Conditions: Malignant Glioma Recurrent Glioblastoma
Keywords: Glioblastoma Multiforme
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 96
Healthy volunteers: no

Brief summary:
The goal of this Phase I portion of this clinical research study is to find the highest tolerable dose of bevacizumab with or without vorinostat, that can be given to patients with malignant gliomas. The safety of these drug combinations will also be studied.

The goal of this Phase II part of this clinical research study is to learn if bevacizumab when given with or without vorinostat can help to control malignant gliomas. The safety of these drug combinations will also be studied.

Detailed description:
Background

* Glioblastoma (GBM) is the most common primary brain tumor. With optimal treatment, consisting of focal radiotherapy with concurrent chemotherapy, followed by adjuvant chemotherapy, median survival is 14.6 months. Most patients have evidence of tumor progression within one year of diagnosis despite treatment. At progression, treatment options are limited and mostly ineffective.
* Given the importance of angiogenesis in GBM, anti-angiogenic therapy is a promising strategy in recurrent GBM. Bevacizumab, the first angiogenesis inhibitor approved against cancer by FDA based on improved survival of advanced colon cancer patient, has recently been studied in the GBM.
* The present study aims to determine the potential of vorinostat, an HDAC inhibitor plus bevacizumab, versus bevacizumab alone, in an attempt to increase the anti-angiogenic effects of VEGF by blocking the evasive resistance by combination with vorinostat and to also not only provide the potential of the independent effects of both agents but also the potential for synergy.

Objectives

* To determine the maximum tolerated dose (MTD) of vorinostat plus bevacizumab in adult patients with malignant glioma.
* To determine the efficacy of vorinostat plus bevacizumab versus bevacizumab alone in patients with recurrent WHO grade IV glioma (glioblastoma and gliosarcoma) as determined by progression free survival (PFS) using an adaptive randomization phase II trial design.

Eligibility

* Patients must have histologically proven glioblastoma, gliosarcoma or anaplastic glioma to be eligible for the Phase I component of this protocol. Anaplastic gliomas include anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), anaplastic mixed oligoastrocytoma (AMO), or malignant glioma NOS (not otherwise specified). Patients will be eligible if the original histology was low-grade glioma and a subsequent histological diagnosis of a malignant glioma is made. Only patients with histologically proven or imaging proven recurrent glioblastoma or gliosarcoma will be eligible for the Phase II component.
* Patients must have shown unequivocal evidence for tumor progression as determined by an MRI scan done prior to study entry which will be reviewed by the treating physician to confirm and document recurrence.
* No prior treatment with bevacizumab or Vorinostat

Design

The phase I component will assess the MTD of Vorinostat in combination with Bevacizumab. A conventional phase I design will be used and the MTD will be selected using a 3+3 accrual design at each dose level until MTD is determined. A maximum of 18 patients will be recruited to this component of the study.

The phase II component of the trial compares Bevacizumab to Vorinostat+ Bevacizumab in patients with recurrent GBM. The primary outcome is progression free survival. Patients will be randomized between the two arms using a Bayesian adaptive algorithm. Patients will be randomized fairly between the two arms at the start of the trial (for the first 20 patients). Thereafter, as the trial progresses and data accrue, the randomization will become unbalanced in favor of the treatment that, on average, has better results in terms of failure time. Therefore, each successive patient is more likely to receive the treatment with better results, on average. A minimum of 20 and a maximum of 90 patients will be accrued.

Arms:
arm 1: 10 mg/kg/dose by vein on days 1 and 15 of a 28 day cycle. arm 2: Vorinostat: 400 mg/day by mouth on days 1 to 7 and days 15 to 21 of a 28 day cycle.

Bevacizumab: 10 mg/kg/dose by vein on days 1 and 15 of a 28 day cycle.

Interventions: intervention 1: vorinostat intervention 2: bevacizumab
Intervention descriptions: intervention 1: Vorinostat 400mg/day will be administered on day 1 to 7 and day 15 to 21 orally on a 28 day cycle in the arm with combination of vorinostat and bevacizumab. Vorinostat will be administered orally. Vorinostat capsules should not be opened or crushed and must be administered whole. intervention 2: Bevacizumab 10mg/kg will be administered on day 1 and 15 intravenously on a 28 day cycle in both arms.

Protocol document:
Prot_SAP_000.pdf: 
05/13/16
/ 16-C-N116


Abbreviated Title: PhI/II Bev Vorinostat GBM 
NCI Version Date: 04/29/2016 
MDACC Version Date: 09/22/2014 
Page i 
NCI APPENDIX 
Abbreviated Title: PhI/II Bev Vorinostat GBM 
NCI Protocol #: pending 
BTTC Protocol #: BTTC11-02 
Title: Phase I/II Adaptive Randomized Trial of Bevacizumab versus Bevacizumab plus Vorinostat 
in Adults with Recurrent Glioblastoma   
Coordinating Center:  
NCI BTTC Coordinating Center, Center for Cancer Research 
NCI Principal Investigator: 
Mark Gilbert, M.D. 
Neuro Oncology Branch (NOB), CCR, NCI 
9030 Old Georgetown Road, Building 82, Room 235 
Bethesda, MD 20892 
Phone: 301-402-6383 
Fax: 301-480-2246 
Email: mark.gilbert@nih.gov 
Associate Investigator:  
Jing Wu, MD, NOB, CCR, NCI 
NCI Referral Contact(s): 
Christine Bryla, RN, OCD, CCR, NCI 
NCI Study Coordinator(s): 
Christine Bryla, RN, OCD, CCR, NCI 
Neuro Oncology Branch (NOB), CCR, NCI 
9030 Old Georgetown Road, Building 82, Room 231 
Bethesda, MD 20892 
Phone: 301-443-3441 
Fax: 301-480-2246 
Email: christine.bryla@nih.gov  
Investigational Agents: 
None 
Commercial Agents:  
Vorinostat and Bevacizumab was supplied by their respective 
manufacturers, Merck Sharp and Dohme Corp. and Genentech 


Abbreviated Title: PhI/II Bev Vorinostat GBM 
 
NCI Version Date: 04/29/2016 
MDACC Version Date: 09/22/2014 
 
 
 
 
 
 
 
 
 
 
 
Page ii 
 
BTTC Roles: 
 
ACADEMIC PI 
Vinay K. Puduvalli, MD 
Ohio State University 
Division of Neuro-Oncology 
320 W, 10th Ave, M410 
Starling Loving Hall 
Columbus OH 43210 
Phone:614-688-7592 
Email: 
Vinay.Puduvalli@osumc.edu 
FWA00007577 
 
 
ADMINISTRATIVE PI 
Mark R. Gilbert, MD 
Neuro-Oncology Branch 
NCI/NINDS 
National Institutes of Health 
Bloch Bldg. 82, Rm. 235 
9030 Old Georgetown Road 
Bethesda, MD 20892 
Email:  mark.gilbert@nih.gov 
 
BTTC BIOSTATISTICIAN 
Ying Yuan, Ph. D. 
UT MD Anderson Cancer 
Center 
Division of Quantitative 
Science 
1400 Hermann Pressler Dr. 
Unit 1411 
Houston, TX 77030-4008 
Phone: 713-563-4271 
Email: 
yyuan@mdanderson.org 
FWA00000363 
 
PATIENT OUTCOMES       
Terri S. Armstrong, PhD,  
ANP-BC, FAANP 
UT MD Anderson Cancer 
Center 
Neuro-Oncology, Unit 431 
P.O. Box 301402  
Houston, TX  77230-1402 
Phone:  713-745-4621 
Fax:   713-794-4999 
Email:  
tsarmstr@mdanderson.org 
FWA00000363 
 
 
BTTC COORDINATING 
CENTER 
NCI BTTC Coordinating 
Center 
National Cancer Institute, 
National Institutes of Health 
9030 Old Georgetown Road, 
Room 211 
Bethesda, MD 20892 
Phone: 301-451-6009 
Fax: 301-451-5429 
Email: 
NCI_BTTC@mail.nih.gov 
 
 
AGENTS 
Name/s: Vorinostat &  
Bevacizumab 
 
 
A DISCLAIMER STATEMENT FOR BTTC PROTOCOLS 
This is a research protocol of the Brain Tumor Trials Collaborative describing an experimental 
treatment procedure.  It is a privileged document and is not intended to be circulated or used for 
other purposes.  The Brain Tumor Trials Collaborative assumes no responsibility for its use 
outside of the constraints of this research protocol or by investigators other than those approved 
by the Consortium. 
 
 


Abbreviated Title: PhI/II Bev Vorinostat GBM 
 
NCI Version Date: 04/29/2016 
MDACC Version Date: 09/22/2014 
 
 
 
 
 
 
 
 
 
 
 
Page iii 
 
PARTICIPATING INVESTIGATORS  
Mark Gilbert, MD 
Neuro-Oncology Branch, NCI/NINDS, NIH 
Email:    mark.gilbert@nih.gov  
 
 
Vinay Puduvalli, MD 
Ohio State University Wexner Medical Center 
Email: vinay.puduvalli@osumc.edu   
FWA00007577 
 
Ivo Tremont, MD 
UT, MD Anderson Cancer Center 
Email:    itremont@mdanderson.org 
FWA00000363 
 
Marta Penas Prado, MD 
UT, MD Anderson Cancer Center – PI 
Email:   mpenaspr@mdanderson.org 
FWA00000363 
 
Jeffrey Raizer, MD 
Northwestern University, Feinberg School of 
Medicine 
Email: jraizer@nmff.org 
FWA00018700 
 
Howard Colman, MD 
University of Utah Health System – Huntsman 
Cancer Institute 
Email:  howard.colman@hci.utah.edu  
FWA00003745 
 
Karen Fink, MD 
Baylor Neuro-Oncology Associates 
Email: karenfin@baylorhealth.edu 
FWA00004415 
 
David Tran, MD 
Washington University School of Medicine 
Email:  dtran@dom.wustl.edu  
FWA00002284 
 
 
 
 
W.K. Alfred Yung, MD 
UT, MD Anderson Cancer Center 
Email: wyung@mdanderson.org 
FWA00000363 
 
Terri S. Armstrong, APN, Ph.D. 
UT, MD Anderson Cancer Center 
Email:    tarmstr@mdanderson.org 
FWA00000363 
 
John deGroot, MD 
UT, MD Anderson Cancer Center 
Email:    jdegroot@mdanderson.org 
FWA00000363 
 
Monica Loghin, MD 
UT, MD Anderson Cancer Center 
Email:    mloghin@mdanderson.org 
FWA00000363 
 
Nicholas Avgeropoulos, MD 
MD Anderson Cancer Center - Orlando 
Email: 
nicholas.avgeropoulos@orlandohealth.com 
FWA00022392 
 
Scott Lindhorst MD  
Medical University of South Carolina  
Hollings Cancer Center 
Email: lindhors@musc.edu  
FWA00001888 
 
Marc Chamberlain, MD 
University of Washington Medical Center 
Email:  chambemc@u.washington.edu 
FWA00002284 
 
Morris Groves, MD 
Texas Oncology-Austin Brain Tumor Center 
Email:  morris.groves@usoncology.com  
FWA00017020 
 
 
 
 


Abbreviated Title: PhI/II Bev Vorinostat GBM 
 
NCI Version Date: 04/29/2016 
MDACC Version Date: 09/22/2014 
 
 
 
 
 
 
 
 
 
 
 
Page iv 
 
Tobias Walbert, MD 
Henry Ford Health System 
Email:  TWALBER1@hfhs.org 
FWA00005846 
 
Fabio Iwamoto, MD 
Columbia University 
Email: fi2146@columbia.edu   
FWA00002636 
 
Ryan Merrell, MD 
Northshore University Health System 
Email: rmerrell@northshore.org    
FWA00003000 
 
 
Nina Paleologos, MD 
Rush University Medical Center 
Email:  nina_paleologos@rush.edu  
FWA00000482 
 
David Peereboom MD 
Cleveland Clinic 
Email: peerebd@ccf.org 
FWA00005367 
 
Frances Collichio, MD 
University of North Carolina at Chapel Hill 
Email: fcollich@med.unc.edu 
FWA00004507 
 
 
 
 
 


Abbreviated Title: PhI/II Bev Vorinostat GBM 
 
NCI Version Date: 04/29/2016 
MDACC Version Date: 09/22/2014 
 
 
 
 
 
 
 
 
 
 
 
Page v 
 
PRÉCIS 
Background 
 Glioblastoma (GBM) is the most common primary brain tumor.  With optimal treatment, 
consisting of focal radiotherapy with concurrent chemotherapy, followed by adjuvant 
chemotherapy, median survival is 14.6 months. Most patients have evidence of tumor 
progression within one year of diagnosis despite treatment.  At progression, treatment 
options are limited and mostly ineffective. 
 Given the importance of angiogenesis in GBM, anti-angiogenic therapy is a promising 
strategy in recurrent GBM. Bevacizumab, the first angiogenesis inhibitor approved against 
cancer by FDA based on improved survival of advanced colon cancer patient, has recently 
been studied in the GBM. 
 The present study aims to determine the potential of vorinostat, an HDAC inhibitor plus 
bevacizumab, versus bevacizumab alone, in an attempt to increase the anti-angiogenic 
effects of VEGF by blocking the evasive resistance by combination with vorinostat and to 
also not only provide the potential of the independent effects of both agents but also the 
potential for synergy. 
Objectives 
 To determine the maximum tolerated dose (MTD) of vorinostat plus bevacizumab in adult 
patients with malignant glioma. 
 
 To determine the efficacy of vorinostat plus bevacizumab versus bevacizumab alone in 
patients with recurrent WHO grade IV glioma (glioblastoma and gliosarcoma) as 
determined by progression free survival (PFS) using an adaptive randomization phase II 
trial design. 
Eligibility 
 Patients must have histologically proven glioblastoma, gliosarcoma or anaplastic glioma 
to be eligible for the Phase I component of this protocol. Anaplastic gliomas include 
anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), anaplastic mixed 
oligoastrocytoma (AMO), or malignant glioma NOS (not otherwise specified). Patients 
will be eligible if the original histology was low-grade glioma and a subsequent histological 
diagnosis of a malignant glioma is made. Only patients with histologically proven or 
imaging proven recurrent glioblastoma or gliosarcoma will be eligible for the Phase II 
component.  
 Patients must have shown unequivocal evidence for tumor progression as determined by 
an MRI scan done prior to study entry which will be reviewed by the treating physician to 
confirm and document recurrence.   
 No prior treatment with bevacizumab or Vorinostat 
 
 
 


Abbreviated Title: PhI/II Bev Vorinostat GBM 
 
NCI Version Date: 04/29/2016 
MDACC Version Date: 09/22/2014 
 
 
 
 
 
 
 
 
 
 
 
Page vi 
 
Design 
The phase I component will assess the MTD of Vorinostat in combination with Bevacizumab.  A 
conventional phase I design will be used and the MTD will be selected using a 3+3 accrual design 
at each dose level until MTD is determined.  A maximum of 18 patients will be recruited to this 
component of the study. 
The phase II component of the trial compares Bevacizumab to Vorinostat+ Bevacizumab in 
patients with recurrent GBM. The primary outcome is progression free survival. Patients will be 
randomized between the two arms using a Bayesian adaptive algorithm. Patients will be 
randomized fairly between the two arms at the start of the trial (for the first 20 patients).  
Thereafter, as the trial progresses and data accrue, the randomization will become unbalanced in 
favor of the treatment that, on average, has better results in terms of failure time.  Therefore, 
each successive patient is more likely to receive the treatment with better results, on average. A 
minimum of 20 and a maximum of 90 patients will be accrued. 
 
 


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Abbreviated Title: PhI/II Bev Vorinostat GBM 
 
NCI Version Date: 04/29/2016 
MDACC Version Date: 09/22/2014 
 
 
 
 
 
 
 
 
 
 
 
Page xviii 
 
APPENDIX A: CCR PROBLEM REPORT FORM 
NCI Protocol #:  
Protocol Title:  
 
 
Report version: (select one) 
____Initial Report  
____Revised Report 
____Follow-up  
Site Principal Investigator: 
 
  
Date of problem:     
Location of problem: (e.g., patient’s home, 
doctor’s office) 
Date PI was notified of problem: __/__/____  
If delay in reporting to IRB (> 5 days for serious 
events; > 14 days for not serious events), please 
explain: 
 
 
Who identified the problem? (provide role (not name of person): nurse, investigator, monitor, 
etc…) 
 
Brief Description of Subject (if 
applicable)  
(Do NOT include personal 
identifiers)  
Sex:  ___ Male  ___ Female Age:   
 ___ Not applicable (more than one subject is involved) 
 
Diagnosis under study:   
Name the problem: (select all that apply)   
[  ] Adverse drug reaction   
[  ] Abnormal lab value   
[  ] Death   
[  ] Cardiac Arrest/ code  
[  ] Anaphylaxis  
[  ] Sepsis/Infection   
[  ] Blood product reaction 
[  ] Unanticipated surgery/procedure   
[  ] Change in status (e.g. increased level of care required)    
[  ] Allergy (non-medication)  
[  ] Fall  
[  ] Injury/Accident (not fall)  
[  ] Specimen collection issue   
[  ] Informed consent issue   
[  ] Ineligible for enrollment   
[  ] Breach of PII  
[  ] Tests/procedures not performed on schedule  
[  ]  Other, brief  1-2 word description: _________________________ 
 


Abbreviated Title: PhI/II Bev Vorinostat GBM 
 
NCI Version Date: 04/29/2016 
MDACC Version Date: 09/22/2014 
 
 
 
 
 
 
 
 
 
 
 
Page xix 
 
Detailed Description of the problem: (Include any relevant treatment, outcomes or pertinent 
history): 
 
 
*Is this problem unexpected? (see the definition of unexpected in the protocol))  __YES __NO  
Please explain: 
 
 *Is this problem related or possibly related to participation in the research?  __YES __NO  
Please explain: 
 
*Does the problem suggest the research places subjects or others at a greater risk of harm 
than was previously known or recognized?    __YES __NO      Please explain: 
 
 
Is this problem? (select all that apply) 
[  ] An Unanticipated Problem* that is:       [  ] Serious        [  ] Not Serious  
[  ] A Protocol Deviation that is:                [  ] Serious        [  ] Not Serious 
[  ] Non-compliance 
*Note if the 3 criteria starred above are answered, “YES”, then this event is also a UP. 
Is the problem also (select one)  [  ] AE  [  ] Non-AE 
Have similar problems occurred on this protocol at your site? __YES __NO       
If “Yes”, how many? ____      Please describe: 
Describe what steps you have already taken as a result of this problem: 
 
 
In addition to the NCI IRB, this problem is also being reported to: (select all that apply) 
[  ] Local IRB 
[  ] Study Sponsor 
[  ] Manufacturer : ____________________  
[  ] Institutional Biosafety Committee  
[  ] Data Safety Monitoring Board 
[  ] Other: ____________________________________  
[  ] None of the above, not applicable 
INVESTIGATOR’S SIGNATURE:  
 
DATE:   
 


PRIVILEGED COMMUNICATION: FOR INVESTIGATIONAL USE ONLY 
                                                                                                           BTTC11-02   
  9.22.2014 
Page 1 of 94    
                             
Bevacizumab + Vorinostat Protocol  
 
    
 
1 
 
 
BRAIN TUMOR TRIALS COLLABORATIVE (BTTC) 
 
BTTC11-02: Phase I/II Adaptive Randomized Trial of Bevacizumab versus Bevacizumab 
plus Vorinostat in Adults with Recurrent Glioblastoma   
 
 
 
PAGE 
1.0 
OBJECTIVES AND STUDY DESIGN 
4 
2.0 
BACKGROUND 
6 
3.0 
DRUG INFORMATION 
19 
4.0 
ELIGIBILITY CRITERIA 
26 
5.0 
STRATIFICATION/DESCRIPTIVE FACTORS 
31 
6.0 
TREATMENT PLAN 
31  
7.0 
PRETREATMENT EVALUATION 
42 
8.0 
EVALUATION DURING STUDY 
43 
9.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
45 
10.0 
SUBJECT DISCONTINUATION 
47 
11.0 
STATISTICAL CONSIDERATIONS 
48 
12.0 
DISCIPLINE REVIEW 
53 
13.0 
PHARMACOKINETICS 
53 
14.0 
LABORATORY CORRELATES 
53 
15.0 
MULTICENTER PROCEDURES 
53 
16.0 
PATIENT RELATED OUTCOME MEASURES 
66 
17.0 
REFERENCES 
69 
18.0 
APPENDIX 
72 
 
 
 
ADMINISTRATIVE CHAIR  
Mark R. Gilbert, MD 
MD Anderson Cancer Center 
Neuro-Oncology Department 
1515 Holcombe Blvd., Unit 431  
Houston, TX 77030 
Phone: 713-792-4008 
Email: mrgilbert@mdanderson.org 
 
CO-INVESTIGATOR 
Jing Wu MD 
University of North Carolina, Chapel 
Hill 
Department of Neurosurgery 
Chapel Hill, NC 27599-1374 
Phone: 919-966-1374 
Email: jwu@neurology.unc.edu 
BTTC BIOSTATISTICIAN 
Ying Yuan, Ph. D. 
MD Anderson Cancer Center 
Division of Quantitative Science 
1515 Holcombe Blvd., Unit 1411 
Houston, TX 77030-4009 
Phone: 713-563-4271 
Email: yyuan@mdanderson.org 
 
QUALITY OF LIFE CHAIR 
Terri S. Armstrong, Ph. D, ANP-BC, 
FAANP 
MD Anderson Cancer Center 
Neuro-Oncology Department 
1515 Holcombe Blvd., Unit 431  
Houston, TX 77030 
Phone: 713-745-4621 
Email: Tsarmstr@mdanderson.org 
 
ACADEMIC CHAIR (BTTC LEAD) 
Vinay K. Puduvalli, MD 
The Ohio State University Wexner 
Medical Center 
Div.of  Neuro-Oncology,Dept of Surgery 
320 W 10th Avenue, Starling Loving Hall 
Suite M410 
Columbus,  OH 43210 
Phone: 614-688-7592 
Email : Vinay.Puduvalli@osumc.edu 
 
BTTC COORDINATING CENTER 
Office of Multicenter Clinical Research 
MD Anderson Cancer Center 
7007 Bertner Ave., Unit 1664, 
Houston, TX 77030 
Phone: 713-792-8519 
Fax: 713-794-1902 
Email: OMCR_BTTC@mdanderson.org 
A DISCLAIMER STATEMENT FOR BTTC PROTOCOLS 


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This is a research protocol of the Brain Tumor Trials Collaborative describing an experimental treatment procedure.  
It is a privileged document and is not intended to be circulated or used for other purposes.  The Brain Tumor Trials 
Collaborative assumes no responsibility for its use outside of the constraints of this research protocol or by 
investigators other than those approved by the Consortium. 


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PARTICIPATING INVESTIGATORS  
 
Vinay Puduvalli, MD 
Ohio State University Wexner Medical Center 
Email: vinay.puduvalli@osumc.edu   
 
Mark Gilbert, M.D. 
UT, MD Anderson Cancer Center 
Email:    mrgilbert@mdanderson.org 
 
Charles Conrad, M.D. 
UT, MD Anderson Cancer Center 
Email:    cconrad@mdanderson.org 
 
Ivo Tremont, M.D. 
UT, MD Anderson Cancer Center 
Email:    itremont@mdanderson.org 
 
Marta Penas Prado, M.D. 
UT, MD Anderson Cancer Center 
Email:   mpenaspr@mdanderson.org 
 
Jeffrey Raizer, M.D. 
Northwestern University, Feinberg School of Medicine 
Email: jraizer@nmff.org 
 
Karen Fink, MD 
Neuro-Oncology Associates 
Email: karenfin@baylorhealth.edu 
 
Jing Wu, MD 
University of North Carolina- Chapel Hill 
Email:  jwu@neurology.unc.edu 
 
Pamela New, MD 
The Methodist Hospital System 
Email:  pnew@tmhs.org 
 
David Tran, MD 
Washington University School of Medicine 
Email:  dtran@dom.wustl.edu 
 
Tobias Walbert, MD 
Henry Ford Health System 
Email;  TWALBER1@hfhs.org 
 
Fabio Iwamoto, MD 
Columbia University 
Email: fi2146@columbia.edu   
 
 
W.K. Alfred Yung, M.D. 
UT, MD Anderson Cancer Center 
Email: wyung@mdanderson.org 
 
Terri S. Armstrong, APN, Ph.D. 
UT, MD Anderson Cancer Center 
Email:    tarmstr@mdanderson.org 
 
John deGroot, M.D. 
UT, MD Anderson Cancer Center 
Email:    jdegroot@mdanderson.org 
 
Monica Loghin, M.D. 
UT, MD Anderson Cancer Center 
Email:    mloghin@mdanderson.org 
 
Nicholas Avgeropoulos, MD 
MD Anderson Cancer Center - Orlando 
Email: nicholas.avgeropoulos@orlandohealth.com 
 
 Scott Lindhorst MD Medical University of South 
Carolina Hollings Cancer Center 
Email:   lindhors@musc.edu 
 
Howard Colman, MD 
University of Utah Health System – Huntsman Cancer 
Institute 
Email:  howard.colman@hci.utah.edu  
 
Marc Chamberlain, MD 
University of Washington Medical Center 
Email:  chambemc@u.washington.edu 
 
 Morris Groves, MD 
Texas Oncology-Austin Brain Tumor Center 
Email:  morris.groves@usoncology.com 
 
Nina Paleologos, MD 
Rush University Medical Center 
Email:  nina_paleologos@rush.edu  
 
Ryan Merrell, MD 
Northshore University Health System 
Email: rmerrell@northshore.org    
 
David Peereboom M.D 
Cleveland Clinic 
Email: peerebd@ccf.org 
 
 


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1.0 
OBJECTIVES AND STUDY DESIGN 
 
1.1 
OBJECTIVES 
 
Primary endpoint: 
 
Phase I 
 
 
To determine the maximum tolerated dose (MTD) of vorinostat plus bevacizumab in adult 
patients with malignant glioma. 
 
Phase II 
 
 
To determine the efficacy of vorinostat plus bevacizumab versus bevacizumab alone in 
patients with recurrent WHO grade IV glioma (glioblastoma and gliosarcoma) as determined 
by progression free survival (PFS) using an adaptive randomization phase II trial design. 
 
Secondary endpoint: 
 
Phase II 
 
 
To determine the radiological response, TTP and OS in the treatment arms.  
 
 
To determine the efficacy and safety of combination of Vorinostat and Bevacizumab 
including in a subset of patients whose tumors exhibit a mesenchymal-pro-angiogenic 
phenotype associated with poor outcome.   
 
 
To determine the effects of bevacizumab with and without vorinostat upon biomarkers of 
angiogenesis. 
 
 
To evaluate the occurrence of symptoms and correlate to disease progression and tolerance to 
treatment using the MD Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) 
self-reporting tool.  
 
1.2 
STUDY DESIGN  
 
1.2.1 
Description of the Study 
 
Phase 1 component:  
 
A conventional Phase I design will be used and the MTD will be selected using a 3+3 accrual 
design at each dose level until MTD is determined.   
 
Phase II component: 
 
This is a randomized phase II trial of the combination of bevacizumab plus vorinostat compared 
with bevacizumab alone in patients with recurrent grade IV malignant glioma.  The primary 


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endpoint is progression free survival. Patients will be randomized between the two arms using a 
Bayesian adaptive algorithm. Patients will be randomized fairly between the two arms at the start 
of the trial (for the first 20 patients). Thereafter, as the trial progresses and data accrue, the 
randomization will become unbalanced in favor of the treatment that, on average, has better 
results in terms of failure time. Therefore, each successive patient is more likely to receive the 
treatment with better results, on average. A minimum of 20 and a maximum of 90 patients will be 
accrued and there will be 6 months follow up after the last patient is accrued. Based on an 
anticipated accrual rate between 3 and 5 patients per month, the maximum trial accrual period 
will be between 12 and 24 months.  
 
The operating characteristics of the design are detailed in section 11.0 in the detailed table 
provided. The historical median progression free survival used for this study will be 4 months. 
This is in keeping with the data provided from the BRAIN study that led to the recent FDA 
approval of bevacizumab; median PFS in that study for single agent bevacizumab was 4.2 months 
(95% CI, 2.9, 5.8). The calculations used for the current assume an accrual rate of either 3 or 5 
patients per month. The trial will be stopped early and a treatment selected as being “better” if the 
probability that one treatment’s median PFS is larger than the other’s PFS exceeds 0.995. If the 
trial does not stop early and the maximum 90 patients are accrued, a treatment is selected as being 
“better” if the probability that one treatment’s median PFS is larger than the other’s PFS exceeds 
0.975. The “number of patients treated” row is the average number of patients treated on a given 
arm under the given scenario. When the medians are equal, the probability of selecting either of 
the two arms (i.e., a false positive result) is 9% for both accrual rates. The probability of selecting 
the better treatment (i.e., a true positive result) for a doubling in the median PFS is 85% for 3 per 
month and 83% for 5 per month.  
 
At each evaluation when a new patient comes in the study, the data for patients who have been 
followed until that time and not yet progressed are accounted in the analysis. The trial will be 
conducted using a web based program, the Clinical Trial Conduct site, developed by the 
Department of Biostatistics at MD Anderson Cancer Center. Through the website interface, the 
users will have the ability to randomize patients, update the current patients’ status. The results of 
randomization are displayed for the user to review.  
    
1.2.2 
Rationale for Study Design 
 
Phase I component:  
 
A recent phase I trial tested the combination of vorinostat with bevacizumab and CPT-11 in 
patients with recurrent glioblastoma. The MTD of vorinostat has been established at a dose of 400 
mg daily given on days 1-7 and 15-21 on a 4 week cycle when combined with CPT-11 (125 
mg/m2) and bevacizumab (10 mg/kg) given on days 1 and 15.  Toxicities not reaching DLT 
levels have to date included fatigue, diarrhea, mucositis and hematological toxicities.  Common 
toxicities of the combination included fatigue and diarrhea. DLTs included fatigue, 
hypertension/hypotension, and central nervous system ischemia (Chinnaiyan et al 2012).  
  
Given that our study proposes to use bevacizumab and vorinostat only, we anticipate less toxicity 
than seen in the 3-drug combination utilized in the trial described above.  These results provide a 
rationale for our starting dose of 400 mg/day on days 1-7 and 15-21 of vorinostat in combination 
with bevacizumab at 10 mg/kg on days 1 and 15.  We will incorporate dose escalation of 


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vorinostat by one level to 500 mg and also provide two dose de-escalation levels at 300 and 200 
mg/day in the unlikely event that the starting dose level is above MTD. 
 
Phase II component:  
 
To assess the activity of a new treatment regimen, conventional phase II designs use either a 
single arm design compared with historical controls or a randomized design with a control arm of 
standard treatment, if such a standard is identified. For patients with recurrent GBMs, there are no 
extant standards of care. In a paradigm such as the one being studied in the proposed trial, testing 
each combination against historical controls would involve separate trials, a process that will not 
provide timely answers to the question at hand nor allow utilization of resources in an efficient 
manner. To overcome some of these hurdles and test these combinations against each other as 
well as historical controls, this study proposes to utilize a Bayesian adaptive randomization 
design, which will pit the two treatment regimens against each other. This will result in 
progressive bias of randomization towards the best of the two regimens in a single trial. The 
"winner" of these two regimens will be considered the best regimen for further testing in a larger 
trial if it compares favorably with historical controls (Berry and Eick, 1994; Thall et al., 2002; 
Wong et al., 1999).    
 
 
2.0 
BACKGROUND 
 
2.1 
DISEASE BACKGROUND 
 
Glioblastomas are the most common adult gliomas.  In United State, there are 21, 810 new cases 
of primary brain tumor estimated in 2008 and about 13,070 death from the brain tumor. GBM is 
the most common and aggressive malignant primary brain tumor, accounting more than half of 
the primary brain tumor with approximately 4–6 per 100,000 people per year (Gurney and 
Kadan-Lottick, 2001). Malignant gliomas are the second leading cause of cancer death in patients 
under 35 years of age and the fourth leading cause in those patients younger than 45 yrs.  
 
Histologically, glioblastomas display high mitotic index, cellular pleomorphism, extensive 
vascular proliferation or necrosis. They are characterized by their intrinsic heterogeneity, high 
morbidity and mortality. Despite aggressive multimodality treatment approach in surgery, 
radiation therapy and cytotoxic chemotherapeutic agents, the prognosis of patients with GBM is 
only 14.6 month (Stupp et al., 2005) in newly diagnosed GBM. Recurrent GBM has an even more 
dismal prognosis with a median overall survival of~25 weeks (Wong et al., 1999) and PFS6 15%. 
Recent studies of bevacizumab either as a single agent or in combination with irinotecan have 
demonstrated a significant improvement in response rate compared to historical agents. Single-
agent Bevacizumab treatment was associated with an overall response rate of 28.2% with a 
median duration of response was 5.6 months.  Six-month PFS and median overall survival (OS) 
were 42.6% and 9.2 months, respectively; based on the response rate, bevacizumab was recently 
granted FDA approval for use in patients with recurrent GBM. However, progression after 
Bevacizumab therapy is often dramatic and associated with poor prognosis. Hence, there remains 
an unmet need for development of new approaches against these tumors and their characteristic 
biologic heterogeneity  
 


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Therapies targeting a single biological feature or pathway in these tumors have historically been 
unsuccessful in making any meaningful clinical impact. This has led to strategies aimed at 
rationally combining agents that target various processes critical to tumor biology.  On the other 
hand, resistance to anti-angiogenic therapy may cause the overall failure of the therapy. 
Therefore, combination target therapy may be able to inhibit tumor growth by distinct and 
synergistic mechanisms but also have non-overlapping toxicities allowing better tolerability.  
 
2.2 
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). 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 Investigator’s Brochure of 
bevacizumab 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). 


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A Phase II, open-label, multicenter, randomized, non-comparative study (AVF3708g, BRAIN), 
evaluated the efficacy and safety of Bevacizumab alone, or in combination with irinotecan in 167 
glioblastoma (GBM) patients with progressive disease following prior therapy.  For single-agent 
Bevacizumab (n=85), ORR was 28.2% and median duration of response was 5.6 months.  Six-
month PFS and median overall survival (OS) were 42.6% and 9.2 months, respectively; median 
PFS was 4.2 months (95% CI 2.9, 5.8).  Based on these data, Bevacizumab, as a single agent, was 
approved by the FDA for the treatment of glioblastoma with progressive disease following prior 
therapy. 
 
a. Bevacizumab 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). Visceral arterial ischemia and disseminated 
intravascular coagulation resulting in death was reported in a single case recently. These and 
other 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) (Glusker et al., 2006; Ozcan 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-


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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 protein:creatinine (UPC) ratio at least every 6 weeks.  
If the UPC ratio is not available, a dipstick urinalysis may be used to allow treatment to 
proceed. 
 
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 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 


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(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 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 


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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 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 muco-cutaneous 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 Hemorrhage: 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.  


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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).   
 
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 one 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. 


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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). 
 
Additional Adverse Events:  See the bevacizumab Investigator Brochure for additional 
details regarding the safety experience with bevacizumab. 
 
2.3 
Vorinostat clinical experience 
 
As of 07-May-2008, vorinostat has been orally administered to more than 1899 patients in Ph I, II 
and III clinical studies. These studies were sponsored by either Merck, Sharp and Dohme 
Corp.the US National Cancer Institute (NCI) or the Merck Investigator initiated studies program 
(IISP).  The clinical development program being conducted by Merck, Sharp and Dohme Corp. 
for vorinostat includes: Seventeen (Mastronardi et al., 1998) Phase I, II and III studies conducted 
with vorinostat in monotherapy and eleven (Duvic et al., 2005) Phase I, II and III studies 
conducted with vorinostat in combination therapy.  
 
Zolinza® (vorinostat) was approved by the U.S. Food and Drug Administration (FDA) on 06-
Oct-2006 for the treatment of cutaneous manifestations in patients with cutaneous T-cell 
lymphoma who have progressive, persistent or recurrent disease on or following two systemic 
therapies.  The efficacy of vorinostat in CTCL has been demonstrated in a pivotal Phase IIb and a 
supportive Phase IIa study. A total of 107 individual patients with CTCL, 89 of who had Stage 
IIB or higher disease, were treated in these studies.  In this refractory population, the response 
rates for all patients treated with vorinostat at 400 mg orally once daily, the dose and schedule 
approved for clinical use in patients with CTCL, were 30.8% and 29.7% for the overall 
population in these two studies.  For patients with Stage IIB and higher CTCL, the response rates 
were 36.4% and 29.5% respectively.  For patients with Sezary syndrome, the response rate was 
33.3% in both studies.  More information can be found in the prescribing information for 
vorinostat. 
 
Phase I and II clinical studies of vorinostat sponsored by Merck, Sharp and Dohme, Corp. and the 
NCI have demonstrated confirmed anti-tumor activity in patients with acute myeloid leukemia 
(AML), advanced multiple myeloma, B-cell non-Hodgkin’s lymphoma, squamous cell laryngeal 
carcinoma, thyroid carcinoma, breast carcinoma, non-small cell lung carcinoma, glioblastoma 
multiforme and myelodysplastic syndrome.  Studies are ongoing to further evaluate whether these 
observations translate into clinical benefit. 
 
a.  Safety Profile 
 
The total daily oral dose of vorinostat administered in these studies ranges from 200 mg to 
900 mg. The tolerability of oral vorinostat appears to be determined by total daily dose and 
the length of consecutive days of dosing. The maximum tolerated dose (MTD) for continuous 
daily dosing without a rest period is 400 mg once a day or 200 mg twice a day (200 mg 
b.i.d.). The MTD for intermittent dosing is 300 mg b.i.d. x 3 consecutive days per week or 
250 mg t.i.d. x 14 consecutive days followed by a 7-day rest. Dose-limiting toxicities (DLTs) 
are mainly non-hematologic (anorexia, dehydration, diarrhea and weight loss). Hematologic 


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toxicities were primarily anemia and thrombocytopenia, most of which were mild to 
moderate in intensity. The majority of DLTs occurred within the first month on oral 
vorinostat. The DLTs were manageable because these toxicities resolved quickly after drug 
administration was interrupted. The optimal dose, dose frequency, and dose duration remains 
under active investigation. 
 
Adverse experiences considered by the Investigators to be at least possibly related to 
vorinostat reported as of 07-May-2008 by ≥10% of patients across all Merck, Sharp and 
Dohme Corp.& Co., Inc. sponsored vorinostat clinical studies are summarized below by 
medical dictionary for regulatory activities (MedDRA), system organ class (SOC) and 
preferred term: 
 
SOC 
 
Reported Possible Related Adverse 
Experiences in ≥10 % Overall Patients 
Blood and Lymphatic System 
Disorders 
Thrombocytopenia, anemia 
Gastrointestinal disorders 
Nausea diarrhea, vomiting, constipation  
General disorders and 
Administration Site Conditions 
Fatigue 
Investigations 
Blood creatinine increased, weight 
decreased, hemoglobin decreased 
Metabolism and Nutritional 
Disorders 
Anorexia, dehydration, hyperglycemia 
Nervous System Disorders 
Dysgeusia 
 
The types of adverse experiences observed in clinical trials of vorinostat were those usually 
associated with chemotherapy. No new or unique adverse experiences were commonly 
observed. The three major clinical categories of adverse experiences attributable to vorinostat 
include a constellation of gastrointestinal symptoms, constitutional complaints, and 
cytopenias. Most of the adverse experiences were manageable. In fact, most of the very 
common adverse experiences were reversible and could be managed using conventional 
supportive care for chemotherapy.  There does not seem to be an increased incidence of 
venous thromboembolic disease in patients treated with vorinostat. There are no statistically 
significant data to suggest that vorinostat increases the QTc to > 500 ms or induces a change 
from baseline of > 30 msec. Taking these data together, administration of oral vorinostat was 
well tolerated in clinical studies.  A study specifically designed to assess the effect of a single 
dose of vorinostat on the QTc interval in patients with advanced cancer was completed and 
showed a single supratherapeutic dose of vorinostat was not associated with prolongation of 
the QTc interval. (Munster et al., 2009) 
 
Vorinostat should be taken approximately 30 minutes after a meal whenever possible. Altered 
taste and decreased food and liquid intake are associated with vorinostat administration. 
These toxicities can be managed with fluid management and nutritional consultation.   
 
To prevent dehydration, patients should consume at least 2 liters of fluid orally, daily. If 
patients are experiencing dysgeusia, popsicles or electrolyte fluid replacement drinks may be 
recommended. If diarrhea occurs it should be managed with loperamide according to 


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institutional guidelines. It is advisable that patients should receive appropriate anti-emetic 
therapy. In accordance with ASCO, NCCN, MASCC or ESMO guidelines, it is 
recommended that management of CINV should include a 5HT3 receptor antagonist, a 
corticosteroid and fosaprepitant and/or aprepitant in compliance with local prescribing 
information/therapeutic indication for each compound. 
 
Vorinostat should not be administered concomitantly with other HDAC inhibitors (e.g., 
valproic acid) as class-specific adverse reactions may be additive. Severe (Grade 4) 
thrombocytopenia with associated gastrointestinal bleeding and anemia has been reported 
with the concomitant use of vorinostat and valproic acid. 
 
b.  HDAC inhibitors and gliomas  
 
HDAC inhibitors have shown preclinical inhibition of glioma cell lines in vitro and in vivo. In 
particular, vorinostat upregulates p21, decreases VEGF levels and increases apoptosis in 
various glioma cell lines. Also, in vivo glioma xenograft studies demonstrate an increased 
survival time in rats treated with vorinostat. Other HDAC inhibitors, such as trichostatin A, 
FK228 and sodium butyrate, show similar effects in vitro. Ugur et al showed that intracranial 
administration of vorinostat inhibits tumor growth in a orthotopic glioma model; more 
relevant to this study, they also demonstrated that vorinostat significantly inhibited vessel 
formation in a endothelial cell tube forming matrigel assay. In addition, a 30% decrease in 
microvessel density was noted in addition to direct antitumor effects in glioma xenografts 
isolated from vorinostat treated animals resulting in increased survival of the animals (Ugur 
et al, 2007).  Ongoing clinical studies are testing anti-tumor activity of vorinostat either as a 
single agent or in combination with temozolomide in gliomas. Final results of a phase II trial 
of vorinostat as a single agent against recurrent glioblastoma were reported (Galanis et al. 
2009) and showed that in a cohort of 66 patients, 9 of the 52 evaluable patients were 
progression free at 6 months. From an intent to treat analysis, 15.2% of patients were alive 
and progression free at 6 months which was considered superior to historical controls and 
thus met the trial’s primary efficacy endpoint  The study  also showed upregulation of E-
cadherin in a subgroup who received vorinostat prior to surgery, indicating a biologic effect 
of the HDAC inhibitor on the glioblastoma tumors.  
 
2.4 
Study Rationale 
 
 
a)  Angiogenesis, a critical biological feature of GBM 
 
Since the notion of tumor angiogenesis was brought by Dr. Folkman in 1971 (Folkman, 
1971), angiogenesis has been studied widely. Most solid tumors are angiogenesis-dependent 
(Folkman, 2006) and angiogenesis is the key feature in GBM (Jain et al., 2007). A 
mesenchymal/angiogenic gene expression signature was found in poor prognosis subclass of 
GBM patients by several gene profiling studies (Phillips et al., 2006; Tso et al., 2006). GBM 
frequently shift to mesenchymal phenotype at the time of their recurrence. A robust 38-gene 
profile, which is associated with mesenchymal/angiogenesis genes, was identified to predict 
survival in GBM (Colman et al., 2007, 2009). This gene set was subsequently narrowed down 
to a 9-gene set which when expressed as a metagene score was confirmed to be independent 
predictor of outcome in GBM. Because the proposed trial is expected to modify the 
angiogenic phenotype, analysis of improved outcome in patients with a poor metagene score 


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(from the 9-gene signature) could potentially indicate efficacy of the treatment proposed in 
our study. 
 
b)  Anti-angiogenic therapy in GBM 
 
Given the importance of angiogenesis in GBM, anti-angiogenic therapy is a promising 
strategy in recurrent GBM. Bevacizumab, the first angiogenesis inhibitor approved against 
cancer by FDA based on improved survival of advanced colon cancer patient, has recently 
been studied in the GBM. In a prospective phase II trial, 35 patients with recurrent GBM 
were treated with bevacizumab and Irinotecan. The response rate was 57%, PFS 6 was 43%, 
2 year OS 15% (Vredenburgh et al., 2007). A subsequent Phase II, open-label, multicenter, 
randomized, non-comparative study (AVF3708g, BRAIN), evaluated the efficacy and safety 
of Bevacizumab alone, or in combination with irinotecan in 167 glioblastoma (GBM) patients 
with progressive disease following prior therapy.  For single-agent Bevacizumab (n=85), 
ORR was 28.2% and median duration of response was 5.6 months.  Six-month PFS and 
median overall survival (OS) were 42.6% and 9.2 months, respectively; Median PFS for the 
bevacizumab alone arm was 4.2 months.  Based on these data, Bevacizumab, as a single 
agent, was approved by the FDA for the treatment of glioblastoma with progressive disease 
following prior therapy. 
 
However, it has become evident recently despite the radiological response to bevacizumab, 
there is an increased risk of tumor infiltration on brain MRI suggesting development of 
resistance and leading to treatment failure; (Norden et al., 2008); Zuniga et al. 2008; Lassman 
et al., 2008). 
 
c)  Resistance to anti-VEGF therapy 
 
The pattern of tumor stasis and then tumor growth seen in the clinical trials with bevacizumab 
as monotherapy or in combination with other cytotoxic agents highly suggests development 
of resistance to anti-VEGF therapy. Studies in animal models provide evidence that tumor 
cells develop the capability to re-grow in the face of VEGF/VEGFR blockade (Casanovas et 
al., 2005). Both intrinsic and adaptive resistance have been proposed as mechanisms for 
resistance to anti-angiogenic agents (Bergers and Hanahan, 2008). After the initial response 
to anti-VEGF therapy denoted by tumor stasis and reduction in tumor vascularity, alternative 
pro-angiogenic factors/signaling pathways are activated, such as fibroblast growth factor 
(FGF), angiopoietin, platelet-derived growth factor (PDGF), VEGF and placenta growth 
factor (PIGF) (Batchelor et al., 2007; Casanovas et al., 2005; Fernando et al., 2008). The 
upregulation and activation of these pro-angiogenic signaling pathways can further cause 
revascularization and tumor progression. Further, various bone marrow derived cells 
(BMDC) that consists of vascular progenitor cells and vascular modulator cells can be 
recruited secondary to the hypoxia which was induced by anti-VEGF therapy (Du et al., 
2008). HIF-1α, upregulated under such hypoxic condition is the key factor by recruiting pro-
angiogenic BMDCs via stromal cell-derived factor (SDF) 1α to facilitate revascularization 
(Du et al., 2008). In addition, many pericytes can survive the anti-VEGF therapy and support 
the endothelial cell survival as well (Bergers et al., 2003; Mancuso et al., 2006). Finally, 
tumor cells escape from their inability to induce neoangiogenesis in the face of initial anti-
VEGF therapy by becoming more invasive by vessel cooption (Lamszus et al., 2003). 
Therefore, resistance to anti-VEGF therapy is complex multi-step process. An agent targeting 


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these multiple pathways of resistance will potentiate the effects of anti-VEGF therapy and 
repress mechanisms that attempt to bypass VEGF targeted angiogenesis inhibition. 
 
d)  Rationale of combining HDAC inhibitors and bevacizumab 
 
HDAC inhibitors are known to impact several pathways related to angiogenesis. HDAC are 
enzymes responsible for regulation DNA transcription via deacetylation of the lysine tails of 
histones. As transcriptional repressors, there is increasing evidence that HDAC activity is 
altered in many cancers, including gliomas (Marks et al., 2004). Since epigenetic alterations 
in cancer cells affect virtually all cellular pathways that have been associated to 
tumorigenesis, it is not surprising that as epigenetic agents, HDAC inhibitors display 
pleiotropic activities. The anti-angiogenic properties of HDAC inhibitors have been 
associated with decreased expression of pro-angiogenic genes, such as VEGF, bFGF, 
angiopoeitin and tunica intima endothelial kinase 2 (TIE2) (Bolden et al., 2006). More 
importantly, it also has been shown to regulate HIF 1α transcriptional activity (Kim et al., 
2001; Mahon et al., 2001), which is a key factor in mediating anti-VEGF resistance. HDAC 
inhibitors can largely down-regulate HIF-1α expression in both tumor cells and endothelial 
cells. HDAC not only upregulate HIF-1α through down-regulating p53 and VHL suppressor 
gene, but also directly regulate the stability and transcription activity via interaction with 
oxygen-dependent degradation domain (ODDD) of HIF-1α (Kim et al., 2007). There is also 
evidence of HDAC inhibitor decrease chemokine receptor 4 (CXCR4) expression in human 
endothelial cells (Qian et al., 2004). HDAC inhibition also reported to resulted in impaired 
endothelial progenitor cell differentiation (Rossig et al., 2005). Resistance to bevacizumab is 
thought to be related to escape of tumor endothelium from dependency on VEGF. Glioma 
xenografts from animals treated with bevacizumab show increased expression of HIF-1 
alpha. The combination of bevacizumab and HIF-1 alpha inhibition results in better antitumor 
effect than bevacizumab alone (Rapisarda et al).  Thus combining a strategy that using 
vorinostat to inhibit HIF-1 alpha and bevacizumab to inhibit VEGF not only provided the 
potential of the independent effects of both agents but also the potential for synergy based on 
data provide above. In summary, among many anti-angiogenic effects, HDAC inhibitor is 
able to interfere with the endothelial function and down regulate most of the pro-angiogenic 
signals that contribute to evasion resistance of anti-VEGF therapy. It down regulates HIF-1α, 
the factor helps recruiting the pro-angiogenic BMDCs, and further block the 
revascularization. It may overcome the evasive resistance and improve the anti-angiogenic 
therapy. This lead us to propose the present study which aim to determine the potential of 
vorinostat, an HDAC inhibitor plus bevacizumab, versus bevacizumab alone, in an attempt to 
increase the anti-angiogenic effects of VEGF by blocking the evasive resistance by 
combination with vorinostat.   
 
e)  Rationale for dosing schedule 
 
Induction of hypoxia has been described in tumors which have been treated a variety of 
angiogenesis inhibitors (Yu et al., 2002). A study by Casanovas showed that tumor growth 
resulted in triggering of the angiogenic switch and that inhibition of this process with 
angiogenic inhibitors resulted in hypoxia (as detected by pimonidazole); however, this 
rapidly induced hypoxia  was short term and appeared to trigger the expression of several 
angiogenic factors other than VEGF; the authors suggested that persistent subtle hypoxia may 
be the factor that maintain the VEGF independent angiogenic stimulus.(Casanovas et al., 


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2005) Therefore, we hypothesize that the HIF 1 induced upregulation of other pro-angiogenic 
factors such as FGF, SDF, PDGF, PIGF and angiopoietin is largely dependent on the 
relatively transient increased upregulation of HIF 1 and likely the low level persistent 
hypoxia which can be abrogated by treatment with vorinostat. Based on these facts, we 
schedule bevacizumab infusion on day 1 and administer vorinostat on days 1- 7. Again, the 
second infusion of bevacizumab of the same cycle on day 15 will be followed by 7 days of 
vorinostat. This dosing schedule is designed to block the upstream of the cascade of evasive 
mechanism of resistance to anti-angiogenic therapy.  
 
f)  Rationale for obtaining exploratory data 
 
Identification of markers that are associated with tumor during anti angiogenic therapy alone 
or in combination with other therapies will help understand the mechanism of the resistance 
and help identified the key molecules involving this mechanism. A big challenge in 
bevacizumab therapy is lack of identified and validated biomarkers during the treatment. 
HIF1α has been found to stimulate neovascularization by producing a variety of pro-
angiogenic factors, such as VEGF, VEGFR, PDGF, FGF and angiopoetin (Calvani et al., 
2006; Holash et al., 1999; Okuyama et al., 2006). Neo-angiogenesis depends on the 
recruitment of BMDC cells, which includes endothelial progenitor cells and pericyte 
progenitor cells (Kopp et al., 2006).The most important factors in helping the recruitment of 
BMDC cells are HIF1α, SDF and VEGF (Ceradini et al., 2004; Petit et al., 2007).  To study 
these important biomarker during bevacizumab treatment, we propose to measure level of 
VEGF, PIGF, bFGF, SDF1α, angiopoeitin 1 and 2 by ELISA on cycle 1 pretreatment, cycle 1 
day 2, day 15 (pre- and post-infusion) and cycle 2 (pre-infusion) in both treatment arms, 
bevacizumab alone and bevacizumab with vorinostat. Level of circulating endothelial cells 
(CEC) and circulating endothelial progenitor cells (CEPC) will also be measured at the same 
time. 
 
MR imaging study is one of the most commonly used techniques for monitoring tumor 
growth. Analysis of MRI studies at different stages of therapy could potentially be used for 
correlation between disease prognosis and treatment response. Ultimately the goal would be 
that MRI could be used as an imaging correlate to predict the disease prognosis. To do that, 
we propose to use unique MRI sequences in addition to conventional contrast-enhanced (CE) 
MRI to evaluate the tumor response to bevacizumab with and without vorinostat. In this 
context, increased cell density, vascular proliferation and necrosis are the key features of 
higher grade malignant gliomas. Traditional CE-MRI does not adequately reflect the complex 
biology of the malignant glioma. Angiogenesis, the major mean for tumor to survival and 
proliferate, gives dilated, tortuous and hyperpermeable vessels. Anti-angiogenic therapy leads 
to decreased permeability and vascular regression. The traditional CE-MRI is dependent on 
blood brain barrier permeability to the MR contrast agent used as well as on tumor vascular 
density. Thus the amount of contrast entering the tumor decreases in the setting of 
antiangiogenic treatment regardless of changes in the tumor itself. This makes CE-MRI 
unreliable in evaluating tumor growth in the setting of anti-angiogenic therapy. This trial will 
use DCE-MRI to measure permeability, DSC-MRI measure the CBV and CBF, and DWI to 
measure the cell density with ADC maps and DTI to supplement this information. We expect 
that this will overcome the limitation of the traditional CE-MRI in evaluating the tumor 
growth. It will improve the understanding of the imaging changes related to anti-angiogenic 


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therapy and provide preliminary data to support the use of advanced MRI as a noninvasive 
tool to predict the tumor progression and disease prognosis. 
 
 
3.0 
DRUG INFORMATION 
 
3.1  
BEVACIZUMAB DRUG INFORMATION 
 
3.1.1  Drug Name: Bevacizumab or Avastin 
 
3.1.2 
Appearance: Bevacizumab is a clear to slightly opalescent, colorless to pale brown, 
sterile liquid concentrate for solution for intravenous (IV) infusion.    
 
3.1.3 
How supplied: Bevacizumab will be supplied by Genentech in 20-cc (400-mg) glass 
vials containing 16 mL bevacizumab (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. 
 
For further details, see the bevacizumab Investigator Brochure. 
 
3.1.4 
Storage and Stability: 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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.1.5 
Human Toxicity: 
 
Likely (occurring in more than 20% of patients) 


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high blood pressure 
pain  
headache 
dizziness 
hair loss 
abdominal pain  
vomiting 
loss of appetite  
constipation  
diarrhea  
sores in the mouth   
bleeding in the digestive 
system 
upset stomach 
taste disorder  
failure of the ovaries to 
produce hormones, which may 
be permanent (possible 
stopped menstrual cycle) 
weakness 
increased proteins in the urine 
(possible kidney damage)  
airway infection  
nosebleeds  
difficulty breathing  
 
Bevacizumab may likely cause low white blood cell counts.  This means that while you 
take the drug, there is more of a chance of getting an infection, including pneumonia.  
 
Common (occurring in 3-20% of patients)       
 
low blood pressure  
fatigue  
nerve damage (possible 
numbness, tingling, 
and/or burning) 
confusion 
unusual manner of 
walking 
dry skin 
shedding and scaling of 
the skin (possible fatal 
loss of bodily fluids) 
skin discoloration 
nail disorder 
fainting 
low potassium blood 
levels (possible 
weakness) 
low sodium blood levels 
(possible headache, 
confusion, seizures, and/or 
coma)  
gas  
weight loss  
nausea 
dry mouth  
inflammation of the intestines  
decreased intestinal function 
(possible vomiting, swelling, 
and/or pain)  
dehydration 
frequent urination  
strong need to urinate  
vaginal bleeding 
fever, infection, and low 
white blood cell counts 
bleeding  
high levels of bile in the blood 
muscle and/or bone pain  
teary eyes 
voice changes  
lung inflammation  
build-up in the lung tissues  
infection 
infusion reactions 
 
Bevacizumab may commonly cause low blood cell counts (red blood cells and platelets).  
You may become anemic and/or have problems with bleeding, bruising, fatigue, and/or 
shortness of breath.  You may need a blood transfusion. 
 
Bevacizumab may commonly cause blood clots.  The clots can occur in the veins or 
arteries that supply blood to the brain, heart, lungs, or other organs, which may cause 
stroke and/or heart attack. 
 
Bevacizumab may commonly cause the development of a hole through the entire 
thickness of the wall of the stomach, small intestine or large intestine, which can cause 
leakage of the contents of these organs and lead to infection. 
 


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Rare but serious (occurring in fewer than 3% of patients)       
 
heart failure 
heart attack 
chest pain due to heart 
trouble  
severe increase in blood 
pressure  
bleeding in the brain, 
causing stroke 
stroke 
bleeding in the space 
surrounding the brain 
bleeding gums  
pockets of infected fluid in 
the abdomen  
death of tissue in the 
intestines 
intestinal blockage 
vein blockage in the 
abdomen 
destruction of the jaw bone 
eye infection 
blurry vision 
kidney damage 
hole between the nostrils 
coughing up blood 
bleeding in the lung 
increased pressure in the 
blood vessel that leads to 
the lungs (possible 
shortness of breath) 
opening of a healed 
wound 
sudden, rapid loss of a 
skin graft (a patch of 
transplanted skin tissue) 
or other grafted tissue 
wound healing problems 
 
 
Bevacizumab may rarely cause brain damage (encephalopathy), including reversible 
posterior leukoencephalopathy syndrome, a medical condition related to leakiness of 
blood vessels in the brain, which can cause confusion, blindness or vision changes, 
seizure, changes in brain scans, and/or other symptoms.  Leukoencephalopathy may 
occur up to 18 months after the last dose of study drug. 
 
Bevacizumab may rarely cause an abnormal opening that develops between one area of 
the body and another (for example, an abnormal connection and opening in one or more 
places between the trachea [breathing tube] and esophagus, which may interfere with 
swallowing, digestion, and/or choking).  This may result in death. 
 
Other Information about Bevacizumab 
 
Rarely (in about 1-2% of patients), bevacizumab may cause bleeding in the brain in 
patients who have received bevacizumab for the treatment of primary brain tumors. You 
will be monitored for this complication and removed from the study if this were to occur. 
 
In most patients, blood pressure can be controlled with routine medications taken by 
mouth while bevacizumab is continued.  However, uncontrolled high blood pressure and 
high blood pressure resulting in disturbance of organ function may occur. 
 
Bevacizumab may also worsen any pre-existing heart or cerebrovascular disease 
(abnormality of the brain resulting from blood vessel problems). 
 
The impact of bevacizumab on future fertility is currently unknown.  However, it is 
possible that treatment with bevacizumab may affect fertility and decrease the likelihood 
of becoming pregnant in the future. 
 
If you are older than 65, you may have an increased risk of blood vessel problems such as 
stroke and/or heart attack. You also may have a higher chance of low white blood cell, 
low platelet counts, diarrhea, nausea, headache, and/or fatigue. 


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If you are taking Coumadin (warfarin) or other blood-thinning drugs, you may be at 
higher risk of blood clots and/or bleeding. 
 
3.1.6 
Administration:  
 
Bevacizumab 10mg/kg will be administered on day 1 and 15 intravenously on a 28 day 
cycle in both arms. Dilute bevacizumab according to the manufacturer package insert 
and/or institutional standards regarding bevacizumab storage, handling, dose preparation, 
and administration.  Administration will be as a continuous IV infusion.  Anaphylaxis 
precautions should be 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 pre-
medicated 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 pre-medicated.  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. 
 
3.1.7 
Supplier: Bevacizumab is supplied by Genentech Pharmaceuticals 
 
 
3.2 
VORINOSTAT DRUG INFORMATION 
 
3.2.1 
Drug Name: Vorinostat (Zolinza®) 
 
3.2.2 
Appearance: Vorinostat is supplied as a white, opaque gelatin, size 3 capsule, containing 
100 mg of vorinostat. 
 
3.2.3  How supplied: Vorinostat is supplied as a white, opaque gelatin, size 3 capsule, 
containing 100 mg of vorinostat. The inactive ingredients contained in each capsule are 
microcrystalline cellulose, sodium croscarmellose, and magnesium stearate. Vorinostat 
will be supplied in the marketed package (Zolinza®).  
 
3.2.4 
Storage and Stability: Vorinostat capsules should be stored at room temperature (do not 
store above 30°C) in a dry, limited-access area. Care should be taken to maintain 
acceptable storage temperature. Vorinostat capsules should not be opened or crushed and 
must be administered whole. 
 
The shelf-life of the 100 mg capsule is 2 years. 


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3.2.5 
Human Toxicity:  
 
 Likely (occurring in more than 20% of patients) 
 
fatigue 
high blood sugar 
(possible diabetes)  
diarrhea  
 
nausea  
changes in taste 
dry mouth 
weight loss  
loss of appetite  
decreased appetite  
vomiting  
difficulty breathing  
increased proteins in the 
urine (possible kidney 
damage) 
increased creatinine blood 
level (possible kidney 
problems)  
 
Vorinostat may likely cause low platelet counts. You may become anemic and/or have 
problems with bleeding, bruising, fatigue, and/or shortness of breath. You may need a 
blood transfusion if a problem with bleeding occurs. 
 
Common (occurring in 3-20% of patients)      
 
arm and/or leg swelling  
irregular heartbeat  
chills  
dizziness  
headache  
fever  
hair loss  
itching 
dehydration 
constipation 
muscle spasm 
cough 
airway infection 
blood clots in the lung 
squamous cell carcinoma 
(skin cancer) 
 
Vorinostat may commonly cause low red blood cell counts. You may become anemic, 
fatigued, and/or short of breath. You may need a blood transfusion. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rare but serious (occurring in fewer than 3% of patients)  
 


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chest pain 
blood clots in a vein  
high blood pressure 
heart attack 
stroke 
fainting 
 
swelling 
shedding and scaling of 
the skin (possible fatal 
loss of bodily fluids)  
low blood levels of 
calcium (possible 
weakness and/or 
cramping) 
low blood levels of 
sodium (possible 
headache, confusion, 
seizures, and/or coma) 
low blood levels of 
potassium (possible 
weakness) 
bleeding in the digestive 
system 
inflammation of the 
gallbladder 
blockage in the tubes 
that drain urine from the 
kidneys 
inability to urinate 
severe blood infection 
bacterial infection in the 
bloodstream 
blood vessel inflammation 
(possible fever and/or 
fatigue) 
spinal cord injury 
blurred vision 
kidney failure 
coughing up blood 
pneumonia 
infection 
tumor bleeding 
T-cell lymphoma (cancer of 
the lymph nodes) 
 
Vorinostat may rarely cause low white blood cell counts. This means that while you take 
the drug, there is more of a chance of getting an infection, including pneumonia. 
 
Vorinostat can interact with many drugs.  Be sure to tell your study doctor or nurse about 
all drugs that you are currently taking, including any over-the-counter or herbal products.  
While on study, please check with your study doctor or nurse before you start any new 
prescription drugs or over-the-counter or herbal products. 
 
3.2.6 
Administration: Vorinostat 400mg/day will be administered on day 1 to 7 and day 15 to 
21 orally on a 28 day cycle in the arm with combination of vorinostat and bevacizumab.  
 
Vorinostat will be administered orally. Vorinostat capsules should not be opened or 
crushed and must be administered whole. It is recommended that Vorinostat be 
administered with food, but not high fat meal. A pill count will be performed at each 
clinic visit to ensure that the medication is taken appropriately. 
 
Special Handling Requirements: Vorinostat is an anticancer drug. Spills of powder from 
vorinostat capsules due to damaged or broken capsules should be cleaned up carefully to 
minimize inhalation of vorinostat. The affected area must be washed at least 3 times with 
ethyl alcohol, followed by water. Direct contact of the powder in vorinostat capsules with 
the skin or mucous membranes should be avoided. If such contact occurs, wash 
thoroughly. Vorinostat capsules should be stored at room temperature (do not store above 
30°C) in a dry, limited-access area. Care should be taken to maintain acceptable storage 
temperature. Vorinostat capsules should not be opened or crushed and must be 
administered whole.  
 
For further details and molecule characterization, see the vorinostat Investigator 
Brochure. 
 
3.2.7 
Supplier: Vorinostat is supplied by Merck, Sharp and Dohme Corp. 
 


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3.3 
Study Agent Distribution (for the Phase II Multi-Center component):  
 
3.3.1 
Ordering Study Agent/s:  
 
Bevacizumab and vorinostat may be requested by the Principal Investigator (or their 
authorized designees) at each participating institution.   
All regulatory document requirements (including a Pharmacy Initiation Worksheet), as 
described in the BTTC Operations Manual, must be current and up to date in the BTTC 
Coordinating Center. The participating institution must have received an Activation 
memo from the OMCR prior to requesting study agents.  A Study Drug Order form and 
Pharmacy Initiation Worksheet will be provided to the sites by OMCR. 
 
Signed and Dated Drug requests should be emailed to: 
Uintavision 
Attn: Michelle DuBois 
Email: mdubois@uintavision.com 
 
When a number of investigators are participating on a clinical study at the same 
institution, one investigator should be considered or designated the principal or lead 
investigator under whom all investigational agents for that protocol should be ordered.  
 
3.3.2 
Agent Storage and Accountability:  
 
 
The investigator is responsible for the proper and secure physical storage and 
 
record keeping of investigational agents received for BTTC protocols. 
 
Specifically, the investigator must:   
 
 
Maintain a careful record of the receipt, use and final disposition of all 
 
investigational agents received, using the NCI Agent Accountability Record 
 
Form (DARF), http://ctep.cancer.gov/forms/index.html.   
 
 
Store the agent in a secure location, accessible to only authorized personnel, 
 
preferably in the pharmacy. 
 
  
Maintain appropriate storage of the investigational agent to ensure the stability 
 
and integrity of the agent. 
 
  
Return or destroy any unused investigational agents at the completion of the 
 
study or upon notification that an agent is being withdrawn. 
 
The intent of the agent accountability procedures described in this section is to assist the 
investigator in making certain that agents received from BTTC are used only for patients 
entered onto an approved protocol. The record keeping described in this section is 
required under FDA regulation. Investigators are responsible for the use of 
investigational agents shipped in their name. Even if a pharmacist or chemotherapy nurse 
has the actual task of handling these agents upon receipt, the investigator is the 
responsible individual and has agreed to accept this responsibility by signing the FDA 
1572, http://www.fda.gov/opacom/morechoices/fdaforms/FDA-1572.doc. 
 
3.3.3 
Returning or destroying unused and/or defective Agent:  
 


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Investigators/Designees should make every effort to minimize the amount of 
agent ordered and returned unused, (e.g. limit inventories to an 8 week supply or 
less). The BTTC Operations Manual describes a generic Policy for returning or 
destroying supplied study agents. Procedures specific to this study are described 
here.  
 
Agent Return/Destruction Procedure  
 
All unused or expired investigational drug should be destroyed in accordance with the 
local institutional policies and procedures. The on site destruction of unused or expired 
product should be documented in the DARF, and forwarded to BTTC Coordinating 
center which in turn will notify Genentech and Merck Sharp and Dohme along with 
documentation of lot numbers and number of vials destroyed.  
 
Destroy opened, partially used or unused vials/bottles. Do NOT return opened or 
partially used vials/bottles unless specifically requested otherwise in the protocol.  
 
 
4.0 
ELIGIBILITY CRITERIA 
 
Subject Selection 
 
This study was designed to include women and minorities, but was not designed to measure 
differences of intervention effects.  Males and females will be recruited with no preference to 
gender.  No exclusion to this study will be based on race.  Minorities will actively be recruited to 
participate. 
 
All patients who meet the following eligibility criteria must be registered with the Brain Tumor 
Trials Collaborative via the Office of Multicenter Clinical Research (MD ANDERSON 
CANCER CENTER OMCR) at the University of Texas, MD Anderson Cancer Center prior to 
receiving treatment with study drug.  The OMCR’s registration procedures are described in the 
Multicenter Procedures section of this protocol. Patients must initiate study treatment within 
96 hours after registration. 
 
Inclusion Criteria  
 
Patients will be included in the study based on the following criteria. 
4.1  
Patients must have histologically proven glioblastoma, gliosarcoma or anaplastic glioma 
to be eligible for the Phase I component of this protocol. Anaplastic gliomas include 
anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), anaplastic mixed 
oligoastrocytoma (AMO), or malignant glioma NOS (not otherwise specified). Patients 
will be eligible if the original histology was low-grade glioma and a subsequent 
histological diagnosis of a malignant glioma is made. Only patients with histologically 
proven or imaging proven recurrent glioblastoma or gliosarcoma will be eligible for the 
Phase II component. Wafer acceptable if recurrence is confirmed. 


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4.2 
All patients must sign an informed consent indicating their awareness of the 
investigational nature of this study. Patients must have signed an authorization for the 
release of their protected health information.  
 
4.3 
Patients must be 18 years old or older. 
 
4.4 
Patients must have a Karnofsky performance status (KPS) equal or greater than 60 (See 
Appendix  18.2). 
 
4.5 
At the time of registration:   
4.5.1  Patients must have recovered from the toxic effects of prior therapy to < grade 2 
toxicity per CTC version 4 (except deep vein thrombosis – see section 6.1.4  
 
28 days from any investigational agent, 
 
4 weeks (28 days) from prior cytotoxic therapy, 
 
2 weeks (14 days) from vincristine,  
 
6 weeks (42 days) from nitrosoureas,  
 
3 weeks (21 days) from procarbazine administration,  
 
>1 week (7 days) for non-cytotoxic agents, e.g., interferon, tamoxifen, 
thalidomide, cis-retinoic acid, etc. (radiosensitizer does not count).   
4.5.2  Patients who receive anticancer agents for non-therapeutic purposes unrelated to 
this study (such as presurgically for obtaining pharmacology data for the agent) 
will be eligible to enter the study provided they have recovered from the toxic 
effects of the agent if any. Any questions related to the definition of non-
cytotoxic agents should be directed to the Study Chair. 
 
4.6 
Patients must have adequate bone marrow function (ANC > 1,500/mm3, platelet count of 
> 100,000/mm3), adequate liver function (SGPT < 3 times upper limit normal and 
alkaline phosphatase < 2 times upper limit normal, total bilirubin < 1.5mg/dl, “Patients 
with high bilirubin levels related to known diagnosis of benign hyperbilirubinemia 
(Gilbert’s syndrome) will be eligible “., and adequate renal function (BUN < 1.5 times 
institutional normal and Creatinine < 1.5 mg/dl) prior to registration.  These tests must be 
performed within 14 days prior to registration.   
 
4.7 
Patients must have shown unequivocal evidence for tumor progression as determined by 
an MRI scan done prior to study entry which will be reviewed by the treating physician to 
confirm and document recurrence.   
         . Patients with prior therapy that included interstitial brachytherapy or stereotactic 
radiosurgery must have confirmation of true progressive disease rather than radiation 
necrosis using the local institutional standards for such determination including advanced 
imaging or surgery.  .  
 
4.8  
The baseline on-study MRI scan should be performed within 14 days (+ 3 working days) 
prior to registration but before starting treatment and on a steroid dose that has been 
stable or decreasing for at least 5 days. If the steroid dose is increased between the date of 
imaging and registration (or at that time), a new baseline MRI is required. The same type 
of scan, i.e., MRI must be used throughout the period of protocol treatment for tumor 
measurement. 


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4.9  
Patients having undergone recent resection of recurrent or progressive tumor will be 
eligible as long as all of the following conditions apply: 
 
a) 
At least 4 weeks (28 days ) have elapsed from the date of surgery and the patients 
have recovered from the effects of surgery.  
 
b) 
Evaluable or measureable disease following resection of recurrent Malignant 
Glioma is not mandated for eligibility into the study.  
 
c) 
To best assess the extent of residual disease post-operatively, a MRI should be 
done no later than 96 hours in the immediate post-operative period or at least 4 
weeks post-operatively, within 14 days prior to registration.  If the 96-hour scan 
is more than 14 days before registration, the scan needs to be repeated.  If the 
steroid dose is increased between the date of imaging and registration, a new 
baseline MRI is required on a stable steroid dosage for at least 5 days. 
 
4.10 
Patients must have failed prior radiation therapy and must have an interval of greater than 
or equal to 12 weeks (84 days) from the completion of radiation therapy to study entry 
except if there is unequivocal evidence for tumor recurrence (such as histological 
confirmation or advanced imaging data such as PET scan) in which case at least 4 weeks 
(28 days) from completion of radiation therapy will suffice (Note: for patients who have 
undergone surgery to confirm recurrence after radiation therapy, guidelines in 4.9a 
should be followed). 
 
4.11 
Patients with prior therapy that included interstitial brachytherapy or stereotactic 
radiosurgery must have confirmation of true progressive disease rather than radiation 
necrosis based upon either PET or Thallium scanning, MR spectroscopy or 
surgical/pathological documentation of disease. 
 
4.12 
Women of childbearing potential must have a negative B-HCG pregnancy test 
documented within 14 days prior to registration. Women of childbearing potential must 
not be pregnant, must not be breast-feeding, and must practice adequate contraception 
(please refer to Appendix  18.11 for details and definitions – woman of childbearing 
potential; adequate methods of contraception) for the duration of the study, and for 30 
days after the last dose of study medication. Patients must not be pregnant because 
animal studies show that bevacizumab and Vorinostat are teratogenic. 
 
4.13 
Male patients on treatment with Vorinostat must agree to use an adequate method of 
contraception for the duration of the study, and for 30 days after the last dose of study 
medication (please refer to Appendix 18.11 for definition of adequate methods of 
contraception).  
 
4.14 
Patient must be able to tolerate the procedures required in this study including periodic 
blood sampling, study related assessments, and management at the treating institution for 
the duration of the study. 
 


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4.15 
Patients receiving treatment with any antiepileptic medications except Valproic acid 
(because of its HDAC inhibitory activity) can be included in the study.  Vorinostat is not 
metabolized by Cytochrome P450 3A4 (CYP 3A4); however, Vorinostat may potentially 
suppress CYP 3A4 activity. Therefore, patients should preferably be treated with non-
enzyme inducing anti-epileptic medications although this is not mandatory. If enzyme-
inducing antiepileptic drugs are used, monitoring of these drug levels should be 
considered, as considered clinically appropriate by the treating physician (See Appendix 
18.3). 
 
4.16. 
For the Phase II portion of the study, patients may have had treatment for no more than 2 
prior relapses.  There is no limit to the number of relapses for the phase I portion of the 
study provided the functional status and other eligibility criteria for enrollment are met. 
Relapse is defined as progression following initial therapy (i.e. radiation+/- chemo if that 
was used as initial therapy).  The intent therefore is that patients had no more than 3 prior 
therapies (initial and treatment for 2 relapses). If the patient had a surgical resection for 
relapsed disease and no anti-cancer therapy was instituted for up to 12 weeks, and the 
patient undergoes another surgical resection, this is considered as 1 relapse.  For patients 
who had prior therapy for a low-grade glioma, the surgical diagnosis of a high-grade 
glioma will be considered the first relapse 
 
General Exclusion Criteria 
 
4.17  Inability to comply with protocol or study procedures (for example, an inability to 
swallow tablets). 
 
4.18  
Prior treatment with bevacizumab or Vorinostat. 
 
4.19  
Patients receiving valproic acid (VPA), an anticonvulsant drug with HDAC inhibitor 
properties, will be excluded, unless they are switched to an alternative agent prior to 
treatment initiation. A 5-day wash out period is required. Patients who have failed prior 
treatment with other histone deacetylase inhibitors will be excluded. 
 
4.20 
Any serious medical condition, laboratory abnormality, or psychiatric illness that would 
prevent the subject from providing informed consent.  
 
4.21  
Any condition, including the presence of clinically significant laboratory abnormalities, 
which places the patient at unacceptable risk if he/she were to participate in the study or 
confounds the ability to interpret data from the study. These would include 
 
a) Active infection (including persistent fever) including known AIDS or Hepatitis C 
infection 
 
b) Diseases or conditions that obscure toxicity or dangerously alter drug metabolism   
 
c) Serious intercurrent medical illness (e.g. symptomatic congestive heart failure).  
 
4.22  
Current, recent (within 4 weeks (28 days) of the first infusion of this study, or planned 
participation in an experimental antitumor drug study (other than the current one). 


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4.23  
Patients with a history of any other cancer (except non-melanoma skin cancer or 
carcinoma in-situ of the cervix or bladder), unless in complete remission and off of all 
therapy for that disease for a minimum of 3 years are ineligible. 
 
4.24    Patients with spinal disease (metastasis) and/or leptomeningeal disease will not be allowed 
in the study. 
 
 
Bevacizumab-Specific Exclusion Criteria 
 
4.25  
Inadequately controlled hypertension (defined as systolic blood pressure > 140 mmHg 
and/or diastolic blood pressure > 90 mmHg). 
 
4.26  
Prior history of hypertensive encephalopathy. 
 
4.27  
New York Heart Association (NYHA) Grade II or greater congestive heart failure (see 
Appendix 18.9). 
 
4.28  
History of myocardial infarction or unstable angina within 6 months prior to Day 1. 
 
4.29   History of stroke or transient ischemic attack within 6 months prior to Day1. 
 
4.30  
Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent 
peripheral arterial thrombosis) within 6 months prior to Day 1. 
 
4.31  
History of hemoptysis ( 1/2 teaspoon of bright red blood per episode) within 1 month 
prior to Day 1. 
 
4.32  
Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic 
anticoagulation). 
 
4.33  
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.  “Patients with recent resection will be eligible for entry into the surgical arm 
of the study but will follow guidelines as in section 4.9”.  
 
4.34  
Core biopsy or other minor surgical procedure, excluding placement of a vascular access 
device, within 7 days prior to Day 1. 
 
4.35  
History of abdominal fistula or gastrointestinal perforation within 6 months prior to Day 
1. 
 
4.36  
Serious, non-healing wound, active ulcer, or untreated bone fracture. 
 
4.37  
Proteinuria as demonstrated by: 
 
Urine protein: creatinine (UPC) ratio   1.0 (Appendix 18.10) at screening OR  
 


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 
Urine dipstick for proteinuria ≥ 2+ (patients discovered to have ≥2+ proteinuria on 
dipstick urinalysis at baseline should undergo a 24 hour urine collection and must 
demonstrate ≤ 1g of protein in 24 hours to be eligible). 
 
4.38  
Known hypersensitivity to any component of bevacizumab. 
 
4.39  
Pregnancy (positive pregnancy test) or lactation. Use of effective means of contraception 
(men and women) in subjects of child-bearing potential is required for study treatment. 
 
 
5.0 
STRATIFICATION/DESCRIPTIVE FACTORS 
 
See section 11.0 Statistical Considerations. 
 
 
6.0 
TREATMENT PLAN 
 
6.1 
General 
 
All patients who meet eligibility criteria must be registered with the Brain Tumor Trials 
Collaborative Office of Multicenter Clinical Research (MD ANDERSON CANCER CENTER 
OMCR) at the University of Texas, MD Anderson Cancer Center (UT MD ANDERSON 
CANCER CENTER).  Patients must initiate study treatment within 96 hours after registration. 
 
6.1.1 
Patients will be monitored for hematologic or serologic evidence of myelosuppression, 
hepatic injury, renal injury, and electrolyte disturbances and for clinical evidence of other 
toxicity as is described in section 8.0. 
 
6.1.2 
G-CSF Administration 
 
G-CSF and erythropoietin administration: Routine prophylactic use is not permitted. 
However, therapeutic use in patients with complications (severe neutropenia with fever or 
anemia), may be considered at the investigator’s discretion. 
 
6.1.3 
Supportive Care 
 
a. Corticosteroids should be used in the smallest dose to control symptoms of cerebral 
edema and mass effect, and discontinued if possible. 
 
b. Anti-seizure medications should be used as indicated. Treatment with valproic acid is 
not allowed. Patients should preferably be treated with non-enzyme inducing 
antiepileptic medications to avoid any potential interactions with vorinostat. For 
patients on treatment with enzyme-inducing antiepileptic drugs, clinically relevant 
monitoring of drug levels is recommended, as considered appropriate by the treating 
physician 
 
c. Febrile neutropenia may be managed according to the local institution's Infectious 
Disease guidelines.  Measures may include appropriate laboratory testing, including 


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blood and urine cultures and the institution of broad-spectrum antibiotics.  If a source 
for the fever is not identified or the fever resolves when the neutrophil count 
recovers, antibiotics may be discontinued and the patient observed. 
 
d.  Antiemetics: prophylactic and therapeutic use is allowed. 
 
e. Other Concomitant Medications 
 
Therapies considered necessary for the well-being of the patient may be given at the 
discretion of the treating physician. All concomitant medications must be recorded. 
 
f. Other Anticancer or Experimental Therapies 
 
No other anticancer therapy (including chemotherapy, radiation, hormonal treatment 
or immunotherapy) of any kind is permitted during the study period. No other 
antitumor drugs under investigation may be used concomitantly with the study drug. 
 
g. Surgery 
 
If neurosurgical management is required for reasons not due to tumor progression, 
these procedures must be documented, including the indications for surgery, the 
surgical operative note and pathology report. 
 
6.1.4  Definition of dose limiting toxicities (DLT) (Phase I portion) 
 
All patients in the phase I study will be evaluable for assessment of toxicity in order to 
define DLT.  Toxicities will be graded according to the Common Terminology Criteria 
for Adverse events (CTCAE) Version 4.0.  If multiple toxicities are seen, the presence of 
DLT should be based on the most severe toxicity experienced. DLT will be defined as 
any of the following events occurring in the first cycle of treatment (4 weeks) and 
attributable to the study drugs: 
 
Any grade 4 hematological toxicity except neutropenia and thrombocytopenia, as 
indicated below 
-  
febrile neutropenia defined as grade 3-4 neutropenia with fever ≥38.5ºC and/or 
infection requiring antibiotic or antifungal treatment OR any grade 4 neutropenia 
lasting 5 days or more is considered a DLT 
-  
Grade 4 thrombocytopenia OR platelet count <25,000/ul of any duration is 
considered a DLT; 
 
 
Any non-hematologic grade 3 or 4 toxicity, except the following   
– 
nausea or vomiting that responds to symptomatic therapy 
-  
fatigue that responds to symptomatic therapy  
-  
alopecia 
-  
lymphopenia,  
-  
weight gain (in patients on steroids),  
-  
venous thromboembolic disease*.  


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-  
In case of isolated laboratory abnormalities that may not reach clinical 
significance, a determination will be made in consultation with the IRB on a case 
by case basis to determine if DLT needs to be declared.  
 
 
Failure to recover from treatment related toxicities to be eligible for re-treatment 
within 4 weeks of the last dose of the drugs.   
 
*Non-Relevant Toxicities for Brain Tumor Protocols 
 
Lymphopenia is a common finding among patients with primary brain tumors and is 
directly attributable to concurrent use of corticosteroids.  To date, even Grade III 
lymphopenia has not been associated with a worsening of clinical outcome.  Therefore, 
we will not consider this parameter in the determination of optimal dosing of drugs. 
 
Weight gain is a common finding among patients with primary brain tumors.  This too is 
directly attributed to the concurrent use of corticosteroids. Doses of steroids or study 
agents will not be modified as a consequence of weight gain.  Corticosteroid dosage will 
be based on maintenance of control of edema in the brain and the standard clinical 
practice to use the minimal effective dose of corticosteroids will be employed. 
 
Alopecia is a common occurrence in patients with brain tumors as a consequence of 
cranial radiotherapy.  Alopecia will not be recorded or graded as toxicity. 
 
Venous thromboembolic disease is a common complication occurring in up to 30% of 
patients with malignant gliomas (Wen and Marks, 2002; Semrad et al., 2006). In this 
study, patients who develop deep vein thrombosis may receive anticoagulation and 
resume therapy once they are stable on anticoagulation. Grade III deep vein thrombosis 
will not be considered a DLT for the phase I portion. 
 
 
The routine use of filgrastim or other white cell growth factors is not permitted during 
cycle 1 of the Phase I portion unless clinically indicated (see section 6.1.2), but it may be 
used beyond this period or once the assessment of DLT has been completed.   
 
6.2 
Phase I Treatment Plan 
The Phase I study has been completed in MDACC. The Phase II dose has been determined.  Brief 
details of the phase I study are included in this section to indicate the doses explored and the final 
phase II dose identified.  
 
6.2.1 
Drug Dose/s: 
 
In this component, the combination treatment arm was tested and several dose levels 
planned.. The starting dose was bevacizumab 10mg/kg administered on day 1 and 15 
intravenously and vorinostat at 400 mg/day orally on days 1 to 7 and days 15 to 21.  This 
dose of vorinostat is also the recommended dose for combination trials based on other 
ongoing studies.     
 
 


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6.2.2 
Dose Escalations and definition of maximum tolerated dose (MTD): 
 
A conventional Phase 1 design was used with 3 patients enrolled into level 0 and 
monitored for 4 weeks. Dose-limiting toxicity was as defined in section 6.1.4.  If no DLT 
was seen in the first cohort, the next 3 patients would be enrolled to level 1. If no DLT 
was noticed after dose escalation to level 1, this dose was to be used for Phase II 
component of the study. If 1/3 of the patients experience DLT, the cohort was to be 
expanded to 3 more patients; if 1/6 patients experience DLT, the MTD was to be 
considered reached and this dose would be used for the phase II part of the study. If 2/6 
patients experience DLT, the MTD was considered exceeded and the previous dosage 
level would be declared as MTD of vorinostat in combination of bevacizumab. 
 
6.2.3 
Results of the Phase I Study 
 
The Phase I study enrolled 3 patients in the first cohort at 400 mg/daily of vorinostat and 
10 mg/kg of bevacizumab. One patient experienced a grade 3 ALT elevation and grade 3 
hyperglycemia which were designated as possibly related to vorinostat – these toxicities 
constituted a DLT for this dose level.  The cohort was hence expanded by 3 more 
patients. None of these patients experienced a DLT in the first cycle.  Per protocol 
guidelines as noted in section 6.2.2, given that 1/6 patients experienced DLT at the 
starting dose level and because this dose level was also the recommended dose for 
combination studies based on other ongoing trials, the starting dose level of bevacizumab 
and vorinostat was declared the Phase II dose.        
 
6.3 
Phase II Treatment Plan 
 
6.3.1 
Drug Dose/s: 
 
The dose for phase II study of the combination has been identified as follows: 
bevacizumab 10mg/kg administered on day 1 and 15 intravenously and vorinostat at 400 
mg/day orally on days 1 to 7 and days 15 to 21. On cycle 1 day 1, vorinostat should be 
taken prior to the bevacizumab infusion. 
 
6.3.2  Non- Surgical Arm: 
 
In this component, patients will be randomized between two competing treatment arms: 
Vorinostat + bevacizumab versus bevacizumab alone using an adaptive randomization 
design (see Statistical Section). The dosage for the vorinostat + bevacizumab arm as 
derived from the MTD of the combination determined in the phase I component of the 
study is as described in section 6.3.1. The treatment schedule will be identical to that 
described above in the phase I component, with each course comprising 28 days. Patients 
will continue treatment until tumor progression or unacceptable toxicity occurs. 
 
6.3.3 
Surgical Arm:  
 
Patients who need a surgical resection for their recurrent tumors are eligible for this part 
of the study. These patients will be primarily accrued in MD Anderson Cancer Center. 


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Other interested sites may participate on the surgical arm provided  there are available 
local resources for appropriate sample collection and shipment. This will be decided on 
an institution specific manner after discussion with the Study Chair. Such participating 
institutions are expected to ensure that participation of such subjects as well as shipment 
of tissue to MDACC are in compliance with institutional and federal human subjects 
protection guidelines. Based on prior experience with such accrual it is anticipated that no 
more than 10 patients will be accrued into this portion of the study. Tumor tissue from 
the resection will be sent for qRT-PCR assessment of a prognostic 9 gene profile (Aldape 
and Colman, unpublished data). This profile distinguishes between an angiogenic (poor 
prognosis) mesenchymal group and a proneural (good prognosis) group. We hypothesize 
that the current treatment can modify the poor prognosis of the mesenchymal subgroup 
and improve their PFS and OS; this will be preliminarily tested in this study. Patients on 
this arm will be eligible after surgery to be randomized to two treatment arms (as 
described above in section 6.3.2) using a Bayesian adaptive algorithm after a 4 week  
recovery period. PFS in patients in the surgical arm will be determined from the date of 
randomized to the treatment arms and not from the date of registration in the trial. Tissue 
will also be collected from all patients (including from the nonsurgical arm) from their 
original or most recent resection for this assessment.  
 
6.3.3.1 Pre and Post-operative evaluations as a result of this part of the study will consist of 
history and physical examination, laboratory studies, baseline toxicity assessments and 
postsurgical symptoms assessment as described in sections 7.0 and 8.0.  
 
6.3.3.2 Once patients have recovered from the effects of surgery, they will embark upon the 
phase II component of the study.  Patients are not required to have residual disease to 
continue onto the phase II component. 
 
6.3.3.3 Following surgery, a MRI scan should be done no later than 96 hours after surgery; given 
that patients are required to be at least 4 weeks after surgery to begin treatment in the 
adaptive randomized portion of the trial, the MRI should be repeated prior to initiation of 
treatment and on a steroid dose that is stable or decreasing. Treatment with bevacizumab 
or bevacizumab+vorinostat post-operatively should start no later than 14 days after the 
scan.  
 
6.4 
Dose Modifications:  
 
Treatment cycles are 28 days (+3 days if needed for scheduling around holidays); treatment will 
be continued if there is no tumor progression and patients recovered from treatment-related 
adverse events associated with the prior cycle. Recovery has occurred once all the following 
conditions have been met: 
 
1. ANC > 1000/ml; 
2. Platelet > 100,000/ml;  
3. All drug associated non- hematological toxicity have recovered to grade 0 or 1 (except for 
DVT as below).  
 
If recovery has not occurred by Day 28 (+ 3 days), the subsequent cycle will be delayed until 
these criteria have been met. If the patient has not recovered within 4 weeks of rest, he/she will be 


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taken off  treatment However, if the patient develops a lower extremity deep venous thrombosis 
and requires anticoagulation or intervention (grade 3 toxicity), treatment may be restarted after a 
2 week rest period if the patient is stably anticoagulated and is judged medically stable to begin 
chemotherapy, in the opinion of the treating physician. (Please note: DVT is graded in the CTC 
version 4.0 as grade 1= superficial thrombosis, grade 2= DVT, medical intervention indicated, 
grade 3= uncomplicated pulmonary embolism, medical intervention indicated, grade 4=life-
threatening pulmonary embolism, cerebrovascular event, arterial insufficiency, urgent 
intervention indicated). 
 
The dose of Vorinostat will be initiated at MTD dose from the phase I part of the trial. The same 
dose will be continued unless > or = grade 3 drug related toxicity occurs; treatment will be held 
until toxicity resolves to less than grade 2.  The dose for next cycle will be reduced to one level 
below the dose that caused the grade 3 toxicity. If grade 3 toxicity occurs again at lower dose, the 
dose will be further reduced to the next lower level. A maximum of 2 dose reductions will be 
allowed for vorinostat. 
 
 
There is no dose reduction for bevacizumab. If any drug related adverse event occurs that 
necessitate holding bevacizumab, the dose will remain unchanged once treatment resumes. The 
maximum allowable length of treatment interruption is 4 weeks. 
  
6.4.1 
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 provided 
these events do not require discontinuation of the agent (Table 1). 
 
 
Any toxicity 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. Blood pressure should be checked prior to each bevacizumab infusion and 
standard practice guidelines followed for determining initiation and continued 
infusion of Bevacizumab If resting systolic blood pressure is >140 and or resting 
diastolic blood pressure >90 mmHg on two separate measurements at least 5 minutes 
apart, Bevacizumab should be deferred until the hypertension is managed with 
appropriate antihypertensive medication.  Treatment may be initiated once the criteria for 
blood pressure outlined above are met. If unmanageable toxicity including events such as 
medically uncontrolled hypertension or hypertensive encephalopathy 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 v. 4.0 Grade 3 or 4 allergic reaction / hypersensitivity, adult respiratory distress 


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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 
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 study drug treatment, the maximum allowable length 
of treatment interruption is 4 weeks. 
 
 
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 140/90 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. 


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Grade 4  
non-pulmonary or  
non-CNS hemorrhage 
 
Discontinue bevacizumab. 
Grade 1 pulmonary 
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.as clinically 
determined 
 
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. 
 
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 study drug treatment.  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. 


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Proteinuria 
 
No dose modifications for grade 1/2 events 
 
Grade 3 
(UPC> 3.5, urine 
collection > 3.5 g/24 
hr)   
 
Hold bevacizumab treatment until  Grade 2, as determined by either 
UPC ratio ≤ 3.5 or 24 hr collection ≤ 3.5 g 
 
 
Grade 4 (nephritic 
syndrome) 
 
Discontinue bevacizumab 
GI Perforation 
Discontinue bevacizumab. 
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. 
 
 


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6.4.2 
Vorinostat Dose Modification and Toxicity Management 
 
Vorinostat will be administered from day 1 to day 7 and day 15 to day 21 in each 28-day 
cycle in arm receiving vorinostat and bevacizumab. Treatment will be initiated at the 
MTD dose determined in the phase I component of the trial. This dose will be maintained 
as long as there are no vorinostat related toxicities > grade 2. For grade 2 vorinostat 
related toxicities, treatment will be withheld and the patients will be monitored until 
toxicities resolve to < grade 2 (except for deep venous thrombosis as noted in section 
5.3). For subsequent treatment the dose will be unchanged provided the recovery occurs 
within 2 weeks of treatment hold; if it is longer than 2 weeks, the next cycle will be at 
one dose level below the one that caused the toxicity. If there is grade 3 or greater non-
hematologic toxicity, a minimum of 2-week rest period will be required. Subsequently, 
patients will restart treatment at one dose level less than the one that resulted in the 
toxicity as indicated below after the toxicities resolve to < grade 2 (except for deep 
venous thrombosis as noted in section  6.4). 
 
 
 
Dose adjustments for the subsequent cycles: dose will be one level below the dose that 
produced toxicity of grade 3 or greater per dose schedule changes indicated below. If 
grade 3 or 4 toxicity recurs, patients will again discontinue the vorinostat until toxicity 
returns to grade 1 or less. The estimated dose levels below are shown for various MTD 
that may be determined in the phase I study. 
 
Dose Level 
-2 
-1 
0 
Drug: Vorinostat 
N/A 
100 mg/day 
200 mg/day 
 
100 mg/day 
200 mg/day 
300 mg/day 
 
200 mg/day 
300 mg/day 
400 mg/day 
 
300 mg/day 
400 mg/day 
500 mg/day 
 
Only 2 dose reductions of vorinostat are permitted as above. If the patient experiences 
grade 3 or greater toxicity after 2 dose reductions, he/she will be taken off   treatment. If 
starting dose is 200 mg once daily, only 1 dose reduction of vorinostat is allowed.  
 
Regardless of the reason for holding study drug treatment, the maximum allowable length 
of treatment interruption is 4 weeks after which the patient will be taken off the study. 
 
6.5 
CONCOMITANT ASPIRIN 
 
 
Low-dose aspirin (≤ 325 mg/d) may be continued in subjects at higher risk for arterial 
thromboembolic disease. Subjects developing signs of arterial ischemia or bleeding on study 
should be evaluated for possible bevacizumab discontinuation per Table 1, Bevacizumab Dose 
Management Due To Adverse Events. 
 
6.6 
For treatment or dose modification related questions, please contact the Study Chair or the MD 
ANDERSON CANCER CENTER OMCR at UT MD ANDERSON CANCER CENTER at (713) 
792-8519 or OMCR_BTTC@mdanderson.org. 
 
 
 


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7.0 
PRETREATMENT EVALUATION 
 
General Requirements 
 
7.1 
A complete history and physical (including baseline blood pressure measurement) and 
neurological examination (include documentation of the patients height, weight and 
Karnofsky Performance Status), as well as documentation of measurable and/or evaluable 
disease shall be performed on all patients within 14 calendar days (+ 3 working days) of 
study entry.   
 
7.2 
The treating physician will review a contrast enhanced MRI scan done prior to study 
entry documenting progression. For non-surgical arm patients, a baseline scan should be 
performed within 14 calendar days (+ 3 working days) of registration, with day 
0=registration date. The baseline on-study MRI should be performed on a steroid dosage 
that has been stable or decreasing for at least 5 days. If the steroid dose is increased 
between the date of imaging and the initiation of therapy (or at that time), a new baseline 
MRI is required.  
 
7.3  
Baseline pre and post contrast MRI scan (with T1, T2, DWI, and T2 FLAIR images 
sequences and when feasible, T2* and DTI sequences) will be done in all patients within 
14 days of entry into the study.  Optional studies including dynamic contrast enhanced 
(DCE) and dynamic susceptibility contrast (DSC) are preferred if individual sites can 
obtain the same but are not required. If DCE/DSC sequences can be obtained, it is 
important to obtain them at baseline and at each imaging follow-up.   
7.4 
Pre-treatment laboratory tests will include CBC, differential, platelets, , total protein, 
albumin, calcium, , , glucose, BUN, creatinine, sodium, potassium,  total bilirubin, 
alkaline phosphatase, LDH, SGPT (ALT), SGOT (AST), Urine protein: Creatinine ratio 
or urine dipstick and a pregnancy test for women of child bearing potential. PT, PTT, 
INR, phosphorus, magnesium and uric acid will be done at the discretion of the treating 
physician.  Blood tests must be performed within 14 calendar days (+ 3 working days) of 
registration, with day 0 = registration date. Pregnancy test must be obtained 14 calendar 
days (+ 3 working days) of registration before treatment starts. Patient’s whose clinical 
condition has significantly changed between the time of these tests and the initiation of 
treatment in the judgment of the treating physician, will have a repeat chemistry panel 
prior to the start of treatment.  
7.5  
About 5 cc blood samples will be collected for testing levels of biomarkers including 
VEGF, PIGF, bFGF, SDF1 α, angiopoietin 1 and 2, at baseline before treatment in those 
patients that have consented to the optional procedures.  
 
7.6  
About 7 cc of blood for isolation of peripheral blood monocytes will be collected for 
circulating endothelial cells (CEC) and circulating endothelial progenitor cells (CEPC) 
analysis at baseline before starting treatment in those patients that have consented to the 
optional procedures.. 
 
7.7  
If available, unstained paraffin tissue from surgical samples will be obtained. A 
representative paraffin tissue block (at least 5 mm x 5 mm) will be obtained from recent 
surgery to confirm the recurrence and original surgery, before entry into the clinical trial. 


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The tissue will be used to test the 9 gene signature expression profile using qRT-PCR. 
These will be correlated with response.  
           
7.8  
Documentation of tumor diagnosis by pathology report from the patient’s initial or most 
recent surgery or biopsy 
  
 
7.9 
(*) Patients will complete a baseline MD Anderson Symptom Inventory-Brain Tumor 
Module (MDASI-BT) (Appendix 18.12) after registration but before initiating treatment 
on the clinical trial (*). The MDASI-BT will be completed only by the patient, unless 
changes in vision or weakness make this difficult. If this occurs, then the caregiver or 
research assistant may read the questions to the patient or assist with marking the severity 
number or score as described by the patient. A patient caregiver may complete the 
questionnaires as a patient-preference proxy if the patient’s deficits preclude self report. 
 
* Note: 7.9 is an optional procedure, and will be obtained if the patient gives his or her informed 
consent. 
 
 
8.0 
EVALUATIONS DURING STUDY 
 
General Requirements 
 
8.1  
Blood pressure monitoring every 2 weeks prior to bevacizumab infusion. 
 
8.2  
 Proteinuria will be monitored by urine protein: creatinine (UPC) ratio or dipstick every 2 
weeks in the first cycle then prior to every subsequent cycle.  
 
8.3 
CBC, differential and platelets will be performed every two weeks (± 3 days) during 
treatment and prior to each new cycle. In addition, all patients will have the following 
tests every  4 weeks (± 3 days) prior to each new cycle if no significant toxicities are 
noted: total protein, albumin, calcium, glucose, BUN, creatinine, sodium, potassium, total 
bilirubin, alkaline phosphatase, LDH, SGPT, SGOT, urine protein: creatinine. Patients 
may also be evaluated with labs at any time clinically indicated.  PT, PTT, INR, 
phosphorus, magnesium, and uric acid will be done at the discretion of the treating 
physician. 
 
8.4 
A pre and post contrast MRI scan (with T1, T2, DWI, and T2 FLAIR images sequences 
and when feasible, T2* and DTI sequences) shall be done pretreatment, and subsequently 
after each 2 cycles of treatment. MRI scans may also be done at any time clinically 
indicated. Optional DCE/DSC MRI scans will be obtained at baseline, after cycle 2 (at 
week 8) and subsequently every 2 cycles prior to initiating the next cycle (or within 3 
working days of starting the cycle).   
 
8.5  
About 5 cc of blood for measuring VEGF, PIGF, bFGF, SDF1 α, angiopoietin 1 and 2, 
will be drawn at baseline before treatment, cycle 1 day 2, day 15 (pre-infusion and post-
infusion)  and cycle 2 (pre-infusion) in those patients that have consented to the optional 
procedures. The post-infusion blood will be drawn between 12-24 hr after infusion.  


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8.6  
About 7 cc of blood will be collected for CEC and CEPC  analysis at baseline, on cycle 1 
day 2 (post-infusion), and day 15 (pre-infusion and post-infusion) in those patients that 
have consented to the optional procedures. The post-infusion blood drawn between 12-24 
hr after infusion. Subsequently, pretreatment samples will be drawn cycle 2. 
 
8.7  
Physical and neurologic examinations will be performed after each cycle for the first 2 
cycles and subsequently after each 2 cycles of treatment prior to initiating the next cycle. 
Patients will also be evaluated anytime their clinical situation demands an assessment. 
 
8.8  
All relevant information regarding drug doses, concomitant medications, and doses, 
measurable lesions with measurements, tumor response, laboratory examinations, and 
treatment-related toxicities shall be documented in the patient’s medical record and flow 
sheets. 
 
8.9  
Pregnancy testing for FCBP (Appendix 18.11) 
 
8.10 
(*)The patient will complete the MDASI-BT (Appendix 18.12) at the time of clinical 
evaluation with MRI as long as the clinical therapy is being administered, unless clinical 
deterioration makes self-report not possible before that time.  The time when patients are 
unable to complete the self- report questionnaires will be used as part of the study 
analysis.  The MDASI-BT will be completed only by the patient, unless changes in vision 
or weakness make this difficult. If this occurs, then the caregiver or research assistant 
may read the questions to the patient or assist with marking the severity number or score 
as described by the patient. A patient caregiver may complete the questionnaires as a 
patient-preference proxy if the patient’s deficits preclude self- report. 
 
* Note: 8.10 is an optional procedure, and will be obtained if the patient gives his or her informed 
consent. 
 
 
8.11 
Phase II patients will be evaluated for adverse events  after each cycle for the first two 
cycles and subsequently after each two cycles of treatment prior to initiating the next 
cycle. In addition all serious adverse events will be reported to the OMCR and the study 
chair as directed in section 15.7. 
 
8.12 
After treatment on protocol is discontinued patients will be followed for overall survival, 
when possible. 
 
a) Patients who discontinue treatment due to progression will be followed for 
survival every 3 months. 
 
b) Patients who come off therapy for reasons other than progression will be 
followed every 2 months with an MRI until progression or institution of new 
anti-tumor therapy.  They will then be followed for survival every three 
months. 
 
 


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9.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
 
9.1 
The primary efficacy endpoint for BTTC studies will be progression free survival (PFS) 
at six months from patient registration.  However, objective response status should be 
measured and recorded. For this and for all other time to event analyses that use 
registration date, if a patient is registered on the pre-operative portion of the study, the 
start date for calculation of time to event will be the date of first post-operative study 
drug administration. 
 
9.2 
Definitions of Response 
 
9.2.1. Measurable Disease: Bidimensionally measurable lesions with clearly defined 
margins by MRI scan. 
 
9.2.2 
Evaluable Disease: Unidimensionally measurable lesions, masses with margins 
not clearly defined. Patients with only this kind of imaging will not be allowed to 
enter this study unless they have recently undergone surgery and have 
histologically proven recurrent disease. 
 
9.2.3 
Non-Evaluable Disease: Not Applicable for response evaluation. 
 
9.2.4. Objective Status, To Be Recorded at Each Evaluation: If there are too many 
measurable lesions to measure at each evaluation, choose the largest two to be 
followed before a patient is entered on study.  The remaining lesions will be 
considered evaluable for the purpose of objective status determination.  Unless 
progression is observed, objective status can only be determined when ALL 
measurable and evaluable sites and lesions are assessed. 
 
Response Criteria (Modified MacDonald Criteria) 
 
9.2.4.1 Complete Response (CR):  Complete disappearance of all measurable 
and evaluable disease.  No new lesions.  No evidence of non-evaluable 
disease.  All measurable, evaluable and non-evaluable lesions and sites 
must be assessed using the same techniques as baseline.  Patients must be 
on none or only physiologic doses of steroids. 
 
9.2.4.2. Partial Response (PR):  Greater than or equal to 50% decrease under 
baseline in the sum of products of perpendicular diameters of all 
measurable lesions.  No progression of evaluable disease.  No new 
lesions.  All measurable and evaluable lesions and sites must be assessed 
using the same techniques as baseline. Responders must be on the same 
or decreasing doses of dexamethasone and have stable or improved 
neurological exams. 
 
9.2.4.3. Partial Response, Non-Measurable (PRNM): Not applicable. 
 


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9.2.4.4. Stable/No Response: Does not qualify for CR, PR, or progression.  All 
measurable and evaluable sites must be assessed using the same 
techniques as baseline.  Responders must be on the same or decreasing 
doses of dexamethasone and have stable or improved neurological 
exams. 
 
9.2.4.5. Progression: 25% increase in the sum of products of all measurable 
lesions over smallest sum observed (over baseline if no decrease) using 
the same techniques as baseline, OR clear worsening of any evaluable 
disease, OR appearance of any new lesion/site, OR failure to return for 
evaluation due to death or deteriorating condition (unless clearly 
unrelated to this cancer). 
. 
9.2.4.6. Unknown: Progression has not been documented and one or more 
measurable or evaluable sites have not been assessed 
 
 
9.3 
Best Response: This will be calculated from the sequence of objective statuses. 
 
For patients with all disease sites assessed every evaluation period, the best response will 
be defined as the best objective status as measured according to Section 9.3.  If the 
response does not persist at the next regular scheduled MRI, the response will still be 
recorded based on the prior scan, but will be designated as a non-sustained response.  If 
the response is sustained, e. g. still present on the subsequent MRI, it will be recorded as 
a sustained response, lasting until the time of tumor progression.  Best response is 
unknown if the patient does not qualify for a best response or increasing disease and if all 
objective status determinations before progression are unknown. 
 
9.4 
Neurological Exam: Although not used for determining response, it is useful to evaluate 
improvement in the neurologic exam, (as compared to the baseline assessment), that 
should coincide with objective measurement of tumor size.  
 
 
 
 
 
 
 
 
 
+2 Definitely Better 
 
 
 
 
+1 Possibly Better 
 
 
 
 
  0 Unchanged 
 
 
 
 
-1 Possibly Worse 
 
 
 
 
-2 Definitely Worse 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.5 
Performance Status: Patients will be graded according to Karnofsky Performance Status 
(see Appendix 18.2). 
 


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9.6 
Time to Treatment Failure: From date of  registration to the date of first observation of 
progressive disease (as defined in Section 9.3), non-reversible neurologic progression or 
permanently increased steroid requirement (applies to stable disease only), death due to 
any cause, or early discontinuation of treatment. If a patient is registered on the pre-
operative portion of the study, the start date for calculation of time to event will be the 
date of first post-operative study drug administration. 
 
9.7 
Time to Death: From date of registration to date of death due to any cause. 
 
9.8 
Documenting FLAIR: Although not part of Macdonald criteria, investigators will be 
asked to measure tumor related changes on FLAIR sequence as best as possible, as non-
enhancing patterns of recurrence can occur.  If this occurs within the setting of clinical 
decline, the patient will be considered to have progressive disease. Investigators will also 
be asked to document if recurrence of disease is multifocal. 
 
 
10.0 
SUBJECT DISCONTINUATION 
 
10.1 
Criteria for Removal from Protocol Treatment: 
 
a. 
After administration of 12 cycles (unless there is clear evidence of clinical 
benefit to justify continuation of treatment) . 
 
b. 
Progression of disease as defined in Section 9.3, after 1 cycle of treatment.  
 
 
c. 
Unacceptable toxicity (including the following). 
 
Grade 4 hypertension or Grade 3 hypertension not controlled with 
medication 
 
Nephrotic syndrome 
 
Grade ≥ 2 pulmonary or CNS hemorrhage; any Grade 4 hemorrhage 
 
Symptomatic Grade 4 venous thromboembolic event  
 
Any grade arterial thromboembolic event 
 
Grade 4 congestive heart failure 
 
Gastrointestinal perforation  
 
Tracheoesophageal fistula (any grade) or Grade 4 fistula 
 
Grade ≥ 2 bowel obstruction that has not fully recovered despite medical or 
surgical   intervention 
 
Wound dehiscence requiring medical or surgical intervention 
 
Determination by the investigator that it is no longer safe for the subject to 
continue therapy 
 
Grade 4 events thought to be related to bevacizumab by the investigator 
 
d. 
The patient may withdraw from the study at any time for any reason. 
 
e. 
Medical or psychiatric illness which in the investigator's judgement renders the 
patient incapable of further therapy. 


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f. 
Treatment related adverse events not resolved within a 4 weeks rest period or 
requiring more than two dose de-escalations of any drug whichever is earlier. 
 
 
g. 
Pregnancy 
 
Patients who have an ongoing bevacizumab 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. 
 
Patients may remain on treatment as long as disease progression is not observed and the 
patient is not experiencing unacceptable toxicity (see Section 10.1).  Although therapy is 
planned for one year, the patient may remain on treatment beyond this time if both the 
patient and physician agree that further therapy is in the patient’s best interests.           
 
10.2 
Criteria from Removal from the Study 
 
 
Protocol Defined Follow-up Completed 
 
Patient Lost to Follow-up 
 
Patient Refused Follow-up 
 
Death  
 
10.3 
All reasons for discontinuation of treatment and/or removal from the study must be 
documented in the source records and the BTTC study database.  
 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
All statistical components of the study will be analyzed in collaboration with Dr. Ying Yuan, 
Department of Biostatistics at MD Anderson Cancer Center. 
11.1  
Statistical Analysis 
 
11.1.1 Phase I component: The phase I component will assess the MTD of Vorinostat in 
combination with Bevacizumab as shown in the table.  A conventional phase I design will be 
used and the MTD will be selected using a 3+3 accrual design at each dose level until MTD is 
determined.  A maximum of 18 patients will be recruited to this component of the study. 
 
11.1.2 Phase II component: This is a randomized phase II trial to Bevacizumab to Vorinostat+ 
Bevacizumab in patients with recurrent GBM. The primary outcome is progression free survival. 
Patients will be randomized between the two arms using a Bayesian adaptive algorithm. Patients 
will be randomized fairly between the two arms at the start of the trial (for the first 20 patients).  
Thereafter, as the trial progresses and data accrue, the randomization will become unbalanced in 
favor of the treatment that, on average, has better results in terms of failure time.  Therefore, each 
successive patient is more likely to receive the treatment with better results, on average. A 
minimum of 20 and a maximum of 90 patients will be accrued.  Based on an anticipated accrual 


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rate between 3 and 5 patients per month, the maximum trial accrual period will be between 12 
and 24 months.  
The table given below summarizes the operating characteristics of the design.  The historical 
median progression free survival is 4 months.  The tables below assume an accrual rate of either 3 
or 5 patients per month. The trial will be stopped early and a treatment selected as being “better” 
if the probability that one treatment’s median PFS is larger than the other’s PFS exceeds 0.995.  If 
the trial does not stop early and the maximum 90 patients are accrued, a treatment is selected as 
being “better” if the probability that one treatment’s median PFS is larger than the other’s PFS 
exceeds 0.975.  A treatment arm will be dropped at any point during the trial if the probability 
that the treatment’s median PFS is larger than 4 months is less than 0.01.    The “# of patients 
treated” row is the average number of patients treated on a given arm under the given scenario.  
When the medians are equal, the probability of selecting either of the two arms (i.e., a false 
positive result) is 8% for both accrual rates. The probability of selecting the better treatment (i.e., 
a true positive result) for a doubling in the median PFS is 82% for 3 per month and 80% for 5 per 
month. 
 
Accrual Rate: 3 Per Month 
 
Accrual Rate: 5 Per Month 
 
 
 
 
 
 
 
Treatment 
 
 
Treatment 
 
BEV 
BEV+V  
 
BEV 
BEV+V 
True Median PFS  
4* 
4 
 
True Median PFS  
4 
4 
# Patients Treated 
42.3 
41.6 
 
# Patients Treated 
41.4 
41.6 
Pr(Selected) 
0.04 
0.04 
 
Pr(Selected) 
0.04 
0.04 
Pr(Selected Early) 
0.02 
0.01 
 
Pr(Selected Early) 
0.01 
0.02 
 
 
 
 
 
 
 
 
True Median PFS 
4 
6 
 
True Median PFS 
4 
6 
# Patients Treated 
25.7 
53.9 
 
# Patients Treated 
27.5 
54.1 
Pr(Selected) 
0.00 
0.42 
 
Pr(Selected) 
0.00 
0.42 
Pr(Selected Early) 
0.00 
0.23 
 
Pr(Selected Early) 
0.00 
0.20 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
True Median PFS 
4 
8 
 
True Median PFS 
4 
8 
# Patients Treated 
18.8 
47.4 
 
# Patients Treated 
20.9 
51.2 
Pr(Selected) 
0.00 
0.82 
 
Pr(Selected) 
0.00 
0.80 
Pr(Selected Early) 
0.00 
0.60 
 
Pr(Selected Early) 
0.00 
0.50 
 
 
 
 
  *True median failure times are given in month; V: vorinostat; BEV: bevacizumab 
 
At each evaluation when a new patient comes in the study, the data for patients who have been 
followed till that time and not yet progressed are accounted in the analysis. The trial will be 
conducted using a web based program developed by the Department of Biostatistics and Applied 


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Mathematics at MD Anderson Cancer Center. Through the website interface, the Clinical Trial 
Conduct site, the users will have the ability to randomize patients, update the current patients’ 
status. The results of randomization are displayed for user to review. When a patient is 
randomized the calculations are based on all available data entered into the website.  The results 
of the randomization are displayed to the screen for the user to view.  All data is stored in a 
secure SQL server database. 
 
Time-to-event outcomes, including PFS and OS will be estimated using Kaplan-Meier method. 
The log rank test will be performed to test the difference in time-to-event distributions between 
two groups. Cox proportional hazards model will be utilized as regression technique to adjust the 
covariates in the time-to-event analysis. 
 
11.1.3 Correlative studies: 
 
11.1.3.1 Gene Profile analysis:  Tumor tissue will be collected for qRT-PCR analysis to 
determine the established 9 gene profile and identify the presence of mesenchyme/angiogenic 
(poor prognosis) genotype versus the proneural (good prognosis) genotype. The response for each 
of the treatment arms will be correlated with the two expected genotypic prognostic groups of 
patients.  Because this is an optional procedure and the trial is powered to detect differences in 
clinical outcome and not for biomarker analysis, these data will be used to generate preliminary 
data regarding identification of specific patient populations who may benefit from the treatments 
and for a future genomic-profile driven personalization of treatment in future studies. 
 
11.1.3.2 Biomarker analysis: measurement of plasma angiogenic proteins including VEGF, PIGF, 
bFGF, SDF1α, angiopoeitin 1 and 2 by ELISA on cycle 1 pretreatment, cycle 1 day 2, day 15 
(pre- and post-infusion) and cycle 2 (pre-infusion). 
 
11.1.3.3 Blood circulating cells study: blood cells experiment will be enumerated by flow 
cytometric analyses of CD31, CD 34, CD 45 and CD 133 using fluorescence-labeled monoclonal 
antibodies (Duda et al., 2006, 2007). Cell concentration will be calculated as percentage of total 
number of mononuclear cells. The quantitative analyses end point will be the change in fraction 
of CD31+ CD34+CD45- and CD133+CD34+ within the mononuclear blood cell population in 
patients receiving treatment. Percent value will be obtained at baseline prior to every treatment 
cycle, and in addition on cycle 1 day 2 (post-infusion), and day 15 (pre- and post-infusion). 
Subsequently, pretreatment samples will be drawn on cycle 2.Post-treatment values in cycle 1 
will be compared with pretreatment value in each individual using Wilcoxon signed rank test. 
 
11.1.3.4 Imaging study (for MDACC patients: other sites may participate if interested and able 
to): Imaging parameter analysis and statistical analysis, based on the published study by 
Batchelor et al. (Batchelor et al., 2007), will be conducted in collaboration with Dr. Ed Jackson, 
imaging physicist. 
 
-Volumetrics: Enhancing lesion and areas of T2 abnormality on FLAIR imaging will be 
quantified by a neuroradiologist. The lesions will be outlined by using a volumetric approach 
(Sorensen et al., 2001). 
 
-Diffusion imaging assessment: Apparent diffusion coefficient are created from high and low b 
value image using the standard Steskjal-Tanner diffusion approximation (Oh et al., 2005). This 


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provides an estimate of relative water motility on a voxel-by-voxel basis.  The units of the map 
are in area/time, mm2/s. 
 
- Permeability: DCE-MRI data will be processed following published approach, including Ktrans 
(Tofts et al., 1999) and Ve (extracellular-extravascular volume fraction). 
 
 - Statistical analysis: The comparison between the MRI parameters, protein level and cell counts 
that measured on the different days will be performed with a two tailed paired Wilcoxon test 
(Hollander and Wolge, 1973).  
 
11.2 
Determination of Sample Size  
 
11.2.1 Phase I component: The Phase I component will assess the MTD of vorinostat in 
combination with bevacizumab as shown in the table.  A conventional phase I design will be used 
and the MTD will be selected using a 3+3 accrual design at each dose level until MTD is 
determined.   A maximum of  18 patients will be recruited into this part of the study.  
 
11.2.2 Phase II component: This is a randomized phase II trial to bevacizumab to vorinostat+ 
bevacizumab in patients with recurrent GBM. The primary outcome is progression free survival. 
Patients will be randomized between the two arms using a Bayesian adaptive algorithm. Patients 
will be randomized fairly between the two arms at the start of the trial (for the first 20 patients). 
Thereafter, as the trial progresses and data accrue, the randomization will become unbalanced in 
favor of the treatment that, on average, has better results in terms of failure time.  Therefore, each 
successive patient is more likely to receive the treatment with better results, on average. A 
minimum of 20 and a maximum of 90 patients will be accrued.  Based on an anticipated accrual 
rate between 3 and 5 patients per month, the maximum trial accrual period will be between 12 
and 24 months.  
 
The table given in Section 10 summarizes the operating characteristics of the design.  The 
historical median time to progress is 4 months.  The tables below assume an accrual rate of either 
3 or 5 patients per month. The trial will be stopped early and a treatment selected as being 
“better” if the probability that one treatment’s median PFS is larger than the other’s PFS exceeds 
0.995.  If the trial does not stop early and the maximum 90 patients are accrued, a treatment is 
selected as being “better” if the probability that one treatment’s median PFS is larger than the 
other’s PFS exceeds 0.975.  The number of patients treated row is the average number of patients 
treated on a given arm under the given scenario.  When the medians are equal, the probability of 
selecting either of the two arms (i.e., a false positive result) is 9% for both accrual rates. The 
probability of selecting the better treatment (i.e., a true positive result) for a doubling in the 
median PFS is 85% for 3 per month and 83% for 5 per month. At each evaluation when a new 
patient comes in the study, the data for patients who have been followed till that time and not yet 
progressed are accounted in the analysis. The trial will be conducted using a web based program 
developed by the Department of Biostatistics and Applied Mathematics at MD Anderson Cancer 
Center. Through the website interface, the users will have the ability to randomize patients, 
update the current patients’ status. The results of randomization are displayed for user to review. 
  
If the study reaches the total enrollment specified in section 11, allowance will be made for the 
enrollment of 10 or more additional patients in the phase II component to be treated in order to 
fulfill the minimal number for the pre-operative study for tissue correlates. 


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11.3  
SAFETY PLAN  
 
 
11.3.1 GENERAL PLAN TO MANAGE SAFETY  
 
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 (see Section 4.0) 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.  
 
A.  Bevacizumab-Specific 
 
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 protein: creatinine (UPC) ratio or dipstick 
every 2 weeks in the first cycle then prior to every subsequent cycle.  
 
 
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. Patients undergoing a major surgical procedure should not begin/restart 
bevacizumab until 4 weeks after that procedure (in the case of high risk procedures 
eg.  liver resection, or thoracotomy, it is recommended that chemotherapy be 
restarted no earlier than 6 wk and bevacizumab no earlier than 8 wk after surgery).  
 
 
If the surgery is not due to tumor progression or due to adverse event attributable to 
study drugs, the patient may resume treatment once medically stable and per 
guidelines above. The provision to continue treatment after surgery will constitute 
an exception to the provision in section  6.4.1 and permits the patient to continue 
on the study despite a 4 weeks or greater break from treatment if this is considered 
in the patient’s best interest. A new baseline scan will be necessary before beginning 
such treatment. If the patient has disease progression on this scan, the date of this 
scan will be considered as the progression date for the purposes of PFS calculation.    
 


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B.  Vorinostat-Specific 
 
Specific monitoring procedures are as follows: 
 
Anorexia and other constitutional symptoms, including weight loss, fatigue will be 
monitored through routine evaluation including body weight at every clinic follow up 
visit during the vorinostat treatment.   
 
Cytopenia, especially thrombocytopenia will be monitored by CBC every 2 weeks.  
 
Gastrointestinal symptoms, such as nausea, vomiting, diarrhea, constipation will be 
monitored through routine evaluation at week 4 then every 8 weeks during the treatment 
with vorinostat. Patients are also encouraged to communicate with the clinical nurse to 
report severe GI symptoms. 
 
12.0 
DISCIPLINE REVIEW  
 
 
12.1 
Pathology Review 
 
Not Applicable . 
 
12.2 
Radiology Review 
 
Not Applicable 
 
 
13.0 
PHARMACOKINETICS 
 
N/A 
 
 
14.0 
LABORATORY CORRELATES 
  
See Appendices 18.4 and 18.5 
 
 
15.0 
MULTICENTER PROCEDURES 
 
15.1 
General Procedures 
 
The BTTC Operations Manual and Data Submission Forms, on file at all BTTC 
institutions, document the data management and quality assurance programs for this 
collaboration.  BTTC institutions will follow the guidelines as addressed below and 
throughout this protocol. 
 
15.2 
Principal Investigators 
 


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The principal investigator(s) will be responsible for the conduct of the study and 
monitoring its progress.  The responsibility for all reports and forms required by BTTC 
will be that of the principal investigator(s). 
 
15.3 
Procedures for Patient Entry 
 
15.3.1 Centralized Patient Registrations 
 
Patients who are candidates for the study will first be evaluated for eligibility by 
the local investigator. All patients must be registered both locally and centrally 
with BTTC. 
 
Before an institution may begin participating in a BTTC protocol, they must 
complete the following steps: 
 
 
Submit all required regulatory documents to the MD ANDERSON CANCER 
CENTER Office of Multicenter Clinical Research (OMCR) as outlined in the 
BTTC Operations Manual 
 
Participate in a site initiation visit, webcast, or conference call 
 
Receive training regarding study specific CRF’s and/or databases 
 
Execute all relevant contractual agreements 
 
After these requirements have been fulfilled, the participating institution will 
receive by fax, e-mail, or hard copy memo a Site Activation Notification.  Once 
the Site Activation Notification has been received, the participating institution 
may begin to register patients to the protocol 
 
 
15.3.2  Patient Registration Procedures 
 
BTTC patients will be registered with the MD ANDERSON CANCER CENTER 
OMCR by fax & phone at UT MD ANDERSON CANCER CENTER.  All 
eligibility requirements will be checked prior to registration.  The status of all 
regulatory documents will be checked prior to registration. No patient will be 
entered on protocol if they do not satisfy all regulatory document and eligibility 
requirements. Generic MD ANDERSON CANCER CENTER OMCR 
registration procedures are also described in the BTTC Operations Manual. 
 
Informed Consent/Authorization 
 
Prior to protocol enrollment and initiation of treatment, subjects must sign and 
date an Institutional Review Board (IRB) approved consent form. 
 
Patient Registration Procedures 
 
Participating institutions must register patients via EDMS, fax, and phone with 
the MD ANDERSON CANCER CENTER Office of Multicenter Clinical 
Research at: 
 


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EDMS: https://iview.mdanderson.org/ 
Fax: (713) 794-1902 
Phone: (713) 792-8519 
 
Registration hours are 8:00 a.m. to 5:00 p.m. Central Standard Time, Monday 
through Friday, except holidays. 
 
Registrations must be completed after the patient has signed the informed 
consent and has been determined to be eligible by the local investigator.  
 
At the time of registration the following information will be requested by the MD 
ANDERSON CANCER CENTER Office of Multicenter Clinical Research 
(OMCR): 
 
 
A copy of a completed and signed, protocol specific, Eligibility Checklist 
form  
 
One copy of a Pathology report from the patient’s most recent surgery or 
biopsy 
 
One copy of the signed and dated Informed Consent/Authorization.  
 
The eligibility checklist form should be prepared and signed prior to sending to 
the MD ANDERSON CANCER CENTER OMCR. The submission should be 
followed by a phone call to the MD ANDERSON CANCER CENTER OMCR to 
verify receipt. If the patient fails eligibility screening do not proceed to the 
registration process.  
 
Patient Number for Participating Institutions 
 
Once eligibility has been established during Registration, the patient from the 
participating institution is assigned a six character MD ANDERSON CANCER 
CENTER OMCR patient ID number and a protocol specific Accession Number.  
The patient ID number is unique to the patient and, except for SAE reports, must 
be used for registrations onto subsequent protocols and written on all data and 
correspondence for the patient. The SAE reports must use the protocol specific 
Accession Number. 
 
Verification of Registration 
 
For participating institutions, a Registration Verification Letter for patients 
registered to BTTC protocols will be faxed or emailed to the registering 
institution within one working day after the registration is received. The OMCR 
must be notified in advance of patient cases that may require an expedited 
registration.   
 
Initiation of Therapy 
 


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Treatment may not be initiated until the participating institution receives a faxed 
or emailed copy of the patient’s Registration Verification Letter from the MD 
ANDERSON CANCER CENTER OMCR.  
 
All Patients that are eligible to receive therapy must initiate treatment within 96 
hours after the registration.   
 
The MD ANDERSON CANCER CENTER OMCR must be notified in writing 
of any exceptions to this policy.  
 
Eligibility Exceptions 
 
Eligibility Exceptions will not be granted. 
 
 
15.4 
Data Management 
 
All data will be entered into the computerized web accessible data management system 
located at the MD ANDERSON CANCER CENTER OMCR at MD ANDERSON 
CANCER CENTER.  Designated research staff from the registering institution will enter 
the data.  The protocol specific electronic forms are to be used by the participating sites.  
All investigators will utilize these forms for Baseline, Treatment, Tumor Evaluation, Off 
Treatment, Survival, and Off-study data.   
 
Confidentiality  
 
All documents, investigative reports, or information relating to the patient are strictly 
confidential. Any patient specific reports (i.e. Pathology Reports, MRI Reports, 
Operative Reports, etc.) submitted to the MD ANDERSON CANCER CENTER OMCR 
must have the patient’s full name & social security number “blacked out” and the 
assigned MD ANDERSON CANCER CENTER patient ID number, protocol number and 
event time point written on every page of the document. Patient initials may be included 
or retained for cross verification of identification. 
 
 
15.5 
Data Monitoring 
 
All submitted data will be monitored by the MD ANDERSON CANCER CENTER 
Protocol Manager specifically assigned to this protocol.  Requests for correction of data 
deficiencies will be sent via email to the Institutional Coordinator.  Any major 
deficiencies will be corrected by telephone communication followed by amendments to 
the study documents.  All data will be monitored for completeness.  Key parameters such 
as drug dosages including attenuations and escalations, toxicity documentation and tumor 
measurements will be analyzed.  All data deficiencies will be corrected within two 
weeks. 
 
The schedule for data & source document submission is outlined as follows. Source 
document requirements are subject to increase for a given participating institution or 


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patient case in the event of questionable study conduct, data quality, and/or non-
compliance with the following submission schedule. 
 
 
 
 
 
  
Data Set / Source Documents 
Schedule for Submission 
Regulatory Documents 
(as described in the BTTC Operations 
Manual) 
Prior to Patient Registration 
Eligibility Checklist  
Prior to Patient Registration  
Copy of signed & dated Informed Consent 
w/ HIPAA Authorization 
Prior to Patient Registration  
Pathology Report (from the most recent 
pre-registration diagnostic biopsy or 
surgery) 
Prior to registration 
Baseline Data 
(To include prior disease/treatment history, 
and baseline clinical evaluation 
information) 
Within 14 days after the registration 
date 
Baseline Source Documents 
(To include all source documents that 
support all data reported on the Baseline 
form and Eligibility Checklist/s) 
Within 14 days after the registration 
date 
Baseline MDASI – BT Questionnaire 
Within 14 days after the registration 
date 
Treatment (Cycle) Data 
(To include treatment, AE, concurrent 
medications, and clinical evaluation 
information) 
Within 38 days after the first day of 
each treatment cycle. 
Treatment (Cycle) Source Documents 
(To include Infusion records, Physician 
Orders, Prescriptions, Patient Diaries, Pill 
Count records) 
Within 38 days after the first day of 
each treatment cycle. 
Disease Evaluation Data 
(To include response, measurements, and 
clinical evaluations used to determine the 
response) 
Within 14 days after registration (for 
baseline) and then REAL TIME after 
each protocol defined on-therapy 
assessment time point. 
Disease Evaluation Source Documents 
(To include MRI Scans or any other 
assessment used to determine the patients 
baseline status and/or response to protocol 
therapy) 
Within 14 days after registration (for 
baseline) and then  REAL TIME after 
each protocol defined assessment time 
point. 
Off Treatment Data 
REAL TIME after the last date of any 
modality of protocol treatment 


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Off Treatment Source Documents 
Within 10 days after off treatment 
decision has been made. 
Follow-up (Survival) Data 
Within 40 days after the last treatment 
date and then every 90 days until Off 
Study (unless otherwise specified by 
the protocol) 
Follow-up Source Documents 
On Request 
Non-Treatment Data 
(May include Quality of Life questionnaires 
(MDASI_BT), Specimen Tracking 
information, Pathology Specimen 
Submission, etc. when applicable) 
Within 10 days after each scheduled 
assessment, event, or activity 
Off Study Data 
Within 10 days after the date the patient 
is removed from the study. 
Off Study Source Documents 
 Within 10 days after the date the 
patient is removed from the study. 
 
15.6 
Safety Assessments and Toxicity Monitoring 
 
All patients receiving study agents will be evaluated for safety.  The safety parameters 
include all laboratory tests and hematological abnormalities, CNS observations, physical 
examination findings, and spontaneous reports of adverse events reported to the 
investigator by patients.  All toxicities encountered during the study will be evaluated 
according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0 and recorded prior to each course of therapy during the first two cycles and 
subsequently after each two cycles of treatment and prior to initiating the next cycle .  
Life-threatening toxicities that are unexpected and assessed to be possibly related to the 
study agent/s should be reported immediately to the study Coordinator, Institutional 
Review Board (IRB), and those that are unexpected and assessed to be possibly related to 
the study agents should also be reported to the FDA. MD Anderson Cancer Center 
OMCR will notify Genentech Drug Safety and Merck Sharp and Dohme Corp 
Worldwide safety of ANY serious treatment emergent adverse event (STEAE) as 
soon as possible. 
 
Information about all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or 
other means, will be collected and recorded on the Adverse Event Case Report Form and 
followed as appropriate. An adverse event is any undesirable sign, symptom or medical 
condition occurring after starting study drug (or therapy) even if the event is not 
considered to be related to study drug. 
 
Medical conditions/diseases present before starting study treatment are only considered 
adverse events if they worsen after starting study treatment (any procedures specified in 
the protocol). Adverse events occurring before starting study treatment but after signing 
the informed consent form are recorded on the Baseline Evaluations_Adverse Events 
Case Report Form. Abnormal laboratory values or test results constitute adverse events 


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only if they induce clinical signs or symptoms or require therapy, and are also recorded 
on the Adverse Events Case Report Form. 
 
Adverse events for Phase II patients will be reported prior to the beginning of each new 
cycle for the first two cycles, and subsequently after each two cycles of treatment prior to 
initiating the next cycle. In addition all serious adverse events will be reported to the 
study chair, and the MD ANDERSON CANCER CENTER OMCR as directed in section 
15.7. 
 
The study will be monitored by the Data Safety Monitoring Board (DSMB) of MD 
Anderson Cancer Center. All adverse events submitted to the IRB will also be reviewed 
by the DSMB. In addition, the principal investigator and the biostatistician will submit 
data relating to safety and efficacy to the DSMB annually. 
 
Safety Monitoring and Early Stopping Rule 
 
Patients will be monitored on an ongoing basis for development of grade 3 or higher drug 
related toxicities.  Persistent toxicities that may affect treatment schedule and dose will 
also be monitored on an ongoing basis. In addition, we will have a review of the toxicities 
of all enrolled patients after the first 20 patients in the phase II portion have completed 
one cycle of treatment and subsequently for every 20 patients enrolled until study 
completion.  This will ensure identification of any unexpected toxicities.  If unexpected 
toxicities are seen in more than 30% of the patients at the time of any of the periodic 
reviews noted above, the trial will be placed on hold and the dosing and schedule of the 
treatment re-evaluated.   
 
A serious adverse event is any adverse drug experience at any dose that results in any of 
the following outcomes: Death, a life-threatening adverse drug experience, inpatient 
hospitalization or prolongation of existing hospitalization, a persistent or significant 
disability/incapacity, or a congenital anomaly/birth defect.  Important medical events that 
may not result in death, be life-threatening, or require hospitalization may be considered 
serious when, based upon appropriate medical judgment, they may jeopardize the patient 
or may require medical or surgical intervention to prevent one of the outcomes listed in 
this definition.  Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions in a patient who has never had seizure activity in the past that do not result in 
inpatient hospitalization, or the development of drug dependency or abuse. 
 
Events not considered to be serious adverse events are hospitalizations for the purposes 
of this protocol and include:  
 
 
Routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition.  
 
Treatment, which was elective or pre-planned, for a pre-existing condition that did 
not worsen 
 
Treatment on an emergency, outpatient basis for an event not fulfilling any of the 
definitions of serious given above and not resulting in hospital admission. 
 


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Pregnancy, although not itself a serious adverse event, should also be reported on a 
serious adverse event form and be followed up to determine outcome, including 
spontaneous or voluntary termination, details of birth, and the presence or absence of 
any birth defects or congenital abnormalities. 
 
The study will utilize the Cancer Therapy Evaluation Program (BTTC) Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.0 for Toxicity and Adverse 
Event reporting.  A copy of the CTCAE version 4.0 can be downloaded from the BTTC 
home page ((http://BTTC.cancer.gov/reporting/ctc.html).  All appropriate treatment areas 
should have access to either a hard copy of the CTCAE version 4.0 or the www version. 
 
Serious Adverse Events will be reported via the BTTC SAE reporting process. See 
section 15.7 for BTTC SAE reporting guidelines. 
 
Notification of Investigators of Expedited Adverse Events Reported to the FDA 
 
Safety Reports or Updates –Investigators will be sent a copy of expedited adverse 
events, which BTTC has sent to the FDA or that BTTC receives from the agent suppliers. 
BTTC will notify consortium investigators via the MD ANDERSON CANCER 
CENTER Office of Multicenter Clinical Research. Within 7 business days of receipt of 
the notification the MD ANDERSON CANCER CENTER OMCR will forward the 
reports to the participating members with protocol specific instructions for IRB 
submissions, patient notifications, etc. For routine IND Safety Reports BTTC does not 
generally require an immediate revision to the master protocol and/or model informed 
consent documents maintained at the MD ANDERSON CANCER CENTER Office of 
Multicenter Clinical Research. The investigators are to file a copy with their protocol file 
and send a copy to their IRB according to their local IRB’s policies and procedures. 
 
IND AE Action Letters - These letters are issued by BTTC for those serious adverse 
events, which warrant an immediate change in the informed consent form and/or 
protocol. Investigators will be sent a copy of expedited adverse events, which BTTC has 
sent to the FDA or that BTTC has received from the agent supplier/s. BTTC will notify 
consortium investigators via the MD ANDERSON CANCER CENTER Office of 
Multicenter Clinical Research with the requirement that the model informed consent and 
or master protocol be amended to include the new event. Immediately upon receipt of the 
notification the MD ANDERSON CANCER CENTER OMCR will forward the letters to 
the participating members with protocol specific instructions for IRB submissions, 
patient notifications, etc. BTTC provides a time frame for which to submit the 
amendment to the BTTC Protocol and Information Office. The letter from BTTC will 
specify if accrual to the protocol is to be suspended until the revision is made and 
whether patients already on study require re-consenting.  
 
 
 
 
 
 
 
 


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15.7 
Guidelines for Reporting Serious Adverse Events to BTTC 
 
All patients receiving agents will be evaluated for safety. Both local IRB and BTTC SAE 
reporting procedures are to be followed by all Institutions.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participating 
Institution
 Coordinating 
Center
(MDACC)
Lead PI
Sponsor or 
Pharma
(If applicable)
MDACC IRB
(Lead IRB)
Participating IRB
All SAE
Reports
All SAE 
Reports
SAE Reports
Unexpected & Related SAEs
SAEs per
Local SOP
BTTC 
Routine SAE Report 
Processing WorkFlow
All SAEs
(if applicable)
FDA
(If Applicable)
Unexpected & 
Related SAEs
Lead IRB
All SAE
Reports


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BTTC SAE reporting requirements and time frames for reporting to the BTTC Coordinating 
Center are described below: 
 
What to Report? 
When to Report? 
How to Report? 
 
 
 
Serious Adverse Events (SAE’s) 
1. All Deaths occurring from 
the time the consent is signed 
through 30 days after the last 
day of active treatment 
Within 1 working day (24 
hours) from the time the 
research team becomes 
aware of event 
 
 
 
 
Unless otherwise specified in 
the protocol use the MD 
ANDERSON SAE Report 
Form for Multicenter 
Reporting (Multicenter 
Participants outside MD 
ANDERSON) 
 
 
 
2. Other SAE’s (that did not 
result in death) that are serious 
AND unexpected AND 
related occurring from the 
time the consent is signed 
through 30 days after the last 
day of active treatment 
Within 5 working days from 
the time the research team 
becomes aware of event 
Unless otherwise specified in 
the protocol use the MD 
ANDERSON SAE Report 
Form for Multicenter 
Reporting (Multicenter 
Participants outside MD 
ANDERSON) 
 
3.  Other SAE’s (that did not 
result in death) that do not meet 
the above criteria occurring 
from the time the consent is 
signed through 30 days after 
the last day of active treatment 
(the SAE is unrelated) 
Within 5 working days from 
the time the research team 
becomes aware of event 
Unless otherwise specified in 
the protocol use the MD 
ANDERSON SAE Report 
Form for Multicenter 
Reporting (Multicenter 
Participants outside MD 
ANDERSON) 
 
 
Serious Adverse Events are to be reported to the local IRB in accordance with local 
policy and procedures. However, all SAE’s are to be reported to the OMCR in 
accordance with BTTC policy even when the local IRB does not require a report, or does 
not require a prompt report.  In these cases a formal memo explaining the local policy 
must accompany the report that is submitted to the OMCR. 
 
The BTTC Coordinating Center will maintain documentation of all Serious Adverse 
Events from each institution. The BTTC Coordinating Center will notify all investigators 
of any serious and unexpected adverse experiences that are possibly related to the study 
agent/s.  The investigators are to file a copy with their protocol file and send a copy to 
their IRB according to their local IRB’s policies and procedures.  
 
All serious adverse events that are unexpected and assessed to be possibly related to the 
study agents must be reported to the FDA by the lead investigator (or their designee) as a 


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15-day post-marketing ‘Alert Report’. An unexpected adverse event is one that is not 
already described in the study agent Investigator Brochure(s). The lead principal 
investigator (or their designee) also has the obligation to report serious adverse events to 
their IRB, Genentech Drug Safety and Merck Sharp and Dohme Corp Worldwide safety.   
 
The BTTC Coordinating Center will forward all SAE reports to the lead IRB via the lead 
investigator, FDA (when applicable), and , Genentech Drug Safety and Merck Sharp and 
Dohme Corp Worldwide safety. 
 
Genentech Drug Safety and Merck 
Sharp and Dohme Corp Worldwide 
safety 
FDA MedWatch 15-day Alert Report 
 
 
Genentech Drug Safety  
Fax: 
(650) 225-4682 or (650) 225-
5288 
(Using the safety reporting fax cover 
sheet attached to this document) 
 
Merck Sharpe and Dohme Corp.  
(Attn: Worldwide Product Safety) 
 
Fax: 215-993-1220 
 
AND: 
 
Study Coordination Center/Principal 
Investigator 
Contact Information and fax # (713) 792-
2883  and (713) 794-4999 
 
Phone: 1-800-FDA-1088 
FAX: 1-800-FDA-0178 or by mail to 
MedWatch 
Center for Biologics Evaluation and 
Research  
Food and Drug Administration  
Suite 200N 1401 Rockville Pike  
Rockville, MD 20852-1448  
FAX: 1-800-FDA-0178 or by mail to 
MedWatch, 
Food 
and 
Drug 
Administration, 
5600 Fishers Lane, Rockville, MD 
20857- 
9787 
 
SAEs should be recorded on a Multicenter Serious Adverse Event Form (Appendix 
18.8).The completed SAE form is to be imported or faxed to: 
 
MD ANDERSON CANCER CENTER Office of Multicenter Clinical Research 
Attn: BTTC Project 
EDMS: https://iview.mdanderson.org/ 
Fax: 713-794-1902 
 
Follow-up information:   
 
Additional information may be added to a previously submitted report by any of 
the following methods: 
 
 
Adding to the original SAE report and submitting it as follow-up. 
 
Adding supplemental summary information and submitting it as follow-up 
with the original SAE report.  


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Occasionally BTTC may contact the reporter for additional information, 
clarification, or current status of the subject for whom an adverse event was 
reported.  
 
Assessing Causality: 
 
Investigators are required to assess whether there is a reasonable possibility that 
the study agent/s caused or contributed to an adverse event.  The following 
general guidance may be used. 
 
Yes: 
If the temporal relationship of the clinical event to the study agent/s 
administration makes a causal relationship possible, and other drugs, 
therapeutic interventions or underlying conditions do not provide a 
sufficient explanation for the observed event. 
 
No: 
If the temporal relationship of the clinical event to the study agent/s 
administration makes a causal relationship unlikely, or other drugs, 
therapeutic interventions or underlying conditions provide a sufficient 
explanation for the observed event. 
 
15.8 
Guidelines & Procedures for reporting Violations, Deviations and Unanticipated 
Problems 
 
Neither the FDA nor the ICH GCP guidelines define the terms “protocol violation” or 
“protocol deviation.”  The definition is often left to the Lead Institution IRB.  
Accordingly, since MD ANDERSON CANCER CENTER is the Coordinating Center 
and the Protocol Chair must adhere to those policies set by the MD ANDERSON 
CANCER CENTER IRB, the definitions for protocol violation and deviation as described 
by the MD ANDERSON CANCER CENTER IRB will be applied for reporting purposes 
for all institutions participating in the MD ANDERSON CANCER CENTER Multi-
center Project. Definitions, reporting guidelines and procedures for reporting violations, 
deviations and/or unanticipated problems are described in the BTTC Operations Manual. 
 
Protocol violations/deviations/unanticipated problems occurring at a participating 
institution will be submitted to that institution’s own IRB.   A copy of the participating 
institution’s IRB violation/deviation/unanticipated problem report will be forwarded to 
the BTTC Coordinating Center by importing into EDMS or by faxing within 7 calendar 
days after the original submission.  
 
MD ANDERSON CANCER CENTER Office of Multicenter Clinical Research 
 
EDMS: https://iview.mdanderson.org/ 
Fax: 713-794-1902 
 
BTTC Coordinating Center:  Upon receipt of the violation/deviation/unanticipated 
problem report from the participating institution, the BTTC Coordinating Center will 
submit the report to the lead Protocol Chair for review. Subsequently, the participating 


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institution’s IRB violation/deviation/unanticipated problem report will be submitted to 
the MD Anderson Cancer Center IRB for review. 
 
15.9 
Institutional Review 
 
Each cooperating center will submit the protocol to its own IRB.  Documentation of the 
IRB approval will be forwarded to the MD ANDERSON CANCER CENTER OMCR at 
UT MD ANDERSON CANCER CENTER before a patient from that institution can be 
registered on protocol.  No changes in the protocol will be allowed unless approved by 
the principal investigator and BTTC. 
 
15.10 Protocol Revisions and Closure 
 
Non life-threatening revisions: BTTC investigators will receive written notification of 
protocol revisions regarding non life-threatening events. 
 
Life-threatening revisions: BTTC investigators will receive telephone notification of life-
threatening revisions with follow-up by fax and/or e-mail.  Life-threatening protocol 
revisions will be implemented immediately. 
 
Protocol closures and temporary holds: BTTC investigators will receive email 
notification of protocol closures and holds.  Closures and holds will be effective 
immediately.  Centers will be updated on an ongoing basis about protocol accrual data so 
that they will be aware of imminent protocol closures. 
 
15.11 Quality Assurance 
 
The BTTC Quality Assurance procedures and reports are described in detail in the BTTC 
Operations Manual. However, an abbreviated description is provided below. 
 
BTTC Quality assurance measures are provided by three mechanisms: ongoing in-house 
monitoring of protocol compliance, on-site audits, and response reviews.  All data 
submitted to the MD ANDERSON CANCER CENTER OMCR at UT MD ANDERSON 
CANCER CENTER will be monitored in-house for timeliness of submission, 
completeness, and adherence to protocol requirements.  Data monitoring will begin at the 
time of patient registration and will continue during protocol performance and 
completion.  The MD ANDERSON CANCER CENTER Protocol Manager will perform 
the ongoing protocol compliance monitoring with the support of the BTTC study 
investigators. 
 
 
In the absence of a sponsor monitoring requirement, or agency, institutions participating 
in BTTC Protocols may be subject to on-site auditing conducted by the MD 
ANDERSON CANCER CENTER OMCR as described in the MD ANDERSON 
CANCER CENTER OMCR’s Multi-Center Audit Plan for the BTTC consortium.  The 
Multi-Center Audit Plan does not replace the in-house monitoring described in this 
manual. On-Site auditing combined with the in-house monitoring are intended to enhance 
the reliability and validity of clinical trial data from BTTC institutions through the use of 
routine monitoring & auditing procedures. 


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15.12  Retention of Records 
 
Retain all documentation of adverse events, records of study drug receipt and 
dispensation, and all IRB correspondence for at least 2 years after the investigation is 
completed. 
 
15.13  Data confidentiality Plan 
 
The investigator will assure that subjects’ anonymity will be maintained and that their 
identities are protected from unauthorized parties. The Informed Consent Form will 
incorporate (or, in some cases, be accompanied by a separate document incorporating) 
wording that complies with relevant data protection and privacy legislation. Pursuant to 
this wording, patients will authorize the collection, use and disclosure of their study data 
by the Investigator and by those persons who need that information for the purposes of 
the study. 
 
The use of the samples for research will be done in accordance with the guidelines 
defined by the FDA document “Guidance on Informed Consent for In Vitro Diagnostic 
Device Studies Using Leftover Human Specimens that are Not Individually Identifiable” 
(issued 25 April 2006). The subject’s personal information will be removed before the 
research samples are used. The research samples will be de-identified by setting a study 
code /initials. If a subject requests destruction of their banked research tissue and blood 
samples, and the samples have not yet been de-identified, the investigator will destroy the 
samples as described in this FDA guidance.  
 
 
16.0 
PATIENT RELATED OUTCOMES MEASURES 
 
This study seeks to establish effective therapies at recurrence and improve on current clinical 
results.  We hypothesize that using a combination of vorinostat and bevacizumab will result in 
improved outcome compared to bevacizumab alone.  However, given the intensive nature of this 
regimen, it will be important to determine whether if any determined survival benefit is 
associated with improvements in symptoms or does a worsening of these parameters offset the 
increase in survival.  
 
Precedence for measuring “non-therapeutic” endpoints exists in oncology research.  For example, 
Gemcitabine was approved by the FDA partially as a consequence of the decrease in pain 
reported in pancreatic patients who were treated, not on the basis of survival improvement which 
was modest, at best1 (Carmichael, Fink et al. 1996).  There have been efforts in neuro-oncology to 
evaluate secondary endpoints using validated instruments as an additional indicator of benefit.   
 
The MD Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) allows the self-
reporting of symptom severity and interference with daily activities.  The MDASI-BT has 
demonstrated reliability and validity in the adult primary brain tumor patient population2 
(Armstrong, Mendoza et al. 2006). This tool represents a modification of the widely used and 
validated MDASI, with particular attention to symptoms common in patients with brain tumors.   
The availability of validated instruments provides an opportunity to prospectively assess the 


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66 
 
impact of treatment, both positive and negative, on patients.  This evaluation of symptom burden 
in this study will assist in finding the best possible treatment with the least toxicity. 
 
16.1 
Patient Related Outcome Objectives: 
 
1. To evaluate longitudinal changes in symptom measures and determine the impact of 
the therapy on these parameters. 
2. To measure symptom burden over the course of therapy to evaluate differences 
between patients individual symptom severity, overall mean symptom severity, and 
difference in scores on the interference items between responders and non-responders. 
3. To describe the variability of symptom severity longitudinally over the treatment 
course and follow-up period.  
 
16.2 
Patient Related Outcome Methods: 
 
16.2.1 Patient Related Outcome Instruments: 
 
The MDASI-BT will be utilized for this portion of the study. Full instruments are 
provided in the appendix.  In addition, information regarding demographics and 
treatment history will be collected as part of the larger study and used in this 
analysis.    
 
The MDASI-BT consists of 23 symptoms rated on an 11-point scale (0 to 10) to 
indicate the presence and severity of the symptom, with 0 being “not present” 
and 10 being “as bad as you can imagine.” Each symptom is rated at its worst in 
the last 24 hours. Symptoms included on the instrument include those commonly 
associated with cancer therapies, those associated with increased intracranial 
pressure, and those related to focal deficits.  The questionnaire also includes 
ratings of how much symptoms interfered with different aspects of a patient’s life 
in the last 24 hours. These interference items include: general activity, mood, 
work (includes both work outside the home and housework), relations with other 
people, walking, and enjoyment of life. The interference items are also measured 
on 0 - 10 scales. The average time to complete these instruments is 5 minutes. 
The MDASI-BT has been translated into 18 languages ( Armstrong, Mendoza et 
al. 2006). 
 
16.2.2  Patient Related Outcome Data collection:   
 
After enrollment on the clinical trial, patients will complete as baseline measures 
the MDASI-BT.  The patient will continue to complete the MDASI-BT at the 
time of clinical evaluation with MRI as long as the clinical therapy is being 
administered, unless clinical deterioration makes self-report not possible before 
that time.  The time when patients are unable to complete the self-report 
questionnaires will be used as part of the study analysis.  The MDASI-BT will be 
completed only by the patient, unless changes in vision or weakness make this 
difficult. If this occurs, then the caregiver or research assistant may read the 
questions to the patient or assist with marking the severity number or score as 
described by the patient. A patient caregiver may complete the questionnaires as 


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67 
 
a patient-preference proxy if the patient’s deficits preclude self-report. These 
reports will be used for descriptive purposes only. 
 
16.3 
Patient Related Outcome Statistical Section: 
 
The sample size for this trial was based on the primary end point of the study. 
 
Received MDASI-BT forms will be checked versus the timing schedule and considered 
as valid if they fall within ten days of the scheduled assessment.  Compliance rates will 
be calculated as the number of received valid forms over the number of expected forms. 
Differences between groups in compliance will be tested by use of Fisher’s exact test at 
every time point. 
 
We will use descriptive statistics to describe how patients rate symptom severity and 
interference with function at each time point.  Error bar graphs for each of the symptoms 
will be constructed at each time point.  The proportion of patients rating their symptoms 
to be 7 or greater (on a 0-10 scale) will also be reported.  We will construct individual 
patient profiles for each of the selected symptoms to describe the individual patients’ 
patterns of change over time. We will calculate the mean core symptom severity, mean 
severity of the MDASI-BT and mean symptom interference at the time of clinical 
evaluation. Estimates of differences in the mean symptom severity and mean symptom 
interference between responders and non-responders will be estimated in the intent to 
treat population.  All patients with at least one valid questionnaire will be included in the 
analyses.  Questionnaires completed at study registration will be considered baseline.  All 
questionnaire data received after randomization will be used in the primary analyses. 
 
Differences of at least 2 points will be classified as the minimum clinically meaningful 
change in the symptom severity and symptom interference measures. For example, an 
increase of 2 points or more would mean a moderate improvement, whereas a decrease of 
2 points or more would be interpreted as moderate worsening. For individual symptoms, 
a rise in a symptom score means deterioration, whereas a reduced score means 
improvement of the specific symptom. 
 
 
 


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17.0 
REFERENCES 
 
 
Carmichaeil, J., et al (1996).  Phase II study of gemcitabine in patients with advanced pancreatic 
cancer.  British Journal of Cancer, 73(1), 101-105. 
 
Chinnaiyan et al. (2012). Phase I trial of vorinostat combined with bevacizumab and CPT-11 in 
recurrent glioblastoma. Neurooncology. 2012 Jan;14(1):93-100. 
 
Armstrong, T.S., Mendoza, T., Gning, et al (2006).  Validation of the MD Anderson Symptom 
Inventory Brain Tumor Module (MDASI-BT).  Journal of Neuro-Oncology, 80(1), 27-35. 
 
Batchelor, T. T., Sorensen, A. G., di Tomaso, E., Zhang, W. T., Duda, D. G., Cohen, K. S., 
Kozak, K. R., Cahill, D. P., Chen, P. J., Zhu, M., et al. (2007). AZD2171, a pan-VEGF receptor 
tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma 
patients. Cancer Cell 11, 83-95. 
 
Bergers, G., and Hanahan, D. (2008). Modes of resistance to anti-angiogenic therapy. Nat Rev 
Cancer 8, 592-603. 
 
Bergers, G., Song, S., Meyer-Morse, N., Bergsland, E., and Hanahan, D. (2003). Benefits of 
targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J 
Clin Invest 111, 1287-1295. 
 
Bolden, J. E., Peart, M. J., and Johnstone, R. W. (2006). Anticancer activities of histone 
deacetylase inhibitors. Nat Rev Drug Discov 5, 769-784. 
 
Calvani, M., Rapisarda, A., Uranchimeg, B., Shoemaker, R. H., and Melillo, G. (2006). Hypoxic 
induction of an HIF-1alpha-dependent bFGF autocrine loop drives angiogenesis in human 
endothelial cells. Blood 107, 2705-2712. 
 
Casanovas, O., Hicklin, D. J., Bergers, G., and Hanahan, D. (2005). Drug resistance by evasion of 
antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 8, 
299-309. 
 
Ceradini, D. J., Kulkarni, A. R., Callaghan, M. J., Tepper, O. M., Bastidas, N., Kleinman, M. E., 
Capla, J. M., Galiano, R. D., Levine, J. P., and Gurtner, G. C. (2004). Progenitor cell trafficking 
is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 10, 858-864. 
 
Du, R., Lu, K. V., Petritsch, C., Liu, P., Ganss, R., Passegue, E., Song, H., Vandenberg, S., 
Johnson, R. S., Werb, Z., and Bergers, G. (2008). HIF1alpha induces the recruitment of bone 
marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer 
Cell 13, 206-220. 
 
Fernando, N. T., Koch, M., Rothrock, C., Gollogly, L. K., D'Amore, P. A., Ryeom, S., and Yoon, 
S. S. (2008). Tumor escape from endogenous, extracellular matrix-associated angiogenesis 
inhibitors by up-regulation of multiple proangiogenic factors. Clin Cancer Res 14, 1529-1539. 
 
Folkman, J. (1971). Tumor angiogenesis: therapeutic implications. N Engl J Med 285, 1182-
1186. 
 
Folkman, J. (2006). Angiogenesis. Annu Rev Med 57, 1-18. 
 
Glusker, P., Recht, L., and Lane, B. (2006). Reversible posterior leukoencephalopathy syndrome 
and bevacizumab. N Engl J Med 354, 980-982; discussion 980-982. 
 
Gurney, J. G., and Kadan-Lottick, N. (2001). Brain and other central nervous system tumors: 
rates, trends, and epidemiology. Curr Opin Oncol 13, 160-166. 
 
Holash, J., Maisonpierre, P. C., Compton, D., Boland, P., Alexander, C. R., Zagzag, D., 
Yancopoulos, G. D., and Wiegand, S. J. (1999). Vessel cooption, regression, and growth in 
tumors mediated by angiopoietins and VEGF. Science 284, 1994-1998. 
 
Jain, R. K., di Tomaso, E., Duda, D. G., Loeffler, J. S., Sorensen, A. G., and Batchelor, T. T. 
(2007). Angiogenesis in brain tumours. Nat Rev Neurosci 8, 610-622. 


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69 
 
 
Karp, J. E., Gojo, I., Pili, R., Gocke, C. D., Greer, J., Guo, C., Qian, D., Morris, L., Tidwell, M., 
Chen, H., and Zwiebel, J. (2004). Targeting vascular endothelial growth factor for relapsed and 
refractory 
adult 
acute 
myelogenous 
leukemias: 
therapy 
with 
sequential 
1-beta-d-
arabinofuranosylcytosine, mitoxantrone, and bevacizumab. Clin Cancer Res 10, 3577-3585. 
 
Kim, M. S., Kwon, H. J., Lee, Y. M., Baek, J. H., Jang, J. E., Lee, S. W., Moon, E. J., Kim, H. S., 
Lee, S. K., Chung, H. Y., et al. (2001). Histone deacetylases induce angiogenesis by negative 
regulation of tumor suppressor genes. Nat Med 7, 437-443. 
 
Kim, S. H., Jeong, J. W., Park, J. A., Lee, J. W., Seo, J. H., Jung, B. K., Bae, M. K., and Kim, K. 
W. (2007). Regulation of the HIF-1alpha stability by histone deacetylases. Oncol Rep 17, 647-
651. 
 
Kopp, H. G., Ramos, C. A., and Rafii, S. (2006). Contribution of endothelial progenitors and 
proangiogenic hematopoietic cells to vascularization of tumor and ischemic tissue. Curr Opin 
Hematol 13, 175-181. 
 
Lamszus, K., Kunkel, P., and Westphal, M. (2003). Invasion as limitation to anti-angiogenic 
glioma therapy. Acta Neurochir Suppl 88, 169-177. 
 
Mahon, P. C., Hirota, K., and Semenza, G. L. (2001). FIH-1: a novel protein that interacts with 
HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev 15, 
2675-2686. 
 
Mancuso, M. R., Davis, R., Norberg, S. M., O'Brien, S., Sennino, B., Nakahara, T., Yao, V. J., 
Inai, T., Brooks, P., Freimark, B., et al. (2006). Rapid vascular regrowth in tumors after reversal 
of VEGF inhibition. J Clin Invest 116, 2610-2621. 
 
Marks, P. A., Richon, V. M., Miller, T., and Kelly, W. K. (2004). Histone deacetylase inhibitors. 
Adv Cancer Res 91, 137-168. 
 
Mastronardi, L., Puzzilli, F., Couldwell, W. T., Farah, J. O., and Lunardi, P. (1998). Tamoxifen 
and carboplatin combinational treatment of high-grade gliomas. Results of a clinical trial on 
newly diagnosed patients. J Neurooncol 38, 59-68. 
 
Miller, D. L., Dou, C., and Armstrong, W. F. (2005). The influence of agent delivery mode on 
cardiomyocyte injury induced by myocardial contrast echocardiography in rats. Ultrasound Med 
Biol 31, 1257-1263. 
 
Munster, P. N., Rubin, E. H., Van Belle, S., Friedman, E., Patterson, J. K., Van Dyck, K., Li, X., 
Comisar, W., Chodakewitz, J. A., Wagner, J. A., and Iwamoto, M. (2009). A Single 
Supratherapeutic Dose of Vorinostat Does Not Prolong the QTc Interval in Patients with 
Advanced Cancer. Clinical Cancer Research 15, 7077-7084. 
 
Norden, A. D., Young, G. S., Setayesh, K., Muzikansky, A., Klufas, R., Ross, G. L., Ciampa, A. 
S., Ebbeling, L. G., Levy, B., Drappatz, J., et al. (2008). Bevacizumab for recurrent malignant 
gliomas: efficacy, toxicity, and patterns of recurrence. Neurology 70, 779-787. 
 
Oh, J., Cha, S., Aiken, A. H., Han, E. T., Crane, J. C., Stainsby, J. A., Wright, G. A., Dillon, W. 
P., and Nelson, S. J. (2005). Quantitative apparent diffusion coefficients and T2 relaxation times 
in characterizing contrast enhancing brain tumors and regions of peritumoral edema. J Magn 
Reson Imaging 21, 701-708. 
 
Okuyama, H., Krishnamachary, B., Zhou, Y. F., Nagasawa, H., Bosch-Marce, M., and Semenza, 
G. L. (2006). Expression of vascular endothelial growth factor receptor 1 in bone marrow-derived 
mesenchymal cells is dependent on hypoxia-inducible factor 1. J Biol Chem 281, 15554-15563. 
 
Ozcan, C., Wong, S. J., and Hari, P. (2006). Reversible posterior leukoencephalopathy syndrome 
and bevacizumab. N Engl J Med 354, 980-982; discussion 980-982. 
 
Petit, I., Jin, D., and Rafii, S. (2007). The SDF-1-CXCR4 signaling pathway: a molecular hub 
modulating neo-angiogenesis. Trends Immunol 28, 299-307. 


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 
Phillips, H. S., Kharbanda, S., Chen, R., Forrest, W. F., Soriano, R. H., Wu, T. D., Misra, A., 
Nigro, J. M., Colman, H., Soroceanu, L., et al. (2006). Molecular subclasses of high-grade glioma 
predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. 
Cancer Cell 9, 157-173. 
 
Qian, D. Z., Wang, X., Kachhap, S. K., Kato, Y., Wei, Y., Zhang, L., Atadja, P., and Pili, R. 
(2004). The histone deacetylase inhibitor NVP-LAQ824 inhibits angiogenesis and has a greater 
antitumor effect in combination with the vascular endothelial growth factor receptor tyrosine 
kinase inhibitor PTK787/ZK222584. Cancer Res 64, 6626-6634. 
 
Rossig, L., Urbich, C., Bruhl, T., Dernbach, E., Heeschen, C., Chavakis, E., Sasaki, K., Aicher, 
D., Diehl, F., Seeger, F., et al. (2005). Histone deacetylase activity is essential for the expression 
of HoxA9 and for endothelial commitment of progenitor cells. J Exp Med 201, 1825-1835. 
 
Scappaticci, F. A., Fehrenbacher, L., Cartwright, T., Hainsworth, J. D., Heim, W., Berlin, J., 
Kabbinavar, F., Novotny, W., Sarkar, S., and Hurwitz, H. (2005). Surgical wound healing 
complications in metastatic colorectal cancer patients treated with bevacizumab. J Surg Oncol 91, 
173-180. 
 
Sorensen, A. G., Patel, S., Harmath, C., Bridges, S., Synnott, J., Sievers, A., Yoon, Y. H., Lee, E. 
J., Yang, M. C., Lewis, R. F., et al. (2001). Comparison of diameter and perimeter methods for 
tumor volume calculation. J Clin Oncol 19, 551-557. 
 
Stupp, R., Mason, W. P., van den Bent, M. J., Weller, M., Fisher, B., Taphoorn, M. J., Belanger, 
K., Brandes, A. A., Marosi, C., Bogdahn, U., et al. (2005). Radiotherapy plus concomitant and 
adjuvant temozolomide for glioblastoma. N Engl J Med 352, 987-996. 
 
Tofts, P. S., Brix, G., Buckley, D. L., Evelhoch, J. L., Henderson, E., Knopp, M. V., Larsson, H. 
B., Lee, T. Y., Mayr, N. A., Parker, G. J., et al. (1999). Estimating kinetic parameters from 
dynamic contrast-enhanced T(1)-weighted MRI of a diffusable tracer: standardized quantities and 
symbols. J Magn Reson Imaging 10, 223-232. 
 
Tso, C. L., Shintaku, P., Chen, J., Liu, Q., Liu, J., Chen, Z., Yoshimoto, K., Mischel, P. S., 
Cloughesy, T. F., Liau, L. M., and Nelson, S. F. (2006). Primary glioblastomas express 
mesenchymal stem-like properties. Mol Cancer Res 4, 607-619. 
 
Vredenburgh, J. J., Desjardins, A., Herndon, J. E., 2nd, Marcello, J., Reardon, D. A., Quinn, J. A., 
Rich, J. N., Sathornsumetee, S., Gururangan, S., Sampson, J., et al. (2007). Bevacizumab plus 
irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 25, 4722-4729. 
 
Wong, E. T., Hess, K. R., Gleason, M. J., Jaeckle, K. A., Kyritsis, A. P., Prados, M. D., Levin, V. 
A., and Yung, W. K. (1999). Outcomes and prognostic factors in recurrent glioma patients 
enrolled onto phase II clinical trials. J Clin Oncol 17, 2572-2578. 
 
Yu, J. L., Rak, J. W., Coomber, B. L., Hicklin, D. J., and Kerbel, R. S. (2002). Effect of p53 
status on tumor response to antiangiogenic therapy. Science 295, 1526-1528. 
 


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18.0 
APPENDIX 
 
18.1 
NCI Common Terminology Criteria for Adverse Events 
 
18.2 
Karnofsky Performance Status and Neurologic Function 
 
18.3 
EIAEDs and Non-EIAEDs 
 
18.4 
Peripheral Blood Mononuclear Cell (PBMC) Isolation for Circulating Endothelial Cells 
Assays 
 
18.5 
Blood and tissue biomarker collection and analysis 
 
18.6 
Bayesian Adaptive Algorithm: Technical Details 
 
18.7 
Study Flow Chart / Schema 
 
18.8 
 Multicenter Serious Adverse Event Form 
 
18.9 
New York Heart Association (NYHA) Guidelines 
 
18.10 Procedure for Obtaining a Urine Protein: Creatinine Ratio 
 
18.11 Pregnancy Tests for Females of Childbearing Potential and Adequate Methods of 
Contraception 
 
18.12  MD Anderson Symptom Inventory for Brain Tumors (MDASI – BT) 
 
18.13  Drug Accountability 
 
 
18.14     Patient Study Drug Diary 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 


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18.1 
NCI Common Terminology Criteria for Adverse Events 
 
This study will utilize the CTCAE version 4.0 for Toxicity and Adverse Event reporting.  A copy 
of the CTCAE version 4.0 can be downloaded from the www at  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
18.2 
Karnofsky Performance Status Score and Neurological Function 
 
Patient's performance status and Neurologic Functions will be graded according to the following 
scales: 
Karnofsky Performance Status 
 
KPS 100 
Normal; no complaints; no evidence of disease 
KPS   90 
Able to carry on normal activity; minor signs or symptoms of disease 
KPS   80 
Normal activity with effort; some sign or symptoms of disease 
KPS   70 
Cares for self; unable to carry on normal activity or do active work 
KPS   60 
Requires occasional assistance, but is able to care for most personal needs 
KPS   50 
Requires considerable assistance and frequent medical care 
KPS   40 
Disabled; requires special care and assistance 
KPS   30 
Severely disabled; hospitalization is indicated, although death no imminent 
KPS   20 
Very sick; hospitalization necessary; active support treatment is necessary 
KPS   10 
Moribund; fatal processes progressing rapidly 
KPS     0 
Dead 
 
 
Neurologic Function 
 
 
 
 
 
 
 
 
 
+2 
Definitely Better 
 
+1 
Possibly Better 
 
  0 
Unchanged 
 
-1 
Possibly Worse 
 
-2 
Definitely Worse 


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18.3 
LIST OF ENZYME INDUCING & NON_ENZYME INDUCING ANTICONVULSANTS 
 
 
Enzyme inducing antiepileptic medications 
 
Carbamazipine  (Tegretol, Tegretol XR, Carbatrol) 
Oxcarbazepine (Trileptal) 
Phenytoin 
(Dilantin, Phenytek) 
Fosphenytoin 
(Cerebyx) 
Phenobarbital (Solfoton) 
Primidone 
(Mysoline) 
 
Non enzyme inducing antiepileptic medications 
 
Benzodiazepines 
 
Oxcarbazepine* (Trileptal) 
Topiramate* 
(Topamax, Topiragen) 
Ethosuximde 
(Zarontin) 
Gabapentin 
(Neurontin, Fanatrex, Gabarone, Horizant) 
Lacosamide 
(Vimpat) 
Lamotrigine* 
(Lamictal) 
Levatiracetam (Keppra) 
Pregabalin 
(Lyrica) 
Tiagabine 
(Gabatril) 
Valproic acid** (Depakote, Depakene, Epilim, Stavzor) 
Vigabatrin 
(Sabril) 
Zonisamide 
(Zonegran) 
Clonazepam  
(Klonopin, Klonipin Wafer, Ceberclon, Valpax) 
Clobazam 
(Frisium, Urbanol) 
 
* Weak inducers of Cyp3A4 and only at higher doses 
 


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75 
 
B.  Labeling and Storage of Samples: Cryotubes should be labeled with the following information 
(do not include any patient identifiers other than the ones indicated below): 
 
Patient  BTTC Number 
Protocol number BTTC 11-02 
Collection date 
Tube number 
Cells (PBMC) or plasma  
 
 
Samples should be stored at -70° to -80°C and shipped as soon as possible – specimens have to be 
analyzed within 3 months of collection. Shipping should be on DRY ICE 
Analysis of CECs and other peripheral blood mononuclear populations will be performed by 
four-color flow cytometry.  Briefly, analysis will be conducted with using a panel of antibodies to 
identify different cellular populations such as: CD146 as a marker of mature ECs; CD133 as a 
marker of EC precursors; CD45 to exclude hematopoeitic cells; and anti-KDR as a marker of 
both precursor and mature endothelial cells.  Apoptosis markers (i.e. annexin V) will also be 
incorporated. Standard analysis gates will be used to exclude dead cells and platelets. The number 
of mature CECs, expressed as a percentage of PBMCs, will be recorded and the absolute number 
of CECs and CEPCs (number per microliter of blood) will be derived using the patients white 
count and differential.   
C.  Packaging of Blood Specimens: For clinical blood samples, the following four layers of 
packaging should be included: 
1. Primary watertight inner receptacle. Use watertight containers for liquid specimens with a 
positive closure such as a screw-on, snap-on or push-on lid, taped for an additional seal. If you 
place multiple fragile primary receptacles in a single secondary receptacle, they must be 
individually wrapped or separated to prevent contact between them. 
2. Absorbent material. Place absorbent material such as paper towels or cotton balls between the 
primary and secondary receptacles, using enough material to absorb the entire contents of all 
primary receptacles. 
3. Secondary watertight inner receptacle. Use a watertight sealed plastic bag or plastic canister  
4. Sturdy outer packaging. Use rigid outer packaging constructed of corrugated fiberboard 
appropriately sized for the contents. 
D.  Shipping Instructions: The samples should be shipped to the following address ON DRY ICE in 
appropriately labeled package (include dry ice label – ensure that sufficient amount of dry ice is 
included to maintain samples frozen) in accordance with local and federal regulations for 
biological material. (Note: The samples may be batched with the PBMC/CEC samples from 
section 18.5)  
 
   
Jihong Xu/Puduvalli Lab 
Room 370 CCC, Wiseman Hall, 
400 W Twelfth Ave 
Columbus ,OH 43210 
Ph : 614-292-6618 or 614-688-7592 
Email : jihong.xu@osumc.edu  
 
 


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76 
 
Prior to shipping the samples, please contact Dr. Xu by phone or email to ensure 
appropriate tracking and receipt of the sample. Samples can be batched and sent as a single 
shipment Mondays through Wednesdays by overnight shipment to ensure timely arrival of 
samples during working days and not on a weekend. 
 
18.4.   Alternative Method of PBMC Processing (If BD Vacutainer CPT Tubes are not procurable) 
 
1.  Collect 7 cc of whole blood in a Sodium citrate blood collection tube and gently invert to ensure good    
mixing. Pipet  this collected sample into a 50-ml conical centrifuge tube and add 13 ml room 
temperature PBS 
2.  Using a 10-ml pipet, underlay with 5 ml room temperature Ficoll-Hypaque solution. 
3.  Separate cells by centrifuging for 20 min at 800 × g (2000 rpm in H-1000 rotor), at 20°C, with the 
brake off. 
4.  Gently aspirate most of the plasma- and platelet-containing supernatant above the interface band 
(granulocytes and erythrocytes will be in red pellet; see Fig below – A. Before centrifugation; B: After 
centrifugation).  
Aspirate the interface band (which includes 
the monocytes) along with no more than 2 ml 
of fluid above the pellet into a 10-ml pipet, 
then transfer to a new 50-ml conical 
centrifuge tube, Add PBS to 50-ml mark.  
 
 
 
 
 
 
 
 
 
5.  Centrifuge 10 min at 600 × g (1500 rpm in H-1000 rotor), 20°C, with the brake on. 
6.  Aspirate supernatants and resuspend the pellet in the tube with 10 ml room temperature PBS.  
7.  Centrifuge 15 min 300 × g (750 rpm in H-1000 rotor), 20°C, with brake on. This low-speed 
centrifugation permits as many platelets as possible to remain above the pellet of monocytes. 
8.  Prepare and label cryotubes as specified in protocol 18.4 B.  
9.  After centrifugation, the mononuclear cells will be visible in a whitish layer just under the plasma. 
Remove and discard nearly all the overlying  plasma (about 7 ml) leaving about 1 ml of plasma behind 
in the tube ( as the top layer); carefully extract this 1 ml of plasma without disturbing the lower layer 
using a 3 ml pipette and put into cryotube #1. 
10.  Then remove ALL of the mononuclear layer (1.5 ml) and put into cryotube #2.  
11.  Then transfer half of mononuclear cells from cryotube 2 (750 microliters) to cryotube #3.   
12.  Add 750 microliters of freezing media (RPMI-1640 media with 20% dimethyl sulfoxide) to PBMC 
cryotubes (#2 and #3). All three cryotubes should immediately be placed in a –80 degree freezer.   
 
monocytes 


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77 
 
18.5 
Blood and Tissue biomarker collection and analysis  
A. Guidelines for Collection, storage and shipment of Blood Samples for Biomarkers 
 
Collect 5 mL of whole blood into a CTAD (Becton-Dickinson Cat #367947 Hemogard, 4.5 mL 
tubes) vacutainer tube, being careful to minimize agitation of the sample and using the largest-
bore needle that is feasible for the patient.   
 
Mix by gently inverting the tube 4 times.    
 
Centrifuge at 2000 x g for 15 minutes at room temperature within 1 hour of draw.  
 
Within 30 minutes after centrifugation, draw off plasma very slowly with transfer pipette to 
within 0.5 cm of the buffy coat, taking great care not to disturb the buffy coat.  (NOTE: Any 
contamination may invalidate the assay. If there is inadvertent mixing of these layers, please 
indicate this in the shipment paperwork)    
 
Pipette the plasma specimen equally into TWO separate pre-chilled plastic cryovials.  Do not 
transfer more than 1.5 mL into each tube.   
 
All specimens must be stored frozen at -20˚C (or colder) in a freezer.   
 
One vial is labeled VEGF/bFGF and the other vial is labeled as reserve.  These reserve tubes will 
be used to measure soluble VEGFR-1 and -2, placental growth factor (PlGF), SDF1α, 
angiopoeitin-1 and 2. 
 
Labeling of samples:  All samples should be labeled with the following information: (do not 
include any patient identifiers other than the ones indicated below): 
Patient  BTTC Number 
Protocol number 
Collection date 
Tube number 
Cells or plasma  
 
Packaging and Shipping instructions: The samples should be packaged as described in Section 
18.4 C and shipped to the following address ON DRY ICE in appropriately labeled package 
(include dry ice label shown– ensure that sufficient amount of dry ice is added to cover the 
sample and keep it frozen for overnight shipment) in accordance with local and federal 
regulations for biological material. (Note: The samples may be batched with the PBMC/CEC 
samples from section 18.4)  
 
   
Hong Xu/Puduvalli Lab 
Room 370 CCC, Wiseman Hall 
400 W Twelfth Ave 
Columbus, OH 43210 
Ph: 614-292-6618 or 614-688-7592 
Email: jihong.xu@osumc.edu 
 
 
 
Prior to shipping the samples, please contact Dr. Xu by phone or email to ensure 
appropriate tracking and receipt of the sample. Samples can be batched and sent as a single 


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shipment Mondays through Wednesdays by overnight shipment to ensure timely arrival of 
samples during working days and not on a weekend. 
 
 
B. Guidelines for Collection, Processing and Shipment of Tissue and Intraoperative Blood 
Samples 
 
1. Presurgical Tissue Sample- Surgical Arm: Patients who are candidates for surgery (in MDACC 
or other participating sites) and consent to taking part in the pre-surgical portion of the phase II 
study will be assessed under the following guidelines to ensure uniform tissue collection and 
processing 
 
 
After a patient has consented for the pre-surgical portion of the study, the laboratory 
personnel (jihong.xu@osumc.edu)at 614-292-6618 or 614- 688-7592, should be notified by 
the research nurse regarding the planned date of surgery. 
 
 
 
Following surgery and verification of tumor recurrence, two specimens of tissue will be 
collected  
1. Snap Frozen: One part (1 cm3) will be collected as soon as possible after resection and 
snap frozen for genomic profiling (see instructions below). To ensure that the highest 
quality data can be obtained, it is essential that tissue should be processed in an expedited 
manner. If this tissue cannot be processed right after resection, it should be transported to 
the lab on ice as soon as possible and snap-frozen and stored as indicated below. 
Standard Instructions for Collecting Snap Frozen Tissue  
 Pre-label one cryovial according to the specimen labeling requirements indicated in 
the Labeling Instructions below.  
 Pre-chill cryovial by placing on dry ice.  
 Tissue specimen should be a minimum of 1 cm3 in size. If needed, remove any blood 
from the specimen by touching the tissue with a sterile swab.  
 Snap freeze tissue as soon as possible after resection on dry ice or in the vapor phase 
liquid nitrogen (do not submerge the tissue in liquid nitrogen).  
 Transfer frozen specimen to pre-chilled tube to prevent thawing of the tissue  
 Store snap frozen tissue in a -70°C to -80°C freezer until ready to ship. 
2. FFPE Specimen: A second part will be obtained from the routinely processed formalin 
fixed and paraffin-embedded (FFPE) blocks generated for immunohistochemical studies, 
This part can either be provided as 20 unstained slides or an equivalent section from the 
paraffin block and should be verified to contain non-necrotic tumor tissue.   
 
 
Intraoperative blood samples should be processed as described in Section 18.5 A above 
 
Contact the following personnel for sample processing guidelines prior to shipment to 
MDACC 
 
Jihong Xu/Puduvalli Lab            
Room 370 CCC, Wiseman Hall               
400 W Twelfth Ave,                                     
Columbus, OH 43210  
Ph: 614-292-6618 or 614-688-7592     


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3. Tissue samples from PRIOR surgeries 
Samples from prior surgeries (sections of paraffin blocks) should be collected whenever available 
from patients who consented to optional procedures. If paraffin blocks are unavailable, 20 
unstained slides can be provided. The samples should be shipped to OSU and will be stored in the   
Puduvalli Lab for correlative studies. These specimens will not be used to determine treatment or 
procedures; hence, they can be procured whenever feasible from the initial surgery source (e.g. 
outside hospitals) and any subsequent surgeries (from participating centers or outside center by a 
formal request based on this IRB approved protocol). 
 
 
Labeling Instructions for tissue specimens 
Labels on all samples should include the following information (Do not include any other 
personal identification details):  
 
Patient  BTTC Number 
Protocol number BTTC 11-02 
Collection date and time 
Vial # and type of specimen (e.g.snap frozen tissue) 
Number of tubes, specimens or slides 
 
 
 
 
Instructions for Packaging and Shipping Snap Frozen Tissue (The following are general 
guidelines– Each institution should  ensure that all required regulation for clinical sample 
shipment are followed) 
Packaging: To eliminate the possibility of thawing of frozen samples during packaging and 
shipment, prepare packaging material in advance 
 The cryovial must be wrapped in absorbable material such as paper towels and secured 
with a rubber band.  
 Place the specimen in an secondary container such as a sealable plastic bag compatible 
with frozen specimens and seal the same.  
 Place packaged specimen in an appropriate shipping container (composed of an inner 
styrofoam and outer cardboard layer) containing dry ice. Surround the package with dry 
ice.  
 Mark the outside shipping container with an "Exempt Human Specimen" label and a 
dry ice label. 
 Shipping: 
a. Ship frozen tissue on DRY ICE using Federal Express Priority Overnight service in 
accordance with the required regulations. Use of other courier services may delay 
package receipt. 
b. Frozen specimens may only be shipped Monday through Wednesday using only overnight 
delivery to arrive on weekdays. Do NOT ship frozen specimens on Friday for Saturday 
delivery. 
c. The samples should be shipped to the following address in appropriately labeled package in 
accordance with local and federal regulations for biological material. Prior to shipping the 
samples, please contact  Dr. Xu by phone or email to ensure appropriate tracking and 


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receipt of the sample. Samples can be batched and sent as a single shipment by overnight 
shipment Mondays through Wednesdays to ensure timely arrival of samples during working 
days. 
 
Jihong Xu/Puduvalli Lab             
Room 370 CCC Wiseman Hall,              
400 W Twelfth Ave.                                    
Columbus, OH 43210                                      
Ph: 614-292-6618 or 614-688-7592         
Email jihong.Xu@osumc.edu  
 
 
Standard Instructions for Packaging and Shipping FFPE Tissue Specimens (The following are 
general guidelines– Each institution should  ensure that all required regulation for clinical sample 
shipment are followed) 
 
Packaging 
 
The specimen should be in a plastic container (for blocks) or in a slide container (for 
unstained slides). It must be wrapped in absorbable material such as paper towels and secured 
with a rubber band.  
 
Place the specimen in an AIRTIGHT container (must have a primary and secondary 
container, ex a Saf-T-Pak).  
 
Place packaged specimen in an appropriate shipping container (ex. FedEx box or clinical 
pack).  
 
Mark the outside shipping container with an "Exempt Human Specimen" label. 
 
Shipping 
 
The samples should be shipped to the following address in appropriately labeled package in 
accordance with local and federal regulations for biological material.  
 
Prior to shipping the samples, please contact Dr. Xu/Puduvalli Lab by phone or email to 
ensure appropriate tracking and receipt of the sample.  
 
Samples can be batched and sent as a single shipment by overnight shipment Mondays 
through Thursdays to ensure timely arrival of samples during working days. 
 
 
Jihong.Xu/Puduvalli Lab          
Room 370 CCC, Wiseman Hall             
400 W Twelfth Ave.                                    
Columbus, OH 43210                                      
Ph: 614-292-6618 or 614-688-7592         
Email: jhong.xu@osumc.edu     


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18.6 
BAYESIAN ADAPTIVE ALGORHYTHM: TECHNICAL DETAILS 
Approved by UTMDACC IRB#3 on December 17, 2003 
 
Denote the time to progression for the patients as T1,T2,…and index the two treatment arms by t 
= 1,2.  Assume that the T’i are independent, [Ti |t]~ exponential with median t , for t = 1,2 and 
that a priori {12} are independent following an inverse gamma distribution with parameters 
= 2.016 and = 4.064.  This parameterization was chosen to set the mean of the prior equal to 4 
(the historical median TTP in months) and a variance of 1000.  This gives a 95% credible interval 
for the median TTP of (0.73, 16.44).  For each patient, the randomization probability for treatment 
t=1 will be the posterior probability that it has the largest median TTP, that is 1(data) = Pr(1 > 
2| data); the randomization probability for treatment t =2 is 2(data) = Pr(2 > 1| data).  If at any 
point during the trial i(data) > 0.995 (< 0.005) the trial will be terminated and treatment i will be 
selected as superior (inferior).  If the maximum accrual is reached and i(data) > 0.975 (< 0.025), 
treatment i will be selected as superior (inferior).  A treatment arm will be dropped at any point 
during the trial if Pr(i > 4 |data) < 0.01, for i=1,2. 
 
Prior Distribution (Time-To-Event Trial) 
The time-to-event (TTE) variable, Tji, for each arm j is assumed to be Exponential with mean 
jp( Tji | j)  = 1/ (iDi ) exp(Tj+ / i).  However, since most of the time we are interested in the 
median tte, jlog(2) * j,  therefore, p( Tji | j) = ( log(2)Dj ) / (jDj ) exp( ( log(2) * Tj+ ) 
/j ).  Where Tj+  = i Tji =event or censoring times for arm j and Dj = # of events for arm j. 
a priori jInverse Gamma(jj
E(j) = j / (j- 1) ; > 1  
Var(j) = j2 / [(j - 1)2 (j - 2)] ;  > 2  
Therefore; j | Tji ~ Inverse Gamma (j + Djj + log(2 )*Tj+  


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18.7 
STUDY FLOW CHART/SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Study Flow Chart 
 
Phase I/II Adaptive Randomized Trial of Bevacizumab versus Bevacizumab plus Vorinostat Adults with Recurrent Glioblastoma 
 
 
 
BL 
Cycle 1 
Cycle 2 
Subsequent every 2 Cycles 
Off Treatment 
Procedure 
 
Wk 
1 
Wk  
2 
Wk 
3 
Wk 
4 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
2 
Wk 
4 
Wk 
6 
Wk 
8 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam1 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
BP Recorded9 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
MDASI-BT8 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
MRI (with 
DCE/DSC7) 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 7  
X 
Hematology2 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Chemistry3 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
Urine protein: 
creatinine ratio 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
Pregnancy Test 4  
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
Tumor Pathology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Paraffin Tissue 
block5  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker 
measurement6  
X 
D2 
 
D1 
 
D1 
 
 
 
 
 
 
 
 
 
1. Physical examination includes vital signs, neurological exam, neurological function score, Karnofsky performance score., 
2. Includes CBC with differential 
3. Includes: Total protein, albumin, Ca,   glucose, BUN, creatinine, Na, K, , total bilirubin, alkaline phosphatase, LDH, SGPT (ALT), 
SGOT (AST). 
4. Only for women of childbearing potential as defined by Appendix 18.11. To be performed before each new cycle of therapy. 


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5. Optional procedure.  
6. Optional procedure. Including 5 cc blood sample for VEGF, PIGF, bFGF, SDF1 α, angiopoietin 1 and 2 and 7 cc of blood for isolation 
of peripheral blood monocytes will be collected for CEC and CEPC, at baseline before  treatment, cycle 1 day 2, day 15 (pre-infusion 
and post-infusion)  and cycle 2 (pre-infusion). The post-infusion blood drawn between 12-24 hr after infusion.  
7. MRI scan with and without contrast to be obtained every 2 cycles during treatment and every other cycle until disease progression if 
treatment is discontinued for reasons other than progressive disease and no other new treatment is started. Optional DCE/DSC studies 
are preferred but not required. 
8. MDASI-BT at Baseline, prior to results of each MRI Evaluation are shared with the patient, and at end of therapy (optional procedure). 
9. Blood Pressure monitoring every 2 weeks prior to Bevacizumab infusion. 


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18.8 
Multicenter SAE Form 
 
 
 
 
SPONSOR:  
UT MD ANDERSON 
CANCER 
CENTER/BRAIN TUMOR 
TRIALS 
COLLABORATION 
 
IND#:  NA 
SITE’S PROTOCOL NO. 
      
PROTOCOL TITLE:      
PRINCIPAL INVESTIGATOR 
      
 INITIAL REPORT 
 F/U REPORT 
(CHECK ONLY ONE) 
PROTOCOL STATUS (CHECK ONE):       
  
  ACTIVE  
 TERMINATED 
  CLOSED TO NEW PATIENT ENTRY AND PATIENTS ON TREATMENT 
  CLOSED TO NEW PATIENT ENTRY AND PATIENTS OFF TREATMENT 
DATE 
RESEARCH 
TEAM 
NOTIFIED OF 
EVENT OR 
FOLLOW-UP 
      
DATE 
SUBMITTED 
TO LOCAL 
IRB 
      
SITE 
NAME 
      
TOTAL NO. OF 
PT’S ON 
PROTOCOL 
AT THIS SITE 
      
PATIENT REACTION INFORMATION 
MEDICAL RECORD 
NUMBER 
      
 
REACTION OUTCOME: 
DEATH (PROVIDE 
DATE OF DEATH) 
      
PATIENT STUDY NUMBER 
      
HOSPITALIZATION 
      
PATIENT INITIALS 
      
DISABILITY 
      
AGE 
      
CONGENITAL 
ANOMALY 
      
GENDER 
      
LIFE THREATENING 
      
REACTION ONSET 
(MO/DAY/YEAR) 
      
 
IMPORTANT MEDICAL 
EVENT 
      
PLEASE WRITE A SHORT SUMMARY DESCRIBING THE EVENT(S) IF NEEDED 
 
Event/Reaction (use appropriate Title from 
NCI CTC for all events reported) (More than 
one event may be listed if related and 
occurs around same time) 
 
Attribution(s): 
 
Event 
Grade 
(1-5) 
Definite 
Probable 
Possible 
Unlikely 
Unrelated 
IS EVENT 
EXPECTED? 
(NOTED IN THE DRUG 
INFORMATION) 
      
      
      
      
      
      
      
      
      
      
  
  
  
  
 
  
  
  
  
 
  
  
  
  
 
  
  
  
  
 
  
  
  
  
 
YES 
  NO 
 
YES 
  NO 
 
YES 
  NO 
 
YES 
  NO 
 
YES 
  NO 
 
MULTICENTER SERIOUS ADVERSE EVENT REPORT 


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CURRENT CONDITION BEING TREATED 
WITH INVESTIGATIONAL AGENT 
      
OTHER RELEVANT MEDICAL HISTORY 
      
LIST OR ATTACH RELEVANT TESTS, 
NOTES, AND LABORATORY DATA 
      
LIST OR ATTACH ALL CONCOMITANT 
MEDICATIONS PT TAKING AT TIME OF 
THE EVENT 
      
 
 
NAME OF AGENT OR DEVICE 
(LIST MANUFACTURER AND LOT 
# #) 
      
DID REACTION ABATE AFTER STOPPING THE DRUG? 
YES 
      
DATE 
      
DOSE 
( LIST FREQUENCY OR  
SCHEDULE) 
      
NO 
      
NOT KNOWN 
      
ROUTE OF ADMINISTRATION 
      
DID REACTION REAPPEAR AFTER REINTRODUCTION? 
DATE(S) OF ADMINISTRATION 
      
 
HAVE YOU ALSO REPORTED THIS 
REACTION TO THE 
MANUFACTURER? 
 
      
YES 
      
DATE: 
      
NO 
      
NA 
      
 
 
PRINTED NAME OF PI 
 
 
PERSON FILLING OUT THIS 
FORM 
      
PHONE # 
 
COMPLETED SAE REPORT FORMS FOR MULTICENTER REPORTING ARE TO BE SUBMITTED TO THE OMCR VIA EDMS OR FAX AT: 
 
EDMS: HTTPS://IVIEW.MDANDERSON.ORG/ 
FAX: 713-794-1902 
 
THE SITE REPORTING THE SAE MUST IMMEDIATELY ALERT THE OMCR VIA EMAIL OR PHONE THAT AN SAE HAS BEEN SUBMITTED. 
 
FOR PROBLEMS SENDING THE FORM OR OTHER QUESTIONS, PLEASE CONTACT THE PROJECT MANAGER. 
 
 
 
 
 
 
 
 


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18.9 
New York Heart Association (NYHA) Guidelines 
 
 
 
18.10  PROCEDURE FOR OBTAINING A URINE PROTEIN: CREATININE RATIO 
 
1)  Obtain at least 4 ml of a random urine sample (does not have to be a 24 hour urine)  
2)  Determine protein concentration (mg/dL)  
3)  Determine creatinine concentration (mg/dL)  
4)  Divide #2 by #3 above:  urine protein / creatinine ratio = protein concentration (mg /dL) / 
creatinine concentration (mg /dL) 
 
The UPC directly correlates with the amount of protein excreted in the urine per 24 hrs (i.e. a 
UPC of 1 should be equivalent to 1g protein in a 24hr urine collection) 
                                            
Protein and creatinine concentrations should be available on standard reports of urinalyses, not 
dipsticks. If protein and creatinine concentrations are not routinely reported at an Institution, their 
measurements and reports may need to be requested. 
 
 
 
 
 
 


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18.11 Pregnancy tests for females of childbearing potential and adequate methods of 
contraception  
 
A female of childbearing potential (FCBP) is a sexually mature female who: 1) has not undergone 
a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at 
least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive 
months). 
 
Pregnancy tests must occur within 14 days prior to initiation of study.  FCBP must have a 
pregnancy test before each new cycle; at discontinuation of vorinostat and at Day 28 post the last 
dose of vorinostat.   
 
Required Pregnancy test: Serum -HCG  
 
Adequate method of contraception: one highly effective method or more than one additional 
methods. 
 
Highly effective methods: 
 
Intrauterine device (IUD) 
 
Hormonal (birth control pills, injections, implants) 
 
Tubal ligation 
 
Partner’s vasectomy 
 
Additional effective methods: 
 
Latex condom 
 
Diaphragm 
 
Cervical Cap 
 
 
 
 


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18.12 MD ANDERSON SYMPTOM INVENTORY FOR BRAIN TUMORS (MDASI-BT) 
 
 
(The MDASI – BT is created by the OMCR programming staff upon request for each protocol. 
The standard MDASI – BT questionnaire is used as a template. This form will contain coding 
“landmarks”  that enable the data to be scanned into the MD ANDERSON CANCER CENTER 
data repository for MDASI results. Please contact the OMCR to obtain the questionnaire that is 
to be attached to the protocol before submission to the IRB.) 
 
 
(Rest of this page is left blank on purpose) 


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18.13   Drug Accountability 
 
 
BTTC11-02      DRUG ACCOUNTABILITY DOCUMENTATION: 
 
 
 
 
TO BE COMPLETED BY CLINICAL RESEARCH STAFF 
 
PATIENT INITIALS: ________________________                         BTTC I.D. # _________       
 
Cycle #  ________ 
 
 
DOSE OF VORINOSTAT PRESCRIBED: __________ MG  _____ CAPSULES (DAILY) 
 
VORINOSTAT CAPSULES are 100MG EACH. 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
DATE DISPENSED: _____________ (mm/dd/yy) 
 
 
QUANTITY OF BOTTLES DISPENSED OF 100 MG : ________  
   QUANTITY OF 100 MG TABLETS PER BOTTLE: ___________ 
 
NUMBER OF 100  MG TABLETS PER DAY REQUIRED TO ACHIEVE PRESCRIBED DOSE: _____________ 
 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
**********DO NOT RETURN UNUSED TABLETS TO THE PATIENT************* 
 
RETURN PILL/BOTTLE COUNT DATE: ___________  (mm/dd/yy)     Has the patient taken the dose scheduled for this date?  YES     NO 
 
 
 
 
 
 
    
QUANTITY OF EMPTY BOTTLES RETURNED: _____________ 
QUANTITY OF CAPSULES RETURNED: ______________ 
 
Please document any discrepancies between number of capsules returned and patient’s diary, or any other discrepancies: ____________________ 
 
_____________________________________________________________________________________________________________________ 
 
Study Coordinator Name:_______________________________       Signature and date: _____________________________________________ 
 
 


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18.14   
BTTC11-02 Patient Study Drug Diary 
 
 
PATIENT INITIALS: _______________________                     BTTC I.D. # _________         Cycle# ______ Start Date: _________ 
 
 
 
 
This calendar is for you to indicate that you took the study drug as instructed.  Please put a check mark or your initials after each dose.  If not taken, write 0 mg. 
Please sign this calendar at the end of the cycle and bring the calendar and all study drug bottle(s) back to your next clinic visit. 
  
 DOSE prescribed:  Vorinostat   ______mg (_____ capsules) by mouth on days 1 to 7 and 15 to 21.  
 
Vorinostat capsules should not be opened or crushed and must be administered whole. 
 
Day 1 __________ 
 
____________ mg 
 
 
Day 2 __________ 
 
____________ mg 
 
 
Day 3  __________ 
 
_____________ mg 
 
 
Day  4 __________ 
 
______________mg 
 
 
Day 5 __________ 
 
______________mg 
 
 
Day 6 __________ 
 
______________ mg 
 
 
Day 7 __________ 
 
______________mg 
 
 
Day 8 __________ 
 
 
 
Day 9 __________ 
 
 
 
Day 10 __________ 
 
 
 
Day 11 __________ 
 
 
 
Day 12 __________ 
 
 
 
Day 13 __________ 
 
 
 
Day 14 __________ 
 
 
Day 15  
 
____________ mg 
Day 16 _ 
 
___________ mg 
 
 
Day 17 __________ 
 
____________ mg 
 
 
Day 18 __________ 
 
____________ mg 
 
   
Day 19 __________ 
 
____________ mg 
 
 
Day 20 __________ 
 
______________ mg 
 
 
Day 21 __________ 
 
______________mg 
 
 
Day 22 
__________ 
 
 
Day 23 
__________ 
 
 
Day 24 __________ 
 
 
 
Day 25 __________ 
 
 
Day 26 
___________ 
 
 
Day 27 ___________ 
 
 
Day 28 __________ 
 
 
Day 29 
___________ 
 
 
Day 30 
__________ 
 
 
 
My signature confirms that the study drug was taken as documented 
 
Signature of Patient: _________________________________________ 
Date: _____________________ 
 
 
 
 
 


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