  In metastatic CRC clinical trials, the incidence of VTE events 
was similar in patients receiving chemotherapy + bevacizumab and those receiving the 
control chemotherapy alone.  
In clinical trials across all indications the overall incidence of VTE events was 
2.8%−17.3% in the bevacizumab-containing arms compared with 3.2%−15.6% in the 
chemotherapy control arms.  The use of bevacizumab with chemotherapy does not 
substantially increase the risk of VTE event compared with chemotherapy alone.  
However, patients with metastatic CRC who receive bevacizumab and experienced a 
VTE event may be at higher risk for recurrence of VTE event. 
Arterial Thromboembolic Events:  An increased incidence of ATE events was observed 
in patients treated with bevacizumab compared with those receiving control treatment.  
ATE events include cerebrovascular accidents, myocardial infarction, transient ischemic 
attacks (TIAs), and other ATE events.  In a pooled analysis of data from five randomized 
Phase II and III trials (mCRC [AVF2107g, AVF2192g, AVF0780g]; locally advanced or 
metastatic NSCLC [AVF0757g]; metastatic breast cancer [AVF2119g]), the incidence rate 
of 
ATE 
events 
was 
3.8% 
(37 
of 
963) 
in 
patients 
who 
received 
chemotherapy + bevacizumab compared with 1.7% (13 of 782) in patients treated with 
chemotherapy alone.  ATE events led to a fatal outcome in 0.8% (8 of 963) of patients 
treated with chemotherapy + bevacizumab and 0.5% (4 of 782) of patients treated with 
chemotherapy alone.  Cerebrovascular accidents (including TIAs) occurred in 2.3% of 
patients treated with chemotherapy + bevacizumab and 0.5% of patients treated with 
chemotherapy alone.  Myocardial infarction occurred in 1.4% of patients treated with 
chemotherapy + bevacizumab 
compared 
with 
0.7% 
of 
patients 
treated 
with 
chemotherapy alone (see the Bevacizumab Investigator Brochure for additional details). 
Aspirin is a standard therapy for primary and secondary prophylaxis of arterial 
thromboembolic events in patients at high risk of such events, and the use of aspirin ≤ 
325 mg daily was allowed in the five randomized studies discussed above. Use of aspirin 
was assessed routinely as a baseline or concomitant medication in these trials, though 
safety analyses specifically regarding aspirin use were not preplanned. Due to the 
relatively small numbers of aspirin users and arterial thromboembolic events, 
retrospective analyses of the ability of aspirin to affect the risk of such events were 
inconclusive. However, similarly retrospective analyses suggested that the use of up to 
325 mg of aspirin daily does not increase the risk of grade 1-2 or grade 3-4 bleeding 


 
 
 
 
16 
events, and similar data with respect to metastatic colorectal cancer patients were 
presented at ASCO 2005 (Hambleton et al., 2005). Further analyses of the effects of 
concomitant use of bevacizumab and aspirin in colorectal and other tumor types are 
ongoing. 
Gastrointestinal perforation Patients with metastatic carcinoma may be at increased 
risk for the development of gastrointestinal perforation and fistula when treated with 
bevacizumab and chemotherapy. Bevacizumab should be permanently discontinued in 
patients who develop gastrointestinal perforation. A causal association of intra-abdominal 
inflammatory processes and gastrointestinal perforation to bevacizumab treatment has 
not been established. Nevertheless, caution should be exercised when treating patients 
with intra-abdominal inflammatory processes with bevacizumab. Gastrointestinal 
perforation has been reported in other trials in non-colorectal cancer populations (e.g., 
ovarian, renal cell, pancreas, breast, and NSCLC) and may be higher in incidence in 
some tumor types. 
Fistula:  Bevacizumab use has been associated with serious cases of fistulae including 
events resulting in death.  Fistulae in the GI tract are common (1%–10% incidence) in 
patients with metastatic CRC, but uncommon (0.1%−1%) or rare (0.01%–0.1%) in other 
indications.  In addition, fistulae that involve areas of the body other than the GI tract 
(e.g., tracheoesophageal, bronchopleural, urogenital, biliary) have been reported 
uncommonly (0.1%–1%) in patients receiving bevacizumab in clinical studies and 
postmarketing reports.  Events were reported at various timepoints during treatment, 
ranging from 1 week to  1 year following initiation of bevacizumab, with most events 
occurring within the first 6 months of therapy. 
Permanently discontinue bevacizumab in patients with tracheoesophageal fistulae or 
any Grade 4 fistula.  Limited information is available on the continued use of 
bevacizumab in patients with other fistulae.  In cases of internal fistula not arising in the 
GI tract, discontinuation of bevacizumab should be considered. 
Wound healing complications: Wound-healing complications such as wound 
dehiscence have been reported in patients receiving bevacizumab. In an analysis of 
pooled data from two trials in metastatic colorectal cancer, patients undergoing surgery 
28-60 days before study treatment with 5-FU/LV plus bevacizumab did not appear to have 
an increased risk of wound healing complications compared to those treated with 
chemotherapy alone (Scappaticci et al., 2005). Surgery in patients currently receiving 
bevacizumab is not recommended. No definitive data are available to define a safe 
interval after bevacizumab exposure with respect to wound healing risk in patients 
receiving elective surgery; however, the estimated half life of bevacizumab is 21 days. 
Bevacizumab should be discontinued in patients with severe wound healing 
complications. 
If patients receiving treatment with bevacizumab require elective major surgery, it is 
recommended that bevacizumab be held for 4–8 weeks prior to the surgical procedure.  
Patients undergoing a major surgical procedure should not begin or restart 
bevacizumab until 4 weeks after that procedure (in the case of high-risk procedures 
such as liver resection, thoracotomy, or neurosurgery, it is recommended that 


 
 
 
 
17 
chemotherapy be restarted no earlier than 6 weeks and bevacizumab no earlier than 8 
weeks after surgery). 
Hemorrhage: Overall, grade 3 and 4 bleeding events were observed in 4.0% of 1132 
patients treated with bevacizumab in a pooled database from eight phase I, II, and III 
clinical trials in multiple tumor types (bevacizumab Investigator Brochure, October 2005). 
The hemorrhagic events that have been observed in bevacizumab clinical studies were 
predominantly tumor-associated hemorrhage (see below) and minor mucocutaneous 
hemorrhage.  
Tumor-Associated Hemorrhage:  Major or massive pulmonary hemorrhage or 
hemoptysis has been observed primarily in patients with NSCLC.  Life-threatening and 
fatal hemoptysis was identified as a bevacizumab-related adverse event in NSCLC 
trials.  These events occurred suddenly and presented as major or massive hemoptysis.  
Among the possible risk factors evaluated (including squamous cell histology, treatment 
with anti-rheumatic/anti-inflammatory drugs, treatment with anticoagulants, prior 
radiotherapy, bevacizumab therapy, previous medical history of atherosclerosis, central 
tumor location, and cavitation of tumors during therapy), the only variables that showed 
statistically significant correlations with bleeding were bevacizumab therapy and 
squamous cell histology. 
GI hemorrhages, including rectal bleeding and melena have been reported in patients 
with CRC, and have been assessed as tumor-associated hemorrhages. 
Tumor-associated hemorrhages were also seen rarely in other tumor types and 
locations, including a case of CNS bleeding in a patient with hepatoma with occult CNS 
metastases and a patient who developed continuous oozing of blood from a thigh 
sarcoma with necrosis. 
Mucocutaneous Hemorrage:  Across all bevacizumab clinical trials, mucocutaneous 
hemorrhage has been seen in 20%-40% of patients treated with bevacizumab. These 
were most commonly NCI-CTC Grade 1 epistaxis that lasted less than 5 minutes, 
resolved without medical intervention and did not require any changes in bevacizumab 
treatment regimen.  
There have also been less common events of minor mucocutaneous hemorrhage in other 
locations, such as gingival bleeding and vaginal bleeding.  
Reversible Posterior Leukoencephalopathy Syndrome:  There have been rare 
reports of bevacizumab-treated patients developing signs and symptoms that are 
consistent with RPLS, a rare neurologic disorder that can present with the following 
signs and symptoms (among others):  seizures, headache, altered mental status, visual 
disturbance, or cortical blindness, with or without associated hypertension.  Brain 
imaging is mandatory to confirm the diagnosis of RPLS.  In patients who develop RPLS, 
treatment of specific symptoms, including control of hypertension, is recommended 
along with discontinuation of bevacizumab.  The safety of reinitiating bevacizumab 
therapy in patients previously experiencing RPLS is not known (Glusker et al. 2006; 
Ozcan et al. 2006).   


 
 
 
 
18 
Congestive heart failure:  In clinical trials CHF was observed in all cancer indications 
studied to date, but predominantly in patients with metastatic breast cancer.  In the 
Phase III clinical trial of metastatic breast cancer (AVF2119g), 7 (3%) bevacizumab-
treated patients experienced CHF, compared with two (1%) control arm patients.  
These events varied in severity from asymptomatic declines in left ventricular ejection 
fraction (LVEF) to symptomatic CHF requiring hospitalization and treatment.  All the 
patients treated with bevacizumab were previously treated with anthracyclines 
(doxorubicin cumulative dose of 240−360 mg/m2).  Many of these patients also had prior 
radiotherapy to the left chest wall.  Most of these patients showed improved symptoms 
and/or left ventricular function following appropriate medical therapy (Miller et al. 2005). 
In a randomized, Phase III trial of patients with previously untreated metastatic breast 
cancer (E2100), the incidence of LVEF decrease (defined as NCI-CTC Grade 3 or 4) in 
the paclitaxel + bevacizumab arm was 0.3% versus 0% for the paclitaxel alone arm. 
No information is available on patients with preexisting CHF of New York Heart 
Association (NYHA) Class II−IV at the time of initiating bevacizumab therapy, as these 
patients were excluded from clinical trials. 
Prior anthracyclines exposure and/or prior radiotherapy to the chest wall may be 
possible risk factors for the development of CHF.  Caution should be exercised before 
initiating bevacizumab therapy in patients with these risk factors. 
A Phase II trial in patients with refractory acute myelogenous leukemia reported 5 cases 
of cardiac dysfunction (CHF or LVEF decrease to  40%) among 48 patients treated 
with sequential cytarabine, mitoxantrone, and bevacizumab.  All but 1 of these patients 
had significant prior exposure to anthracyclines as well (Karp et al. 2004).  
Other studies in patients with various tumor types and either a history of anthracycline 
exposure or concomitant use with bevacizumab are ongoing.  
Patients receiving concomitant anthracyclines or with prior exposure to anthracyclines 
should have a baseline MUGA scans or echocardiograms (ECHOs) with a normal 
LVEF. 
Neutropenia:  Increased rates of severe neutropenia, febrile neutropenia, or infection 
with severe neutropenia (including some fatalities) have been observed in patients 
treated with some myelotoxic chemotherapy regimens plus bevacizumab in comparison 
to chemotherapy alone (Sandler et al. 2006). 
Ovarian Failure: The incidence of new cases of ovarian failure (defined as 
amenorrhoea lasting 3 or more months, FSH level≥30 mIU/mL and a negative serum β-
HCG pregnancy test) was prospectively evaluated in a subset of 179 women receiving 
mFOLFOX chemotherapy alone (n=84 or with bevacizumab (n=95). New cases of 
ovarian failure were identified in 34% (32/95) of women receiving bevacizumab in 
combination with chemotherapy compared with 2% (2/84) of women receiving 
chemotherapy alone [relative risk of 14 (95% CI 4, 53)]. After discontinuation of 
bevacizumab treatment, recovery of ovarian function at all time points during the post-
treatment period was demonstrated in 22% (7/32) of the bevacizumab-treated women. 
Recovery of ovarian function is defined as resumption of menses, a positive serum β-


 
 
 
 
19 
HCG pregnancy test, or a FSH level < 30 mIU/mL during the post-treatment period. 
Repeat dose safety studies in animals have shown that bevacizumab may have an 
adverse effect on female fertility. Long term effects of the treatment with bevacizumab 
on fertility are unknown. The risk of ovarian failure will be informed to female with 
reproductive potential and fertility preservation strategies will be discussed prior to 
starting treatment with bevacizumab. 
Additional Adverse Events:  See the bevacizumab Investigator Brochure for additional 
details regarding the safety experience with bevacizumab. 
1.3 
Temozolomide Clinical Experience  
Temozolomide is a second-generation oral alkylating agent that is currently approved for 
the treatment of patients with refractory anaplastic astrocytoma.10,11 Several preclinical 
studies have demonstrated the activity of temozolomide against the leukemia cell lines.12 
Phase I studies in patients with relapsed/refractory acute leukemias suggested 
temozolomide was well tolerated and had significant antileukemic activity when 
administered as a single agent. The maximum tolerated dose for this group of patients 
was determined to be 200 mg/m2/d for 7 days as induction and 200 mg/m2/d for 5 days 
for postremission therapy.13 A Phase II study confirmed the activity of temozolomide as a 
single agent in an elderly group of patients with poor risk disease AML.14 Furthermore, 
this study demonstrated that AML patients can be further stratified into 2 very distinct 
groups of patients: Patients with no detectable expression of O6-alkyl guanine-DNA 
alkyltransferase (MGMT) in leukemic blasts by Western blot had a complete response 
rate of 40% and overall response rate of 60%. In contrast, patients who had detectable 
MGMT in leukemic cells (85-90% of patients), had a 6% response rate to temozolomide 
(p=0.003 comparing absent vs. present MGMT expression).14   
Temozolomide has demonstrated modest single-agent efficacy for advanced pancreatic 
NETs5,15 but even more encouraging results in combination with other agents such as 
thalidomide1 and fluoropyrimidines.6,16,17  In particular, the Strosberg study showed 
particularly encouraging results6.  In this retrospective study, 30 patients were treated 
with capecitabine (750mg/m2 twice daily, days 1-4) and temozolomide (200 mg/m2 
once daily, days 10-14) every 28 days.  Among 30 patients treated, 21 (70%) had 
objective radiographic responses.   Median PFS was 18 months; OS at 2 years was 
92%.  A single arm Ph II prospective study of temozolomide and capecitabine for NETs 
is ongoing (R Fine (PI); NCT00869050). 
 
1.3.1 Clinical Pharmacokinetics of Temozolomide 
Absorption: Temozolomide is rapidly and completely absorbed after oral administration 
with a peak plasma concentration (Cmax) achieved in a median Tmax of 1 hour. Food 
reduces the rate and extent of temozolomide absorption. Mean peak plasma 
concentration and AUC decreased by 32% and 9%, respectively, and median Tmax 
increased by 2-fold (from 1–2.25 hours) when temozolomide was administered after a 
modified high-fat breakfast.  


 
 
 
 
20 
A pharmacokinetic study comparing oral and intravenous temozolomide in 19 patients 
with primary CNS malignancies showed that 150 mg/m2 temozolomide for injection 
administered over 90 minutes is bioequivalent to 150 mg/m2 temozolomide oral capsules 
with respect to both Cmax and AUC of temozolomide and MTIC. Following a single 90-
minute intravenous infusion of 150 mg/m2, the geometric mean Cmax values for 
temozolomide and MTIC were 7.3 mcg/mL and 276 ng/mL, respectively. Following a 
single oral dose of 150 mg/m2, the geometric mean Cmax values for temozolomide and 
MTIC were 7.5 mcg/mL and 282 ng/mL, respectively. Following a single 90-minute 
intravenous infusion of 150 mg/m2, the geometric mean AUC values for temozolomide 
and MTIC were 24.6 mcg∙hr/mL and 891 ng∙hr/mL, respectively. Following a single oral 
dose of 150 mg/m2, the geometric mean AUC values for temozolomide and MTIC were 
23.4 mcg∙hr/mL and 864 ng∙hr/mL, respectively. 
The pharmacokinetics of temozolomide were evaluated in selected patients with 
advanced cancer in phase I clinical trials. Single-dose pharmacokinetics were determined 
in nine patients after intravenous (IV) dosing ranging from 50 to 200 mg/m2, and in 25 
fasted patients following oral doses ranging from 200 to 1200 mg/m2. Pharmacokinetic 
parameters obtained in these patients are summarized in the following table: 
 
Parameter 
Mean Value 
Na 
CV (%)b 
Volume of distribution (L) 
28.30 
43 
39 
Elimination half life (hr) 
1.81 
48 
20 
Distribution half life (hr) 
0.26 
17 
64 
Clearance (L hr-1) 
11.76 
42 
35 
(a)N=number of observations (blood samples obtained). 
(b)CV=coefficient of variation. 
 
Oral bioavailability was studied by the CRC in five patients who received temozolomide 
both orally and intravenously as a one-hour infusion on two separate occasions at least 
four weeks apart. As shown in the following table, complete oral bioavailability was 
demonstrated in five of the subjects at 200 mg/m2. 
 
 


 
 
 
 
21 
 
 
 
Patient Number 
IV AUCa 
(mg·h·L-1) 
Oral AUC 
(mg·h·L-1) 
 
Fb 
5 
32.16 
41.00 
1.27 
7 
33.12 
32.32 
0.98 
15 
35.96 
41.67 
1.16 
17 
23.55 
31.94 
1.36 
19 
25.30 
16.93 
0.67 
 
 
 
Mean: 1.09 
(a)Area under the plasma concentration-time curve calculated by the trapezoidal rule. 
(b)F= bioavailability calculated without consideration of the small differences in apparent 
elimination half life. 
 
As part of SPRI phase I study 193-114-01, the pharmacokinetics of temozolomide were 
evaluated in 15 adult patients on days 1 and 5 of treatment (3 patients each at oral doses 
of 100, 150, or 250 mg/m2/day, and 6 patients at 200 mg/m2/day). Temozolomide was 
rapidly absorbed (mean TMAX range=0.33-1.50 hr) and rapidly eliminated (mean total body 
clearance, CL/F=~200 m./min) following 5 consecutive days of administration. Elimination 
half-life was 1.8 hr. Pharmacokinetic parameters were similar on days 1 and 5, and 
temozolomide did not accumulate in plasma upon multiple dosing. Systemic exposure 
(AUC) increased linearly as dose increased from 100 to 250 mg/m2/day. Intra- and inter-
subject variability in plasma concentrations and pharmacokinetic parameters were small. 
Distribution: Temozolomide has a mean apparent volume of distribution of 0.4 L/kg 
(%CV=13%). It is weakly bound to human plasma proteins; the mean percent bound of 
drug-related total radioactivity is 15%. 
Metabolism and Elimination: Temozolomide is spontaneously hydrolyzed at physiologic 
pH to the active species, MTIC and to temozolomide acid metabolite. MTIC is further 
hydrolyzed to 5-amino-imidazole-4-carboxamide (AIC), which is known to be an 
intermediate in purine and nucleic acid biosynthesis, and to methylhydrazine, which is 
believed to be the active alkylating species. Cytochrome P450 enzymes play only a minor 
role in the metabolism of temozolomide and MTIC. Relative to the AUC of temozolomide, 
the exposure to MTIC and AIC is 2.4% and 23%, respectively. 
Excretion: About 38% of the administered temozolomide total radioactive dose is 
recovered over 7 days: 37.7% in urine and 0.8% in feces. The majority of the recovery of 
radioactivity in urine is unchanged temozolomide (5.6%), AIC (12%), temozolomide acid 
metabolite (2.3%), and unidentified polar metabolite(s) (17%). Overall clearance of 
temozolomide is about 5.5 L/hr/m2. Temozolomide is rapidly eliminated, with a mean 
elimination half-life of 1.8 hours, and exhibits linear kinetics over the therapeutic dosing 
range of 75 to 250 mg/m2/day. 
Effect of Age: A population pharmacokinetic analysis indicated that age (range: 19–78 
years) has no influence on the pharmacokinetics of temozolomide.  


 
 
 
 
22 
Effect of Gender: A population pharmacokinetic analysis indicated that women have an 
approximately 5% lower clearance (adjusted for body surface area) for temozolomide 
than men.  
Effect of Race: The effect of race on the pharmacokinetics of temozolomide has not been 
studied. 
Effect of Tobacco Use: A population pharmacokinetic analysis indicated that the oral 
clearance of temozolomide is similar in smokers and nonsmokers. 
Effect of Renal Impairment: A population pharmacokinetic analysis indicated that 
creatinine clearance over the range of 36 to 130 mL/min/m2 has no effect on the 
clearance of temozolomide after oral administration. The pharmacokinetics of 
temozolomide have not been studied in patients with severely impaired renal function 
(CLcr <36 mL/min/m2). Caution should be exercised when temozolomide is administered 
to patients with severe renal impairment. 
Effect of Hepatic Impairment: A study showed that the pharmacokinetics of temozolomide 
in patients with mild-to-moderate hepatic impairment (Child-Pugh Class I – II) were similar 
to those observed in patients with normal hepatic function.  
Effect of Other Drugs on Temozolomide Pharmacokinetics: In a multiple-dose study, 
administration of temozolomide capsules with ranitidine did not change the Cmax or AUC 
values for temozolomide or MTIC. 
A population analysis indicated that administration of valproic acid decreases the 
clearance of temozolomide by about 5%. 
A population analysis did not demonstrate any influence of coadministered 
dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H2-
receptor antagonists, or phenobarbital on the clearance of orally administered 
temozolomide. 
1.3.2  Adverse Reactions:  
The most common reactions to Temozolomide include nausea, vomiting, 
headache, fatigue and hematologic effects.  These events are usually mild to 
moderate.  Nausea and vomiting is usually readily controlled with antiemetics.  
Myelosuppression (thrombocytopenia and neutropenia) is the dose-limiting side 
effect.  It usually occurs within the first few cycles of therapy and is not cumulative.  
In prior studies, myelosuppression occurred late in the treatment cycle and 
returned to normal, on average, within 14 days of nadir counts. Cases of hepatic 
injury, including fatal hepatic failure, have been reported infrequently in patients 
receiving temozolomide. Liver toxicity may occur several weeks or more after 
initiation of treatment or after temozolomide discontinuation. For patients with 
significant liver function abnormalities the benefits and risks of continuing 
treatment will be carefully considered. 


 
 
 
 
23 
Other less common side effects may include somnolence or insomnia, anorexia, 
constipation, diarrhea, weight loss, abdominal pain, rash, pruritis, anxiety, depression, 
pain when swallowing, hyperglycemia,  ] =-kidney abnormalities, Stevens-Johnson-
Syndrome, PCP infection, secondary malignancy, and aplastic anemia. 
1.3.3 MGMT Methylation Status 
The MGMT gene is located on chromosome 10q26 and encodes a DNA-repair protein 
that removes alkyl groups from the O6 position of guanine, an important site of DNA 
alkylation. The restoration of the DNA consumes the MGMT protein, which the cell must 
replenish. Left unrepaired, chemotherapy-induced lesions, especially O6-methylguanine, 
trigger cytotoxicity and apoptosis.18 Epigenetic silencing of the MGMT gene by promoter 
methylation is associated with loss of MGMT protein expression19,20 and diminished DNA-
repair activity. Based on these findings, several studies have shown that MGMT 
epigenetic silencing through promoter methylation, as determined by methylation-specific 
polymerase-chain-reaction analysis, was an independent favorable prognostic factor in 
patients with glioblastoma multiforme treated with temozolomide.18,21  
Interestingly, there is compelling evidence that protracted schedules of temozolomide 
may lead to an 'autoenhancement' of its inherent cytotoxic potential by cumulative 
reduction of the cell's capacity for MGMT-mediated DNA repair and resistance. O6-alkyl 
guanine-DNA alkyltransferase activity was measured in the PBMCs of patients treated on 
two phase I protracted temozolomide studies. Patients were treated daily with various 
temozolomide doses (75-175 mg m-2) and treatment duration (7-21 days), and levels of 
MGMT inactivation and regeneration, as well as the relation between MGMT inactivation 
and toxicity, were studied. This study determined that protracted, relatively low-doses 
(100mg/m2) of temozolomide given daily for 14 days leads to marked inactivation of 
MGMT (~80%).22 
1.4 
Capecitabine Clinical Experience 
Capecitabine is an oral fluoropyrimidine that mimics continuous infusion 5-FU and has 
since replaced it in the treatment of many gastrointestinal malignancies.  The conversion 
to 5-FU is dependent on the enzyme thymidine phosphorylase, which is more highly 
expressed in tumor tissue than healthy tissue resulting in the preferential generation of 5-
FU at the tumor site23. Capecitabine is currently approved in the United States for 
treatment of advanced breast and colorectal cancers.   
 
1.4.1 Capecitabine Safety Profile 
 
Capecitabine Monotherapy –in Colorectal and Breast carcinoma: The safety 
database for monotherapy consists of 630 patients with mCRC from two phase III 
studies and one phase II study and 319 patients with metastatic breast cancer from four 
phase II studies. The most frequently reported adverse events (AEs) among patients 
receiving capecitabine monotherapy as treatment for breast and CRC were hand-foot 
syndrome (HFS), diarrhea, nausea, vomiting, stomatitis and fatigue. The majority of 
treatment-related AEs were mild to moderate in intensity. The treatment-related grade 
3and 4 AEs with the highest incidences were HFS (grade 3 only), diarrhea, and nausea. 


 
 
 
 
24 
Most of the grade 4 treatment-related AEs was in the gastrointestinal (GI) system. The 
incidence of treatment-related serious AEs (SAEs) was low. The most frequent 
treatment-related SAEs (i.e., those reported in ≥2% of patients) were diarrhea, 
dehydration, vomiting, nausea, and stomatitis. HFS was reported as a SAE in only two 
patients (<1%). The overall safety profile of capecitabine monotherapy as adjuvant 
treatment for stage III colon cancer was similar to that observed in the pooled 
monotherapy metastatic CRC and breast cancer safety database. 
 
Capecitabine in combination with oxaliplatin and bevacizumab (XELOX+BV) in 
colorectal cancer: the most frequently occurring AEs in patients with mCRC who 
received first-line treatment with XELOX+BV were nausea, vomiting and parasthesia. 
There was a moderate increase in the incidence of vomiting and PPE. Diarrhea was the 
most common grade 3/4 AE (unrelated and related to treatment) as well as the most 
common treatment-related SAE. An increase in the incidence of vascular disorders was 
observed, mainly due to the incidence of deep vein thrombosis. 
 
Additional Adverse Events:  See the capecitabine Investigator Brochure for additional 
details regarding the safety experience with capecitabine. 
1.5 
Study Rationale 
 
Recent temozolomide-based studies in pancreatic NETs have demonstrated 
encouraging results and acceptable toxicity profiles.  Temozolomide can safely be 
combined with capecitabine and may in fact be synergistic.2  Additionally, temozolomide 
can safely be combined with bevacizumab8.  For patients who need an objective 
response (due to rapid disease progression, bulky tumors, or symptomatic disease) we 
are in need of a well-tolerated regimen that yields high response rates.  To date, the 
temozolomide/capecitabine restrospective data is the most promising chemotherapy 
backbone.  There is sound scientific rationale that bevacizumab is also active in this 
disease and will hopefully be additive or synergistic with temozolomide/capecitabine.  
Capecitabine and Bevacizumab are routinely used safely in the setting of metastatic 
colorectal cancer.  We do not anticipate safety issues for the 
Temozolomide/Capecitabine/Bevacizumab drug combination.  We, therefore, propose a 
multi-institution, phase II, single-arm, non-randomized study investigating bevacizumab 
in combination with temozolomide and capecitabine for patients with unresectable or 
metastatic pancreatic neuroendocrine tumors. 
1.6 
Correlative Studies Background 
CT perfusion will be performed on all patients who consent to the imaging research study. 
 
Tissue will be obtained from all patients who consent to participate in banking. 
 
Blood will be obtained from all patients who consent to participate in the laboratory 
research studies.  
 
CT Perfusion:  


 
 
 
 
25 
Perfusion computed tomography (CT) imaging has been established for many years in 
stroke imaging. With the introduction of multi-detector row CT technology increasing 
substantially the spatial and temporal resolution as well as offering new detector array 
configurations, CT perfusion imaging has become feasible for assessment of tumor 
perfusion in applications outside the brain, including the abdomen. Recent studies 
indicate that perfusion CT can be performed successfully in patients with NETs.24,25  
Different parameters of tumor perfusion have been assessed in patients with NETs and 
compared to normal tissue including blood flow (BF), blood volume (BV), mean transit 
time (MTT), time to peak (TTP), permeability surface, and volume transfer constant 
(Ktrans). The implications of those parameters on grade of tumor vascularization, 
correlation with ex vivo parameters of angiogenesis including microvessel density (MVD), 
or expression profiles of molecular markers of tumor angiogenesis such as vascular 
endothelial growth factor receptor (VEGFR) or integrins in NETs still need to be assessed. 
However, a recent study in patients with pancreatic endocrine tumors undergoing 
preoperative perfusion CT has shown high correlation between the tumor BV parameter 
as assessed by perfusion CT and ex vivo MVD analysis, as well as histoprognostic factors 
such as proliferation index and WHO classification obtained from tumor samples.26 
Another recent study in patients with locally advanced pancreatic cancer has shown that 
the parameter Ktrans may be a valuable quantitative biomarker for predicting favorable 
treatment response to concurrent chemotherapy and radiotherapy.27 
 
Although the technique of CT perfusion is still evolving and the value of different perfusion 
parameters in different tumor types still warrants further evaluation, the use of perfusion 
CT as a non-invasive biomarker to determine treatment response following the application 
of bevacizumab in NETs is intriguing. CT imaging in general is a robust, widely available 
imaging technology that has been used for cancer imaging for several decades. It is the 
preferred imaging modality due to its reliability, comparability and robustness. Since the 
perfusion analysis part of the CT examination can be easily integrated into current CT 
imaging protocols, there is no need to schedule another exam for a dedicated perfusion 
exam at the standard baseline and follow-up CT scans in cancer patients. 
 
In this phase II protocol using bevacizumab with capecitabine and temozolomide for 
metastatic or unresectable pancreatic NETs we propose to include CT perfusion 
imaging as an integral part of the regular CT imaging protocol. Isovue 370 will be used 
as the intravenous contrast agent.  The premixed agent from Bracco will be used up to 
120 ml depending on patient weight for diagnostic CT, 50 ml for perfusion CT portion  
The perfusion portion of the CT Scan will take a few extra minutes and the dose will be 
approximately 24-28 mSv of radiation which is just over half the dose of a normal CT 
study.  The CT perfusion part can be included into the standard baseline and 3-month 
follow-up CT scan. In addition, we propose to include an early, 2-week dedicated CT 
perfusion examination to assess functional perfusion data shortly after the first doses of 
bevacizumab. 
MGMT testing: 
Evaluation of MGMT status by Immunohistochemistry (IHC) 
Temozolomide is an alkylating agent initially developed as an oral and more easily 
tolerated alternative to dacarbazine. The cytotoxic effect of temozolomide has been 


 
 
 
 
26 
attributed to its ability to induce DNA methylation at the O6 position of guanine. 
Methylation of guanine results in DNA mismatch, ultimately resulting in apoptosis and 
tumor cell death.17 The sensitivity of tumor cells to alkylating agents, including 
temozolomide, has been associated with decreased levels of the DNA repair enzyme, 
O6-methylguanine DNA methyltransferase (MGMT), which, through its ability to restore 
DNA to its normal form, can prevent chemotherapy-induced cell death.18 Decreased 
levels of MGMT have been associated with clinical benefit and enhanced survival in 
melanoma and glioblastoma patients treated with temozolomide.19-23 
In a study by Kulke, et al., 97 archival neuroendocrine tumors specimens were 
evaluated for MGMT deficiency by immunohistochemistry.8 Among 37 pancreatic 
neuroendocrine tumors evaluated, 19 (51%) were MGMT deficient. Non-functional 
tumors included similar proportions of MGMT intact and MGMT deficient tumors. Three 
of 10 insulinomas were MGMT deficient; both gastrinomas and the single evaluated 
glucagonoma were also MGMT deficient. In contrast, MGMT was present in all 60 
carcinoid tumors (20 typical bronchial carcinoids, 20 atypical bronchial carcinoids and 
20 small intestine carcinoids) evaluated.   Among 21 patients with evaluable tumor 
tissue who had also received treatment with temozolomide, 4 of 5 patients with MGMT-
deficient tumors (all pancreatic NETs) and 0 of 16 patients with MGMT-intact tumors 
responded to treatment (p=0.001). 
 
Evaluation of MGMT status by Promoter Methylation 
The clinical utility of assessing MGMT promoter methylation status was first 
demonstrated in patients with gliomas. Gliomas are the most common primary brain 
tumors. Grade IV gliomas, also known as glioblastoma multiforme (GBM) are highly 
malignant tumors that account for almost a third of primary brain tumors in adults. 
Patients with gliomas that exhibited promoter methylation of the MGMT gene showed 
modestly longer survival after treatment with alkylating chemotherapeutics than patients 
whose gliomas did not show MGMT promoter methylation.  Clinical trials to evaluate the 
use of MGMT promoter methylation to predict response to alkylating agents have also 
been designed for patients with acute myeloid leukemia, neuroendocrine tumors, and 
other cancers. 
 
The mechanisms of MGMT regulation in neuroendocrine tumors remain unknown. 
Silencing of the MGMT gene by CpG island promoter methylation is a common 
mechanism of MGMT regulation in other tumor types. In patients with glioblastoma, 
MGMT promoter methylation is associated with improved survival and benefit from 
temozolomide.22,24 Limited studies of CpG island methylation in neuroendocrine tumors 
however, have found either no significant difference in MGMT promoter methylation 
rates between carcinoid and pancreatic neuroendocrine tumors, or higher rates of 
promoter methylation in carcinoid tumors compared to pancreatic neuroendocrine 
tumors.25,26 
 
Further studies to evaluate whether promoter methylation is a common MGMT silencing 
mechanism in neuroendocrine tumors, and whether promoter methylation correlates 
with immunohistochemical absence of MGMT, are warranted. 
 


 
 
 
 
27 
2.0 
Objectives 
a. Primary Objective 
i. To investigate if the combination of capecitabine and temozolomide with 
bevacizumab for metastatic or unresectable neuroendocrine tumors will 
improve RR by 62% over historical controls (null RR of 40% to true RR 
65%). 
ii. Assess the toxicities using CTCAE v4.0. 
 
b. Secondary Objectives 
i. To evaluate progression-free survival (PFS) and overall survival (OS) 
using Kaplan-Meier analysis 
ii. To assess MGMT by central path review 
iii. To assess serum hormone marker levels 
iv. To evaluate CT Perfusion as a tool to predict early therapeutic response 
(OPTIONAL) 
v. To bank serum for future correlative analyses 
3.0 
Study Design  
3.1 
Description of the Study 
We propose a multi-institution, phase II, single-arm, non-randomized study investigating 
bevacizumab in combination with capecitabine and temozolomide for unresectable or 
metastatic pancreatic neuroendocrine tumors.  Treatment will be given every 28 days as 
per the schema outlined below.  Patients will receive CT scans at baseline and after every 
3 cycles (approximately 3 months) and be evaluated by RECIST criteria.  We estimate 
that most patients will complete 6-9 cycles of treatment.  Dose reductions are allowed 
after cycle 1. If, after 3 cycles, patients develop significant toxicities attributed to either 
temozolomide (including nausea, cytopenias, etc) or capecitabine (including diarrhea, 
hand-foot skin syndrome, etc) patients may discontinue these agents and continue 
receiving bevacizumab as a single agent.  We will continue treatment indefinitely until one 
of the following occurs: patient withdraws consent and decides to discontinue study 
treatment, development of unacceptable toxicities, or evidence for progression of 
disease. If a patient is on single-agent bevacizumab at the time of disease progression, 
temozolomide and capecitabine may be restarted at the discretion of the investigator.  
 
 
Bevacizumab 10 mg/kg IV day 1 and 15 
Capecitabine 750 mg/m2 po BID days 1-14 
Temozolomide 200 mg/m2 po QD days 10-14 
Repeat Q28 days x 3 cycles 
R
E
G
I
S
T
E
R 
Screening 
evaluation 
Continue until 
disease 
progression 


 
 
 
 
28 
This will be a Phase II study evaluating capecitabine, temozolomide, and bevacizumab 
in patients with unresectable or metastatic pancreatic neuroendocrine tumors.   
 
A sample size of 30 patients would give 80% power to reject the null RR of 40% if the 
true RR is 65% or higher.  The null hypothesis is based on a prospective phase II study 
conducted by Kulke, et al evaluating the efficacy of temozolomide and thalidomide.1  In 
this study, 29 patients with mixed metastatic NETs were treated with temozolomide 150 
mg/m2 for 7 days every other week and thalidomide at doses of 50-400 mg daily.  The 
overall radiographic response was 25% (45% in patients with pancreatic NETs).  The 
alternative hypothesis is based on the more recent retrospective study reported by 
Strosberg, et al in which patients were treated with capecitabine (750mg/m2 twice daily, 
days 1-14) and temozolomide (200 mg/m2 once daily, days 10-14) every 28 days6.  Of 
30 patients treated, the RR was 70%. 
3.2 
Rationale for Study Design 
We selected a single arm study as the best way to determine preliminary efficacy and 
safety of this regimen for pancreatic NETs.  We have chosen a multisite study for this rare 
disease to enhance accrual rates.  Our planned doses of bevacizumab, capecitabine, and 
temozolomide are routinely used in GI and other malignancies. 
3.3 
Outcome Measures  
3.3.1 Primary 
a. RR % (by RECIST v1.1) 
b. Toxicities according to CTCAE v4.0. 
3.3.2  Secondary 
c. PFS (median in months) and OS (median in months) 
d. MGMT by central pathology review 
e. Serum hormone marker analysis 
f. CT perfusion 
i. Correlation of the CT perfusion parameters with: 
1. Progression free survival 
2. Overall survival 
3. RECIST criteria 
ii. Correlation of early perfusion parameters (from baseline, 2-week, and 
9-week follow-up scans) 
g. Serum to be stored for future correlative studies 
 
3.3.3 Safety Outcome Measures 
Toxicities will be assessed per CTCAE v4.0.  Patients will be monitored for systemic, 
renal, gastrointestinal, hematologic, neurological and liver toxicities.  Specifically, 
patients will have laboratory tests (including CBC with differential and comprehensive 
metabolic panel) performed every 4 weeks.  In addition, patients will be seen in the 
clinic for history and physical and assessed for side effects and toxicities every 4 weeks.   


 
 
 
 
29 
4.0 
Safety Plan 
4.1 
Bevacizumab-specific 
A number of measures will be taken to ensure the safety of patients participating in this 
trial.  These measures will be addressed through exclusion criteria and routine monitoring 
as follows. 
Patients enrolled in this study will be evaluated clinically and with standard laboratory 
tests before and at regular intervals during their participation in this study.  Safety 
evaluations will consist of medical interviews, recording of adverse events, physical 
examinations, blood pressure, and laboratory measurements.  Patients will be evaluated 
for adverse events (all grades), serious adverse events, and adverse events requiring 
study drug interruption or discontinuation at each study visit for the duration of their 
participation in the study.  Patients discontinued from the treatment phase of the study for 
any reason will be evaluated ~30 days (28–42 days) after the decision to discontinue 
treatment.  
Specific monitoring procedures are as follows: 
• Hypertension will be monitored through routine evaluation of blood pressure prior to 
each bevacizumab treatment.  Optimal control of blood pressure according to standard 
public health guidelines is recommended for patients on treatment with or without 
bevacizumab. 
• Proteinuria will be monitored by urine dipstick, urinalysis, or 24hour urine and graded 
as shown in the following table.31,32 Proteinuria will be managed per guidelines outlined 
in section 6.1.3 
Protein dipstick grading 
 
Designation 
Approx. amount 
 
Concentration 
Daily 
Trace 
5–20 mg/dL 
 
 
 
1+ 
30 mg/dL 
 
Less than 0.5 g/day 
 
2+ 
100 mg/dL 
 
0.5–1 g/day 
 
3+ 
300 mg/dL 
 
1–2 g/day 
 
4+ 
More than 300 mg/dL 
 
More than 2 g/day 
 
 
• If patients on treatment with bevacizumab require elective major surgery, it is 
recommended that bevacizumab be held for 4-8 weeks prior to the surgical procedure. 


 
 
 
 
30 
Patients undergoing a major surgical procedure should not begin/restart bevacizumab 
until 4 weeks after that procedure (in the case of high risk procedures such as liver 
resection, thoracotomy, or neurosurgery, it is recommended that chemotherapy be 
restarted no earlier than 6 wk and bevacizumab no earlier than 8 wk after surgery).  
Temozolomide and/or capecitabine may also be held at the discretion of the 
investigator. 
4.2 
Other Study Drug(s)-Specific 
Please see Section 6.0 for detailed instructions for the management of study drug–
related toxicities. 
5.0 
Study Subjects 
5.1 
Inclusion Criteria 
1. Patients must have histologically confirmed pancreatic neuroendocrine tumors 
that are considered low or intermediated grade as defined by Klimstra, et al (to 
include Ki-67 and mitotic index).28 
2. Patients must have metastatic or unresectable disease 
3. Patients with prior surgical resection who develop radiological or clinical 
evidence of metastatic cancer do not require separate histological or cytological 
confirmation of metastatic disease unless an interval of > 5 years has elapsed 
between the primary surgery and the development of metastatic disease.  
Clinicians should consider biopsy of lesions to establish diagnosis of metastatic 
disease if there is substantial clinical ambiguity regarding the nature or source 
of apparent metastases. 
4. Prior sunitinib and everolimus will be permitted.  A wash-out period of 2 weeks 
is required prior to first dose on this study.  
5. Concurrent somatostatin analogues are allowed provided that patients 1) have 
been on stable doses x 8 weeks and 2) have documented disease progression 
on that dose. 
6. Prior liver directed therapies will be permitted (ie. chemoembolization, 
radioembolization) as long as target lesions in the liver have demonstrated 
growth since the liver directed treatment. 
7. Prior peptide receptor radionuclide therapy (PRRT) will be permitted as long as 
target lesions in the liver have demonstrated growth since the liver directed 
treatment. 
8. Low-dose aspirin (≤ 325 mg/d) may be continued in subjects at higher risk for 
arterial thromboembolic disease. 
9. Patients must have a primary or metastatic lesion measurable in at least one 
dimension by Modified RECIST criteria v1.1 (see Section 4.2) within 4 weeks 
prior to entry of study. 


 
 
 
 
31 
10. Patients must have ECOG performance status of 0-2 
11. Patients must be ≥ 18 years of age. 
12. Laboratory values ≤ 2 weeks prior to start date (may be supported by 
transfusion and/or hematopoetic growth factors): 
• Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L (≥ 1500/mm3)  
• Platelets (PLT) ≥ 100 x 109/L (≥ 100,000/mm3) 
• Hemoglobin (Hgb) ≥ 9 g/dL  
• Serum creatinine ≤ 1.5 x ULN  
• Serum bilirubin ≤ 1.5 x ULN   
• Aspartate aminotransferase (AST/SGOT), alanine aminotransferase 
(ALT/SGPT) ≤ 3.0 x ULN (≤ 5.0 x ULN if liver metastases present).  
Note:  ERCP or percutaneous stenting may be used to normalize the 
liver function tests. 
13. Life expectancy ≥ 12 weeks. 
14. Ability to give written informed consent according to local guidelines. 
5.2 
Exclusion Criteria     
Disease-Specific Exclusions 
1. Prior bevacizumab and any cytotoxic chemotherapy. 
2. Poorly differentiated or high grade pancreatic neuroendocrine tumors 
3. Prior full field radiotherapy ≤ 4 weeks or limited field radiotherapy ≤ 2 weeks 
prior to enrollment.  Patients must have recovered from all therapy-related 
toxicities.  The site of previous radiotherapy should have evidence of 
progressive disease if this is the only site of disease. 
4. Diagnosis of another malignancy, unless the patient was diagnosed at least 
3 years earlier and has been disease-free for at least 6 months following 
the completion of curative intent therapy, specifics as follows: 
• Curatively resected non-melanomatous skin cancer  
• Curatively treated cervical carcinoma in situ 
• Patients with organ-confined prostate cancer with no evidence of 
recurrent or progressive disease based on prostate-specific antigen 
(PSA) values are also eligible for this study if hormonal therapy has 
been initiated or a radical prostatectomy has been performed. 


 
 
 
 
32 
• Other primary solid tumor curatively treated with no known active 
disease present and no treatment administered for the last 3 years. 
5. Concurrent use of other investigational agents and patients who have 
received investigational drugs ≤ 4 weeks prior to enrollment. 
6. Known hypersensitivity to capecitabine, temozolomide, or any component 
of the formulation and or a known deficiency of dihyropyrimidine 
dehydrogenase. 
General Medical Exclusions 
Subjects meeting any of the following criteria are ineligible for study entry:   
7. Inability to comply with study and/or follow-up procedures. 
8. Current, recent (within 4 weeks of the first infusion of this study), or planned 
participation in an experimental drug study. 
9. Pregnancy (positive pregnancy test) or lactation- breast feeding Lack of of 
effective means of contraception (men and women) in subjects of child-
bearing potential. 
10. Uncontrolled systemic fungal, bacterial, viral, or other infection (defined as 
exhibiting ongoing signs/symptoms related to the infection and without 
improvement, despite appropriate antibiotics or other treatment). 
11. Known history of HIV, HBV, or HCV  
12. Current, ongoing treatment with full-dose warfarin.  However patients may 
be on stable doses of a low molecular weight heparin are allowed (ie. 
Lovenox).   
Bevacizumab-Specific Exclusions 
13. Inadequately controlled hypertension (defined as systolic blood pressure 
150 mmHg and/or diastolic blood pressure > 100 mmHg). 
14. Prior history of hypertensive crisis or hypertensive encephalopathy. 
15. New York Heart Association (NYHA) Grade II or greater congestive heart 
failure (see Appendix E). 
16. History of myocardial infarction or unstable angina within 6 months prior to 
Day 1. 
17. History of stroke or transient ischemic attack within 6 months prior to Day 
1. 
18. Known CNS metastases 
19. Significant vascular disease (e.g., aortic aneurysm, requiring surgical 
repair or recent peripheral arterial thrombosis) within 6 months prior to 
Day 1. 


 
 
 
 
33 
20. History of GI bleeding (hemoptysis/melena/hematochezia,   1/2 teaspoon 
of bright red blood per episode) within 1 month prior to Day 1. 
21. Evidence of bleeding diathesis or significant coagulopathy (in the absence 
of therapeutic anticoagulation). 
22. Major surgical procedure, open biopsy, or significant traumatic injury 
within 28 days prior to Day 1 or anticipation of need for major surgical 
procedure during the course of the study. 
23. Core biopsy or other minor surgical procedure, excluding placement of a 
vascular access device, within 7 days prior to Day 1. 
24. History of abdominal fistula or gastrointestinal perforation within 6 months 
prior to Day 1. 
25. Serious, non-healing wound, active ulcer, or untreated bone fracture. 
26. Proteinuria: Patients are allowed to have 0, trace, or 1+ protein by urine 
dipstick or urinalysis to enroll, if >= 2+ must check 24h urine protein and 
must be < 1g to start study.   
27. Known hypersensitivity to any component of bevacizumab.  
 
6.0 
Study Medications  
 
6.1  
Bevacizumab administration, storage, and toxicity management 
Bevacizumab is a clear to slightly opalescent, colorless to pale brown, sterile liquid 
concentrate for solution for intravenous (IV) infusion.  Bevacizumab may be supplied in 
5-cc (100-mg) and 20-cc (400-mg) glass vials containing 4 mL or 16 mL bevacizumab, 
respectively (all at 25 mg/mL).  Vials contain bevacizumab with phosphate, trehalose, 
polysorbate 20, and Sterile Water for Injection (SWFI), USP.  Vials contain no 
preservative and are suitable for single use only. 
Bevacizumab will be supplied by Genentech/Roche as the commercially available form 
of this medication. 
For further details and molecule characterization, see the bevacizumab Investigator 
Brochure. 
6.1.1 Bevacizumab Administration 
Bevacizumab will be initiated at a dose of 10 mg/kg IV on days 1 and 15 of a 28-day 
cycle. Dose will be based on actual weight and subsequent doses will remain the same 
unless there is a +/- 5% change from the actual weight.  
It will be diluted in a total volume of 100mL of 0.9% Sodium Chloride Injection, USP.  
Administration will be as a continuous IV infusion.  Anaphylaxis precautions should be 


 
 
 
 
34 
observed during study drug administration.  It is not necessary to correct dosing based 
on ideal weight. 
The initial dose will be delivered over 9015 minutes.  If the first infusion is tolerated 
without infusion-associated adverse events (fever and/or chills) the second infusion may 
be delivered over 6010 minutes.  If the 60-minute infusion is well tolerated, all 
subsequent infusions may be delivered over 3010 minutes.   
If a subject experiences an infusion–associated adverse event, he or she may be 
premedicated for the next study drug infusion; however, the infusion time may not be 
decreased for the subsequent infusion.  If the next infusion is well tolerated with 
premedication, the subsequent infusion time may then be decreased by 3010 minutes 
as long as the subject continues to be premedicated.  If a subject experiences an 
infusion-associated adverse event with the 60-minute infusion, all subsequent doses 
should be given over 9015 minutes.  Similarly, if a subject experiences an 
infusion-associated adverse event with the 30-minute infusion, all subsequent doses 
should be given over 6010 minutes. 
6.1.2 Bevacizumab Storage 
Upon receipt of the study drug, vials are to be refrigerated at 2C–8C  
(36F–46F) and should remain refrigerated until just prior to use.  DO NOT FREEZE.  
DO NOT SHAKE.  Vials should be protected from light. 
Opened vials must be used within 8 hours.  VIALS ARE FOR SINGLE USE ONLY.  Vials 
used for 1 subject may not be used for any other subject.  Once study drug has been 
added to a bag of sterile saline, the solution must be administered within 8 hours. 
6.1.3 Bevacizumab Dose Modification and Toxicity Management 
There are no reductions in the bevacizumab dose. If adverse events occur that require 
holding bevacizumab, the dose will remain the same once treatment resumes. 
Any toxicities associated or possibly associated with bevacizumab treatment should be 
managed according to standard medical practice. Discontinuation of bevacizumab will 
have no immediate therapeutic effect. Bevacizumab has a terminal half-life of 21 days; 
therefore, its discontinuation results in slow elimination over several months. There is no 
available antidote for bevacizumab.  
Subjects should be assessed clinically for toxicity prior to, during, and after each infusion. 
If unmanageable toxicity occurs because of bevacizumab at any time during the study, 
treatment with bevacizumab should be discontinued.  
Infusion Reaction: Infusion of bevacizumab should be interrupted for subjects who 
develop dyspnea or clinically significant hypotension. Subjects who experience a NCI 
CTCAE v4.0 Grade 3 or 4 allergic reaction / hypersensitivity, adult respiratory distress 
syndrome, or bronchospasm (regardless of grade) will be discontinued from bevacizumab 
treatment. 
The infusion should be slowed to 50% or less or interrupted for subjects who experience 
any infusion-associated symptoms not specified above. When the subject’s symptoms 


 
 
 
 
35 
have completely resolved, the infusion may be continued at no more than 50% of the rate 
prior to the reaction and increased in 50% increments every 30 minutes if well tolerated.  
Infusions may be restarted at the full rate during the next cycle.  
Adverse events requiring delays or permanent discontinuation of bevacizumab are listed 
in Table 1  
Regardless of the reason for holding bevacizumab, the maximum allowable length of 
treatment interruption is 2 months. 


 
 
 
 
36 
Table1:  
Bevacizumab Dose Management Due to Adverse Events 
 
Event 
Action to be Taken 
Hypertension 
No dose modifications for grade 1/2 events 
Grade 3 
If not controlled to 150/100 mmHg with medication, discontinue 
bevacizumab. 
Grade 4 (including 
hypertensive 
encephalopathy) 
Discontinue bevacizumab. 
Hemorrhage 
No dose modifications for grade 1/2 non-pulmonary and non-CNS events 
  Grade 3   
  Non-pulmonary and 
    non-CNS 
hemorrhage 
Subjects who are also receiving full-dose anticoagulation will be 
discontinued from receiving bevacizumab.   
All other subjects will have bevacizumab held until all of the 
following criteria  are met: 
• The bleeding has resolved and hemoglobin is stable. 
• There is no bleeding diathesis that would increase the 
risk of therapy. 
• There is no anatomic or pathologic condition that 
significantly increases the risk of hemorrhage 
recurrence. 
Subjects who experience a repeat Grade 3 hemorrhagic event 
will be discontinued from receiving bevacizumab. 
  Grade 4  
     non-pulmonary or  
    non-CNS 
hemorrhage 
Discontinue bevacizumab. 
   Grade 1pulmonary 
or CNS hemorrhage 
Subjects who are also receiving full-dose anticoagulation will be 
discontinued from receiving bevacizumab.   
All other subjects will have bevacizumab held until all of the 
following criteria  are met: 
• The bleeding has resolved and hemoglobin is stable. 
• There is no bleeding diathesis that would increase the 
risk of therapy. 
• There is no anatomic or pathologic condition that 
significantly increases the risk of hemorrhage 
recurrence. 
 


 
 
 
 
37 
Grade 2, 3, or 4 
pulmonary or CNS 
hemorrhage 
Discontinue bevacizumab 
Venous Thrombosis 
No dose modifications for grade 1/2 events 
Grade 3 or 4 
Hold bevacizumab.  If the planned duration of full-dose 
anticoagulation is <2 weeks, bevacizumab  should be held until 
the full-dose anticoagulation period is over.  If the planned 
duration of full-dose anticoagulation is >2 weeks, bevacizumab 
may be resumed during the period of full-dose anticoagulation if 
all of the following criteria  are met: 
• The subject must have an in-range INR (usually 
between 2 and 3) if on warfarin; LMWH, warfarin, or 
other anticoagulant dosing must be stable prior to 
restarting bevacizumab treatment. 
• The subject must not have had a Grade 3 or 4 
hemorrhagic event while on anticoagulation. 
Arterial Thromboembolic event 
(New onset, worsening, or unstable angina, myocardial infarction, transient ischemic 
attack, cerebrovascular accident, and any other arterial thromboembolic event) 
 Any grade 
Discontinue bevacizumab. 
Congestive Heart Failure (Left ventricular systolic dysfunction) 
No dose modifications for grade 1/2 events 
Grade 3 
Hold bevacizumab until resolution to Grade ≤ 1. 
Grade 4 
Discontinue bevacizumab. 
Proteinuria (note: urine protein-to-creatinine ratio not allowed) 
 
Grade 1 
No bevacizumab dose modifications. 
 
Grade 2 
 
 
Suspend bevacizumab for ≥ 2 grams / 24 hours, and resume 
when proteinuria is < 2 grams / 24 hours.  
For 2+ urinalysis/dipstick: Ok to treat, but obtain 24 hour urine 
prior to next bevacizumab dose. 
For 3+ urinalysis/dipstick: Ok to treat, but obtain 24 hour urine 
prior to bevacizumab dose. 
 
Grade 3 
Suspend bevacizumab. Resume when proteinuria is < 2 grams / 
24 hours as determined by 24 hour urine collection 
Grade 4 
(nephrotic 
syndrome) 
Discontinue bevacizumab. 
GI Perforation 
Discontinue bevacizumab. 


 
 
 
 
38 
Fistula  
 
Any grade (TE 
fistula) 
Discontinue bevacizumab. 
Grade 4 fistula 
Discontinue bevacizumab. 
Bowel Obstruction 
Grade 1 
 
Continue patient on study for partial obstruction NOT requiring 
medical intervention. 
Grade 2 
Hold bevacizumab for partial obstruction requiring medical 
intervention.  Patient may restart upon complete resolution. 
Grade 3/4 
Hold bevacizumab for complete obstruction.  If surgery is 
necessary, patient may restart bevacizumab after full recovery 
from surgery, and at investigator’s discretion. 
Wound dehiscence 
Any grade (requiring 
medical or surgical 
therapy) 
 
Discontinue bevacizumab. 
Reversible Posterior Leukoencephalopathy 
Any grade 
(confirmed by MRI) 
Discontinue bevacizumab. 
Other Unspecified Bevacizumab-Related Adverse Events 
Grade 3 
Grade 4 
Hold bevacizumab until recovery to ≤ Grade 1 
Discontinue bevacizumab. 
 
 
Hematological Toxicities (for Day 15, Bevacizumab infusion only) 
ANC 
Grade 1/2/3 
No dose modifications 
Grade 4 
Hold dose 
Platelets 
Grade 1/2 
No dose modifications 
Grade 3/4 
Hold dose 
 
 
 
 


 
 
 
 
39 
6.2 
Temozolomide administration, storage, and toxicity management 
Temozolomide 
[8-carbamoyl-3-methylimidazo(5,1-d)-1,2,3,5-tetrazin-4(3H)-one] 
(Temodal) is an imidazole tetrazinone compound developed by Schering-Plough for use 
as an antineoplastic agent.  TMZ is a prodrug that spontaneously hydrolyzes to 5-(3-
methyltriazen-1-yl)imidazole-4-carboxamide (MTIC), which is also the active metabolite 
of dacarbazine. Dacarbazine, however, requires hepatic metabolism for formation of this 
metabolite, which results in variable levels.  TMZ is stable at an acidic pH, allowing oral 
absorption, and has a broad biodistribution. 
Temozolomide is not directly active but undergoes rapid nonenzymatic conversion at 
physiologic pH to the reactive compound 5-(3-methyltriazen-1-yl)-imidazole-4-
carboxamide (MTIC). The cytotoxicity of MTIC is thought to be primarily due to alkylation 
of DNA. Alkylation (methylation) occurs mainly at the O6 and N7 positions of guanine. 
The inactive ingredients for temozolomide Capsules are as follows: lactose anhydrous 
(132.8 mg), colloidal silicon dioxide (0.2 mg), sodium starch glycolate (7.5 mg), tartaric 
acid (1.5 mg), and stearic acid (3 mg). 
 
The body of the capsules are made of gelatin, and are opaque white. The cap is also 
made of gelatin, and the colors vary based on the dosage strength. The capsule body 
and cap are imprinted with pharmaceutical branding ink, which contains shellac, 
dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, purified water, 
strong ammonia solution, potassium hydroxide, and ferric oxide. 
 
Temozolomide capsules are supplied in amber glass bottles containing 5, 14, or 20 
capsules per bottle. Temozolomide is supplied in preservative free, 2-piece hard gelatin 
capsules in the following p.o. dose strengths: 5mg. 20mg. 100mg. 140mg. 180mg, and 
250mg. Each capsule contains the active drug substance in combination with lactose, 
anhydrous NF, colloidal silicon dioxide NF, sodium starch glycolate NF, tartaric acid NF, 
and stearic acid NF.  The capsule shells contain gelatin NF, titanium dioxide USP, and 
sodium lautyl sulfate NF.  Temozolomide is commercially available. Temozolomide is 
supplied in preservative free, 2-piece hard gelatin capsules.   
 
Agent Ordering 
Temozolomide is being provided by Merck.  Commercial Temozolomide will be used in 
this study. Temozolomide will be shipped directly to all sub-sites from Merck. 
 
6.2.1 Temozolomide Administration:  
Oral temozolomide will be given at a dose of 200 mg/m2 PO once daily for days 10-14 at 
bedtime.  Body Surface Area (BSA) will be calculated based on adjusted ideal body 
weight. The temozolomide dose will be capped at 400 mg daily and given as only 100 or 
180 mg capsules.  Ondansetron will be given as a premedication to prevent nausea 30-
60 min prior to the temozolomide dose. Temozolomide should be taken by mouth after 
fasting from solid food for two hours. Temozolomide tablets must not be crushed and 
must be administered whole. Temozolomide missed doses will not be made up, and 
patients should not double-up on missed doses during treatment. 


 
 
 
 
40 
 
6.2.2 Temozolomide Storage:  
As a solid, temozolomide is thermally stable and does not decompose when exposed to 
light. In solution, temozolomide undergoes rapid hydrolysis in a basic environment. The 
product label recommends storage at room temperature 25°C (77°F).  Temozolomide 
should be stored at 20-25°C (68-77°F), excursions permitted between 15-30°C (59-86°F). 
Care will be taken to maintain an acceptable storage temperature. The clinical supplies 
storage area at the site will be monitored by the site staff for temperature consistency with 
the acceptable storage temperature range specified in this protocol or in the product label 
attached to the protocol. Documentation of temperature monitoring will be maintained on 
site. 
 
Agent Accountability 
Investigational clinical supplies must be received by a designated person at the study 
site, handled and stored safely and properly, and kept in a secured location to which only 
the investigator and designated assistants have access. Clinical supplies are to be 
dispensed only in accordance with the protocol. The investigator is responsible for 
keeping accurate records of the clinical supplies received from the manufacturer, the 
amount dispensed to and returned by the subjects/patients, and the amount remaining at 
the conclusion of the study. Stanford pharmacy must be kept informed of subsite drug 
shipments, use, and destruction.  
 
In accordance with Good Pharmacy Practices, gloves should always be worn by study 
personnel if directly handling tablets or capsules that are returned (i.e., when counting 
returns). The Principal Investigator, Stanford study coordinator, or the investigative 
pharmacy at Stanford should be contacted with any questions concerning investigational 
products where special or protective handling is indicated.  
 
Due to biohazard concerns, unused study drug will be destroyed locally and not sent back 
to Merck & Co, Inc. Drug will be destroyed according to standard operating procedures 
of the institutional pharmacy. 
 
Drug accountability: temozolomide may not be used outside the scope of this protocol, 
nor can temozolomide be transferred or licensed to any party not participating in this 
clinical study. Opened bottles returned by patients should be documented in the patient-
specific investigational Agent Accountability Record (i.e. logged in as “returned by 
patients” and logged out as “for destruction”) and destroyed on-site in accordance with 
institutional policy. 
 
6.2.3  Temozolomide Dose Modifications:   
The dose of temozolomide will be determined according to (1) non-hematologic AEs 
during the previous cycle, as well as (2) the lowest ANC and platelet counts during that 
cycle.  
 


 
 
 
 
41 
• Dose reductions: For non-hematologic grade 3 AEs (except for nausea and 
vomiting as well as AEs unrelated to treatment) the dose should be reduced 
according to the Temozolomide Dose Level Table. Dose reductions for treatment 
day ANC and platelet counts should also be made according to the Dose Level 
Table below. Each dose reduction will be a 20% reduction from the prior level. 
No dose escalation of temozolomide is permitted  
 
• Discontinuation: For patients who require more than 2 dose reductions, 
temozolomide will be permanently discontinued. For any non-hematologic drug-
related grade 4 AEs that does not resolve within the allowed 4 weeks, then 
temozolomide treatment will be permanently discontinued. Also, except for 
nausea and vomiting, if any of the same non-hematologic grade 3 AEs that are at 
least possibly related to study treatment recur after reduction for that AE, then 
temozolomide will be stopped. 
 
Temozolomide Dose Level Table 
Dose Level 
Dose in 
mg/m2 
0 
200 
-1 
160 
-2 
128 
* Note this is a 20% dose reduction with each dose level 
 
Hematologic Toxicity 
ANC (/mm³) 
 
Platelets (/mm³) 
% of Planned 
Temozolomide 
> 1500/mm³ 
And 
> 100,000/mm3 
100% 
750-1499/mm³ 
Or 
50,000-
99,999/mm3 
Hold then dose 
reduce* 
< 750/mm³ 
or 
< 50,000/mm3 
Hold then dose 
reduce** 
 
*Upon recovery to ANC ≥ 1,500/mm3 and platelets to ≥ 100,000/mm3, the dose 
level -1 will be administered (160 mg/m2). Discontinue dose if patients do not 
recover within ≤ 4 weeks. If patient was already receiving Temozolomide at the -1 
dose level, reduce to the -2 dose (128 mg/m2).  
 
**Upon recovery to ANC ≥ 1,500/mm3 and platelets to ≥ 100,000/mm3, the dose 
level -2 will be administered (128 mg/m2). Discontinue dose if patients do not 


 
 
 
 
42 
recover within ≤ 3 weeks. If patient was already receiving Temozolomide at the -2 
dose level, treatment should be discontinued. 
 
Non-hematologic Toxicity 
For non-hematologic toxicities, dose reductions of temozolomide will be at the 
discretion of the investigator.  Dose-reductions should follow the Temozolomide 
Dose Level Table above.  A maximum of 2 dose reductions can be performed. 
6.3 
Capecitabine administration, storage, and toxicity management 
Capecitabine will be dosed at 750 mg/m2 PO BID for days 1-14.  The dose will be capped 
at 1500 mg PO BID.  The dose will be rounded to the nearest 500 mg.  Adjusted ideal 
body weight will be used for BSA calculations.   
Capecitabine is a fluoropyrimidine carbamate that is an orally active prodrug of 5-
fluorouracil.  Normal cells, as well as tumor cells, metabolize 5- fluorouracil into 5-fluoro-
2’deoxyuridinemonophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). Both 
are metabolites that cause cell injury by two different mechanisms.  FdUMP and the folate 
factor, N5-10-methylenetetrahydrofolate, bind to thymidylate synthase (TS) to inhibit the 
formation of thymidylate. This deficiency of thymidylate causes cell cycle division to halt. 
This is because thymidylate is necessary for thymidine triphosphate production, which is 
essential for DNA synthesis.  FUTP works by incorporating itself into transcription in place 
of uridine triphosphate therefore interfering with RNA transcription and protein synthesis. 
Capecitabine will be supplied by Genentech/Roche as the commercially available form of 
this medication. 
For further details and molecule characterization, see the Capecitabine Investigator 
Brochure. 
6.3.1 Capecitabine Administration 
Capecitabine will be administered at an initial dose of 750 mg/m2 by mouth twice daily, 
on days 1-14 of a 28-day cycle.    
Capecitabine is supplied as biconvex, oblong film-coated tablets, available as 150 mg 
tablets (light peach) and 500 mg tablets (peach).  Capecitabine is stored at 25 oC, with 
excursions permitted to 15 to 30 oC.   
Capecitabine tablets should be swallowed with water within 30 minutes after a meal.  The 
calculated dose by body surface area (BSA) will be rounded down to allow doses using 
500 mg tablets.    
 


 
 
 
 
43 
6.3.2 Capecitabine Dose Modification and Toxicity Management 
Capecitabine will be initiated at 750 mg/m2 PO BID x 14 days on a 28-day cycle. 
Two total dose reductions are permitted before capecitabine will be discontinued.    
 
 


 
 
 
 
44 
Hematologic Toxicities 
ANC (/mm³) 
 
Platelets (/mm³) 
Modification 
<1500/mm3  
AND/OR  
< 100,000/mm3 
Hold until ANC ≥ 1500/mm3 
and PLT ≥ 
100,000/mm3; 
resume at 20% dose 
reduction  
≥ 1500/mm3 
AND  
≥ 100,000/mm3 
No dose modification  
Mucositis, Diahhrea, or Esophagitis  
Grade 
Toxicities/Symptoms 
Modification 
1 
Mucositis,diarrhea, or 
esophagitis 
No dose modification 
2 
Diarrhea 
No dose modification 
2 
Mucositis or esophagitis 
Hold until < grade 1; 
resume at 20% dose 
reduction 
3 
Diarrhea 
Hold until < grade 1 
;resume at 20% dose 
reduction 
3/4 
Mucositis or esophagitis 
Hold until < grade 1; 
resume at 20% dose 
reduction 
 
Hand and Foot Rash 
Grade 
Modification 
1 
No dose modification 
2 
Hold until symptoms resolve to grade 0 or 1.  Resume at 
20% dose reduction. 
> 3 
Hold until symptoms resolve to grade 0 or 1.  
Resume at 20% dose reduction. 
 
Non-hematologic Toxicity 


 
 
 
 
45 
For other non-hematologic toxicities, dose reductions of capecitabine will be at the 
discretion of the investigator.  A 20% dose reduction should be performed with 
each subsequent reduction.  A maximum of 2 dose reductions can be performed. 
6.4 
General Dose Modifications 
All toxicity grades above are described using the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0.   
 
Dose reduction will be based on day 1 labratory values of each cycle. 
 
Dose reductions will be based on current dose. If dose reduction is required, reduction 
is permanent. Missed doses will not be made up.  
 
Dose will be modified for all drugs if there is a ≥ 5% change in patient’s weight while on 
study.  
 
If multiple toxicities are seen, the dose administered in a subsequent cycle should be 
based on the most severe toxicity experienced in the current cycle.  
 
AEs determined to be unrelated to study treatment will not require dose reduction.  
 
If toxicities have not resolved within ≤ 4 weeks of next planned cycle start date, patients 
must discontinue protocol treatment.  
 
After 3 cycles of treatment, any of the three drugs can be discontinued at the 
investigator’s discretion for any adverse event with severity of grade 3 or more. 
If patient is on maintenance bevacizumab, upon documentation of first disease 
progression by RECIST criteria, the patient can restart the original schedule of 
temozolomide, capecitabine, and bevacizumab at the investigator’s discretion. 
 
6.5 
Concomitant and Supportive Medications  
6.5.1 Concomitant medications 
Capecitabine Drug Interactions 
Capecitabine Cmax and AUC have been shown to increase by approximately 20-35% 
when given concurrently with antacids.  Therefore administration of capecitabine should 
be separated by two hours from any antacids. 
Capecitabine increases the serum level of warfarin with concomitant administration.  
Therefore, a patient who takes both requires more frequent testing of INR and PT so the 
appropriate dose adjustment can be made. 


 
 
 
 
46 
Capecitabine also increases the serum level of phenytoin. The patient may need more 
frequent monitoring of phenytoin levels so dosing adjustments can be made 
appropriately. 
Capecitabine has not been shown to interact with CYP450 isoenzymes although extra 
care should be expressed when administering CYP2C9 substrates. 
6.5.2 Pre-medications  
Ondansetron is required as a premedication 30 minutes prior to temozolomide. 
Otherwise, anti-emetics, anxiolytics, and analgesics may be provided at physicians’ 
discretion. 
6.5.3  Supportive Care Guidelines  
Supportive treatment may include anti-emetics, antidiarrheal medications, anti-pyretics, 
anti-histamines, analgesics, antibiotics, and others, such as blood products.  Patients who 
experience indigestion or gastroesophageal reflux symptoms may be treated with Proton 
Pump Inhibitors (PPIs) as well as H2 blockers as clinically indicated. 
Blood products transfusions will be administered according to institutional guidelines. 
Plasma products, antibiotic and antifungal therapy will be administered on as needed on 
an individual case basis. Hematopoetic growth factors will be permitted for the 
management of anemia and/or neutropenia per ASCO guidelines.  Patients will be 
permitted to receive appropriate supportive care measures as deemed necessary by the 
treating physician.  
 
7.0 
Clinical and Laboratory Evaluations 
Cycle 
Screen 
1a 
1b 
2a 
2b 
3a 
3b 
Follow Up 
(Every 6 
month + 1 
month) 
Withdrawal 
of study 
treatmentg 
Dayd 
0 
1 
15 
1 
15 
1 
15 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
Medical history 
(including hormone 
functional status) 
X 
X 
 
X 
 
X 
 
 
X 
Physical examination 
X 
X 
 
X 
 
X 
 
 
X 
Performance Status 
X 
X 
 
X 
 
X 
 
Xe 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
 
X 
Hematology/chemistry  
X 
X 
X 
X 
X 
X 
X 
 
X 
Urinalysis or dipstickb 
X 
X 
 
X 
 
X 
 
 
X 
Biomarkersc 
X 
X 
 
X 
 
X 
 
 
X 
Pregnancy test 
X 
 
 
 
 
 
 
 
 


 
 
 
 
47 
Cycle 
Screen 
1a 
1b 
2a 
2b 
3a 
3b 
Follow Up 
(Every 6 
month + 1 
month) 
Withdrawal 
of study 
treatmentg 
Dayd 
0 
1 
15 
1 
15 
1 
15 
 
 
RECIST 
Xa 
 
 
 
 
Xa 
 
Xf 
Xa 
Tolerability/AE reporting 
 
X 
 
X 
 
X 
 
 
X 
Concurrent medication 
(Somatostatin analogue 
only) h 
X 
X 
 
X 
 
X 
 
 
X 
Bevacizumab (d1 + 15) 
 
X 
X 
X 
X 
X 
X 
 
 
Capecitabine (d1-14) 
 
X 
 
X 
 
X 
 
 
 
Temozolomide (d10-14) 
 
X 
 
X 
 
X 
 
 
 
a- 
Measurement of tumor will be done at baseline, every 3 cycles (end of cycle 3, 6, 9, etc.) and at withdrawal of study 
treatment 
b- 
Urinalysis or dipstick obtained at screening and at least every 4 weeks. See section 6.1.3 for further details. 
c- 
Sampling of serum for chromogranin A levels will be done on the first day of each cycle, other hormone markers may be 
checked at the investigator’s discretion. 
d- 
Patients may be seen within a +/- 7 -days window of the assigned study visit. 
e- 
Survival follow up can be done by phone call or clinic visit 
f- 
Till disease progression 
g- 
If patient doesn’t want to be followed up. 
h- 
Start and stop dates and dose of somatostatin analogue (SSA) should be recorded. SSAs include short and long-acting  
Octreotide and Lanreotide. 
 
 
7.1 
Pre-Treatment Evaluations 
• Screening visit to occur ≤ 14 days prior to start date. 
• Vital signs, including blood pressure 
• Medical history, physical exam, and assessment of performance status 
• Functional status should be recorded as “Yes or No.”  Functional status is defined as 
elevated hormone biomarker with symptoms attributable to that hormone elevation 
(i.e. flushing or diarrhea associated with elevated serotonin or urine 5HIAA).  To be 
determined by treating physician. 
• Blood: Complete blood count with differential, comprehensive metabolic panel, 
Chromogranin A, other neuroendocrine markers at the investigator’s discretion, and 
serum banked for future studies (banked serum is mandatory). 
• Urine:  
• Urinanalysis (pH, specific gravity, glucose, protein, ketones and blood) OR urine 
dipstick are allowed.  Patients with 0, trace, or 1+ protein are eligible to enroll, if >= 
2+ must check 24h urine protein and must be < 1g to start study.   
• Pregnancy test if female 
• Tissue: MGMT deficiency (optional depending on availability, centrally tested at 
Stanford).  See below in section 7.3 for details. 
• Imaging:  
• Radiographic imaging, multi-phasic CT or MRI preferred, of measurable disease 
for assessment by RECIST criteria (standard clinical care).  This must be done 
within 30 days of starting on study. 


 
 
 
 
48 
• CT Perfusion will be performed at baseline as a correlative study (Optional) 
 
7.2 
Evaluations During Treatment 
On the first day of each cycle: 
• Medical history, physical exam, and assessment of performance status 
• Vital signs, including blood pressure 
• Blood: Complete blood count with differential, comprehensive metabolic panel, 
Chromogranin A, and other neuroendocrine markers at the investigator’s discretion 
within 48 hours before treatment. 
• Chromogranin A and other neuroendocrine markers need not be repeated if it is done 
within last 3 weeks in case of delayed cycle or chemotherapy break. 
* 
Urine: Urinanalysis (pH, specific gravity, glucose, protein, ketones and blood) OR 
urine dipstick are allowed.  Patients with 0, trace, or 1+ protein are eligible to get 
treated.  For the first occurrence of a 2+ value, 24-hour urine confirmation is required.  
If the confirming 24-hour urine is <2g/24h, subsequent 2+ urinalysis or dipstick values 
for that patient are acceptable.  
• Imaging:  
o Multi-phasic CT or MRI scans with measurement of target lesions by RECIST 
criteria will be done at the conclusion of every 3 cycles  
o CT Perfusion will be performed after 2 wks and after 3 cycles as a correlative 
study. (Optional) 
 
7.3 
Post-Treatment Evaluations 
Upon patient withdrawal from study, every effort will be undertaken to obtain the following 
(unless done within 4 weeks of study withdrawal): 
• Medical history, physical exam, and assessment of performance status 
• Vital signs, including blood pressure 
• Blood: Complete blood count with differential, comprehensive metabolic panel, 
Chromogranin A, and other neuroendocrine markers at the investigator’s discretion. 
• Imaging:  
• Multiphasic CT or MRI scans with measurement of target lesions by RECIST 
criteria and CT Perfusion (OPTIONAL) as a correlative study will be performed if 
not done within 4 weeks prior to withdrawal from study. 
• Additional imaging will be at the investigator’s discretion per standard of care. 
 
7.4 
Correlative Tissue/Blood Studies 
Representative tumor tissue samples will be used in the studies described below.  The 
results of these studies are for the purposes of the trial only and will not be returned to 
the site or reported to the patient.  Tissue for MGMT testing will be optional depending 
on availability and will not be an eligibility requirement. 


 
 
 
 
49 
Priority of tissue use: 
1.   MGMT status by IHC 
2.   MGMT status by promoter methylation 
 
Evaluation of MGMT status by IHC 
Mouse monoclonal antibody to MGMT will be used (1:25 dilution; clone MT 3.1; Lab 
Vision), a biotinylated secondary antibody (mouse IgG), and then avidin-horseradish 
peroxidase (Vectastain Elite ABC Kit; Vector Laboratories) according to the 
manufacturer’s instructions. Immunohistochemical MGMT expression will be scored as 
either ‘‘intact’’ or ‘‘deficient’’ in tumor cells using a prospective classification scheme. 
Tumors will be scored as ‘‘intact’’ when there is nuclear staining for MGMT in any tumor 
cells. Tumors will be scored as ‘‘deficient’’ when there is a complete absence of nuclear 
staining for MGMT in all tumor cells. Non-neoplastic cells (lymphocytes, stromal cells, 
and endothelial cells) served as an internal positive control in all tissue sections.  We 
will additionally use an external tissue array control slide with known negative tumor. 
The assay will be performed in a CLIA certified lab under the direction of Teri Longacre, 
MD at Stanford University. 
 
Evaluation of MGMT status by promoter methylation 
DNA is purified from formalin-fixed paraffin embedded and then treated with bisulfite. 
Bisulfite treatment chemically converts unmethylated cytosines to uracil but does not 
affect methylated cytosine. Two PCR reactions are then performed using primers 
corresponding to bisulfite modified (unmethylated) or unmodified (methylated) MGMT 
promoter sequence. The products of the PCR reaction are analyzed by agarose gel 
electrophoresis.  Methylation-specific PCR performed on paraffin-embedded tissue 
specimens is dependent on tissue quality and quantity. It is important that there is little 
tissue necrosis since amplification could otherwise be compromised. It is to be expected 
to frequently see amplification of both methylated and unmethylated MGMT promoter 
sequences in the same specimen, which likely represents heterogeneity among tumor 
cells and/or the presence in the specimen of non-neoplastic cells. Presence of promoter 
methylation, which causes epigenetic silencing of the MGMT gene, a DNA repair gene 
on chromosome 10q26, is a positive predictive factor for chemotherapeutic response to 
alkylating agents. The assay will be performed in a CLIA certified lab under the direction 
of Iris Schrijver M.D at Stanford University. 
 
Corrleative Specimen Submission Requirements 
Diagnostic material from previously collected tissue (core biopsy or surgical specimen 
preferred over FNA) must be submitted for optional laboratory research studies. 
Peripheral blood is to be submitted from consenting patients for future research studies. 
The IRB-approved consent must allow patients the option to provide specimens to for 
use in the optional laboratory studies and for undefined future research.   
 
Specimen Preparation Guidelines 
Tissue Samples 
The following materials are to be submitted: 


 
 
 
 
50 
• 
One representative diagnostic formalin-fixed paraffin-embedded tumor block, 
core biopsy or surgical specimen preferred.    
• 
NOTE: If a block is unavailable for submission, submit the following: 
o For MGMT IHC: 3 unstained slides, 4 microns thick 
o For MGMT promoter methylation: 3 unstained slides, 20 microns thick 
 
Peripheral Blood, ACD or EDTA 
• 
Blood specimens will be collected during routine care on cycle 1 day 1 using three 
tubes, for whole blood (6 cc purple top), serum (6cc red top) and plasma (6 cc 
purple top) 
• 
All blood samples will be processed within 3 to 4 hours of collection. The serum 
sample should be kept at room temperature for at least 30 minutes prior to 
centrifugation. 
• 
For serum and plasma, samples will be spun in a centrifuge for 15 minutes at 
3000 rpm at room temperature.  After spinning plasma will be pipetted into five 
storage tubes of one milliliter each and serum will be pipetted into two storage 
tubes of one milliliter each. One tube of whole blood will be stored without 
processing. 
• 
These samples may be stored at the individual sites until the time of analysis in a 
-80C freezer per institutional protocols at Stanford, UCSF and Moffitt. 
 
Pathology Contact information 
Tissue samples should be labeled: 
“For Kunz Ph II Trial Tem/Cape/Bev central MGMT review” 
 
Tissue samples should be mailed to: 
Pamela Kunz, MD 
Stanford Cancer Institute 
875 Blake Wilbur Drive 
Stanford, CA 94305-5826 
pkunz@stanford.edu 
 
 
Pathology samples will be distributed by Dr. Kunz and her team to the appropriate 
investigators as follows to: 
 
For MGMT immunohistochemistry: 
Teri Longacre, M.D. 
Professor of Pathology 
Stanford University School of Medicine 
Department of Pathology 
300 Pasteur Drive 
Stanford, CA 94305 
Phone: xxx-xxx-xxxx 
Email: cccccccccccccccccc 
  


 
 
 
 
51 
  
For MGMT promoter methylation: 
Iris Schrijver M.D.  
Associate Professor of Pathology 
Stanford University School of Medicine 
Department of Pathology / Molecular Pathology 
300 Pasteur Drive 
Stanford, CA 94305-5627  
Phone:  
Fax:  
Email:   
  
8.0 
Subject Discontinuation 
Patients will continue on treatment until one of the following occurs: 
1. 
Patient chooses to withdraw from study 
2. 
Unacceptable toxicity occurs 
3. 
Evidence of progressive disease by RECIST criteria  
Specific reasons for discontinuation are listed below:  
1. Patient removes consent 
2. Completion of protocol treatment 
3. Patient relapses or progresses to a point that additional or alternative therapy is 
indicated 
4. The patient may withdraw from the study at any time for any reason. 
5. Patient is now excluded 
6. Patient fails to meet scheduled clinical visits leading to a sufficiently incomplete 
dataset for analysis 
7. Patient is diagnosed with a new tumor requiring treatment  
8. The patient has a clinically significant treatment adverse event as determined by 
the Principal Investigator. 
9. The development of circumstances which prevent study evaluations/visits 
10. The patient requires a dose level of <100 mg/m2/day for 5 days for TEMODAR. 
11. Evidence of disease progression prior to completion of 3 cycles 
12. Patient is non-compliant with study medication 
13. Grade 4 hypertension or Grade 3 hypertension not controlled with medication 
14. Nephrotic syndrome 
15. Grade ≥ 2 pulmonary or CNS hemorrhage; any Grade 4 hemorrhage 


 
 
 
 
52 
16. Symptomatic Grade 4 venous thromboembolic event (for lung protocols: any 
venous thromboembolic event requiring full dose warfarin or equivalent (i.e., 
unfractionated or low molecular weight heparin)  
17. Any grade arterial thromboembolic event 
18. Grade 4 congestive heart failure 
19. Gastrointestinal perforation  
20. Tracheoesophageal fistula (any grade) or Grade 4 fistula 
21. Grade 3 or greater bowel obstruction that has not fully recovered despite medical 
or surgical intervention 
22. Wound dehiscence requiring medical or surgical intervention 
23. Unwillingness or inability of subject to comply with study requirements 
24. Determination by the investigator that it is no longer safe for the subject to continue 
therapy 
25. All Grade 4 events thought to be related to bevacizumab by the investigator 
26. Becomes pregnant 
27. Withdrawal of consent 
28. Development of a serious intercurrent medical condition or need for concomitant 
treatment that precludes further participation in the trial 
29. Progressive disease 
NOTE: Patients who have an ongoing drug-related Grade 4 or serious adverse event at 
the time of discontinuation from study treatment will continue to be followed until 
resolution of the event or until the event is considered irreversible. 
9.0 
Study Follow Up 
After study treatment discontinued patients will be followed every 6 months till death for 
disease progression and survival. (See section 7.0)  Discontinuation of the study will be 
considered after review of the data by the DSMC for any of the following events: 
• Major toxicity (i.e. life-threatening hemorrhage) attributable to study treatment. 
• Determination by the DSMC that excessive toxicity attributed to the regimen has been 
identified that does not meet the safety reason 1 above. 
10.0 Statistical Methods 
10.1 Determination of Sample size 
A sample size of 30 patients would give 80% power to reject the null RR of 40% if the true 
response rate (RR) is 65% or higher. The null hypothesis is based on a prospective phase 
II study conducted by Kulke, et al evaluating the efficacy of temozolomide and 
thalidomide1.  In this study, 29 patients with mixed metastatic NETs were treated with 
temozolomide 150 mg/m2 for 7 days every other week and thalidomide at doses of 50-
400 mg daily.  The overall radiographic response was 25% (45% in patients with 


 
 
 
 
53 
pancreatic NETs).  The alternative hypothesis is based on the more recent retrospective 
study in patients with pancreatic NETs reported by Strosberg, et al in which 30 patients 
were treated with capecitabine (750mg/m2 twice daily, days 1-14) and temozolomide (200 
mg/m2 once daily, days 10-14) every 28 days; the RR was 70%6.  RR is defined as the 
proportion of patients with complete response + partial response (CR+PR) based on a 
patient’s best response.  
 
The study will be stopped if there are excessive toxicities associated with the study 
regimen.  An interim analysis for safety will be performed after the first 10 patients have 
been treated.  All patients receiving at least one dose of protocol therapy will be 
included in the analyses.  Specifically, we will stop the study and re-evaluate the 
approach if it is determined that ≥3 of the first 10 patients experience grade 3/4 non-
hematologic treatment-related adverse events despite adequate supportive care 
(excluding alopecia), or grade 4 hematologic treatment-related adverse events despite 
adequate supportive care, or other excessive toxicity resulting in death or removal from 
study (as outlined in Section 6.0). The patients included in these analyses will be 
followed without stopping study accrual.   
10.2 Planned Efficacy Evaluations 
Primary Efficacy Variables 
• RR and AEs 
Secondary Efficacy Variables 
• PFS and OS 
• Biomarkers 
• MGMT 
• CT perfusion (if performed) 
Efficacy Assessment using Response Evaluation Criteria in Solid Tumors 
Guideline (RECIST v 1.1)29  
 
Definitions: At baseline, tumor lesions/lymph nodes will be categorized measurable or 
non-measurable as follows: 
 
Measurable: 
• Tumor lesions: Must be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of: 
o 10mm by CT scan (CT scan slice thickness no greater than 5 mm). 
o 10mm caliper measurement by clinical exam (lesions which cannot be 
accurately measured with calipers should be recorded as non-
measurable). 
o 20mm by chest X-ray. 
• Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥15mm in short axis when assessed by CT 


 
 
 
 
54 
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: 
• All other lesions, including small lesions (longest diameter <10mm or pathological 
lymph nodes with P10 to <15mm short axis) as well as truly non-measurable 
lesions. Lesions considered truly non-measurable include: leptomeningeal 
disease, ascites, pleural or pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, abdominal masses/abdominal 
organomegaly identified by physical exam that is not measurable by reproducible 
imaging. 
 
Specifications by methods of measurements 
Measurement of lesions:  
• All measurements should be recorded in metric notation, using calipers if 
clinically assessed. All baseline evaluations should be performed as close as 
possible to the treatment start and never more than 4 weeks before the 
beginning of the treatment. 
 
Method of assessment 
• The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging based evaluation should always be done rather than clinical examination 
unless the lesion(s) being followed cannot be imaged but are assessable by 
clinical exam. 
 
• Clinical lesions: Clinical lesions will only be considered measurable when they 
are superficial and ≥10mm diameter as assessed using calipers (e.g. skin 
nodules). For the case of skin lesions, documentation by colour photography 
including a ruler to estimate the size of the lesion is suggested. As noted above, 
when lesions can be evaluated by both clinical exam and imaging, imaging 
evaluation should be undertaken since it is more objective and may also be 
reviewed at the end of the study. 
 
• Chest X-ray: Chest CT is preferred over chest X-ray, particularly when 
progression is an important endpoint, since CT is more sensitive than X-ray, 
particularly in identifying new lesions. However, lesions on chest X-ray may be 
considered measurable if they are clearly defined and surrounded by aerated 
lung.  
 
• CT, MRI: CT is the best currently available and reproducible method to measure 
lesions selected for response assessment, but MRI is acceptable.This guideline 
has defined measurability of lesions on CT scan based on the assumption that 
CT slice thickness is 5mm or less.  
 


 
 
 
 
55 
• Ultrasound: Ultrasound is not useful in assessment of lesion size and should not 
be used as a method of measurement. 
 
• Endoscopy, laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised.  
 
• Tumor markers: Tumor markers alone cannot be used to assess objective tumor 
response. If markers are initially above the upper normal limit, however, they 
must normalize for a patient to be considered in complete response.  
 
• Cytology, histology: These techniques can be used to differentiate between PR 
and CR in rare cases if required by protocol. 
 
Tumor response evaluation 
 
Baseline documentation of ‘target’ and ‘non-target’ lesions 
• When more than one measurable lesion is present at baseline all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) 
representative of all involved organs should be identified as target lesions and 
will be recorded and measured at baseline. 
 
• Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should 
be those that lend themselves to reproducible repeated measurements.  
 
• A sum of the diameters (longest for non-nodal lesions, short axis for nodal 
lesions) for all target lesions will be calculated and reported as the baseline sum 
diameters. If lymph nodes are to be included in the sum, then as noted above, 
only the short axis is added into the sum. The baseline sum diameters will be 
used as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease. 
 
 
Response criteria 
• Complete Response (CR): Disappearance of all target lesions. Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to 
<10 mm. 
 
• Partial Response (PR): At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters.  
 
• Progressive Disease (PD): At least a 20% increase in the sum of diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study). In addition to the relative increase 
of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. 
(Note: the appearance of one or more new lesions is also considered 
progression). 
 


 
 
 
 
56 
• Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sumdiameters while 
on study.  
 
For other details and special circumstances of the RECIST guidelines refer directly to 
reference. 
 
Time point response: patients with target (+/- non-target lesions) disease 
 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive 
disease, and NE = inevaluable 
 
Definitions of Other Efficacy Markers 
Radiographic Response Rate (RR): The proportion of patients with complete response 
+ partial response (CR+PR) based on a patient’s best response. 
 
Overall Survival (OS):  Time from the date of enrollment to the date of death due to any 
cause or the last date the patient was known to be alive (censored observation) at the 
date of data cutoff for the final analysis 
Time to Progression (TTP):  Time from the date of enrollment to the date of the first 
observation of documented disease progression or death to due cancer 
Progression-Free Survival (PFS): Duration of time from start of treatment to time of 
documented progression or death.  
 
NOTE: Imaging will be performed and reviewed at the separate sites; a central radiology 
review will not be performed. 
 
10.3 Plan of analysis 
The proportion of RR (CR+PR) will be estimated along with a one-sided lower 95% exact 
confidence bound to allow an informal assessment of the null hypothesis (RR=40%) 
based on binomial probabilities; assessment will be regarded as informal since we do not 
expect to be able to adjust for differences in clinical and demographic in the comparator 
study.  Proportions will be estimated along with 95% exact confidence intervals.  Time to 


 
 
 
 
57 
event data will be evaluated using Kaplan-Meier estimates with 95% confidence intervals 
at multiples of 12 months based on Greenwood’s formula with a log transform.  
Confidence intervals for median times to event, if relevant, will be constructed using the 
method of Brookmeyer and Crowley. Biomarkers will be summarized using medians and 
interquartile ranges; changes in biomarkers will be assessed using Wilcoxon’s signed 
rank test. Adverse events will be tabulated by organ system and severity.  Patient clinical 
and demographic characteristics will be reported with the appropriate summary statistic 
(mean, range, proportion etc.) Progression-free survival (PFS) and overall survival (OS) 
will be evaluated using Kaplan-Meier analysis.  For PFS analyses, patients will be 
censored at time last known alive if no progression has occurred. De-identified patient 
data will be used for all analyses. 
 
11.0 Safety Reporting of Adverse Events  
11.1  Genentech-specific Safety Reporting (for both capecitabine and 
bevacizumab) 
Assessment of Safety 
Specification of Safety Variables  
Safety assessments will consist of monitoring and reporting adverse events (AEs) and 
serious adverse events (SAEs) that are considered related to capecitabine or 
bevacizumab, all events of death, and any study specific issue of concern. 
Adverse Events 
An AE is any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of an investigational medicinal product (IMP) or other protocol-
imposed intervention, regardless of attribution. 
 
This includes the following: 
• AEs not previously observed in the subject that emerge during the protocol-
specified AE reporting period, including signs or symptoms associated with 
advanced pancreatic neuroendocrine tumors that were not present prior to the 
AE reporting period. 
• Complications that occur as a result of protocol-mandated interventions (e.g., 
invasive procedures such as cardiac catheterizations). 
 
If applicable, AEs that occur prior to assignment of study treatment associated with 
medication washout, no treatment run-in, or other protocol-mandated intervention. 
 
Preexisting medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during 
the protocol-specified AE reporting period. 


 
 
 
 
58 
Serious Adverse Events 
An AE should be classified as an SAE if the following criteria are met: 
• It results in death (i.e., the AE actually causes or leads to death). 
• It is life threatening (i.e., the AE, in the view of the investigator, places the subject 
at immediate risk of death. It does not include an AE that, had it occurred in a 
more severe form, might have caused death.). 
• It requires or prolongs inpatient hospitalization. 
• It results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the subject’s ability to conduct normal life functions). 
• It results in a congenital anomaly/birth defect in a neonate/infant born to a mother 
exposed to the IMP. 
• It is considered a significant medical event by the investigator based on medical 
judgment (e.g., may jeopardize the subject or may require medical/surgical 
intervention to prevent one of the outcomes listed above). 
Methods and Timing for Assessing AND Recording Safety variables 
The investigator is responsible for ensuring that all AEs and SAEs that are observed or 
reported during the study, are collected and reported to the FDA, appropriate IRB(s), 
and Genentech, Inc. in accordance with CFR 312.32 (IND Safety Reports).  
Adverse Event Reporting Period 
The study period during which all AEs and SAEs must be reported begins after informed 
consent is obtained and initiation of study treatment and ends 30 days following the last 
administration of study treatment or study discontinuation/termination, whichever is 
earlier. After this period, investigators should only report SAEs that are attributed to 
prior study treatment. 
Assessment of Adverse Events 
All AEs and SAEs whether volunteered by the subject, discovered by study personnel 
during questioning, or detected through physical examination, laboratory test, or other 
means will be reported appropriately. Each reported AE or SAE will be described by its 
duration (i.e., start and end dates), regulatory seriousness criteria if applicable, 
suspected relationship to the {study drug} (see following guidance), and actions taken. 
 
To ensure consistency of AE and SAE causality assessments, investigators should 
apply the following general guideline: 
Yes 
There is a plausible temporal relationship between the onset of the AE and 
administration of the {study drug}, and the AE cannot be readily explained by the 
subject’s clinical state, intercurrent illness, or concomitant therapies; and/or the AE 
follows a known pattern of response to the {study drug}; and/or the AE abates or 
resolves upon discontinuation of the {study drug} or dose reduction and, if applicable, 
reappears upon re-challenge. 
No 


 
 
 
 
59 
Evidence exists that the AE has an etiology other than the {study drug} (e.g., preexisting 
medical condition, underlying disease, intercurrent illness, or concomitant medication); 
and/or the AE has no plausible temporal relationship to {study drug} administration (e.g., 
cancer diagnosed 2 days after first dose of study drug). 
 
Expected adverse events are those adverse events that are listed or characterized in 
the Package Insert or current Investigator Brochure.  
 
Unexpected adverse events are those not listed in the Package Insert (P.I.) or current 
Investigator Brochure (I.B.) or not identified. This includes adverse events for which the 
specificity or severity is not consistent with the description in the P.I. or I.B. For 
example, under this definition, hepatic necrosis would be unexpected if the P.I. or I.B. 
only referred to elevated hepatic enzymes or hepatitis. 
Procedures for Eliciting, Recording, and Reporting Adverse Events 
Eliciting Adverse Events 
A consistent methodology for eliciting AEs at all subject evaluation timepoints should be 
adopted. Examples of non-directive questions include:  
• “How have you felt since your last clinical visit?” 
• “Have you had any new or changed health problems since you were last here?”  
Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting AEs or 
SAEs. Avoid colloquialisms and abbreviations. 
 
a. 
Diagnosis vs. Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather than individual 
signs and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, 
asterixis, and elevated transaminases). However, if a constellation of signs and/or 
symptoms cannot be medically characterized as a single diagnosis or syndrome at the 
time of reporting, it is ok to report the information that is currently available. If a 
diagnosis is subsequently established, it should be reported as follow-up information. 
 
b. 
Deaths 
All deaths that occur during the protocol-specified AE reporting period (see Section 
11.1), regardless of attribution, will be reported to the appropriate parties. When 
recording a death, the event or condition that caused or contributed to the fatal outcome 
should be reported as the single medical concept. If the cause of death is unknown and 
cannot be ascertained at the time of reporting, report “Unexplained Death”. 
 
c. 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start of the study. Such 
conditions should be reported as medical and surgical history. A preexisting medical 
condition should be re-assessed throughout the trial and reported as an AE or SAE only 


 
 
 
 
60 
if the frequency, severity, or character of the condition worsens during the study. When 
reporting such events, it is important to convey the concept that the preexisting 
condition has changed by including applicable descriptors (e.g., “more frequent 
headaches”). 
 
d. 
Hospitalizations for Medical or Surgical Procedures 
Any AE that results in hospitalization or prolonged hospitalization should be 
documented and reported as an SAE. If a subject is hospitalized to undergo a medical 
or surgical procedure as a result of an AE, the event responsible for the procedure, not 
the procedure itself, should be reported as the SAE. For example, if a subject is 
hospitalized to undergo coronary bypass surgery, record the heart condition that 
necessitated the bypass as the SAE. 
 
Hospitalizations for the following reasons do not require reporting: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for preexisting conditions 
• Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study or 
• Hospitalization or prolonged hospitalization for scheduled therapy of the target 
disease of the study. 
•  
e. 
Pregnancy 
If a female subject becomes pregnant while receiving investigational therapy or within 
90 days after the last dose of study drug, a report should be completed and 
expeditiously submitted to the Genentech, Inc. Follow-up to obtain the outcome of the 
pregnancy should also occur. Abortion, whether accidental, therapeutic, or 
spontaneous, should always be classified as serious, and expeditiously reported as an 
SAE. Similarly, any congenital anomaly/birth defect in a child born to a female subject 
exposed to the {study drug} should be reported as an SAE. 
 
f. 
Post-Study Adverse Events 
The investigator should expeditiously report any SAE occurring after a subject has 
completed or discontinued study participation if attributed to prior {study drug} exposure. 
If the investigator should become aware of the development of cancer or a congenital 
anomaly in a subsequently conceived offspring of a female subject who participated in 
the study, this should be reported as an SAE.  
 
g. 
SAE Reporting 
Investigators must report all SAEs to Genentech within the timelines described below. 
The completed Medwatch/case report should be faxed immediately upon completion to 
Genentech Drug Safety at: 
 
(XXX-xxx-xxxx 
OR 


 
 
 
 
61 
(xxx) xxx-xxxx 
 
• Relevant follow-up information should be submitted to Genentech Drug Safety as 
soon as it becomes available. 
• Serious AE reports that are related to capecitabine or bevacizumab will be 
transmitted to Genentech within fifteen (15) calendar days of the Awareness 
Date. 
• Serious AE reports that are unrelated to capecitabine or bevacizumab will be 
transmitted to Genentech within thirty (30) calendar days of the Awareness Date. 
• Additional Reporting Requirements to Genentech include the following: 
• Any reports of pregnancy following the start of administration with the 
capecitabine or bevacizumab will be transmitted to Genentech within thirty (30) 
calendar days of the Awareness Date.  
• All Non-serious Adverse Events originating from the Study will be forwarded, at 
most, on a quarterly report to Genentech. 
 
Note: Investigators should also report events to their IRB as required. 
MedWatch 3500A Reporting Guidelines 
In addition to completing appropriate patient demographic and suspect medication 
information, the report should include the following information within the Event 
Description (section 5) of the MedWatch 3500A form: 
• Protocol description (and number, if assigned) 
• Description of event, severity, treatment, and outcome if known 
• Supportive laboratory results and diagnostics 
• Investigator’s assessment of the relationship of the adverse event to each 
investigational product and suspect medication 
Follow-up Information 
Additional information may be added to a previously submitted report by any of the 
following methods: 
• Adding to the original MedWatch 3500A report and submitting it as follow-up 
• Adding supplemental summary information and submitting it as follow-up with the 
original MedWatch 3500A form  
• Summarizing new information and faxing it with a cover letter including patient 
identifiers (i.e. D.O.B. initial, patient number), protocol description and number, if 
assigned, brief adverse event description, and notation that additional or follow-
up information is being submitted (The patient identifiers are important so that the 
new information is added to the correct initial report) 
Occasionally Genentech may contact the reporter for additional information, 
clarification, or current status of the patient for whom and adverse event was reported. 
For questions regarding SAE reporting, you may contact the Genentech Drug Safety 
representative noted above or the MSL assigned to the study. Relevant follow-up 
information should be submitted to Genentech Drug Safety as soon as it becomes 
available and/or upon request. 
 


 
 
 
 
62 
MedWatch 3500A (Mandatory Reporting) form is available at 
http://www.fda.gov/medwatch/getforms.html  
Additional Reporting Requirements for IND Holders 
For Investigator-Sponsored IND Studies, some additional reporting requirements for the 
FDA apply in accordance with the guidance set forth in 21 CFR § 600.80. 
 
Events meeting the following criteria need to be submitted to the Food and Drug 
Administration (FDA) as expedited IND Safety Reports according to the following 
guidance and timelines: 
 
7 Calendar Day Telephone or Fax Report: 
The Investigator is required to notify the FDA of any fatal or life-threatening adverse 
event that is unexpected and assessed by the investigator to be possibly related to the 
use of capecitabine or bevacizumab. An unexpected adverse event is one that is not 
already described in the capecitabine or bevacizumab Investigator Brochures. Such 
reports are to be telephoned or faxed to the FDA and Genentech within 7 calendar days 
of first learning of the event. 
 
15 Calendar Day Written Report 
The Investigator is also required to notify the FDA and all participating investigators, in a 
written IND Safety Report, of any serious, unexpected AE that is considered reasonably 
or possibly related to the use of capecitabine or bevacizumab .An unexpected adverse 
event is one that is not already described in the capecitabine or bevacizumab 
investigator brochures. 
 
Written IND Safety reports should include an Analysis of Similar Events in accordance 
with regulation 21 CFR § 312.32. All safety reports previously filed by the investigator 
with the IND concerning similar events should be analyzed and the significance of the 
new report in light of the previous, similar reports commented on. 
 
Written IND safety reports with Analysis of Similar Events are to be submitted to the 
FDA, Genentech, and all participating investigators within 15 calendar days of first 
learning of the event. The FDA prefers these reports on a Medwatch 3500 form, but 
alternative formats are acceptable (e.g., summary letter). 
 
FDA fax number for IND Safety Reports: 
Fax: 1 (800) FDA 0178 
 
All written IND Safety Reports submitted to the FDA by the Investigator must also 
be faxed to Genentech Drug Safety: 
Fax: ( 


 
 
 
 
63 
 
AND to the Site IRB: 
Stanford IRB / Research Compliance Office 
1501 S. California Avenue, [Mail Code: 5579] 
Palo Alto, CA 94304 
Fax: x 
 
AND to Stanford (for subsites UCSF and Moffitt): 
 
Study Coordination Center/Principal Investigator 
Pamela Kunz, MD 
Stanford Cancer Center 
875 Blake Wilbur Drive 
Stanford, CA 94305-5826 
x 
pkunz@stanford.edu 
 
For questions related to safety reporting, please contact Genentech Drug Safety: 
x 
IND Annual Reports 
Copies to Genentech: 
All IND annual reports submitted to the FDA by the Sponsor-Investigator should be 
copied to Genentech. Copies of such reports should be faxed to Genentech Drug 
Safety: 
 
x 


 
 
 
 
64 
Study Close-Out 
Any study report submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech. This includes all IND annual reports and the Clinical Study Report (final 
study report). Additionally, any literature articles that are a result of the study should be 
sent to Genentech. Copies of such reports should be mailed to the assigned Clinical 
Operations contact for the study: 
 
Avastin Protocols 
Email: avastin-gsur@gene.com 
Fax : xxxxxxxxxxx 
11.2  Merck Safety Reporting 
Follow same AE and SAE definitions as above. 
 
For Merck, all SAEs should be recorded on a MedWatch 3500a Form and faxed to: 
 
Merck (Attn: Worldwide Product Safety; FAX 215 993-1220) must be provided with copies 
of all serious adverse experiences, within two working days regardless of drug 
relationship.  Any pregnancy occurring in association with use of a Merck Product must 
also be reported to Merck (Attn: Worldwide Product Safety; FAX x).   
 
AND: 
 
Stanford IRB / Research Compliance Office 
1501 S. California Avenue, [Mail Code: 5579] 
Palo Alto, CA 94304 
Fax : xxxxxxxxxx 
 
AND (for subsites UCSF and Moffitt): 
 
Study Coordination Center/Principal Investigator 
Pamela Kunz, MD 
Stanford Cancer Center 
875 Blake Wilbur Drive 
Stanford, CA 94305-5826 
xxxxxxxxxxx) 
pkunz@stanford.edu 
 
Merck follow-up period. Patients will be followed for 30 days after they have been taken 
off trial regardless of causality.  
 
12.0 Retention of Records 
Research data will be recorded on study-specific Case Report Forms (CRFs) using a 
unique patient number for each patient to assure patient confidentiality. Data from 
source documents are used to transcribe critical protocol data on CRFs. Source 


 
 
 
 
65 
documents are documents where patient data are recorded and documented for the first 
time. They include, but are not limited to, hospital records, clinical and office charts, 
laboratory notes, memoranda, quality of life assessments, pharmacy dispensing 
records, recorded data from automated instruments, copies of transcriptions that are 
certified after verification as being accurate and complete, X-rays, patient filed, and 
records kept at the pharmacy, laboratories, and medico-technical departments involved 
in the clinical trial.  
 
Any publication or presentation will refer to patients by this number and not by name. The 
licensed medical records department, affiliated with the institution where the patient 
receives medical care, maintains all original inpatient and outpatient chart documents. 
Patient research files are maintained by a designated research coordinator and kept in a 
locked room with access restricted to personnel authorized by the Division of Clinical 
Research. A study-specific database will also use the unique patient number and will not 
include patient names. Access to the database will be restricted by electronic password 
protection and restricted access to computers (i.e., locked offices). 
13.0 Data and Safety Monitoring Plan 
Stanford Cancer Institute will be the coordinating institution.  Ongoing trial oversight is 
carried out by the principal investigator, Dr. Pamela Kunz and her research staff. Adverse 
events will be reviewed in real time. Additionally, summaries of SAEs and AEs will be 
reviewed weekly at the Developmental Therapeutics Meeting and monthly with the 
subsites to discuss trends. The data recorded within the research charts and protocol 
database is compared with the actual data that is available from the medical record and/or 
clinical histories. Stanford will perform twice yearly on site audits of source documents. 
Data detailed in the research case report forms includes the nature and severity of all 
toxicities, which are also reported as described above. All investigators on the protocol 
have received formal training in the ethical conduct of human research. Institutional 
support of trial monitoring is provided in accordance with the Stanford University 
Institutional Data and Safety Monitoring Plan. Under the provisions of this plan, the 
Stanford Research Trials Office coordinates monitoring for data accuracy and compliance 
by consultants, contract research organizations, or Stanford employees unaffiliated with 
the conduct of the study. Independent monitoring visits occur at specified intervals 
determined by the assessed risk level of the study and the findings of previous visits. In 
addition, protocols are reviewed at least annually by the Data and Safety Monitoring 
Committee (DSMC) and the Institutional Review Board (IRB). The Stanford IRB reviews 
the study progress and safety information to assess continued acceptability of the risk-
benefit ratio for human subjects. Approval of the IRB is necessary to continue the study. 
The trial will comply with the standard guidelines set forth by the regulatory committees 
of the Stanford (Scientific Review Committee, IRB, DSMC) and other state and federal 
guidelines. 
 
To ensure trial-wide data and safety monitoring, the Principal Investigator will obtain 
copies of all local IRB approvals and will have the responsibility for receiving the 
information required for adverse event reporting and safety monitoring from outside sites, 
and disseminating that information to the appropriate Consortium committees. The 


 
 
 
 
66 
Principal investigator is responsible for establishing and carrying out procedures for 
assessing protocol compliance, data accuracy and completeness, and full and timely 
reporting of safety data at outside sites. Written agreements will be obtained from all 
participating sites acknowledging their responsibilities for data and adverse event 
reporting and agreement to provide records, files, case report forms or any other 
documents to verify compliance. 
14.0 Ethical and Regulatory Considerations 
General: Stanford will be the coordinating institution.  As such, all Case Report Forms 
(CRFs) will be reviewed by Stanford research staff for compliance.  Imaging will be 
reviewed separately at each site; a central review will not occur. 
 
Institutional Review Board 
In accordance with federal regulations (21 CFR 312.66), an Institutional Review Board 
(IRB) at Stanford that complies with regulations in 21 CFR 56 must review and approve 
this protocol and the informed consent form prior to initiation of the study. 
 
Independent Ethics Committees/Institutional Review Board 
This protocol and the informed consent will be approved by the Stanford IRB. The 
Principal Investigator is responsible for keeping the IRB advised of the progress of the 
study and of any changes made in the protocol prior to implementation. The Principal 
Investigator will also keep the IRB informed of any significant adverse reactions, and any 
protocol exceptions or deviations. Records of all study review and approval documents 
must be kept on file by the Principal Investigator and are subject to FDA inspection during 
or after completion of the study. The IRB will receive notification of the termination of the 
study. 
 
Consent 
The Principal Investigator or his designee must explain verbally and in writing the nature, 
duration, and purpose of the study and possible consequences of treatment. Patients 
must also be informed that they may withdraw from the study at any time and for any 
reason without jeopardizing their future treatment. In accordance with federal regulations 
(21 CFR 50), all patients enrolled in the study must sign the IRB-approved consent form. 
 
Clinical Trials Database and Results Registration   
The principal investigator will register the clinical trial at www.clinicaltrials.gov, the US 
National Library of Medicine website prior to initiation of the study. This website provides 
regularly updated information about US government and privately supported clinical 
research in human volunteers. In addition, the investigator will make the results of the 
study 
publicly 
accessible 
by 
publication 
and 
by 
posting 
the 
results 
on 
www.clinicaltrials.gov. 
 
Monitoring and Reporting Guidelines 
Investigators will conduct continuous review of data and patient safety at weekly study 
group or site committee meetings where the results of each patient’s data and status are 
discussed and the discussion is documented in the minutes. The discussion will include 


 
 
 
 
67 
any toxicity from temozolomide treatment including dose de-escalations if they were 
required. Quarterly summaries will be submitted to the DSMC for review. All AE’s and 
SAE’s from temozolomide would have been entered into the Stanford Comprehensive 
Cancer Center CTMS database. The study coordinator will keep a log of subject(s) 
temozolomide treatment.  
 
Premature Closure of the Study 
This study may be prematurely terminated, if in the opinion of the investigator, 
Genentech or Merck, there is sufficient reasonable cause.  Written notification 
documenting the reason for study termination will be provided by the terminating party.   
Circumstances that may warrant termination include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to patients 
• Failure to enter patients at an acceptable rate 
• Insufficient adherence to protocol requirements 
• Insufficient complete and/or evaluable data 
• Plans to modify, suspend or discontinue the development of the drug 
Should the study be closed prematurely, all study drugs must be returned to Genentech 
or Merck. 
 
Good Clinical Practice 
The study will be conducted in accordance with the International Conference on 
Harmonisation (ICH) for Good Clinical Practice (GCP) and the appropriate regulatory 
requirement(s).  The investigator will be thoroughly familiar with the appropriate use of 
the drug as described in the protocol and Investigator’s Brochure.  Essential clinical 
documents will be maintained to demonstrate the validity of the study and the integrity of 
the data collected.  Master files should be established at the beginning of the study, 
maintained for the duration of the study and retained according to the appropriate 
regulations.   
 
Ethical Considerations 
The study will be conducted in accordance with ethical principles founded in the 
Declaration of Helsinki.  The IRB/IEC will review all appropriate study documentation in 
order to safeguard the rights, safety and well-being of the patients.  The study will only be 
conducted after FHCRC IRB/IEC approval has been obtained.  The protocol, 
Investigator’s Brochure, informed consent, advertisements (if applicable), written 
information given to the patients (including diary cards), safety updates, annual progress 
reports, and any revisions to these documents will be provided to the IRB/IEC by the 
investigator.  The investigator, Genentech and Merck will review informed consent 
documents prior to IRB/IEC submission.  
 
Patient Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from 
either the patient or his/her guardian or legal representative prior to study participation.  
The method of obtaining and documenting the informed consent and the contents of the 
consent will comply with ICH-GCP and all applicable regulatory requirement(s). 
 


 
 
 
 
68 
Patient Confidentiality 
In order to maintain patient privacy, all data capture records, drug accountability records, 
study reports and communications will identify the patient by initials and the assigned 
patient number. The patient’s confidentiality will be maintained and will not be made 
publicly available to the extent permitted by the applicable laws and regulations. 
 
Protocol Compliance 
The investigator will conduct the study in compliance with the protocol given 
approval/favorable opinion by the IRB/IEC and the appropriate regulatory authority(ies).  
Changes to the protocol will require approval from Genentech and Merck, and written 
IRB/IEC approval/favorable opinion prior to implementation, except when the modification 
is needed to eliminate an immediate hazard(s) to patients.  The IRB/IEC may provide, if 
applicable regulatory authority(ies) permit, expedited review and approval/favorable 
opinion for minor change(s) in ongoing studies that have the approval /favorable opinion 
of the IRB/IEC.  The investigator will submit all protocol modifications to Genenteach, 
Merck and the regulatory authority(ies) in accordance with the governing regulations. Any 
departures from the protocol must be fully documented in the source documents.   
 
 


 
 
 
 
69 
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 [Bevacizumab references provided as separate document on diskette] 
 
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Kulke MH, Stuart K, Enzinger PC, et al. Phase II study of temozolomide and 
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Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic 
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Yung WK, Prados MD, Yaya-Tur R, et al. Multicenter phase II trial of 
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Brandwein JM, Schimmer AD, Schuh AC, et al. A Phase II Study of 
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Isacoff W, Moss R, Pecora A, Fine R. Temozolomode/capecitabine therapy for 
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Pecout S, Baudin E, Paoli A, et al. Efficacy and tolerance of chemotherapy with 
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72 
APPENDICES:  
Appendix A: NCI Common Toxicity Criteria, v4.0 (website provided) 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
 
Appendix B: FDA MedWatch 3500a Form (website provided) 
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm 
 
Appendix C: NYHA Guidelines (included) 
 
Appendix D: Genentech Safety Reporting Cover Sheet (included) 
 
 
ATTACHMENTS: 
Attachment 1:  Informed Consent Form (separate attachment) 
 
 
 
 
 


 
 
 
 
73 
APPENDIX C:  NYHA Guidelines30 
 
Class I (mild): no limitation is experienced in any activities; there are no symptoms from 
ordinary activities. 
 
Class II (mild): slight, mild limitation of activity; the patient is comfortable at rest or with 
mild exertion. 
 
Class III (moderate): marked limitation of any activity; the patient is comfortable only at 
rest. 
 
Class IV (severe): any physical activity brings on discomfort and symptoms occur at 
rest. 
 
 
 


 
 
 
 
74 
APPENDIX D:  
 
 
 
SAFETY REPORTING FAX COVER SHEET 
Genentech Supported Research 
AE / SAE FAX No: xxxxxxxxxx 
Alternate Fax No: xxxxxxxxxxx 
 
Genentech Study Number 
 
Principal Investigator 
 
Site Name 
 
Reporter name 
 
Reporter Telephone # 
 
Reporter Fax # 
 
 
Initial Report Date 
[INSERT investigational product name] / [INSERT 
investigational product name] / [INSERT 
investigational product name] 
Follow-up Report Date 
[INSERT investigational product name] / [INSERT 
investigational product name] / [INSERT 
investigational product name] 
 
Subject Initials 
(Enter a dash if patient has no 
middle name) 
[INSERT investigational product name] - [INSERT 
investigational product name] - [INSERT 
investigational product name] 
 
SAE or Safety Reporting questions, contact Genentech Safety: (xxxxxxxxxxx 
PLEASE PLACE MEDWATCH REPORT or SAFETY REPORT BEHIND THIS COVER 
SHEET